Note: Descriptions are shown in the official language in which they were submitted.
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SCHIZOPHRENIA ASSOCIATED GENES, PROTEINS AND BIALLELIC
MARKERS
FIELD OF THE INVENTION
The invention concerns the human sbgl, g34665, sbg2, g35017 and g35018 genes,
polynucleotides, polypeptides biallelic markers, and human chromosome 13q31-
q33 biallelic
markers. The invention also concerns the association established between
schizophrenia and
bipolar disorder and the biallelic markers and the sbgl, g34665, sbg2, g35017
and g35018 genes
and nucleotide sequences. The invention provides means to identify compounds
useful in the
treatment of schizophrenia, bipolar disorder and related diseases, means to
determine the
predisposition of individuals to said disease as well as means for the disease
diagnosis and
prognosis.
BACKGROUND OF THE INVENTION
Advances in the technological annamentarium available to basic and clinical
investigators have enabled increasingly sophisticated studies of brain and
nervous system
function in health and disease. Numerous hypotheses both neurobiological and
pharmacological
have been advanced with respect to the neurochemical and genetic mechanisms
involved in
central nervous system (CNS) disorders, including psychiatric disorders and
neurodegenerative
diseases. However, CNS disorders have complex and poorly understood
etiologies, as well as
symptoms that are overlapping, poorly characterized, and difficult to measure.
As a result
future treatment regimes and drug development efforts will be required to be
more sophisticated
and focused on multigenic causes, and will need new assays to segment disease
populations, and
provide more accurate diagnostic and prognostic information on patients
suffering from CNS
disorders.
Neurological Basis of CNS Disorders
Neurotransmitters serve as signal transmitters throughout the body. Diseases
that affect
neurotransmission can therefore have serious consequences. For example, for
over 30 years the
leading theory to explain the biological basis of many psychiatric disorders
such as depression
has been the monoamine hypothesis. This theory proposes that depression is
partially due to a
deficiency in one of the three main biogenic monoamines, namely dopamine,
norepinephrine
and/or serotonin.
In addition to the monoamine hypothesis, numerous arguments tend to show the
value
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in taking into account the overall function of the brain and no longer only
considering a single
neuronal system. In this context, the value of dual specific actions on the
central aminergic
systems including second and third messenger systems has now emerged.
Endocrine Basis of CNS Disorders
It is furthermore apparent that the main monoamine systems, namely dopamine,
norepinephrine and serotonin, do not completely explain the pathophysiology of
many CNS
disorders. In particular, it is clear that CNS disorders may have an endocrine
component; the
hypothalamic-pituitary-adrenal (HPA) axis, including the effects of
corticotrophin-releasing
factor and glucocorticoids, plays an important role in the pathophysiology of
CNS disorders.
In the hypothalamus-pituitary-adrenal (HPA) axis, the hypothalamus lies at the
top of
the hierarchy regulating hormone secretion. It manufactures and releases
peptides (small chains
of amino acids) that act on the pituitary, at the base of the brain,
stimulating or inhibiting the
pituitary's release of various hormones into the blood. These hormones, among
them growth
hormone, thyroid-stimulating hormone and adrenocorticotrophic hormone (ACTH),
control the
release of other hormones from target glands. In addition to functioning
outside the nervous
system, the hormones released in response to pituitary hormones also feed back
to the pituitary
and hypothalamus. There they deliver inhibitory signals that serve to limit
excess hormone
biosynthesis.
CNS Disorders
Neurotransmitter and hormonal abnormalities are implicated in disorders of
movement
(e.g. Parkinson's disease, Huntington's disease, motor neuron disease, etc.),
disorders of mood
(e.g. unipolar depression, bipolar disorder, anxiety, etc.) and diseases
involving the.intellect
(e.g. Alzheimer's disease, Lewy body dementia, schizophrenia, etc.). In
addition, these systems
have been implicated in many other disorders, such as coma, head injury,
cerebral infarction,
epilepsy, alcoholism and the mental retardation states of metabolic origin
seen particularly in
childhood.
Genetic Analysis of Complex Traits
Until recently, the identification of genes linked with detectable traits has
relied mainly
on a statistical approach called linkage analysis. Linkage analysis is based
upon establishing a
correlation between the transmission of genetic markers and that of a specific
trait throughout
generations within a family. Linkage analysis involves the study of families
with multiple
affected individuals and is useful in the detection of inherited-traits, which
are caused by a
single gene, or possibly a very small number of genes. But, linkage studies
have proven
difficult when applied to complex genetic traits. Most traits of medical
relevance do not follow
simple Mendelian monogenic inheritance. However, complex diseases often
aggregate in
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families, which suggests that there is a genetic component to be found. Such
complex traits are
often due to the combined action of multiple genes as well as environmental
factors. Such
complex trait, include susceptibilities to heart disease, hypertension,
diabetes, cancer and
inflammatory diseases. Drug efficacy, response and tolerance/toxicity can also
be considered as
multifactoral traits involving a genetic component in the same way as complex
diseases.
Linkage analysis cannot be applied to the study of such traits for which no
large informative
families are available. Moreover, because of their low penetrance, such
complex traits do not
segregate in a clear-cut Mendelian manner as they are passed from one
generation to the next.
Attempts to map such diseases have been plagued by inconclusive results,
demonstrating the
need for more sophisticated genetic tools.
Knowledge of genetic variation in the neuronal and endocrine systems is
important for
understanding why some people are more susceptible to disease or respond
differently to
treatments. Ways to identify genetic polymorphism and to analyze how they
impact and predict
disease susceptibility and response to treatment are needed.
Although the genes involved in the neuronal and endocrine systems represent
major
drug targets and are of high relevance to pharmaceutical research, we still
have scant knowledge
concerning the extent and nature of, sequence variation in these genes and
their regulatory
elements. In the case where polymorphisms have been identified the relevance
of the variation
is rarely understood. While polymorphisms hold promise for use as genetic
markers in
determining which genes contribute to multigenic or quantitative traits,
suitable markers and
suitable methods for exploiting those markers have not been found and brought
to bare on the
genes related to disorders of the brain and nervous system.
The basis for accomplishment of these goals is to use genetic association
analysis to
detect markers that predict susceptibility for these traits. Recently,
advances in the fields of
genetics and molecular biology have allowed identification of forms, or
alleles, of human genes
that lead to diseases. Most of the genetic variations responsible for human
diseases identified so
far, belong to the class of single gene disorders. As this name implies, the
development of
single gene disorders is determined, or largely influenced, by the alleles of
a single gene. The
alleles that cause these disorders are, in general, highly deleterious (and
highly penetrant) to
individuals who carry them. Therefore, these alleles and their associated
diseases, with some
exceptions, tend to be very rare in the human population. In contrast, most
common diseases
and non-disease traits, such as a physiological response to a pharmaceutical
agent, can be
viewed as the result of many complex factors. These can include environmental
exposures
(toxins, allergens, infectious agents, climate, and trauma) as well as
multiple genetic factors.
Association studies seek to analyze the distributions of chromosomes that have
occurred
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in populations of unrelated (at least not directly related) individuals. An
assumption in this type
of study is that genetic alleles that result in susceptibility for a common
trait arose by ancient
mutational events on chromosomes that have been passed down through many
generations in
the population. These alleles can become common throughout the population in
part because
the trait they influence, if deleterious, is only expressed in a fraction of
those individuals who
carry them. Identification of these "ancestral" chromosomes is made difficult
by the fact that
genetic markers are likely to have become separated from the trait
susceptibility allele through
the process of recombination, except in regions of DNA which immediately
surround the allele.
The identities of genetic markers contained within the fragments of DNA
surrounding a
susceptibility allele will be the same as those from the ancestral chromosome
on which the
allele arose. Therefore, individuals from the population who express a complex
trait might be
expected to carry the same set of genetic markers in the vicinity of a
susceptibility allele more
often than those who do not express the trait; that is these markers will show
an association with
the trait.
Schizophrenia
Schizophrenia is one of the most severe and debilitating of the major
psychiatric
diseases. It usually starts in late adolescence or early adult life and often
becomes chronic and
disabling. Men and women are at equal risk of developing this illness;
however, most males
become ill between 16 and 25 years old, while.females develop symptoms between
25 and 30.
People with schizophrenia often experience both "positive" symptoms (e.g.,
delusions,
hallucinations, disorganized thinking, and agitation) and "negative" symptoms
(e.g., lack of
drive or initiative, social withdrawal, apathy, and emotional
unresponsiveness).
Schizophrenia affects 1 % of the world population. There are an estimated 45
million
people with schizophrenia in the world, with more than 33 million of them in
the developing
countries. This disease places a heavy burden on the patient's family and
relatives, both in
terms of the direct and indirect costs involved and the social stigma
associated with the illness,
sometimes over generations. Such stigma often leads to isolation and neglect.
Moreover, schizophrenia accounts for one fourth of all mental health costs and
takes up
one in three psychiatric hospital beds. Most schizophrenia patients are never
able to work. The
cost of schizophrenia to society is enormous. In the United States, for
example, the direct cost
of treatment of schizophrenia has been estimated to be close to 0.5% of the
gross national
product. Standardized mortality ratios (SMRs) for schizophrenic patients are
estimated to be
two to four times higher than the general population, and their life
expectancy overall is 20
shorter than for the general population. The most common cause of death among
schizophrenic
patients is suicide (in 10 % of patients) which represents a 20 times higher
risk than for the
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general population. Deaths from heart disease and from diseases of the
respiratory and
digestive system are also increased among schizophrenic patients.
Bipolar Disorder
Bipolar disorders are relatively common disorders with severe and potentially
disabling
effects. In addition to the severe effects on patients' social development,
suicide completion
rates among bipolar patients are reported to be about 1 S%.
Bipolar disorders are characterized by phases of excitement and often
including
depression; the excitement phases, referred to as mania or hypomania, and
depression can
alternate or occur in various admixtures, and can occur to different degrees
of severity and over
varying time periods. Because bipolar disorders can exist in different forms
and display
different symptoms, the classification of bipolar disorder has been the
subject of extensive
studies resulting in the definition of bipolar disorder subtypes and widening
of the overall
concept to include patients previously thought to be suffering from different
disorders. Bipolar
disorders often share certain clinical signs, symptoms, treatments and
neurobiological features
with psychotic illnesses in general and therefore present a challenge to the
psychiatrist to make
an accurate diagnosis. Furthermore, because the course of bipolar disorders
and various mood
and psychotic disorders can differ greatly, it is critical to characterize the
illness as early as
possible in order to offer means to manage the illness over a long term.
Bipolar disorders appear in about 1.3% of the population and have been
reported to
constitute about half of the mood disorders seen in a psychiatric clinic.
Bipolar disorders have
been found to vary with gender depending of the type of disorder; for example,
bipolar disorder
I is found equally among men and women, while bipolar disorder II is
reportedly more common
in women. The age of onset of bipolar disorders is typically in the teenage
years and diagnosis
is typically made in the patient's early twenties. Bipolar disorders also
occur among the elderly,
generally as a result of a medical or neurological disorder.
The costs of bipolar disorders to society are enormous. The mania associated
with the
disease impairs performance and causes psychosis, and often results in
hospitalization. This
disease places a heavy burden on the patient's family and relatives, both in
terms of the direct
and indirect costs involved and the social stigma associated with the illness,
sometimes over
generations. Such stigma often leads to isolation and neglect. Furthermore,
the earlier the onset,
the more severe are the effects of interrupted education and social
development.
The DSM-IV classification of bipolar disorder distinguishes among four types
of
disorders based on the degree and duration of mania or hypomania as well as
two types of
disorders which are evident typically with medical conditions or their
treatments, or to
substance abuse. Mania is recognized by elevated, expansive or irritable mood
as well as by
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distractability, impulsive behavior, increased activity, grandiosity, elation,
racing thoughts, and
pressured speech. Of the four types of bipolar disorder characterized by the
particular degree
and duration of mania , DSM-IV includes:
- bipolar disorder I, including patients displaying mania for at least one
week;
- bipolar disorder II, including patients displaying hypomania for at least 4
days,
characterized by milder symptoms of excitement than mania, who have not
previously displayed
mania, and have previously suffered from episodes of major depression;
- bipolar disorder not otherwise specified (NOS), including patients otherwise
displaying features of bipolar disorder II but not meeting the 4 day duration
for the excitement
phase, or who display hypomania without an episode of major depression; and
- cyclothymia, including patients who show numerous manic and depressive
symptoms
that do not meet the criteria for hypomania or major depression, but which are
displayed for
over two years without a symptom-free interval of more than two months.
The remaining two types of bipolar disorder as classified in DSM-VI are
disorders
evident or caused by various medical disorder and their treatments, and
disorders involving or
related to substance abuse. Medical disorders which can cause bipolar
disorders typically
include endocrine disorders and cerebrovascular injuries, and medical
treatments causing
bipolar disorder are known to include glucocorticoids and the abuse of
stimulants. The disorder
associated with the use or abuse of a substance is referred to as "substance
induced mood
disorder with manic or mixed features".
Diagnosis of bipolar disorder can be very challenging. One particularly
troublesome
difficulty is that some patients exihibit mixed states, simultaneously manic
and dysphoric or
depressive, but do not fall into the DSM-IV classification because not all
required criteria for
mania and major depression are met daily for at least one week. Other
difficulties include
classification of patients in the DSM-IV groups based on duration of phase
since patients often
cycle between excited and depressive episodes at different rates. In
particular, it is reported that
the use of antidepressants may alter the course of the disease for the worse
by causing "rapid-
cycling". Also making diagnosis more difficult is the fact that bipolar
patients, particularly at
what is known as Stage III mania, share symptoms of disorganized thinking and
behavior with
bipolar disorder patients. Furthermore, psychiatrists must distinguish between
agitated
depression and mixed mania; it is common that patients with major depression
(14 days or
more) exhibit agitiation, resulting in bipolar-like features. A yet further
complicating factor is
that bipolar patients have an exceptionally high rate of substance,
particularly alcohol abuse.
While the prevalence of mania in alcoholic patients is low, it is well known
that substance
abusers can show excited symptoms. Difficulties therefore result for the
diagnosis of bipolar
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patients with substance abuse.
Treatment
As there are currently no cures for bipolar disorder or schizophrenia, the
objective of
treatment is to reduce the severity of the symptoms, if possible to the point
of remission. Due to
the similarities in symptoms, schizophrenia and bipolar disorder are often
treated with some of
the same medicaments. Both diseases are often treated with antipsychotics and
neuroleptics.
For schizophrenia, for example, antipsyehotic medications are the most common
and
most valuable treatments. There are four main classes of antipsychotic drugs
which are
commonly prescribed for schizophrenia. The first, neuroleptics, exemplified by
chlorpromazine
(Thorazine), has revolutionized the treatment of schizophrenic patients by
reducing positive
(psychotic) symptoms and preventing their recurrence. Patients receiving
chlorpromazine have
been able to leave mental hospitals and live in community programs or their
own homes. But
these drugs are far from ideal. Some 20% to 30% of patients do not respond to
them at all, and
others eventually relapse. These drugs were named neuroleptics because they
produce serious
neurological side effects, including rigidity and tremors in the arms and
legs, muscle spasms,
abnormal body movements, and akathisia (restless pacing and fidgeting). These
side effects are
so troublesome that many patients simply refuse to take the drugs. Besides,
neuroleptics do not
improve the so-called negative symptoms of schizophrenia and the side effects
may even
exacerbate these symptoms. Thus, despite the clear beneficial effects of
neuroleptics, even
some patients who have a good short-term response will ultimately deteriorate
in overall
functioning.
The well known deficiencies in the standard neuroleptics have stimulated a
search for
new treatments and have led to a new class of drugs termed atypical
neuroleptics. The first
atypical neuroleptic, Clozapine, is effective for about one third of patients
who do not respond
to standard neuroleptics. It seems to reduce negative as well as positive
symptoms, or at least
exacerbates negative symptoms less than standard neuroleptics do. Moreover, it
has beneficial
effects on overall functioning and may reduce the chance of suicide in
schizophrenic patients. It
does not produce the troubling neurological symptoms of the standard
neuroleptics, or raise
blood levels of the hormone prolactin, excess of which may cause menstrual
irregularities and
infertility in women, impotence or breast enlargement in men. Many patients
who cannot
tolerate standard neuroleptics have been able to take elozapine. However,
clozapine has serious
limitations. It was originally withdrawn from the market because it can cause
agranulocytosis, a
potentially lethal inability to produce white blood cells. Agranulocytosis
remains a threat that
requires careful monitoring and periodic blood tests. Clozapine can also cause
seizures and
other disturbing side effects (e.g., drowsiness, lowered blood pressure,
drooling, bed-wetting,
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and weight gain). Thus it is usually taken only by patients who do not respond
to other drugs.
Researchers have developed a third class of antipsychotic drugs that have the
virtues of
clozapine without its defects. One of these drugs is risperidone (Risperdal).
Early studies
suggest that it is as effective as standard neuroleptic drugs for positive
symptoms and may be
somewhat more effective for negative symptoms. It produces more neurological
side effects
than clozapine but fewer than standard neuroleptics. However, it raises
prolactin levels.
Risperidone is now prescribed for a broad range of psychotic patients, and
many clinicians seem
to use it before clozapine for patients who do not respond to standard drugs,
because they regard
it as safer. Another new drug is Olanzapine (Zyprexa) which is at least as
effective as standard
drugs for positive symptoms and more effective for negative symptoms. It has
few neurological
side effects at ordinary clinical doses, and it does not significantly raise
prolactin levels.
Although it does not produce most of clozapine's most troubling side effects,
including
agranulocytosis, some patients taking olanzapine may become sedated or dizzy,
develop dry
mouth, or gain weight. In rare cases, liver function tests become transiently
abnormal.
1 S Outcome studies in schizophrenia are usually based on hospital treatment
studies and
may not be representative of the population of schizophrenia patients. At the
extremes of
outcome, 20 % of patients seem to recover completely after one episode of
psychosis, whereas
14-19% of patients develop a chronic unremitting psychosis and never fully
recover. In general,
clinical outcome at five years seems to follow the rule of thirds: with about
35 % of patients in
the poor outcome category; 36 % in the good outcome category, and the
remainder with
intermediate outcome. Prognosis in schizophrenia does not seem to worsen after
five years.
Whatever the reasons, there is increasing evidence that leaving schizophrenia
untreated
for long periods early in course of the illness may negatively affect the
outcome. However, the
use of drugs is often delayed for patients experiencing a first episode of the
illness. The patients
may not realize that they are ill, or they may be afraid to seek help; family
members sometimes
hope the problem will simply disappear or cannot persuade the patient to seek
treatment;
clinicians may hesitate to prescribe antipsychotic medications when the
diagnosis is uncertain
because of potential side effects. Indeed, at the first manifestation of the
disease, schizophrenia
is difficult to distinguish from bipolar manic-depressive disorders, severe
depression, drug-
related disorders, and stress-related disorders. Since the optimum treatments
differ among these
diseases, the long term prognosis of the disorder also differs the beginning
of the treatment.
For both schizophrenia and bipolar disorder, all the known molecules used for
the
treatment of schizophrenia have side effects and act only against the symptoms
of the disease.
There is a strong need for new molecules without associated side effects and
directed against
targets which are involved in the causal mechanisms of schizophrenia and
bipolar disorder.
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Therefore, tools facilitating the discovery and characterization of these
targets are necessary and
useful.
Schizophrenia and bipolar disorder are now considered to be brain diseases,
and
emphasis is placed on biological determinants in researching the conditions.
In the case of
schizophrenia, neuroimaging and neuropathological studies have shown evidence
of brain
abnormalities in schizophrenic patients. The timing of these pathological
changes is unclear but
are likely to be a defect in early brain development. Profound changes have
also occurred in
hypotheses concerning neurotransmitter abnormalities in schizophrenia. The
dopamine
hypothesis has been extensively revised and is no longer considered as a
primary causative
model.
The aggregation of schizophrenia and bipolar disorder in families, the
evidence from
twin and adoption studies, and the lack of variation in incidence worldwide,
indicate that
schizophrenia and bipolar disorder are primarily genetic conditions, although
environmental risk
factors are also involved at some level as necessary, sufficient, or
interactive causes. For
example, schizophrenia occurs in 1% of the general population. But, if there
is one grandparent
with schizophrenia, the risk of getting the illness increases to about 3%; one
parent with
Schizophrenia, to about 10%. When both parents have schizophrenia, the risk
rises to
approximately 40%.
Consequently, there is a strong need to identify genes involved in
schizophrenia and
bipolar disorder. The knowledge of these genes will allow researchers to
understand the
etiology of schizophrenia and bipolar disorder and could lead to drugs and
medications which
are directed against the cause of the diseases, not just against their
symptoms.
There is also a great need for new methods for detecting a susceptibility to
schizophrenia and bipolar disorder, as well as for preventing or following up
the development of
the disease. Diagnostic tools could also prove extremely useful. Indeed, early
identification of
subjects at risk of developing schizophrenia would enable early and/or
prophylactic treatment to
be administered. Moreover, accurate assessments of the eventual efficacy of a
medicament as
well as the patent's eventual tolerance to it may enable clinicians to enhance
the benefibrisk
ratio of schizophrenia and bipolar disorder treatment regimes.
SUMMARY OF THE INVENTION
The present invention stems from the identification of novel polymorphisms
including
biallelic markers located on the human chromosome 13q31-q33 locus, the
identification and
characterization of novel schizophrenia-related genes located on the human
chromosome 13q31-
q33 locus, and from the identification of genetic associations between alleles
of biallelic
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markers located on the human chromosome 13q31-q33 locus and disease, as
confirmed and
characterized in a panel of human subjects. The invention furthermore provides
a fine structure
map of the region which includes the schizophrenia-associated gene sequences.
The present invention pertains to nucleic acid molecules comprising the
genomic
sequences of novel human genes encoding sbgl, 834665, sbg2, 835017 and 835018
proteins,
proteins encoded thereby, as well as antibodies thereto. The sbgl, 834665,
sbg2, 835017 and
835018 genomic sequences may also comprise regulatory sequence located
upstream (S'-end)
and downstream (3'-end) of the transcribed portion of said gene, these
regulatory sequences
being also part of the invention. The invention also deals with the cDNA
sequence encoding the
10 sbgl and 835018 proteins.
Oligonucleotide probes or primers hybridizing specifically with a sbgl,
834665, sbg2,
835017 or 835018 genomic or cDNA sequence are also part of the present
invention, as well as
DNA amplification and detection methods using said primers and probes.
A further object of the invention consists of recombinant vectors comprising
any of the
1 S nucleic acid sequences described above, and in particular of recombinant
vectors comprising a
sbgl, 834665, sbg2, 835017 or 835018 regulatory sequence or a sequence
encoding a sbgl,
834665, sbg2, 835017 or 835018 protein, as well as of cell hosts and
transgenic non human
animals comprising said nucleic acid sequences or recombinant vectors.
The invention also concerns to biallelic markers of the sbgl, 834665, sbg2,
835017 or
835018 gene and the use thereof. Included are probes and primers for use in
genotyping
biallelic markers of the invention.
An embodiment of the invention encompasses any polynucleotide of the invention
attached to a solid support polynucleotide may comprise a sequence disclosed
in the present
specification; optionally, said polynucleotide may comprise, consist of, or
consist essentially of
any polynucleotide described in the present specification; optionally, said
determining may be
performed in a hybridization assay, sequencing assay, microsequencing assay,
or an enzyme-
based mismatch detection assay; optionally, said polynucleotide may be
attached to a solid
support, array, or addressable array; optionally, said polynucleotide may be
labeled.
Finally, the invention is directed to drug screening assays and methods for
the screening
of substances for the treatment of schizophrenia, bipolar disorder or a
related CNS disorder
based on the role of sbgl, 834665, sbg2, 835017 and 835018 nucleotides and
polynucleotides in
disease. One object of the invention deals with animal models of
schizophrenia, including
mouse, primate, non-human primate bipolar disorder or related CNS disorder
based on the role
of sbgl in disease. The invention is also directed to methods for the
screening of substances or
molecules that inhibit the expression of sbgl, 834665, sbg2, 835017 or 835018,
as well as with
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methods for the screening of substances or molecules that interact with a
sbgl, g34665, sbg2,
g35017 or g35018 polypeptide, or that modulate the activity of a sbgl, g34665,
sbg2, g35017 or
g35018 polypeptide.
As noted above, certain aspects of the present invention stem from the
identification of
genetic associations between schizophrenia and bipolar disorder and alleles of
biallelic markers
located on the human chromosome 13q31-q33 region, and more particularly on a
subregion
thereof referred to herein as Region D. The invention provides appropriate
tools for
establishing further genetic associations between alleles of biallelic markers
on the 13q31-
13q33 locus and either side effects or benefit resulting from the
administration of agents acting
on schizophrenia or bipolar disorder, or schizophrenia or bipolar disorder
symptoms, includng
agents like chlorpromazine, clozapine, risperidone, olanzapine, sertindole,
quetiapine and
ziprasidone.
The invention provides appropriate tools for establishing further genetic
associations
between alleles of biallelic markers on the 13q31-13q33 locus and a trait.
Methods and
products are provided for the molecular detection of a genetic susceptibility
in humans to
schizophrenia and bipolar disorder. They can be used for diagnosis, staging,
prognosis and
monitoring of this disease, which processes can be further included within
treatment
approaches. The invention also provides for the efficient design and
evaluation of suitable
therapeutic solutions including individualized strategies for optimizing drug
usage, and
screening of potential new medicament candidates.
Additional embodiments are set forth in the Detailed Description of the
Invention and in
the Examples.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 is a diagram showing the exon structure of the sbgl gene.
Figure 2 is a table demonstrating the statistical significance of allelic
frequencies of
selected chromosome 13q31-q33 biallelic markers of the invention in sporadic
and familial
French Canadian schizophrenia cases and controls.
Figure 3 is a table demonstrating the results of a haplotype association
analysis between
total French Canadian schizophrenia cases and haplotypes which consist of
chromosome 13q31
q33 biallelic markers of the invention.
Figure 4 is a table showing the involvement of selected biallelic markers of
the
invention in statistically significant haplotypes.
Figure 5 is a table demonstrating the results of a haplotype association
analysis between
French Canadian schizophrenia cases and haplotypes which consist of chromosome
13q31-q33
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biallelic markers of the invention.
Figure 6 is a table demonstrating the results of a haplotype association
analysis between
French Canadian schizophrenia cases and haplotypes which consist of chromosome
13q31-q33
biallelic markers of the invention.
Figures 7A and 7B show the results of a haplotype association analysis
(Omnibus LR
test value distribution) between schizophrenia cases and haplotypes comprising
Region D
biallelic markers of the invention.
Figures 8A and 8B show the results of a haplotype association analysis
(HaplotMaxM
test value distribution) between schizophrenia cases and haplotypes comprising
Region D
biallelic markers ofthe invention.
Figures 9A and 9B show the results of a haplotype association analysis
(Omnibus LR
test value distribution) between bipolar disorder cases and haplotypes
comprising Region D
biallelic markers of the invention.
Figures l0A and l OB show the results of a haplotype association analysis
(HaploMaxM
test value distribution) between bipolar disorder cases and haplotypes
comprising Region D
biallelic markers of the invention.
Figures 11A and 11B show the results of a haplotype association analysis
(HaploMaxS
test value distribution) between bipolar disorder cases and haplotypes
comprising Region D
biallelic markers ofthe invention.
Figure 12 shows a comparison of the number of significant single and
multipoint
biallelic marker analyses in subregions D1 to D4 of Region D in French
Canadian samples.
Figure 13 shows a summary of the number of significant single and multipoint
biallelic
marker analyses across Region D in French Canadian samples.
Figure 14 shows a comparison of the number of significant single and
multipoint
biallelic marker analyses in subregions Dl to D4 of Region D in United States
schizophrenia
samples.
Figure 15 shows a summary of the number of significant single and multipoint
biallelic
marker analyses across Region D in United States schizophrenia samples.
Figure 16 shows a comparison of the number of significant single and
multipoint
biallelic marker analyses in subregions D1 to D4 of Region D in Argentinian
bipolar disorder
samples.
Figure 17 shows a summary of the number of significant single and multipoint
biallelic
marker analyses across Region D in Argentinian bipolar disorder samples.
Figure 18 shows the effect of injection of an sbgl peptide on locomotor
activity and
stereotypy of mice.
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13
Figure 19 is a block diagram of an exemplary computer system.
Figure 20 is a flow diagram illustrating one embodiment of a process 200 for
comparing a
new nucleotide or protein sequence with a database of sequences in order to
determine the
homology levels between the new sequence and the sequences in the database.
Figure 21 is a flow diagram illustrating one embodiment of a process 250 in a
computer
for determining whether two sequences are homologous.
Figure 22 is a flow diagram illustrating one embodiment of an identifier
process 300 for
detecting the presence of a feature in a sequence.
BRIEF DESCRIPTION OF THE SEQUENCES PROVIDED IN THE
SEQUENCE LISTING
SEQ ID No. 1 contains the approximately 319kb of genomic nucleotide sequence
comprising sbgl, g34665, sbg2, g35017 and g35018 nucleic acid sequences and
the biallelic
markers A1 to A360 and polymorphisms A361 to A489 located on the human
chromosome
13q31-q33 locus.
SEQ ID Nos. 2 to 26 contain cDNA sequences of the sbg 1 gene.
SEQ ID Nos. 27 to 35 contain amino acid sequences of sbgl polypeptides,
encoded by
cDNAs of SEQ ID Nos. 2 to 26.
SEQ ID No. 36 to 40 contain cDNA sequences of the g35018 gene
SEQ ID No. 41 to 43 contain amino acid sequences of an g35018 polypeptides.
SEQ ID No. 44 to 53 contain primers used to isolate sbgl cDNAs
SEQ ID No. 54 to 111 contain genomic nucleotide sequences comprising exons of
the
sbgl gene from several different primates.
SEQ ID Nos. 112 to 229 respectively contain the nucleotide sequence of the
amplicons
which comprise the biallelic markers A243 to A360 located on the human
chromosome 13q31-
q33 locus.
SEQ ID No 230 contains a primer containing the additional PU 5' sequence
described
further in Example 2
SEQ ID No 231 contains a primer containing the additional RP 5' sequence
described
further in Example 2.
In accordance with the regulations relating to Sequence Listings, the
following codes
have been used in the Sequence Listing to indicate the locations of biallelic
markers within the
sequences and to identify each of the alleles present at the polymorphic base.
The code "r" in
the sequences indicates that one allele of the polymorphic base is a guanine,
while the other
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14
allele is an adenine. The code "y" in the sequences indicates that one allele
of the polymorphic
base is a thymine, while the other allele is a cytosine. The code "m" in the
sequences indicates
that one allele of the polymorphic base is an adenine, while the other allele
is an cytosine. The
code "k" in the sequences indicates that one allele of the polymorphic base is
a guanine, while
the other allele is a thymine. The code "s" in the sequences indicates that
one allele of the
polymorphic base is a guanine, while the other allele is a cytosine. The code
"w" in the
sequences indicates that one allele of the polymorphic base is an adenine,
while the other allele
is an thymine.
DETAILED DESCRIPTION OF THE INVENTION
The identification of genes involved in a particular trait such as a specific
central
nervous system disorder, like schizophrenia, can be carried out through two
main strategies
currently used for genetic mapping: linkage analysis and association studies.
Linkage analysis
requires the study of families with multiple affected individuals and is now
useful in the
detection of mono- or oligogenic inherited traits. Conversely, association
studies examine the
frequency of marker alleles in unrelated trait (T+) individuals compared with
trait negative (T-)
controls, and are generally employed in the detection of polygenic
inheritance.
Candidate region on the chromosome 13 (linkage analysis)
Genetic link or "linkage" is based on an analysis of which of two neighboring
sequences on a chromosome contains the least recombinations by crossing-over
during meiosis.
To do this, chromosomal markers, like microsatellite markers, have been
localized with
precision on the genome. Genetic link analysis calculates the probabilities of
recombinations on
the target gene with the chromosomal markers used, according to the
genealogical tree, the
transmission of the disease, and the transmission of the markers. Thus, if a
particular allele of a
given marker is transmitted with the disease more often than chance would have
it
(recombination level between 0 and 0.5), it is possible to deduce that the
target gene in question
is found in the neighborhood of the marker.
Using this technique, it has been possible to localize several genes
demonstrating a
genetic predisposition of familial cancers. In order to be able to be included
in a genetic link
study, the families affected by a hereditary form of the disease must satisfy
the
"informativeness" criteria: several affected subjects (and whose
constitutional DNA is
available) per generation, and at best having a large number of siblings.
By linkage analysis, observations have been made, according to which a
candidate
region for schizophrenia is present on chromosome 13q32 locus (Blouin et al.,
1998). Linkage
analysis has been successfully applied to map simple genetic traits that show
clear Mendelian
inheritance patterns and which have a high penetrance, but this method suffers
from a variety of
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drawbacks. First, linkage analysis is limited by its reliance on the choice of
a genetic model
suitable for each studied trait. Furthermore, the resolution attainable using
linkage analysis is
limited, and complementary studies are required to refine the analysis of the
typical 20 Mb
regions initially identified through this method. In addition, linkage
analysis have proven
5 di~cult when applied to complex genetic traits, such as those due to the
combined action of
multiple genes and/or environmental factors. In such cases, too great an
effort and cost are
needed to recruit the adequate number of affected families required for
applying linkage
analysis to these situations. Finally, linkage analysis cannot be applied to
the study of traits for
which no large informative families are available.
10 In the present invention alternative means for conducting association
studies rather than
linkage analysis between markers located on the chromosome 13q31-q33 locus and
a trait,
preferably schizophrenia or bipolar disorder, are disclosed.
In the present application, additional biallelic markers located on the human
chromosome 13q31-q33 locus associated with schizophrenia are disclosed. The
identification
15 of these biallelic markers in association with schizophrenia has allowed
for the further definition
of the chromosomal region suspected of containing a genetic determinant
involved in a
predisposition to develop schizophrenia and has resulted in the identification
of novel gene
sequences disclosed herein which are associated with a predisposition to
develop schizophrenia.
The present invention thus provides an extensive fine structure map of the
13q31-q33 locus,
including novel biallelic markers located on the human 13q31-q33 locus,
approximately 319kb
of genomic nucleotide sequence of a subregion of the human 13q31-q33 locus,
and
polymorphisms including biallelic markers and nucleotide deletions in said
319kb genomic
sequence. The biallelic markers of the human chromosome 13q31-q33 locus and
the nucleotide
sequences, polymorphisms and gene sequences located in Region D subregion of
the human
chromosome 13q31-q33 locus are useful as genetic and physical markers for
further mapping
studies. The approximately 319kb of genomic nucleotide sequence disclosed
herein can further
serve as a reference in genetic or physical analysis of deletions,
substitutions, and insertions in
that region. Additionally, the sequence information provides a resource for
the further
identification of new genes in that region. Additionally, the sequences
comprising the the
schizophrenia-associated genes are useful, for example, for the isolation of
other genes in
putative gene families, the identification of homologs from other species,
treatment of disease
and as probes and primers for diagnostic or screening assays as described
herein.
These identified polymorphisms are used in the design of assays for the
reliable
detection of genetic susceptibility to schizophrenia and bipolar disorder.
They can also be used
in the design of drug screening protocols to provide an accurate and efficient
evaluation of the
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16
therapeutic and side-effect potential of new or already existing medicament or
treatment regime.
Definitions
As used interchangeably herein, the term "oligonucleotides", and
"polynucleotides"
include RNA, DNA, or RNA/DNA hybrid sequences of more than one nucleotide in
either
single chain or duplex form. The term "nucleotide" as used herein as an
adjective to describe
molecules comprising RNA, DNA, or RNA/DNA hybrid sequences of any length in
single-
stranded or duplex form. The term "nucleotide" is also used herein as a noun
to refer to
individual nucleotides or varieties of nucleotides, meaning a molecule, or
individual unit in a
larger nucleic acid molecule, comprising a purine or pyrimidine, a ribose or
deoxyribose sugar
moiety, and a phosphate group, or phosphodiester linkage in the case of
nucleotides within an
oligonucleotide or polynucleotide. Although the term "nucleotide" is also used
herein to
encompass "modified nucleotides" which comprise at least one modifications (a)
an alternative
linking group, (b) an analogous form of purine, (c) an analogous form of
pyrimidine, or (d) an
analogous sugar, for examples of analogous linking groups, purine,
pyrimidines, and sugars see
for example PCT publication No. WO 95/04064. However, the polynucleotides of
the invention
are preferably comprised of greater than 50% conventional deoxyribose
nucleotides, and most
preferably greater than 90% conventional deoxyribose nucleotides. The
polynucleotide
sequences of the invention may be prepared by any known method, including
synthetic,
recombinant, ex vivo generation, or a combination thereof, as well as
utilizing any purification
methods known in the art.
The term " urp ified" is used herein to describe a polynucleotide or
polynucleotide vector
of the invention which has been separated from other compounds including, but
not limited to
other nucleic acids, carbohydrates, lipids and proteins (such as the enzymes
used in the
synthesis of the polynucleotide), or the separation of covalently closed
polynucleotides from
linear polynucleotides. A polynucleotide is substantially pure when at least
about 50 %,
preferably 60 to 75% of a sample exhibits a single polynucleotide sequence and
conformation
(linear versus covalently close). A substantially pure polynucleotide
typically comprises about
50 %, preferably 60 to 90% weight/weight of a nucleic acid sample, more
usually about 95%,
and preferably is over about 99% pure. Polynucleotide purity or homogeneity
may be indicated
by a number of means well known in the art, such as agarose or polyacrylamide
gel
electrophoresis of a sample, followed by visualizing a single polynucleotide
band upon staining
the gel. For certain purposes higher resolution can be provided by using HPLC
or other means
well known in the art.
The term "isolated" requires that the material be removed from its original
environment
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(e.g., the natural environment if it is naturally occurring). For example, a
naturally-occurring
polynucleotide or polypeptide present in a living animal is not isolated, but
the same
polynucleotide or DNA or polypeptide, separated from some or all of the
coexisting materials in
the natural system, is isolated. Such polynucleotide could be part of a vector
and/or such
polynucleotide or polypeptide could be part of a composition, and still be
isolated in that the
vector or composition is not part of its natural environment.
The term " rp imer" denotes a specific oligonucleotide sequence which is
complementary
to a target nucleotide sequence and used to hybridize to the target nucleotide
sequence. A
primer serves as an initiation point for nucleotide polymerization catalyzed
by either DNA
polymerase, RNA polymerase or reverse transcriptase.
The term " rp obe" denotes a defined nucleic acid segment (or nucleotide
analog
segment, e.g., polynucleotide as defined herein) which can be used to identify
a specific
polynucleotide sequence present in samples, said nucleic acid segment
comprising a nucleotide
sequence complementary of the specific polynucleotide sequence to be
identified.
The terms "trait" and "phenotyne" are used interchangeably herein and refer to
any
clinically distinguishable, detectable or otherwise measurable property of an
organism such as
symptoms of, or susceptibility to a disease for example. Typically the terms
"trait" or
"phenotype" are used herein to refer to symptoms of, or susceptibility to
schizophrenia or
bipolar disorder; or to refer to an individual's response to an agent acting
on schizophrenia or
bipolar disorder; or to refer to symptoms of, or susceptibility to side
effects to an agent acting on
schizophrenia or bipolar disorder.
The term "allele" is used herein to refer to variants of a nucleotide
sequence. A biallelic
polymorphism has two forms. Typically the first identified allele is
designated as the original
allele whereas other alleles are designated as alternative alleles. Diploid
organisms may be
homozygous or heterozygous for an allelic form.
The term "heterozyg_osit~rate" is used herein to refer to the incidence of
individuals in
a population, which are heterozygous at a particular allele. In a biallelic
system the
heterozygosity rate is on average equal to 2Pa(1-Pa), where Pa is the
frequency ofthe least
common allele. In order to be useful in genetic studies a genetic marker
should have an
adequate level of heterozygosity to allow a reasonable probability that a
randomly selected
person will be heterozygous.
The term " eno e" as used herein refers the identity of the alleles present in
an
individual or a sample. In the context of the present invention a genotype
preferably refers to
the description of the biallelic marker alleles present in an individual or a
sample. The term
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18
"genot~ping" a sample or an individual for a biallelic marker involves
determining the specific
allele or the specific nucleotides) carried by an individual at a biallelic
marker.
The term "mutation" as used herein refers to a difference in DNA sequence
between or
among different genomes or individuals which has a frequency below 1%.
The term "ha to e" refers to a combination of alleles present in an individual
or a
sample on a single chromosome. In the context of the present invention a
haplotype preferably
refers to a combination of biallelic marker alleles found in a given
individual and which may be
associated with a phenotype.
The term "polXmorphism" as used herein refers to the occurrence of two or more
alternative genomic sequences or alleles between or among different genomes or
individuals.
"Polymorphic" refers to the condition in which two or more variants of a
specific genomic
sequence can be found in a population. A "polymorphic site" is the locus at
which the variation
occurs. A polymorphism may comprise a substitution, deletion or insertion of
one or more
nucleotides. A single nucleotide polymorphism is a single base pair change.
Typically a single
nucleotide polymorphism is the replacement of one nucleotide by another
nucleotide at the
polymorphic site. Deletion of a single nucleotide or insertion of a single
nucleotide, also give
rise to single nucleotide polymorphisms. In the context of the present
invention "single
nucleotide polymorphism" preferably refers to a single nucleotide
substitution. Typically,
between different genomes or between different individuals, the polymorphic
site may be
occupied by two different nucleotides.
The terms "biallelic polymorphism" and "biallelic marker" are used
interchangeably
herein to refer to a polymorphism having two alleles at a fairly high
frequency in the population,
preferably a single nucleotide polymorphism. A "biallelic marker allele"
refers to the
nucleotide variants present at a biallelic marker site. Typically the
frequency of the less
common allele of the biallelic markers of the present invention has been
validated to be-greater
than 1%, preferably the frequency is greater than 10%, more preferably the
frequency is at least
20% (i.e. heterozygosity rate of at least 0.32), even more preferably the
frequency is at least
30% (i.e. heterozygosity rate of at least 0.42). A biallelic marker wherein
the frequency of the
less common allele is 30% or more is termed a "high quality biallelic marker."
All of the
genotyping, haplotyping, association, and interaction study methods of the
invention may
optionally be performed solely with high quality biallelic markers.
The location of nucleotides in a polynucleotide with respect to the center of
the
polynucleotide are described herein in the following manner. When a
polynucleotide has an
odd number of nucleotides, the nucleotide at an equal distance from the 3' and
5' ends of the
polynucleotide is considered to be "at the center" of the polynucleotide, and
any nucleotide
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19
immediately adjacent to the nucleotide at the center, or the nucleotide at the
center itself is
considered to be "within 1 nucleotide of the center." With an odd number of
nucleotides in a
polynucleotide any of the five nucleotides positions in the middle of the
polynucleotide would
be considered to be within 2 nucleotides of the center, and so on. When a
polynucleotide has an
even number of nucleotides, there would be a bond and not a nucleotide at the
center of the
polynucleotide. Thus, either of the two central nucleotides would be
considered to be "within 1
nucleotide of the center" and any of the four nucleotides in the middle of the
polynucleotide
would be considered to be "within 2 nucleotides of the center", and so on. For
polymorphisms
which involve the substitution, insertion or deletion of 1 or more
nucleotides, the
polymorphism, allele or biallelic marker is "at the center" of a
polynucleotide if the difference
between the distance from the substituted, inserted, or deleted
polynucleotides of the
polymorphism and the 3' end of the polynucleotide, and the distance from the
substituted,
inserted, or deleted polynucleotides of the polymorphism and the 5' end of the
polynucleotide is
zero or one nucleotide. If this difference is 0 to 3, then the polymorphism is
considered to be
"within 1 nucleotide of the center." If the difference is 0 to 5, the
polymorphism is considered
to be "within 2 nucleotides of the center." If the difference is 0 to 7, the
polymorphism is
considered to be "within 3 nucleotides of the center," and so on. For
polymorphisms which
involve the substitution, insertion or deletion of I or more nucleotides, the
polymorphism, allele
or biallelic marker is "at the.center" of a polynucleotide if the difference
between the distance
from the substituted, inserted, or deleted polynucleotides of the polymorphism
and the 3' end of
the polynucleotide, and the distance from the substituted, inserted, or
deleted polynucleotides of
the polymorphism and the 5' end of the polynucleotide is zero or one
nucleotide. If this
difference is 0 to 3, then the polymorphism is considered to be "within 1
nucleotide of the
center." If the difference is 0 to S, the polymorphism is considered to be
"within 2 nucleotides
of the center." If the difference is 0 to 7, the polymorphism is considered to
be "within 3
nucleotides of the center," and so on.
The term "upstream" is used herein to refer to a location which, is toward the
5' end of
the polynucleotide from a specific reference point.
The terms "base paired" and "Watson & Crick base paired" are used
interchangeably
herein to refer to nucleotides which can be hydrogen bonded to one another be
virtue of their
sequence identities in a manner like that found in double-helical DNA with
thymine or uracil
residues linked to adenine residues by two hydrogen bonds and cytosine and
guanine residues
linked by three hydrogen bonds (See Stryer, L., Biochemistry, 4th edition,
1995).
The terms "complementarx" or "complement thereof?' are used herein to refer to
the
sequences of polynucleotides which is capable of forming Watson & Crick base
pairing with
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another specified polynucleotide throughout the entirety of the complementary
region. This
term is applied to pairs of polynucleotides based solely upon their sequences
and not any
particular set of conditions under which the two polynucleotides would
actually bind.
The terms "sbgl ._eg-nerve ", when used herein, encompasses genomic, mRNA and
cDNA
5 sequences encoding the sbgl protein, including the untranslated regulatory
regions of the
genomic DNA.
The terms " 834665 ,_~ene ", when used herein, encompasses genomic, mRNA and
cDNA sequences encoding the 834665 protein, including the untranslated
regulatory regions of
the genomic DNA.
10 The terms "sbg~ ", when used herein, encompasses genomic, mRNA and cDNA
sequences encoding the sbg2 protein, including the untranslated regulatory
regions of the
genomic DNA.
The terms " 835017 gene ", when used herein, encompasses genomic, mRNA and
cDNA sequences encoding the 835017 protein, including the untranslated
regulatory regions of
15 the genomic DNA.
The terms " 3g 5018 gene ", when used herein, encompasses genomic, mRNA and
cDNA sequences encoding the 835018 protein, including the untranslated
regulatory regions of
the genomic DNA.
As used herein the term "13q31-q33-related biallelic marker" relates to a set
of biallelic
20 markers residing in the human chromosome 13q31-q33 region. The term 13q31-
q33-related
biallelic marker encompasses all of the biallelic markers disclosed in Table
6b and any biallelic
markers in linkage disequilibrium therewith ,as well as any biallelic markers
disclosed in Table
6c and any biallelic markers in linkage disequilibrium therewith. The
preferred chromosome
13q31-q33-related biallelic marker alleles of the present invention include
each one the alleles
described in Tables 6b individually or in groups consisting of all the
possible combinations of
the alleles listed.
As used herein the term "Region D-related biallelic marker" relates to a set
of biallelic
markers in linkage disequilibrium with the subregion of the chromosome 13q31-
q33 region
referred to herein as Region D. The term Region D-related biallelic marker
encompasses the
biallelic markers A1 to A242, A249 to A251, A257 to A263, A269 to A270, A278,
A285 to
A299, A303 to A307, A324, A330, A334 to A335, A346 to 357 and A361 to A489
disclosed in
Table 6b and any biallelic markers in linkage disequilibrium with markers A1
to A242, A249 to
A251, A257 to A263, A269 to A270, A278, A285 to A299, A303 to A307, A324,
A330, A334
to A335, A346 to 357 and A361 to A489.
As used herein the term "sb~l-related biallelic marker" relates to a set of
biallelic
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markers in linkage disequilibrium with the sbgl gene or an sbgl nucleotide
sequence. The term
sbgl-related biallelic marker encompasses the biallelic markers A85 to A219
disclosed in Table
6b and any biallelic markers in linkage disequilibrium therewith.
As used herein the term "g34665-related biallelic marker" relates to a set of
biallelic
markers in linkage disequilibrium with the g34665 gene or an sbgl nucleotide
sequence. The
term g34665-related biallelic marker encompasses the biallelic markers A230 to
A236 disclosed
in Table 6b and any biallelic markers in linkage disequilibrium therewith.
As used herein the term "sbg2-related biallelic marker" relates to a set of
biallelic
markers in linkage disequilibrium with the sbg2 gene or an sbg2 nucleotide
sequence. The term
sbg2-related biallelic marker encompasses the biallelic markers A79 to A99
disclosed in Table
6b and any biallelic markers in linkage disequilibrium therewith.
As used herein the term "35017-related biallelic marker" relates to a set of
biallelic
markers in linkage disequilibrium with the g35017 gene or an g35017 nucleotide
sequence. The
term g35017-related biallelic marker encompasses biallelic marker A41
disclosed in Table 6b
and any biallelic markers in linkage disequilibrium therewith.
As used herein the term "g35018-related biallelic marker" relates to a set of
biallelic
markers in linkage disequilibrium with the g35018 gene or a g35018 nucleotide
sequence. The
term g35018-related biallelic marker encompasses the biallelic markers AI to
A39 disclosed in
Table 6b and any biallelic markers in linkage disequilibrium therewith.
The term "polypeptide" refers to a polymer of amino acids without regard to
the length
of the polymer; thus, peptides, oligopeptides, and proteins are included
within the definition of
polypeptide. This term also does not specify or exclude prost-expression
modifications of
polypeptides, for example, polypeptides which include the covalent attachment
of glycosyl
groups, acetyl groups, phosphate groups, lipid groups and the like are
expressly encompassed by
the term polypeptide. Also included within the definition are polypeptides
which contain one or
more analogs of an amino acid (including, for example, non-naturally occurring
amino acids,
amino acids which only occur naturally in an unrelated biological system,
modified amino acids
from mammalian systems etc.), polypeptides with substituted linkages, as well
as other
modifications known in the art, both naturally occurring and non-naturally
occurring.
The term " urified" is used herein to describe a polypeptide of the invention
which has
been separated from other compounds including, but not limited to nucleic
acids, lipids,
carbohydrates and other proteins. A polypeptide is substantially pure when at
least about 50%,
preferably 60 to 75% of a sample exhibits a single polypeptide sequence. A
substantially pure
polypeptide typically comprises about 50%, preferably 60 to 90% weight/weight
of a protein
sample, more usually about 95%, and preferably is over about 99% pure.
Polypeptide purity or
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22
homogeneity is indicated by a number of means well known in the art, such as
agarose or
polyacrylamide gel electrophoresis of a sample, followed by visualizing a
single polypeptide
band upon staining the gel. For certain purposes higher resolution can be
provided by using
HPLC or other means well known in the art.
As used herein, the term "non-human animal" refers to any non-human
vertebrate, birds
and more usually mammals, preferably primates, farm animals such as swine,
goats, sheep,
donkeys, and horses, rabbits or rodents, more preferably rats or mice. As used
herein, the term
"animal" is used to refer to any vertebrate, preferable a mammal. Both the
terms "animal" and
"mammal" expressly embrace human subjects unless preceded with the term "non-
human".
As used herein, the term "antibody" refers to a polypeptide or group of
polypeptides
which are comprised of at least one binding domain, where an antibody binding
domain is
formed from the folding of variable domains of an antibody molecule to form
three-dimensional
binding spaces with an internal surface shape and charge distribution
complementary to the
features of an antigenic determinant of an antigen., which allows an
immunological reaction
with the antigen. Antibodies include recombinant proteins comprising the
binding domains, as
wells as fragments, including Fab, Fab', F(ab)2, and F(ab')2 fragments.
As used herein, an "antigenic determinant" is the portion of an antigen
molecule, in this
case an sbgl polypeptide, that determines the specificity of the antigen-
antibody reaction. An
"epitope" refers to an antigenic determinant of a polypeptide. An epitope can
comprise as few
as 3 amino acids in a spatial conformation which is unique to the epitope.
Generally an epitope
comprises at least 6 such amino acids, and more usually at least 8-10 such
amino acids.
Methods for determining the amino acids which make up an epitope include x-ray
crystallography, 2-dimensional nuclear magnetic resonance, and epitope mapping
e.g. the
Pepscan method described by Geysen et al. 1984; PCT Publication No. WO
84/03564; and
PCT Publication No. WO 84/03506.
Variants and Fragments
The invention also relates to variants and fragments of the polynucleotides
described
herein, particularly of a nucleotide sequence of SEQ ID Nos. 1 to 26, 36 to 40
and 54 to 229,
and particularly of a nucleotide sequence of SEQ ID Nos. 1 to 26, 36 to 40 and
54 to 229
containing one or more biallelic markers and/or other polymorphisms according
to the
invention.
Variants of polynucleotides, as the term is used herein, are polynucleotides
that differ
from a reference polynucleotide. A variant of a polynucleotide may be a
naturally occurring
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23
variant such as a naturally occurring allelic variant, or it may be a variant
that is not known to
occur naturally. Such non-naturally occurring variants of the polynucleotide
may be made by
mutagenesis techniques, including those applied to polynucleotides, cells or
organisms.
Generally, differences are limited so that the nucleotide sequences of the
reference and the
variant are closely similar overall and, in many regions, identical.
Variants of polynucleotides according to the invention include, without being
limited to,
nucleotide sequences which are at least 95% identical to a polynucleotide
selected from the
group consisting of the nucleotide sequences SEQ ID Nos. 1 to 26, 36 to 40 and
54 to 229 or to
any polynucleotide fragment of at least 8 consecutive nucleotides of a
polynucleotide selected
from the group consisting of the nucleotide SEQ ID Nos. I to 26, 36 to 40 and
54 to 229, and
preferably at least 99% identical, more particularly at least 99.5% identical,
and most preferably
at least 99.8% identical to a polynucleotide selected from the group
consisting of the nucleotide
SEQ ID Nos. 1 to 26, 36 to 40 and 54 to 229 or to any polynucleotide fragment
of at least 30,
35, 40, 50, 70, 80; 100, 250, 500 , 1000 or 2000, to the extent that the
length is consistent with
the particular sequence ID, consecutive nucleotides of a polynucleotide
selected from the group
consisting of the nucleotide sequences of SEQ ID Nos. 1 to 26, 36 to 40 and 54
to 229.
Nucleotide changes present in a variant polynucleotide may be silent, which
means that
they do not alter the amino acids encoded by the polynucleotide. However,
nucleotide changes
may also result in amino acid substitutions, additions, deletions, fusions and
truncations in the
polypeptide encoded by the reference sequence. The substitutions, deletions or
additions may
involve one or more nucleotides. The variants may be altered in coding or non-
coding regions
or both. Alterations in the coding regions may produce conservative or non-
conservative amino
acid substitutions, deletions or additions.
A polynucleotide fragment is a polynucleotide having a sequence that is
entirely the
same as part but not all of a given nucleotide sequence, preferably the
nucleotide sequence of an
sbgl polynucleotide, and variants thereof, or of a polynucleotide of any of
SEQ ID Nos 1 to 26,
36 to 40 and 54 to 229, or a polynucleotide comprising one ofthe biallelic
markers A1 to A360
or polymorphism A361 to A489, or the complements thereof. Such fragments may
be "free-
standing", i.e. not part of or fused to other polynucleotides, or they may be
comprised within a
single larger polynucleotide of which they form a part or region. Indeed,
several of these
fragments may be present within a single larger polynucleotide. Optionally,
such fragments
may comprise, consist of, or consist essentially of a contiguous span of at
least 8, 10, 12, 15, 18,
20, 25, 30, 35, 40, 50, 70, 80, 100, 250, 500 , 1000 or 2000 nucleotides in
length of any of SEQ
ID Nos 1 to 26, 36 to 40 and 54 to 229.
Identity Between Nucleic Acids Or Polypeptides
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24
The terms "percentage of sequence identity" and "percentas,e homolop~" are
used
interchangeably herein to refer to comparisons among polynucleotides and
polypeptides, and
are determined by comparing two optimally aligned sequences over a comparison
window,
wherein the portion of the polynucleotide or polypeptide sequence in the
comparison window
may comprise additions or deletions (i.e., gaps) as compared to the reference
sequence (which
does not comprise additions or deletions) for optimal alignment of the two
sequences. The
percentage is calculated by determining the number of positions at which the
identical nucleic
acid base or amino acid residue occurs in both sequences to yield the number
of matched
positions, dividing the number of matched positions by the total number of
positions in the
window of comparison and multiplying the result by 100 to yield the percentage
of sequence
identity. Homology is evaluated using any of the variety of sequence
comparison algorithms
and programs known in the art. Such algorithms and programs include, but are
by no means
limited to, TBLASTN, BL ASTP, FASTA, TFASTA, and CLUSTALW (Pearson and
L.ipman,
1988, Proc. Natl. Acad. Sci. USA 85(8):2444-2448; Altschul et al., 1990, J.
Mol. Biol.
215(3):403-410; Thompson et al., 1994, Nucleic Acids Res. 22(2):4673-4680;
Higgins et al.,
1996, Methods Enzymol. 266:383-402; Altschul et al., 1990, J. Mol. Biol.
215(3):403-410;
Altschul et al., 1993, Nature Genetics 3:266-272). In a particularly preferred
embodiment,
protein and nucleic acid sequence homologies are evaluated using the Basic
Local Alignment
Search Tool ("BLAST") which is well known in the art (see, e.g., Karlin and
Altschul, 1990,
Proc. Natl. Acad. Sci. USA 87:2267-2268; Altschul et al., 1990, J. Mol. Biol.
215:403-410;
Altschul et al., 1993, Nature Genetics 3:266-272; Altsehul et al., 1997, Nuc.
Acids Res.
25:3389-3402). In particular, five specific BLAST programs are used to perform
the following
task:
( 1 ) BLASTP and BLAST3 compare an amino acid query sequence against a protein
sequence database;
(2) BLASTN compares a nucleotide query sequence against a nucleotide sequence
database;
(3) BLASTX compares the six-frame conceptual translation products of a query
nucleotide sequence (both strands) against a protein sequence database;
(4) TBLASTN compares a query protein sequence against a nucleotide sequence
database translated in all six reading frames (both strands); and
(5) TBLASTX compares the six-frame translations of a nucleotide query sequence
against the six-frame translations of a nucleotide sequence database.
The BLAST programs identify homologous sequences by identifying similar
segments,
which are referred to herein as "high-scoring segment pairs," between a query
amino or nucleic
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acid sequence and a test sequence which is preferably obtained from a protein
or nucleic acid
sequence database. High-scoring segment pairs are preferably identified (i.e.,
aligned) by
means of a scoring matrix, many of which are known in the art. Preferably, the
scoring matrix
used is the BLOSUM62 matrix (Gonnet et al., 1992, Science 256:1443-1445;
Henikoff and
5 Henikoff, 1993, Proteins 17:49-61 ). Less preferably, the PAM or PAM250
matrices may also
be used (see, e.g., Schwartz and Dayhoff, eds., 1978, Matrices for Detecting
Distance
Relationships: Atlas of Protein Sequence and Structure, Washington: National
Biomedical
Research Foundation). The BLAST programs evaluate the statistical significance
of all high-
scoring segment pairs identified, and preferably selects those segments which
satisfy a user-
10 specified threshold of significance, such as a user-specified percent
homology. Preferably, the
statistical significance of a high-scoring segment pair is evaluated using the
statistical
significance formula of Karlin (see, e.g., Karlin and Altschul, 1990, Proc.
Natl. Acad. Sci. USA
87:2267-2268).
The BLAST programs may be used with the default parameters or with modified
15 parameters provided by the user.
Stringent Hybridization Conditions
By way of example and not limitation, procedures using conditions of high
stringency
are as follows: Prehybridization of filters containing DNA is carried out for
8 h to overnight at
65°C in buffer composed of 6X SSC, 50 mM Tris-HC1 (pH 7.5), 1 mM EDTA,
0.02% PVP,
20 0.02% Ficoll, 0.02% BSA, and 500 pg/ml denatured salmon sperm DNA. Filters
are hybridized
for 48 h at 65°C, the preferred hybridization temperature, in
prehybridization mixture
containing 100 pg/ml denatured salmon sperm DNA and 5-20 X 106 cpm of 3zP-
labeled probe.
Subsequently, filter washes can be done at 37°C for 1 h in a solution
containing 2 x SSC, 0.01%
PVP, 0.01% Ficoll, and 0.01% BSA, followed by a wash in 0.1 X SSC at
50°C for 45 min.
25 Following the wash steps, the hybridized probes are detectable by
autoradiography. Other
conditions of high stringency which may be used are well known in the art and
as cited in
Sambrook et al., 1989; and Ausubel et al., 1989. These hybridization
conditions are suitable
for a nucleic acid molecule of about 20 nucleotides in length. There is no
need to say that the
hybridization conditions described above are to be adapted according to the
length of the desired
nucleic acid, following techniques well known to the one skilled in the art.
The suitable
hybridization conditions may for example be adapted according to the teachings
disclosed in the
book of Hames and Higgins (1985) or in Sambrook et al.(1989).
Genomic Sequences of the polynucleotides of the invention
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26
The present invention concerns genomic DNA sequences of the sbgl, g34665,
sbg2,
g35017 and g35018 genes, as well as DNA sequences of the human chromosome
13q31-q33
region, and more particularly, a subregion thereof referred to herein as
region D.
As referred to herein, genomic sequences of sbg2, g35017 and g35018 are
indicated by
nucleotide position in the 5' to 3' orientation on SEQ ID No 1. sbgl and
g34665 are transcribed
in the opposite direction, ie. from the nucleic acid strand complementary to
SEQ ID No 1.
Genomic sequences of sbgl and g34665 are thus indicated by nucleotide position
in the 3'to 5'
orientation on SEQ ID No 1.
Preferred nucleic acids of the invention include isolated, purified, or
recombinant
polynucleotides comprising a contiguous span of at least 12, 15, 18, 20, 25,
30, 35, 40, 50, 60,
70, 80, 90, 100, 150, 200, 500, 1000 or 2000 nucleotides of nucleotide
positions 31 to 292651
and 292844 to 319608 of SEQ ID No. 1, or the complements thereof. Further
nucleic acids of
the invention include isolated, purified, or recombinant polynucleotides
comprising a
contiguous span of at least 12, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80,
90, 100, 150, 200, 500,
1000 or 2000 nucleotides, to the extent that the length of said span is
consistent with the length
of the SEQ ID, of SEQ ID Nos. 112 to 229. Optionally, said span is at least
12, 15, 18, 20, 25,
30, 35, 40, S0, 60, 70, 80, 90, 100, 150, 200, 500, 1000 or 2000 nucleotides
of SEQ ID Nos. 112
to 114, 115 to 117, 119, 121, 125 to 145, 147 to 150, 159 to 170, and 176 to
229.
The invention also encompasses a purified, isolated, or recombinant
polynucleotide
comprising a nucleotide sequence having at least 70, 75, 80, 85, 90, or 95%
nucleotide identity
with a nucleotide sequence of of nucleotide positions 31 to 292651 and 292844
to 319608 of
SEQ ID No. 1, or a complementary sequence thereto or a fragment thereof.
Another object of
the invention consists of a purified, isolated, or recombinant nucleic acid
that hybridizes with a
contiguous span of at least 12, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80,
90, 100, 150, 200, 500,
1000 or 2000 nucleotides of SEQ ID No 1 or a complementary sequence thereto or
a variant
thereof, under the stringent hybridization conditions as defined above.
Additional preferred nucleic acids of the invention include isolated,
purified, or
recombinant polynucleotides comprising a contiguous span of at least 12, 15, I
8, 20, 25, 30, 35,
40, 45, 50, 55, 60, 65, 70, 75, 80, 90, 100 or 200 nucleotides of SEQ ID No 1
or the
complements thereof, wherein said contiguous span comprises a biallelic
marker. Optionally,
said contiguous span comprises ar biallelic marker selected from the group
consisting of A1 to
A69, A71 to A74, A76 to A94, A96 to A 106, A 108 to A 112, A 114 to A 177, A
179 to A 197,
A199 to A222, A224 to A242. Optionally allele 2 is present at the biallelic
marker. It should be
noted that nucleic acid fragments of any size and sequence may be comprised by
the
polynucleotides described in this section.
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27
Another particularly preferred set of nucleic acids of the invention include
isolated,
purified, or recombinant polynucleotides comprising a contiguous span of at
least 12, 1 S, 18, 20,
25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150, 200, 500, 1000 or 2000
nucleotides, to the extent
that such a length is consistent with the lengths of the particular nucleotide
position, of SEQ ID
No. 1 or the complements thereof, wherein said contiguous span comprises at
least 1, 2, 3, 5, or
nucleotide positions of any one of the following ranges of nucleotide
positions, designated
post to pos166, of SEQ ID No. 1 listed in Table 1 below:
Table 1
PositionPosition Position Position
in SEQ in SEQ
ID No ID No 1
1
Begining End Begining End
posl 36 2000 pos84 156001 158000
post 2001 4000 pos85 158001 160000
pos3 4001 6000 pos86 160001 162000
pos4 6001 8000 pos87 162001 164000
posy 8001 10000 pos88 164001 166000
posh 10001 12000 pos89 166001 168000
pos7 12001 14000 . pos90 168001 170000
pos8 14001 16000 pos91 170001 172000
pos9 16001 18000 pos92 172001 174000
pos 18001 20000 pos93 174001 176000
10
pos 20001 22000 pos94 176001 178000
h
posl2 22001 24000 pos95 178001 180000
posl3 24001 26000 pos96 180001 182000
posl4 26001 28000 pos97 182001 184000
posl5 28001 29966 pos98 184001 186000
posl6 30116 32000 pos99 186001 188000
pos 32001 34000 pos100 188001 190000
h
posl8 34001 36000 pos101 190001 192000
posl9 36001 38000 pos102 192001 194000
pos20 38001 40000 pos103 194001 196000
pos21 40001 42000 pos104 196001 198000
pos22 42001 44000 pos105 198001 200000
pos23 44001 46000 pos106 200001 201000
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PositionPosition Position Position
in SEQ in SEQ
ID No ID No 1
1
Begining End Begining End
pos24 46001 48000 pos107 201001 202000
pos25 48001 50000 pos108 202001 204000
pos26 50001 52000 pos109 204001 206000
pos27 52001 54000 pos110 206001 208000
pos28 54001 56000 poslll 208001 210000
pos29 56001 58000 pos112 210001 212000
pos30 58001 60000 pos113 212001 214000
pos31 60001 62000 pos114 214001 216000
pos32 62001 64000 pos115 216001 218000
pos33 64001 66000 pos116 218001 220000
pos34 66001 68000 pos117 220001 222000
pos35 68001 70000 pos118 222001 224000
pos36 70001 72000 pos119 224001 226000
pos37 72001 74000 pos120 226001 228000
pos38 74001 76000 pos121 228001 230000
pos39 76001 78000 pos122 230001 232000
pos40 78001 80000 pos123 232001 234000
pos41 80001 82000 pos124 234001 236000
pos42 82001 84000 pos125 236001 238000
pos43 84001 86000 pos126 238001 240000
pos44 86001 88000 pos127 240001 242000
pos45 88001 90000 pos128 242001 244000
pos46 90001 92000 pos129 244001 246000
pos47 92001 94000 pos130 246001 248000
pos48 94001 96000 posl3l 248001 250000
pos49 96001 98000 pos132 250001 252000
pos50 98001 100000 pos133 252001 254000
pos51 10000 102000 pos134 254001 256000
pos52 10200 104000 pos135 256001 258000
pos53 10400 106000 pos136 258001 260000
pos54 10600 108000 pos137 260001 262000
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PositionPosition Position Position
in SEQ in SEQ
ID No ID No 1
1
Begining End Begining End
pos55 10800 110000 pos138 262001 264000
pos56 11000 102000 posl39 264001 266000
pos57 10200 104000 pos140 266001 268000
pos58 10400 106000 pos141 268001 270000
pos59 10600 108000 pos142 270001 272000
pos60 10800 110000 pos143 272001 274000
pos61 11000 112000 pos144 274001 276000
pos62 11200 114000 pos145 276001 278000
pos63 11400 116000 posl46 278001 280000
pos64 11600 118000 pos147 280001 282000
pos65 11800 120000 pos148 282001 284000
pos66 12000 122000 pos149 284001 286000
pos67 12200 124000 pos150 286001 288000'
pos68 12400 126000 posl5l 288001 290000
pos69 12600 128000 pos152 290001 292000
pos70 12800 130000 posl53 292001 294000
.
pos 13000 132000 pos 154 294001 296000
71
pos 13200 134000 pos155 296001 298000
72
pos 13400 136000 pos156 298001 300000
73
pos 13600 138000 posl57 300001 302000
74
pos75 13800 140000 posl58 302001 304000
pos76 14000 142000 pos159 304001 306000
pos77 14200 144000 pos160 306001 308000
pos78 14400 146000 pos161 308001 310000
pos79 14600 148000 pos162 310001 312000
pos80 148000 150000 pos163 312001 314000
pos81 150001 152000 pos164 314001 316000
pos82 152001 154000 pos165 316001 318000
pos83 154001 156000 pos 166 318001 319608
Nucleic Acid Sequences of sbgl, 834665, sbg2, 835017 and 835018
The present invention encompasses the 834665, 834673, 834667, 835017 and
835018
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genes and nucleotide sequences.
3g 4665
In one aspect, the invention concerns g34665 genomic sequences consisting of,
consisting essentially of, or comprising the sequence of nucleotide positions
292653 to 296047
5 of SEQ ID No 1, a sequence complementary thereto, as well as fragments and
variants thereof.
These polynucleotides may be purified, isolated, or recombinant.
Particularly preferred nucleic acids of the invention include isolated,
purified, or
recombinant polynucleotides comprising a contiguous span of at least 12, 15,
18, 20, 25, 30, 35,
40, 50, 60, 70, 80, 90, 100, 150 or 200 nucleotides, to the extent that the
length of said span is
10 consistent with the nucleotide position range, of nucleotide positions
292653 to 292841, 295555
to 296047 or 295580 to 296047 of SEQ ID No 1. Further preferred nucleic acids
of the
invention include isolated, purified, or recombinant polynucleotides
comprising a contiguous
span of at least 12, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150
or 200 nucleotides, to
the extent that the length of said span is consistent with the nucleotide
position range, of
15 nucleotide positions 292653 to 292841, 295555 to 296047, or 295580 to
296047 of SEQ ID No
1, or the complements thereof, wherein said contiguous span comprises a g34665-
related
biallelic marker. Optionally, said biallelic marker is selected from the group
consisting of A230
to A236. It should be noted that nucleic acid fragments of any size and
sequence may also be
comprised by the polynucleotides described in this section.
20 The invention also encompasses a purified, isolated, or recombinant
polynucleotide
comprising a nucleotide sequence having at least 70, 75, 80, 85, 90, 95, 97,
98 or 99%
nucleotide identity with a nucleotide sequence of of nucleotide positions
290653 to 292652,
292653 to 296047, 292653 to 292841, 295555 to 296047, 295580 to 296047 and
296048 to
298048 of SEQ ID No 1 or a complementary sequence thereto or a fragment
thereof. The
25 nucleotide differences as regards to nucleotide positions 290652 to 292652,
292653 to 296047,
292653 to 292841, 295555 to 296047, 295580 to 296047 and 296048 to 298048 of
SEQ ID No
1 may be generally randomly distributed throughout the entire nucleic acid.
Nevertheless,
preferred nucleic acids are those wherein the nucleotide differences as
regards to the nucleotide
sequence of SEQ ID No I are predominantly located outside the coding sequences
contained in
30 the exons. These nucleic acids, as well as their fragments and variants,
may be used as
oligonucleotide primers or probes in order to detect the presence of a copy of
the g34665 gene
in a test sample, or alternatively in order to amplify a target nucleotide
sequence within the
g34665 sequences.
Another object of the invention consists of a purified, isolated, or
recombinant nucleic
acid that hybridizes with a g34665 nucleotide sequence of any of nucleotide
positions 292653 to
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31
296047, 292653 to 292841, 295555 to 296047, 295980 to 296047 and 296048 to
298048 SEQ
ID No 1 or a complementary sequence thereto or a variant thereof, under the
stringent
hybridization conditions as defined above.
The g34665 genomic nucleic acid comprises at least 3 exons. The exon positions
in
SEQ ID No 1 are detailed below in Table 2.
Table 2
Exon Position Intron Position
in SEQ in SEQ
ID No ID No
1 1
BeginningEnd BeginningEnd
B 292653 292841 B-Ab 292842 295554
Ab 295555 296047 B-A 292842 295979
A 295980 296047
Thus, the invention embodies purified, isolated, or recombinant
polynucleotides
comprising a nucleotide sequence selected from the group consisting of the 3
exons of the
g34665 gene, or a sequence complementary thereto. The invention also deals
with purified,
isolated, or recombinant nucleic acids comprising a combination of two exons
of the g34665
gene.
Intron B-Ab refers to the nucleotide sequence located between Exon B and Exori
Ab,
and so on. The position of the introns is detailed in Table 2. Thus, the
invention embodies
purified, isolated, or recombinant polynucleotides comprising a nucleotide
sequence selected
from the group consisting of the 2 introns of the g34665 gene, or a sequence
complementary
thereto.
While this section is entitled "Genomic Sequences of g34665," it should be
noted that
nucleic acid fragments of any size and sequence may also be comprised by the
polynucleotides
described in this section, flanking the genomic sequences of g34665 on either
side or between
two or more such genomic sequences.
A g34665 polynucleotide or gene may further contain regulatory sequences both
in the
non-coding 5'-flanking region and in the non-coding 3'-flanking region that
border the region
containing said genes or exons.
Polynucleotides derived from 5' and 3' regulatory regions are useful in order
to detect
the presence of at least a copy of a nucleotide sequence comprising a g34665
nucleotide
sequence of SEQ ID No. 1 or a fragment thereof in a test sample.
Polynucleotides carrying the
regulatory elements located at the 5' end and at the 3' end of the genes
comprising the exons of
the present invention may be advantageously used to control the
transcriptional and translational
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32
activity of a heterologous polynucleotide of interest.
Methods for identifying the relevant polynucleotides comprising biologically
active
g34665 regulatory fragments or variants of SEQ ID No I are further described
herein. Thus, the
present invention also relates to a purified or isolated nucleic acid
comprising a polynucleotide
which is selected from the group consisting of the 5' and 3' regulatory
regions of g34665, or a
sequence complementary thereto or a biologically active fragment or variant
thereof.
3g 5017
In one aspect, the invention concerns g35017 genomic sequences consisting of,
consisting essentially of, or comprising the sequence of nucleotide positions
94124 to 94964 of
SEQ ID No 1, a sequence complementary thereto, as well as fragments and
variants thereof.
These polynucleotides may be purified, isolated, or recombinant.
The invention also encompasses a purified, isolated, or recombinant
polynucleotide
comprising a nucleotide sequence having at least 70, 75, 80, 85, 90, or 95%
nucleotide identity
with a nucleotide sequence of of nucleotide positions 94124 to 94964 SEQ ID No
1 or a
complementary sequence thereto or a fragment thereof. The nucleotide
differences as regards to
nucleotide positions 94124 to 94964 SEQ ID No 1 may be generally randomly
distributed
throughout the entire nucleic acid. Nevertheless, preferred nucleic acids are
those wherein the
nucleotide differences as regards to the nucleotide sequence of SEQ ID No 1
are predominantly
located outside the coding sequences contained in the exons. These nucleic
acids, as well as
their fragments and variants, may be used as oligonucleotide primers or probes
in order to detect
the presence of a copy of the g35017 gene in a test sample, or alternatively
in order to amplify a
target nucleotide sequence within the g35017 sequences.
Another object of the invention consists of a purified, isolated, or
recombinant nucleic
acid that hybridizes with a g35017 nucleotide sequence of any of nucleotide
positions 94124 to
94964 of SEQ ID No 1 or a complementary sequence thereto or a variant thereof,
under the
stringent hybridization conditions as defined above.
Particularly preferred nucleic acids of the invention include isolated,
purified, or
recombinant polynucleotides comprising a contiguous span of at least 12, 15,
18, 20, 25, 30, 35,
40, 50, 60, 70, 80, 90, 100, 150, 200 or 500 nucleotides of nucleotide
position 94124 to 94964
of SEQ ID No 1 or the complements thereof. Particularly preferred nucleic
acids of the
invention include isolated, purified, or recombinant polynucleotides
comprising a contiguous
span of at least 12, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150,
200 or 500
nucleotides of nucleotide position 94124 to 94964 of SEQ ID No 1 or the
complements thereof,
wherein said contiguous span comprises a g35017 related biallelic marker.
Optionally, said
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33
biallelic marker is the biallelic marker designated A41 in Table 6b. It should
be noted that
nucleic acid fragments of any size and sequence may also be comprised by the
polynucleotides
described in this section.
While this section is entitled "Genomic Sequences of g35017," it should be
noted that
nucleic acid fragments of any size and sequence may also be comprised by the
polynucleotides
described in this section, flanking the genomic sequences of g35017 on either
side or between
two or more such genomic sequences.
A g35017 polynucleotide or gene may further contain regulatory sequences both
in the
non-coding 5'-flanking region and in the non-coding 3'-flanking region that
border the region
containing said genes or exons.
Polynucleotides derived from g35017 5' and 3' regulatory regions are useful in
order to
detect the presence of at least a copy of a nucleotide sequence comprising an
g35017 nucleotide
sequence of SEQ ID No. 1 or a fragment thereof in a test sample.
Polynucleotides carrying the
regulatory elements located at the 5' end and at the 3' end of the genes
comprising the exons of
the present invention may be advantageously used to control the
transcriptional and translational
activity of a heterologous polynucleotide of interest.
Methods for identifying the relevant polynucleotides comprising biologically
active
regulatory fragments or variants of a g35017 nucleic acid sequence of SEQ ID
No 1 are further
described herein. Thus, the present invention also relates to a purified or
isolated nucleic acid
comprising a polynucleotide which is selected from the group consisting of the
5' and 3'
regulatory regions, or a sequence complementary thereto or a biologically
active fragment or
variant thereof. In one aspect, the 5' regulatory region may comprise a
nucleotide sequence
3g 5018
In one aspect, the invention concenrs g35018 genomic sequences consisting of,
consisting essentially of, or comprising the sequence of nucleotide positions
1108 to 65853 of
SEQ ID No 1, a sequence complementary thereto, as well as fragments and
variants thereof.
These polynucleotides may be purified, isolated, or recombinant.
Particularly preferred nucleic acids of the invention include isolated,
purified, or
recombinant polynucleotides comprising a contiguous span of at least 12, 15,
18, 20, 25, 30, 35,
40, 50, 60, 70, 80, 90, 100, 150, 200, 500, or 1000 nucleotides, to the extent
that said span is
consistent with the nucleotide position range, of SEQ ID No 1, wherein said
contiguous span
comprises at least l, 2, 3, 5, or 10 of the following nucleotide positions of
SEQ ID No 1: 1108
to 65853, 1108 to 1289, 14877 to 14920, 18778 to 18862, 25593 to 25740, 29388
to 29502,
29967 to 30282, 64666 to 64812 and 65505 to 65853, or the complements thereof.
Further
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34
preferred nucleic acids of the invention include isolated, purified, or
recombinant
polynucleotides comprising a contiguous span of at least 12, I 5, 18, 20, 25,
30, 35, 40, 50, 60,
70, 80, 90, 100, 150, 200, 500, or 1000 nucleotides of nucleotide positions
1108 to 65853, 1108
to 1289, 14877 to 14920, 18778 to 18862, 25593 to 25740, 29388 to 29502, 29967
to 30282,
64666 to 64812 or 65505 to 65853 of SEQ ID No 1, or the complements thereof,
wherein said
contiguous span comprises a g35018 related biallelic marker. Optionally, said
biallelic marker
is selected from the group consisting of A1 to A39. It should be noted that
nucleic acid
fragments of any size and sequence may also be comprised by the
polynucleotides described in
this section.
The invention also encompasses a purified, isolated, or recombinant
polynucleotide
comprising a nucleotide sequence having at least 70, 75, 80, 85, 90, or 95%
nucleotide identity
with a nucleotide sequence of nucleotide positions 31 to 1107, 1108 to 65853,
1108 to 1289,
14877 to 14920, 18778 to 18862, 25593 to 25740, 29388 to 29502, 29967 to
30282, 64666 to
64812, 65505 to 65853 and 65854 to 67854 of SEQ ID No I or a complementary
sequence
thereto or a fragment thereof. The nucleotide differences as regards to
nucleotide positions 31
to 1107, 1108 to 65853, I 108 to 1289, 14877 to 14920, 18778 to 18862, 25593
to 25740, 29388
to 29502, 29967 to 30282, 64666 to 64812, 65505 to 65853 and 65854 to 67854 of
SEQ ID No
1 may be generally randomly distributed throughout the entire nucleic acid.
Nevertheless,
preferred nucleic acids are those wherein the nucleotide differences as
regards to the nucleotide
sequence of nucleotide positions 31 to 1107, 1108 to 65853, 1108 to 1289,
14877 to 14920,
18778 to 18862, 25593 to 25740, 29388 to 29502, 29967 to 30282, 64666 to
64812, 65505 to
65853 and 65854 to 67854 of SEQ ID No 1 are predominantly located outside the
coding
sequences contained in the exons. These nucleic acids, as well as their
fragments and variants,
may be used as oligonucleotide primers or probes in order to detect the
presence of a copy of the
g35018 gene in a test sample, or alternatively in order to amplify a target
nucleotide sequence
within the g35018 sequences.
Another object of the invention consists of a purified, isolated, or
recombinant nucleic
acid that hybridizes with a g35018 nucleotide sequence of any of nucleotide
positions 31 to
1107, 1108 to 65853, 1108 to 1289, 14877 to 14920, 18778 to 18862, 25593 to
25740, 29388 to
29502, 29967 to 30282, 64666 to 64812, 65505 to 65853 and 65854 to 67854 SEQ
ID No 1, or
a complementary sequence thereto or a variant thereof, under the stringent
hybridization
conditions as defined above.
Yet further nucleic acids of the invention include isolated, purified, or
recombinant
polynucleotides comprising a contiguous span of at least 12, 15, 18, 20, 25,
30, 35, 40, 50, 60,
70, 80, 90, 100, 150, 200 or 500 nucleotides, to the extent that said span is
consistent with the
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nucleotide position range, of SEQ ID No 1, wherein said contiguous span
comprises at least 1,
2, 3, 5, or 10 of the following nucleotide positions of SEQ ID No 1: 1255 to
1289, 29967 to
30115, 30225 to 30282, or the complements thereof, as well as polynucleotides
having at least
70, 75, 80, 85, 90, or 95% nucleotide identity with said span and
polynucleotides capable of
hybridizing with said span.
The g35018 genomic nucleic acid comprises at least 8 exons. The exon positions
in
SEQ ID No 1 are detailed below in Table 3.
Table 3
Exon Position Intron Position
in SEQ in SEQ
ID No ID No
1 1
BeginningEnd BeginningEnd
A 1108 1289 A 1290 14876
B 14877 14920 B 14921 18777
Bbis 18778 18862 Bbis 18863 25592
C 25593 25740 C 25741 29387
D 29388 29502 D 29503 29966
E 29967 30282 E 30283 64665
F 64666 64812 F 64813 65504
G 65505 65853
10 Thus, the invention embodies purified, isolated, or recombinant
polynucleotides
comprising a nucleotide sequence selected from the group consisting of the 8
exons of the
g35018 gene, or a sequence complementary thereto. The invention also deals
with purified,
isolated, or recombinant nucleic acids comprising a combination of at least
two exons of the
35018 gene, wherein the polynucleotides are arranged within the nucleic acid,
from the 5'-end
15 to the 3'-end of said nucleic acid, in the same order as in SEQ ID No 1.
Intron 1 refers to the nucleotide sequence located between Exon 1 and Exon 2,
and so
on. The position ofthe introns is detailed in Table 3. Thus, the invention
embodies purified,
isolated, or recombinant polynucleotides comprising a nucleotide sequence
selected from the
group consisting of the 7 introns of the g35018 gene, or a sequence
complementary thereto.
20 While this section is entitled "Genomic Sequences of g35018," it should be
noted that
nucleic acid fragments of any size and sequence may also be comprised by the
polynucleotides
described in this section, flanking the genomic sequences of g35018 on either
side or between
two or more such genomic sequences.
A g35018 polynucleotide or gene may further contain regulatory sequences both
in the
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non-coding 5'-flanking region and in the non-coding 3'-flanking region that
border the region
containing said genes or exons.
Polynucleotides derived from 5' and 3' regulatory regions are useful in order
to detect
the presence of at least a copy of a nucleotide sequence comprising an g35018
nucleotide
sequence of SEQ ID No. 1 or a fragment thereof in a test sample.
Polynucleotides carrying the
regulatory elements located at the 5' end and at the 3' end of the genes
comprising the exons of
the present invention may be advantageously used to control the
transcriptional and translational
activity of a heterologous polynucleotide of interest.
Methods for identifying the relevant polynucleotides comprising biologically
active
regulatory fragments or variants of SEQ ID No 1 are further described herein.
Thus, the present
invention also relates to a purified or isolated nucleic acid comprising a
polynucleotide which is
selected from the group consisting of the 5' and 3' regulatory regions, or a
sequence
complementary thereto or a biologically active fragment or variant thereof.
In one embodiment, a 5' regulatory region may comprise an isolated, purified,
or
recombinant polynucleotide comprising a contiguous span of at least 12, 15,
18, 20, 25, 30, 35,
40, 50, 60, 70, 80, 90, 100, 150, 200, 500, or 1000 nucleotides of nucleotide
positions 31 to
1107 of SEQ ID No 1, or the complements thereof. In one embodiment, a 3'
regulatory region
may comprise an isolated, purified, or recombinant polynucleotide comprising a
contiguous
span of at least 12, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150,
200, 500, or 1000
nucleotides of nucleotide positions 65854 to 67854 of SEQ ID No 1, or the
complements
thereof.
Genomic Sequences of sbgl polynucleotides
Particularly preferred nucleic acids of the invention include isolated,
purified, or
recombinant polynucleotides comprising, consisting essentially of, or
consisting of a contiguous
span of at least 12, 15, 18, 20, 25, 30, 35, 40, S0, 60, 70, 80, 90, 100, 150,
200, 500, or 1000
nucleotides of nucleotide positions 213818 to 243685 of SEQ ID No 1, or the
complements
thereof. Also encompassed are purified, isolated, or recombinant
polynucleotide comprising a
nucleotide sequence having at least 70, 75, 80, 85, 90, or 95% nucleotide
identity with
nucleotide positions 213818 to 243685 of SEQ ID No 1, or a complementary
sequence thereto
or a fragment thereof. Nucleic acids of the invention encompass an sbgl
nucleic acid from any
source, including primate, non-human primate, mammalian and human sbgl nucleic
acids.
Further preferred nucleic acids of the invention include isolated, purified,
or
recombinant polynucleotides comprising a contiguous span of at least 12, 15,
18, 20, 25, 30, 35,
40, 50, 60, 70, 80, 90, 100, 150, 200, 500, or 1000 nucleotides of SEQ ID No 1
or the
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37
complements thereof, wherein said contiguous span comprises an sbgl related
biallelic marker.
Optimally, said biallelic marker is selected from the group consisting of A85
to A219.
Optimally, said biallelic marker is selected from the group consisting of A85
to A94, A96 to
A 106, A 108 to A 112, A 114 to A 177, A 179 to A 197 and A 199 to A219.
It should be noted that nucleic acid fragments of any size and sequence may
also be
comprised by the polynucleotides described in this section.
The human sbgl gene comprises exons selected from at least 22 different exons
or exon
forms, referred to herein as exons MS1, Ml, M692, M862, MS2, M1069, M1090,
M1117, N ,
N2, Nbis, O, O1, 02, Obis, P, X, Ql, Q, Qbis, Rbis and R Of these, the
following exon sets
contain sequence overlap and do not occur together in an mRNA: exons M1, M692,
M862,
MS2, M1090 M1069 and M1117; exons MS1, M1, M692 and M862; exons N and N2;
exons
O 1 and 02; exons Q and Qbis; exons R and R bis; and exons Q and Q 1.
The nucleotide positions of sbgl exons in SEQ ID No. 1 are detailed below in
Table 4.
The exon structure of the sbgl gene is further shown in Figure 1.
Table 4
Exon Position
in SEQ
ID No
1
BeginningEnd
R 215819 215941
Rbis 215819 215975
Qbis 216661 216952
Q 216661 217061
Q1 217027 217061
X 229647 229742
P 230408 230721
Obis 231272 231412
02 231787 231880
O1 231870 231879
O 234174 234321
Nbis 237406 237428
N2 239719 239807
N 239719 239853
M117 240528 240569
M1090 240528 240596
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M1069 240528 240617
MS2 240528 240644
M862 240528 240824
M692 240528 240994
Ml 240528 241685
MS1 240800 240993
Thus, the invention embodies purified, isolated, or recombinant
polynucleotides
comprising a nucleotide sequence selected from the group consisting of the
exons of the sbgl
gene, or a sequence complementary thereto. Preferred are purified, isolated,
or recombinant
polynucleotides comprising at least one exon having the nucleotide position
ranges listed in
Table 4 selected from the group consisting of the exons MS1, M1, M692, M862,
MS2, M1069,
M1090, M1117, N , N2, Nbis, O, O1, 02, Obis, P, X, Q1, Q, Qbis, R and Rbis of
the sbgl gene,
or a complementary sequence thereto or a fragment or a variant thereof. Also
encompassed by
the invention are purified, isolated, or recombinant nucleic acids comprising
a combination of at
least two exons of the sbgl gene selected from the group consisting of exons
MS 1, M1, M692,
M862, MS2, M1069, M1090, M1117, N , N2, Nbis, O, O1, 02, Obis, P, X, Q1, Q,
Qbis, R and
Rbis, wherein the polynucleotides are arranged within the nucleic acid in the
same relative order
as in SEQ ID No. 1.
Particularly preferred nucleic acids of the invention include isolated,
purified, or
recombinant polynucleotides comprising a contiguous span of at least 12, 15,
18, 20, 25, 30, 35,
40, 45, 50, 55, 60, 65, 70, 75, 80, 90, 100 or 200 nucleotides of SEQ ID No l,
wherein said
contiguous span comprises at least 1, 2, 3, 5, or 10 ofthe following
nucleotide positions of SEQ
ID No 1: 213818 to 215818, 215819 to 215941, 215819 to 215975, 216661 to
216952, 216661
to 217061, 217027 to 217061, 229647 to 229742, 230408 to 230721, 231272 to
231412, 231787
to 231880, 231870 to 231879, 234174 to 234321, 237406 to 237428, 239719 to
239807, 239719
to 239853, 240528 to 240569, 240528 to 240596, 240528 to 240617, 240528 to
240644, 240528
to 240824, 240528 to 240994, 240528 to 241685, 240800 to 240993 and 241686 to
243685, or
the complements thereof.
Another object of the invention consists of a purified, isolated, or
recombinant nucleic
acid that hybridizes with an sbgl nucleotide sequence of nucleotide positions
213818 to 243685,
213818 to 215818, 215819 to 215941, 215819 to 215975, 216661 to 216952, 216661
to 217061,
217027 to 217061, 229647 to 229742, 230408 to 230721, 231272 to 231412, 231787
to 231880,
231870 to 231879, 234174 to 234321, 237406 to 237428, 239719 to 239807, 239719
to 239853,
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240528 to 240569, 240528 to 240596, 240528 to 240617, 240528 to 240644, 240528
to 240824,
240528 to 240994, 240528 to 241685, 240800 to 240993 or 241686 to 243685 of
SEQ ID No 1,
or a complementary sequence thereto or a variant thereof, under the stringent
hybridization
conditions as defined above.
The present invention further embodies purified, isolated, or recombinant
polynucleotides comprising a nucleotide sequence selected from the group
consisting of the
introns of the sbgl gene, or a sequence complementary thereto.
In other embodiments, the present invention encompasses the sbgl gene as well
as sbgl
genomic sequences consisting of, consisting essentially of, or comprising the
sequence of
nucleotide positions 215819 to 241685 of SEQ ID No 1, a sequence complementary
thereto, as
well as fragments and variants thereof.
The invention also encompasses a purified, isolated, or recombinant
polynucleotide
comprising a nucleotide sequence of sbgl having at least 70, 75, 80, 85, 90,
or 95% nucleotide
identity with a sequence selected from the group consisting of nucleotide
positions 213818 to
215818, 215819 to 215941, 215819 to 215975, 216661 to 216952, 216661 to
217061, 217027 to
217061, 229647 to 229742, 230408 to 230721, 231272 to 231412, 231787 to
231880, 231870 to
231879, 234174 to 234321, 237406 to 237428, 239719 to 239807, 239719 to
239853, 240528 to
240569, 240528 to 240596, 240528 to 240617, 240528 to 240644, 240528 to
240824, 240528 to
240994, 240528 to 241685, 240800 to 240993 and 241686 to 243685 of SEQ ID No.
1 or a
complementary sequence thereto or a fragment thereof. The nucleotide
differences as regards
the nucleotide positions 213818 to 215818, 215819 to 215941, 215819 to 215975,
216661 to
216952, 216661 to 217061, 217027 to 217061, 229647 to 229742, 230408 to
230721, 231272 to
231412, 231787 to 231880, 231870 to 231879, 234174 to 234321, 237406 to
237428, 239719 to
239807, 239719 to 239853, 240528 to 240569, 240528 to 240596, 240528 to
240617, 240528 to
240644, 240528 to 240824, 240528 to 240994, 240528 to 241685, 240800 to 240993
and
241686 to 243685 of SEQ ID No. 1 may generally be distributed throughout the
nucleic acid.
These nucleic acids, as well as their fragments and variants, may be used as
oligonucleotide primers or probes in order to detect the presence of a copy of
a gene comprising
an sbgl nucleic acid sequence in a test sample, or alternatively in order to
amplify a target
nucleotide sequence within an sbgl nucleic acid sequence or adjoining region.
Additional preferred nucleic acids of the invention include isolated,
purified, or
recombinant sbgl polynucleotides comprising a contiguous span of at least 12,
15, 18, 20, 25,
30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 90, 100 or 200 nucleotides of
nucleotide positions
213818 to 215818, 215819 to 215941, 215819 to 215975, 216661 to 216952, 216661
to 217061,
217027 to 217061, 229647 to 229742, 230408 to 230721, 231272 to 231412, 231787
to 231880,
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231870 to 231879, 234174 to 234321, 237406 to 237428, 239719 to 239807, 239719
to 239853,
240528 to 240569, 240528 to 240596, 240528 to 240617, 240528 to 240644, 240528
to 240824,
240528 to 240994, 240528 to 241685, 240800 to 240993, 215819 to 241685 and
241686 to
243685 of SEQ ID No 1, or the complements thereof, wherein said contiguous
span comprises
5 at least one biallelic marker. Optionally, said contiguous span comprises an
sbgl-related
biallelic marker. It should be noted that nucleic acid fragments of any size
and sequence may
also be comprised by the polynucleotides described in this section. Either the
original or the
alternative allele may be present at said biallelic marker.
Yet further nucleic acids of the invention include isolated, purified, or
recombinant
10 polynucleotides comprising a contiguous span of at least 12, 15, 18, 20,
25, 30, 35, 40, S0, 60,
70, 80, 90, 100, 150, 200 or 500 nucleotides, to the extent that said span is
consistent with the
nucleotide position range, of SEQ ID No 1, wherein said contiguous span
comprises at least 1,
2, 3, S, or 10 of the following nucleotide positions of SEQ ID No 1: 21 S 820
to 215941, 216661
to 217009, 230409 to 290721, 231272 to 23141 l, 234202 to 234321, 240528 to
240567, 240528
15 to 240827 and 240528 to 240996, or the complements thereof, as well as
polynucleotides
having at least 70, 75, 80, 85, 90, or 95% nucleotide identity with said span,
and
polynucleotides capable of hybridizing with said span.
The present invention also comprises a purified or isolated nucleic acid
encoding an
sbgl protein having the amino acid sequence of any one of SEQ ID Nos 27 to 35
or a peptide
20 fragment or variant thereof.
While this section is entitled "Genomic Sequences of sbgl," it should be noted
that
nucleic acid fragments of any size and sequence may also be comprised by the
polynucleotides
described in this section, flanking the genomic sequences sbgl on either side
or between two or
more such genomic sequences.
25 Sbgl cDNA Sequences
The expression of the sbgl gene has been shown to lead to the production of
several
mRNA species. Several cDNA sequences corresponding to these mRNA are set forth
in SEQ
ID Nos 2 to 26.
The invention encompasses a purified, isolated, or recombinant nucleic acid
comprising
30 a nucleotide sequence selected from the group consisting of SEQ ID Nos 2 to
26,
complementary sequences thereto, splice variants thereof, as well as allelic
variants, and
fragments thereof. Moreover, preferred polynucleotides of the invention
include purified,
isolated, or recombinant sbgl cDNAs consisting of, consisting essentially of,
or comprising a
nucleotide sequence selected from the group consisting of SEQ ID Nos 2 to 26.
Particularly
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41
preferred nucleic acids of the invention include isolated, purified, or
recombinant
polynucleotides comprising a contiguous span of at least 8, 12, 15, 18, 20,
25, 30, 35, 40, 50, 60,
70, 75, 80, 100, 200 or 500 nucleotides, to the extent that the length of said
contiguous span is
consistent with the length of the SEQ ID, of a nucleotide sequence selected
from the group
consisting of SEQ ID Nos 2 to 26, or the complements thereof.
It should be noted that nucleic acid fragments of any size and sequence may
also be
comprised by the polynucleotides described in this section.
The invention also pertains to a purified or isolated nucleic acid comprising
a
polynucleotide having at least 70, 80, 85, 90 or 95% nucleotide identity with
a polynucleotide
selected from the group consisting of SEQ ID Nos 2 to 26, advantageously 99%
nucleotide
identity, preferably 99.5% nucleotide identity and most preferably 99.8%
nucleotide identity
with a polynucleotide selected from the group consisting of SEQ ID Nos 2 to
26, or a sequence
complementary thereto or a biologically active fragment thereof.
Another object of the invention relates to purified, isolated or recombinant
nucleic acids
comprising a polynucleotide that hybridizes, under the stringent hybridization
conditions
defined herein, with a polynucleotide selected from the group consisting of
SEQ ID Nos 2 to 26,
or a sequence complementary thereto or a variant thereof or a biologically
active fragment
thereof.
The sbgl cDNA forms of SEQ ID Nos 2 to 26 are further described in Table Sa
below.
Shown on the Table Sa are the positions of the 5' UTR, the open reading frame
(ORF), the 3'
UTR and the polyA signal on the respective SEQ ID No. Also shown are the sbgl
exons
comprising the cDNA form of a particular SEQ ID No.
Table Sa
SEQ cDNA Pos Pos Pos Pos
ID range range range range
No of of of of
SUTR ORF 3UTR of
A
si
nal
2 M862NOQbisR 1 253 254 304 305 995 971 976
3 M862NOObisP 1 253 254 304 305 1035 1020 1025
4 M1 1 187 188 520 521 1158 - -
S M862NOP 1 253 254 304 305 894 879 884
6 M1090NOXQbisR 1 25 26 76 77 863 839 844
7 M1117N2001P - - 2 310 311 603 588 593
8 M1117N20P - - 2 358 359 593 578 583
9 M1117NOO1P - - 2 49 50 649 634 639
10 M 1117N002P - - 2 49 50 733 718 723
11 MS 1 MS2NOQbisR1 267 268 318 319 1009 985 990
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12 M1069NOQR 1 46 47 97 98 897 873 878
13 M1069N20Q1QbisR 1 46 47 343 344 777 753 758
14 M 1069NOQ 1 QbisRI 46 47 97 98 823 799 804
15 M 1069N2002QbisRI 46 47 427 428 836 812 817
16 M1069N002QbisR I 46 47 97 98 882 858 863
17 M 1069N2Nbis002X1 46 47 235 236 955 931 936
QbisR
18 M1069N20QR 1 46 47 343 344 851 827 832
19 M1069N20QbisR 1 46 47 508 509 742 718 723
20 M1069NNbisOQR 1 46 47 97 98 920 896 901
21 M1069NNbisOQbisR1 46 47 97 98 811 787 792
22 M1069N002XQbisR 1 46 47 97 98 978 954 959
23 M1069NOXQR 1 46 47 97 98 993 969 974
24 M 1069NOQbisRbis1 46 47 97 98 822 - -
25 M 1069N20QbisRbis1 46 47 508 509 776 - -
26 M1069N20XQR 1 46 47 367 368 947 923 928
Primers used to isolate the particular sbgl cDNAs listed above from RNA from
various
tissues are provided below in Table 56. Primers designed to hybridize to
nucleic acid sequences
of exons MS1, M862, M1090, M1117 and MS2, and exons P and R resulted in the
cloning of
multiple cDNA forms for several sets of primers. The primers used are listed
in SEQ ID Nos 44
of 53.
mRNA forms of sbgl were found to differ among tissues; Table Sc lists cDNA
forms
cloned from various tissues and the relative percentages and numbers of clones
found per tissue
for each listed sbgl mRNA form.
The present inventors have also identified further variations in cDNA sequence
as
obtained from various tissues and compared with the consensus sbgl genomic
nucleotide
sequence. The tissues from which cDNA was cloned were obtained from pooled
individuals
numbering from 11 to 60. Table Sd below describes the identities of variants,
the nucleotide
position of the variation in nucleotide sequence of SEQ ID No 2, and the
number of samples
having the specified sequence for each respective nucleotide position on the
sbgl cDNA
sequence of SEQ ID No. 2. Also indicated in Table Sd are amino acid changes in
the
corresponding sbgl polypeptide sequence (described herein), if any, resulting
from the
nucleotide sequence variations in the cDNA of SEQ ID No 2.
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43
These variants may represent rare polymorphisms or may be the result of tissue-
specific
RNA editing. Alternatively, some variations may be the result of the presence
in the human
genome of one or more sbgl-related genes or a small family of sbgl-related
genes with strict
tissue specificity of expression and small variation in gene structure. The
latter hypothesis was
tested by applicants for the case where the exon-intron structure of these
genes are identical,
demonstrating that variations in at least exons M and N are not the result of
the presence of
related genes.
The present invention thus further encompasses variant sbgl polynucleotides
having at
least one nucleotide substitution as described in Table Sd below. The
nucleotide and amino acid
variations as shown in Table Sd are shown in terms of the nucleotide sequence
of SEQ ID No. 2,
and specify variations as found in exons M862, N, O, Qbis and R. The invention
encompasses
purified, isolated, or recombinant polynucleotides and polypeptides encoded
thereby, wherein
the polynucleotides comprise a contiguous span of at least 8, 12, 15, 18, 20,
25, 30, 35, 40, 45,
50, 60, 70, 80, 100, 150, or 200 nucleotides of SEQ ID No 2 or the complement
thereof, and
wherein said contiguous span further comprises a nucleotide sequence variation
according to
Table Sd.
The present invention comprises a purified or isolated sbgl cDNA encoding an
sbgl
protein or a peptide fragment or variant thereof. In one embodiment, a
purified or isolated
nucleic acid encoding an sbgl protein may have the amino acid sequence of any
of SEQ ID Nos
27 to 35 or a peptide fragment or variant thereof.
Preferred nucleic acids of the invention also include isolated, purified, or
recombinant
polynucleotides comprising a contiguous span of at least 8, 12, 15, 18, 20,
25, 30, 35, 40, 50, 60,
70, 75, 80, 100, 200 or 500 nucleotides of a nucleotide sequence selected from
the group
consisting of SEQ ID Nos 2 to 26, or the complements thereof, wherein said
span comprises a
sbgl-related biallelic marker of the invention. The positions of selected
biallelic markers of the
invention in sbgl cDNA sequences and polypeptide sequences are listed below in
Table Se.
Said contiguous span may comprise a biallelic marker selected from the group
of biallelic
markers listed in Table Se; optionally, said biallelic marker is selected from
the group consisting
of the biallelic markers located in an sbgl cDNA form, as listed in Table Se;
optionally, said
biallelic marker is selected from the group consisting of the biallelic
markers located in an sbgl
coding sequence, as listed in Table Se.
Expression of sbgl mRNA was further confirmed by Northern blotting. Using a
probe
corresponding to exon O of the sbgl gene, a band corresponding to an sbgl mRNA
was
detected.
While this section is entitled "sbgl cDNA Sequences," it should be noted that
nucleic
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44
acid fragments of any size and sequence may also be comprised by the
polynucleotides
described in this section, flanking the genomic sequences of sbgl on either
side or between two
or more such genomic sequences.
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
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CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
SI
Table Se
AmpliconBiallelic AlleleAlleleGenomiccDNA form: position
Marker Name1 2 positionof marker
on SEQ on cDNA (position in
ID No polypeptide)
1
8-132 8-132-179 A T 215838 M862NOQbisR:976
M 1090NOXQbisR:844
MS1
MS2NOQbisR:990
M 1069NOQR:878
M 1069N20Q 1 QbisR:758
M I 069NOQ 1 QbisR:804
M 1069N2002QbisR:817
M 1069N002QbisR:863
M 1069N2Nbis002XQbisR:936
M1069N20QR:832
M 1069N20QbisR:723
M1069NNbisOQR:901
M 1069NNbisOQbisR:792
M 1069N002XQbisR:959
M 1069NOXQR:974
M 1069NOQbisRbis:803
M 1069N20QbisRbis:757
M 1069N20XQR:928
8-132 8-132-164 A G 215853 M862NOQbisR:961
M 1090NOXQbisR:829
MS 1
MS2NOQbisR:975
M 1069NOQR:863
M 1069N20Q 1 QbisR:743
M 1069NOQ 1 QbisR:789
M 1069N2002QbisR:802
M 1069N002QbisR:848
M 1069N2Nbis002XQbisR:921
M 1069N20QR:817
M 1069N20QbisR:708
M 1069NNbisOQR:886
M I 069NNbisOQbisR:777
M 1069N002XQbisR:944
M 1069NOXQR:959
M 1069NOQbisRbis:788
M I 069N20QbisRbis:742
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
52
M 1069N20XQR:913
8-132 8-132-97 A G 215920
M862NOQbisR:894
M 1090NOXQbisR:762
MSI
MS2NOQbisR:908
M 1069NOQR:796
M 1069N20Q 1 QbisR:676
M 1069NOQ 1 QbisR:722
M 1069N2002QbisR:735
M 1069N002QbisR:781
M1069N2Nbis002XQbisR:854
M 1069N20QR:750
M 1069N20QbisR:641
M I 069NNbisOQR:819
M I 069NNbisOQbisR:710
M 1069N002XQbisR:877
M 1069NOXQR:892
M 1069NOQbisRbis:721
M 1069N20QbisRbis:675
M 1069N20XQR:846
99-1392999-13929-201G T 216028
8-131 8-131-363 G T 216538
8-131 8-131-199 G T 216702 M862NOQbisR:831
M1090NOXQbisR:699
MS1
MS2NOQbisR:845
M1069NOQR:733
M 1069N20Q 1 QbisR:613
M 1069NOQ 1 QbisR:659
M 1069N2002QbisR:672
M1069N002QbisR:718
M 1069N2Nbis002XQbisR:791
M1069N20QR:687
M 1069N20QbisR:578
M 1069NNbisOQR:756
M1069NNbisOQbisR:647
M 1069N002XQbisR:814
M 1069NOXQR:829
M1069NOQbisRbis:624
M 1069N20QbisRbis:578
M1069N20XQR:783
8-130 8-130-236 C T 216874 M862NOQbisR:659
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M1090NOXQbisR:527
MS1
MS2NOQbisR:673
M 1069NOQR:561
M 1069N20Q 1 QbisR:441
M 1069NOQ 1 QbisR:487
M 1069N2002QbisR:500
M1069N002QbisR:546
M 1069N2Nbis002XQbisR:619
M 1069N20QR:515
M1069N20QbisR:406
M1069NNbisOQR:584
M 1069NNbisOQbisR:475
M 1069N002XQbisR:642
M 1069NOXQR:657
M 1069NOQbisRbis:452
M I 069N20QbisRbis:406
M 1069N20XQR:611
8-130 8-130-220 G T 216890 M862NOQbisR:643
M1090NOXQbisR:51 I
MS1
MS2NOQbisR:657
M 1069NOQR:545
M 1069N20Q 1 QbisR:425
M 1069NOQ 1 QbisR:471
M 1069N2002QbisR:484
M 1069N002QbisR:530
M 1069N2Nbis002XQbisR:603
M I 069N20QR:499
M1069N20QbisR:390 (115)
M 1069NNbisOQR:568
M 1069NNbisOQbisR:459
M 1069N002XQbisR:626
M 1069NOXQR:641
M1069NOQbisRbis:436
M1069N20QbisRbis:390
(1150
M1069N20XQR:595
8-130 8-130-144 C T 216966 M1069NOQR:469
M 1069N20QR:423
M 1069NNbisOQR:492
M 1069NOXQR:565
M 1069N20XQR:519
8-130 8-130-143 A G 216967 M1069NOQR:468
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M I 069N20QR:422
M 1069NNbisOQR:491
M 1069NOXQR:564
M 1069N20XQR:518
8-130 8-130-102 C T 217008 M1069NOQR:427
M 1069N20QR:381
M 1069NNbisOQR:450
M 1069NOXQR:523
M 1069N20XQR:477
8-130 8-130-101 G T 217009 M1069NOQR:426
M 1069N20QR:380
M 1069NNbisOQR:449
M 1069NOXQR:522
M 1069N20XQR:476
8-130 8-130-83 A C 217027 M1069NOQR:408
M 1069N20Q 1 QbisR:362
M 1069NOQ 1 QbisR:408
M 1069N20QR:362
M 1069NNbisOQR:431
M 1069NOXQR:504
M 1069N20XQR:458
8-143 8-143-245 G T 229669 M1090NOXQbisR:426
M 1069N2Nbis002XQbisR:518
M 1069N002XQbisR:541
M 1069NOXQR:447
M 1069N20XQR:401
8-143 8-143-242 A G 229672
M 1090NOXQbisR:423
M 1069N2Nbis002XQbisR:515
M1069N002XQbisR:538
M 1069NOXQR:444
M 1069N20XQR:398
8-143 8-143-239 C T 229675 M1090NOXQbisR:420
M 1069N2Nbis002XQbisR:512
M 1069N002XQbisR:535
M 1069NOXQR:441
M 1069N20XQR:395
8-143 8-143-232 G C 229682 M1090NOXQbisR:413
M 1069N2Nbis002XQbisR:505
M1069N002XQbisR:528
M 1069NOXQR:434
M 1069N20XQR:388
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8-119 8-119-210 A C 230432 M862NOObisP:1011
M862NOP:870
M 1117N2001 P:579
M 1 I 17N20P:569
M 1117N001 P:625
M 1117N002P:709
8-119 8-119-204 A C 230438 M862NOObisP:1005
M862NOP:864
M 1117N2001 P:573
M 1117N20P:563
M 1117N001 P:619
M 1117N002P:703
8-119 8-119-200 A G 230442 M862NOObisP:1001
M862NOP:860
M 1117N2001 P:569
M 1117N20P:559
M 1117N001 P:615
M 1117N002P:699
8-119 8-119-195 A C 230447 M862NOObisP:996
M862NOP:855
M 1117N2001 P:564
M I 117N20P:554
M I I 17N001 P:610
M 1117N002P:694
8-119 8-119-125 C T 230517 M862NOObisP:926
M862NOP:785
M 1117N2001 P:494
M I 117N20P:484
M I 117N001 P:540
M 1117N002P:624
8-119 8-119-120 A G 230522 M862NOObisP:921
M862NOP:780
M 1117N2001 P:489
M 1117N20P:479
M 1117N001 P:535
M 1117N002P:619
8-119 8-119-97 C T 230545 M862NOObisP:898
M862NOP:757
M 1117N2001 P:466
M 1117N20P:456
M 1117N001 P:512
M 1 I 17N002P:596
8-119 8-119-93 G T 230549 M862NOObisP:894
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M862NOP:753
M 1117N2001 P:462
M 1117N20P:452
M 1117N001 P: 508
M 1117N002P:592
8-119 8-119-38 A T 230604 M862NOObisP:839
M862NOP:698
M 1117N2001 P:407
M 1117N20P:397
M 1117N001 P:453
M 1117N002P:537
8-138 8-138-234 C T 230684 M862NOObisP:759
M862NOP:618
M 1117N2001 P:327
M1117N20P:317 10
M 1117NOO1P:373
M I 117N002P:457
8-138 8-138-218 A G 230700 M862NOObisP:743
M862NOP:602
M 1117N2001 P:311
M 1117N20P:301
M 1117N001 P:357
M 1117N002P:441
8-142 8-142-211 CAAA 231293 M862NOObisP:700
8-142 8-142-132 A G 231372 M862NOObisP:621
8-145 8-145-197 C T 231811 M1117N002P:395
M 1069N2002QbisR:397
M 1069N002QbisR:443
M 1069N2Nbis002XQbisR:420
M 1069N002XQbisR:443
8-145 8-145-154 C T 231854 231854
M 1117N002P:352
M 1069N2002QbisR:354
8-145 8-145-138 A C 231870 M1117N2001P:289 (96)
M1117NOO1P:335
M 1117N002P:336
M1069N2002QbisR:338
(98)
M 1069N002QbisR:384
M 1069N2Nbis002XQbisR:361
M 1069N002XQbisR:384
8-137 8-137-182 C T 234277 M862NOQbisR:477
M862NOObisP:477
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M862NOP:477
M 1090NOXQbisR:249
M1117N2001P:176 (59)
M 1117N20P:176 (59)
M 1117N001 P:222
M 1117N002P:222
MS1
MS2NOQbisR:491
M 1069NOQR:270
M1069N20Q1QbisR:224
(60)
M 1069NOQ 1 QbisR:270
M 1069N2002QbisR:224
(60)
M 1069N002QbisR:270
M 1069N2Nbis002XQbisR:247
M1069N20QR:224 (60)
M1069N20QbisR:224 (60)
8-137 8-137-152 A C 234307 M862NOQbisR:447
M862NOObisP:447
M862NOP:447
M 1090NOXQbisR:219
M 1117N2001 P:146 (49)
M I 117N20P:146 (49)
M I 117N001 P:192
M 1117N002P:192
MS 1
MS2NOQbisR:461
M 1069NOQR:240
M 1069N20Q 1 QbisR:194
(50)
M 1069NOQ 1 QbisR:240
M 1069N2002QbisR:194
(50)
M 1069N002QbisR:240
M1069N2Nbis002XQbisR:217
(57)
M1069N20QR:194 (50)
M1069N20QbisR:194 (50)
M1069NNbisOQR:263
M 1069NNbisOQbisR:263
M 1069N002XQbisR:240
M 1069NOXQR:240
M 1069NOQbisRbis:240
M1069N20QbisRbis:194
(50)
M1069N20XQR:194 (50)
99-1603899-16038-118C T 239763 M862NOQbisR:388
M862NOObisP:388
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M862NOP:388
M 1090NOXQbisR:160
M 1117N2001 P:87 (29)
M1117N20P:87 (29)
M I 117N001 P:133
M 1117N002P:133
MS1
MS2NOQbisR:402
M 1069NOQR:181
M1069N20Q1QbisR:135
(30)
M 1069NOQ l QbisR:181
M1069N2002QbisR:135
(30)
M 1069N002QbisR:181
M1069N2Nbis002XQbisR:135
(30)
M1069N20QR:135 (30)
M1069N20QbisR:135 (30)
M1069NNbisOQR:181
M 1069NNbisOQbisR:181
M1069N002XQbisR:181
M 1069NOXQR:181
M1069NOQbisRbis:181
M 1069N20QbisRbis:135
(30)
M1069N20XQR:135 (30)
8-153 8-153-313 C T 239763 M862NOQbisR:388
M862NOObisP:388
M862NOP:388
M 1090NOXQbisR:160
M1117N2001P:87 (29)
M1117N20P:87 (29)
M 1117N001 P:133
M1117N002P:133
MS 1
MS2NOQbisR:402
M 1069NOQR:181
M1069N20QIQbisR:135
(30)
M 1069NOQ 1 QbisR:
l81
M1069N2002QbisR:135
(30)
M 1069N002QbisR:181
M1069N2Nbis002XQbisR:135
(30)
M1069N20QR:135 (30)
M1069N20QbisR:135 (30)
M 1069NNbisOQR:181
M 1069NNbisOQbisR:181
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M 1069N002XQbisR:181
M 1069NOXQR:181
M 1069NOQbisRbis:181
M1069N20QbisRbis:135
(30)
M1069N20XQR:135 (30)
8-135 8-135-166 G T 240543 M862NOQbisR:282 (10)
M862NOObisP:282 (10)
M1:1143
M862NOP:282 (10)
M1090NOXQbisR:54 (10)
M 1117N2001 P:27 (9)
M 1117N20P:27 (9)
M1117NOO1P:27 (9)
M1117N002P:27 (9)
MSI
MS2NOQbisR:296 (10)
M1069NOQR:75 (10)
M1069N20Q1QbisR:75
(10)
M 1069NOQ 1 QbisR:75
( 10)
M1069N2002QbisR:75
(10)
M1069N002QbisR:75 (10)
M1069N2Nbis002XQbisR:75
(10)
M 1069N20QR:75 ( 10)
M1069N20QbisR:75 (10)
M1069NNbisOQR:75 (10)
M1069NNbisOQbisR:75
(10)
M1069N002XQbisR:75
(10)
M1069NOXQR:75 (10)
M1069NOQbisRbis:75
(10)
M1069N20QbisRbis:75
(10)
M1069N20XQR:75 (10)
8-135 8-135-112 A G 240597 M862NOQbisR:228
M862NOObisP:228
M1:1089
M862NOP:228
MS 1
MS2NOQbisR:242
M 1069NOQR:21
M 1069N20Q 1 QbisR:21
M 1069NOQ 1 QbisR:21
M 1069N2002QbisR:21
M 1069N002QbisR:21
M1069N2Nbis002XQbisR:21
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M 1069N20QR:21
M 1069N20QbisR:21
M 1069NNbisOQR:21
M 1069NNbisOQbisR:21
M 1069N002XQbisR:21
M 1069NOXQR:21
M 1069NOQbisRbis:21
M 1069N20QbisRbis:21
M 1069N20XQR:21
99-1605099-16050-235G C 240772 M862NOQbisR:53
M862NOObisP:53
M I :914
M862NOP:53
8-144 8-144-378 C T 240858 M1:828
MS1
MS2NOQbisR:136
8-144 8-144-234 C T 241002 M 1:684
8-144 8-144-196 A T 241040 M1:646
8-144 8-144-127 TGGAT 241109 M1:577
AC
8-141 8-141-304 C T 241217 M1:469
8-141 8-141-260 C T 241261 M1:425 (80)
8-141 8-141-161 G T 241360 M1:326 (47)
8-140 8-140-286 A G 241507 M1:179
8-140 8-140-173 A C 241620 M1:66
8-140 8-140-108 G C 241685 ~ M1:1
Sbgl Coding Regions
The sbgl open reading frame is contained in the corresponding mRNA of a cDNA
sequence selected from the group consisting of SEQ ID Nos 2 to 26. The
effective sbgl coding
sequence (CDS) may include several forms as indicated above, in some
embodiments
encompassing isolated, purified, and recombinant polynucleotides which encode
a polypeptide
comprising a contiguous span of at least 4 amino acids, preferably 6, more
preferably at least 8
or 10 amino acids, yet more preferably at least 12, 15, 20, 25, 30, 40, 50, or
100 amino acids of
SEQ ID Nos 27 to 35. The effective sbgl coding sequence (CDS) may comprise the
region
between the first nucleotide of the ATG codon and the end nucleotide of the
stop codon of SEQ
10 ID Nos 2 to 26 as indicated in Table Sa above.
The above disclosed polynucleotide that contains the coding sequence of the
sbgl gene
may be expressed in a desired host cell or a desired host organism when this
polynucleotide is
placed under the control of suitable expression signals. The expression
signals may be either
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61
the expression signals contained in the regulatory regions in the sbgl gene of
the invention or in
contrast the signals may be exogenous regulatory nucleic sequences. Such a
polynucleotide,
when placed under the suitable expression signals, may also be inserted in a
vector for its
expression and/or amplification.
Regulatory Sequences Of sbgl
As mentioned, the genomic sequence of the sbgl gene contains regulatory
sequences
both in the non-coding 5'-flanking region and in the non-coding 3'-flanking
region that border
the sbgl coding region containing the exons of the gene.
In one aspect, the 3'-regulatory sequence of the sbgl gene may comprise the
sequence
localized between the nucleotide in position 213818 and the nucleotide in
position 215818 of
the nucleotide sequence of SEQ ID No 1. In one aspect, the 5'-regulatory
sequence of the sbgl
gene may comprise the sequence localized between the 5' end of the particular
form of exon M
and nucleotide position 243685 of SEQ ID No 1.
Polynucleotides derived from the S' and 3' regulatory regions are useful in
order to
detect the presence of at least a copy of an sbgl nucleotide sequence of SEQ
ID No 1 or a
fragment thereof in a test sample.
The promoter activity of the 5' regulatory regions contained in sbgl can be
assessed as
described below.
In order to identify the relevant biologically active polynucleotide fragments
or variants
of an sbgl regulatory region, one of skill in the art will refer to Sambrook
et al.(1989), which
describes the use of a recombinant vector carrying a marker gene (i.e. beta
galactosidase,
chloramphenicol acetyl transferase, etc.) the expression of which will be
detected when placed
under the control of a biologically active polynucleotide fragment or variant
of the sbgl
sequence of SEQ ID No 1. Genomic sequences located upstream of the first exon
of the sbgl
gene are cloned into a suitable promoter reporter vector, such as the pSEAP-
Basic, pSEAP-
Enhancer, p(3gal-Basic, p/3ga1-Enhancer, or pEGFP-1 Promoter Reporter vectors
available from
Clontech, or pGL2-basic or pGL3-basic promoterless luciferase reporter gene
vector from
Promega. Briefly, each of these promoter reporter vectors include multiple
cloning sites
positioned upstream of a reporter gene encoding a readily assayable protein
such as secreted
alkaline phosphatase, luciferase, (3 galactosidase, or green fluorescent
protein. The sequences
upstream of the sbgl coding region are inserted into the cloning sites
upstream of the reporter
gene in both orientations and introduced into an appropriate host cell. The
level of reporter
protein is assayed and compared to the level obtained from a vector which
lacks an insert in the
cloning site. The presence of an elevated expression level in the vector
containing the insert
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62
with respect to the control vector indicates the presence of a promoter in the
insert. If
necessary, the upstream sequences can be cloned into vectors which contain an
enhancer for
increasing transcription levels from weak promoter sequences. A significant
level of expression
above that observed with the vector lacking an insert indicates that a
promoter sequence is
present in the inserted upstream sequence.
Promoter sequence within the upstream genomic DNA may be further defined by
constructing nested 5' and/or 3' deletions in the upstream DNA using
conventional techniques
such as Exonuclease III or appropriate restriction endonuclease digestion. The
resulting
deletion fragments can be inserted into the promoter reporter vector to
determine whether the
deletion has reduced or obliterated promoter activity, such as described, for
example, by Coles
et al.( 1998j. In this way, the boundaries of the promoters may be defined. If
desired; potential
individual regulatory sites within the promoter may be identified using site
directed mutagenesis
or linker scanning to obliterate potential transcription factor binding sites
within the promoter
individually or in combination. The effects of these mutations on
transcription levels may be
determined by inserting the mutations into cloning sites in promoter reporter
vectors. This type
of assay is well-known to those skilled in the art and is described in WO
97/17359, US Patent
No. 5,374,544; EP 582 796; US Patent No. 5,698,389; US 5,643,746; US Patent
No. 5,502,176;
and US Patent 5,266,488.
The strength and the specificity of the promoter of the sbgl gene can be
assessed
through the expression levels of a detectable polynucleotide operab(y linked
to the sbgl
promoter in different types of cells and tissues. The detectable
polynucleotide may be either a
polynucleotide that specifically hybridizes with a predefined oligonucleotide
probe, or a
polynucleotide encoding a detectable protein, including an sbgl polypeptide or
a fragment or a
variant thereof. This type of assay is well-known to those skilled in the art
and is described in
US Patent No. 5,502,176; and US Patent No. 5,266,488. Some of the methods are
discussed in
more detail below.
Polynucleotides carrying the regulatory elements located at the S' end and at
the 3' end
of the sbgl coding region may be advantageously used to control the
transcriptional and
translational activity of an heterologous polynucleotide of interest.
Thus, the present invention also concerns a purified or isolated nucleic acid
comprising
a polynucleotide which is selected from the group consisting of the 5' and 3'
regulatory regions
of sbgl, or a sequence complementary thereto or a biologically active fragment
or variant
thereof. In one aspect, "3' regulatory region" may comprise the nucleotide
sequence located
between positions 213818 and 215818 of SEQ ID No 1. In one aspect, "S'
regulatory region"
may comprise the nucleotide sequence located between the 5' end of a
particular variant of exon
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63
M and nucleotide position 243685 of SEQ ID No 1. The 5' end of particular form
of exon M
may be selected from the group consisting of nucleotide postions 240569,
241596, 240617,
240644, 240824, 240994, 241685 and 240993 of SEQ ID No 1. In a preferred
aspect, the 5'
regulatory region comprises the nucleotides of nucleotide positions 241686 to
243685 of SEQ
ID No 1.
The invention also pertains to a purified or isolated nucleic acid comprising
a
polynucleotide having at least 95% nucleotide identity with a polynucleotide
selected from the
group consisting of the 5' and 3' regulatory regions, advantageously 99 %
nucleotide identity,
preferably 99.5% nucleotide identity and most preferably 99.8% nucleotide
identity with a
polynucleotide selected from the group consisting of the S' and 3' regulatory
regions, or a
sequence complementary thereto or a variant thereof or a biologically active
fragment thereof.
Another object of the invention consists of purified, isolated or recombinant
nucleic
acids comprising a polynucleotide that hybridizes, under the stringent
hybridization conditions
defined herein, with a polynucleotide selected from the group consisting of
the nucleotide
sequences of the 5'- and 3' regulatory regions of sbgl, or a sequence
complementary thereto or
a variant thereof or a biologically active fragment thereof.
Preferred fragments of the 5' regulatory region have a length of about 1500 or
1000
nucleotides, preferably of about 500 nucleotides, more preferably about 400
nucleotides, even
more preferably 300 nucleotides and most preferably about 200 nucleotides.
Preferred fragments of the 3' regulatory region are at least 50, 100, 150,
200, 300 or
400 bases in length.
"Biologically active" sbgl polynucleotide derivatives of SEQ ID No 1 are
polynucleotides comprising or alternatively consisting in a fragment of said
polynucleotide
which is functional as a regulatory region for expressing a recombinant
polypeptide or a
recombinant polynucleotide in a recombinant cell host. It could act either as
an enhancer or as a
repressor.
For the purpose of the invention, a nucleic acid or polynucleotide is
"functional" as a
regulatory region for expressing a recombinant polypeptide or a recombinant
polynucleotide if
said regulatory polynucleotide contains nucleotide sequences which contain
transcriptional and
translational regulatory information, and such sequences are "operably linked"
to nucleotide
sequences which encode the desired polypeptide or the desired polynucleotide.
The regulatory polynucleotides of the invention may be prepared from the
nucleotide
sequence of SEQ ID No 1 by cleavage using suitable restriction enzymes, as
described for
example in Sambrook et al.(1989). The regulatory polynucleotides may also be
prepared by
digestion of SEQ ID No I by an exonuclease enzyme, such as Ba131 (Wabiko et
al., 1986).
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64
These regulatory polynucleotides can also be prepared by nucleic acid chemical
synthesis, as
described elsewhere in the specification.
The sbgl regulatory polynucleotides according to the invention may be part of
a
recombinant expression vector that may be used to express a coding sequence in
a desired host
cell or host organism. The recombinant expression vectors according to the
invention are
described elsewhere in the specification.
A preferred 5'-regulatory polynucleotide of the invention includes the 5'-
untranslated
region (5'-UTR) of the sbgl cDNA, or a biologically active fragment or variant
thereof.
A preferred 3'-regulatory polynucleotide of the invention includes the 3'-
untranslated
region (3'-UTR) of the sbgl cDNA, or a biologically active fragment or variant
thereof.
A further object of the invention consists of a purified or isolated nucleic
acid
comprising:
a) a nucleic acid comprising a regulatory nucleotide sequence selected from
the group
consisting o~
(i) a nucleotide sequence comprising a polynucleotide ofthe sbgl 5' regulatory
region or a
complementary sequence thereto;
(ii) a nucleotide sequence comprising a polynucleotide having at least 95% of
nucleotide
identity with the nucleotide sequence of the sbgl 5' regulatory region or a
complementary
sequence thereto;
(iii) a nucleotide sequence comprising a polynucleotide that hybridizes under
stringent
hybridization conditions with the nucleotide sequence of the sbgl 5'
regulatory region or a
complementary sequence thereto; and
(iv) a biologically active fragment or variant of the polynucleotides in (i),
(ii) and (iii);
b) a polynucleotide encoding a desired polypeptide or a nucleic acid of
interest,
operably linked to the nucleic acid defined in (a) above; and
c) optionally, a nucleic acid comprising a 3'- regulatory polynucleotide,
preferably a 3'-
regulatory polynucleotide ofthe sbgl gene.
In a specific embodiment of the nucleic acid defined above, said nucleic acid
includes
the 5'-untranslated region (5'-UTR) of the sbgl cDNA, or a biologically active
fragment or
variant thereof.
In a second specific embodiment of the nucleic acid defined above, said
nucleic acid
includes the 3'-untranslated region (3'-UTR) of the sbgl cDNA, or a
biologically active
fragment or variant thereof.
The regulatory polynucleotide of the 5' regulatory region, or its biologically
active
fragments or variants, is operably linked at the 5'-end of the polynucleotide
encoding the
CA 02361408 2001-08-08
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desired polypeptide or polynucleotide.
The regulatory polynucleotide of the 3' regulatory region, or its biologically
active
fragments or variants, is advantageously operably linked at the 3'-end of the
polynucleotide
encoding the desired polypeptide or polynucleotide.
The desired polypeptide encoded by the above-described nucleic acid may be of
various
nature or origin, encompassing proteins of prokaryotic or eukaryotic origin.
Among the
polypeptides expressed under the control of an sbgl regulatory region include
bacterial, fungal
or viral antigens. Also encompassed are eukaryotic proteins such as
intracellular proteins, like
"house keeping" proteins, membrane-bound proteins, like receptors, and
secreted proteins like
10 endogenous mediators such as cytokines. The desired polypeptide may be the
sbgl protein,
especially the protein of the amino acid sequences of SEQ ID Nos 27 to 35, or
a fragment or a
variant thereof.
The desired nucleic acids encoded by the above-described polynucleotide,
usually an
RNA molecule, may be complementary to a desired coding polynucleotide, for
example to the
15 sbgl coding sequence, and thus useful as an antisense polynucleotide.
Such a polynucleotide may be included in a recombinant expression vector in
order to
express the desired polypeptide or the desired nucleic acid in host cell or in
a host organism.
Suitable recombinant vectors that contain a polynucleotide such as described
herein are
disclosed elsewhere in the specification.
Genomic Sequences of sbg2 polynucleotides
Particularly preferred sbg2 nucleic acids of the invention include isolated,
purified, or
recombinant polynucleotides comprising a contiguous span of at least 12, 15,
18, 20, 25, 30, 35,
40, 50, 60, 70, 80, 90, 100, 150, 200 nucleotides, to the extent that the
length of said span is
consistent with said nucleotide position range, of nucleotide positions 201188
to 216915,
201188 to 201234, 214676 to 214793, 215702 to 215746 and 216836 to 216915 of
SEQ ID No
1, or the complements thereof.
It should be noted that nucleic acid fragments of any size and sequence may be
comprised by the polynucleotides described in this section.
The human sbg2 gene comprises exons selected from at least 4 exons, referred
to herein
as exons S, T, U and V. The nucleotide positions of sbg2 exons in SEQ ID No. 1
are detailed
below in Table 5~
Table Sf
Exon Position Intron Position
in SEQ in SEQ
ID No ID No
1 1
BeginningEnd BeginningEnd
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S 201188 201234 S 201235 214675
T 214676 214793 T 214794 215701
U 215702 215746 U 215747 216835
V 216836 216915
Thus, the invention embodies purified, isolated, or recombinant
polynucleotides
comprising a nucleotide sequence selected from the group consisting of the
exons of the sbg2
gene, or a sequence complementary thereto. Preferred are purified, isolated,
or recombinant
polynucleotides comprising at least one exon having the nucleotide position
ranges listed in
Table Sf selected from the group consisting of the exons S, T, U and V of the
sbg2 gene, or a
complementary sequence thereto or a fragment or a variant thereof. Also
encompassed by the
invention are purified, isolated, or recombinant nucleic acids comprising a
combination of at
least two exons of the sbg2 gene selected from the group consisting of exons
S, T, U and V,
wherein the polynucleotides are arranged within the nucleic acid in the same
relative order as in
SEQ ID No. 1.
The present invention further embodies purified, isolated, or recombinant
polynucleotides comprising a nucleotide sequence selected from the group
consisting of the
introns of the sbg2 gene, or a sequence complementary thereto. The position of
the introns is
detailed in Table Sf. Intron S refers to the nucleotide sequence located
between Exon S and
Exon T, and so on. Thus, the invention embodies purified, isolated, or
recombinant
polynucleotides comprising a nucleotide sequence selected from the group
consisting of the 3
introns of the sbg2 gene, or a sequence complementary thereto.
The invention also encompasses a purified, isolated, or recombinant
polynucleotide
comprising a nucleotide sequence of sbg2 having at least 70, 75, 80, 85, 90,
95, 98 or 99%
nucleotide identity with a sequence selected from the group consisting of
nucleotide positions
201188 to 216915, 201188 to 201234, 214676 to 214793, 215702 to 215746 and
216836 to
216915 of SEQ ID No. 1 or a complementary sequence thereto or a fragment
thereof. The
nucleotide differences as regards the nucleotide positions 201188 to 216915,
201188 to 201234,
214676 to 214793, 215702 to 215746 and 216836 to 216915 of SEQ ID No. 1 may be
generally
randomly distributed throughout the entire nucleic acid.
Another object of the invention relates to purified, isolated or recombinant
nucleic acids
comprising a polynucleotide that hybridizes, under the stringent hybridization
conditions
defined herein, with a polynucleotide selected from the group consisting of
nucleotide positions
201188 to 216915, 201188 to 201234, 214676 to 214793, 215702 to 215746 and
216836 to
216915 of SEQ ID No 1, or a sequence complementary thereto or a variant
thereof or a
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biologically active fragment thereof.
Additional preferred nucleic acids of the invention include isolated,
purified, or
recombinant sbg2 polynucleotides comprising a contiguous span of at least 12,
15, 18, 20, 25,
30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 90, 100 or 200 nucleotides of
nucleotide positions
201188 to 21691 S, 201188 to 201234, 214676 to 214793, 215702 to 215746 and
216836 to
216915 of SEQ ID No 1 or the complements thereof, wherein said contiguous span
comprises
an sbg2-related biallelic marker. Optionally, said biallelic marker is
selected from the group
consisting of A79 to A99. It should be noted that nucleic acid fragments of
any size and
sequence may also be comprised by the polynucleotides described in this
section. Either the
original or the alternative allele may be present at said biallelic marker.
An sbg2 polynucleotide or gene may further contain regulatory sequences both
in the
non-coding 5'-flanking region and in the non-coding 3'-flanking region that
border the region
containing said genes or exons. Polynucleotides derived from 5' and 3'
regulatory regions are
useful in order to detect the presence of at least a copy of a nucleotide
sequence comprising an
sbg2 nucleotide sequence of SEQ ID No. 1 or a fragment thereof in a test
sample.
Polynucleotides carrying the regulatory elements located at the 5' end and at
the 3' end of the
genes comprising the exons of the present invention may be advantageously used
to control the
transcriptional and translational activity of a heterologous polynucleotide of
interest.
While this section is entitled "sbg2 cDNA Sequences," it should be noted that
nucleic
acid fragments of any size and sequence may also be comprised by the
polynucleotides
described in this section, flanking the genomic sequences of sbg2 on either
side or between two
or more such genomic sequences.
Polynucleotide Constructs
The terms "polynucleotide construct" and "recombinant pol~nucleotide" are used
interchangeably herein to refer to linear or circular, purified or isolated
polynucleotides that
have been artificially designed and which comprise at least two nucleotide
sequences that are
not found as contiguous nucleotide sequences in their initial natural
environment. It should be
noted that the present invention embodies recombinant vectors comprising any
one of the
polynucleotides described in the present invention.
DNA Constructs that Enables Directing Temporal and Spatial Expression of sbgl,
834665, sbg2, 835017 and 835018 Nucleic Acid Sequences in Recombinant Cell
Hosts and
in Transgenic Animals
In order to study the physiological and phenotypic consequences of a lack of
synthesis
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68
of a protein encoded by a nucleotide sequence comprising an sbgl, g34665,
sbg2, g35017 or
g35018 polynucleotide, both at the cell level and at the multi cellular
organism level, the
invention also encompasses DNA constructs and recombinant vectors enabling a
conditional
expression of a specific allele of a nucleotide sequence comprising an sbgl,
g34665, sbg2,
g35017 or g35018 polynucleotide and also of a copy of a sequence comprising a
nucleotide
sequence of an sbgl, g34665, sbg2, g35017 or g35018 polynucleotide, or a
fragment thereof,
harboring substitutions, deletions, or additions of one or more bases. These
base substitutions,
deletions or additions may be located either in an exon, an intron or a
regulatory sequence, in
particular a 5' regulatory sequence of an sbgl, g34665, sbg2, g35017 or g35018
polynucleotide.
In a preferred embodiment, the nucleotide sequence comprising an sbgl, g34665,
sbg2, g35017
or g35018 polynucleotide further comprises a biallelic marker of the present
invention.
A first preferred DNA construct is based on the tetracycline resistance operon
tet from
E. coli transposon Tn 110 for controlling the expression of an sbgl, g34665,
sbg2, g35017 or
g35018 polynucleotide, such as described by Gossen et al. (1992, 1995) and
Furth et al.(1994).
Such a DNA construct contains seven tet operator sequences from TnlO (tetop)
that are fused to
either a minimal promoter or a S'-regulatory sequence of the sbgl, g34665,
sbg2, g35017 or
g35018 polynucleotide, said minimal promoter or said sbgl, g34665, sbg2,
g35017 or g35018
polynucleotide regulatory sequence being operably linked to a polynucleotide
of interest that
codes either for a sense or an antisense oligonucleotide or for a polypeptide,
including an sbgl,
g34665, sbg2, g35017 or g35018 polynucleotide-encoded polypeptide or a peptide
fragment
thereof. This DNA construct is functional as a conditional expression system
for the nucleotide
sequence of interest when the same cell also comprises a nucleotide sequence
coding for either
the wild type (tTA) or the mutant (rTA) repressor fused to the activating
domain of viral
protein V P 16 of herpes simplex virus, placed under the control of a
promoter, such as the
HCMVIE1 enhancer/promoter or the MMTV-LTR. Indeed, a preferred DNA construct
of the
invention comprises both the polynucleotide containing the tet operator
sequences and the
polynucleotide containing a sequence coding for the tTA or the rTA repressor.
In a specific embodiment, the conditional expression DNA construct contains
the
sequence encoding the mutant tetracycline repressor rTA, the expression of the
polynucleotide
of interest is silent in the absence of tetracycline and induced in its
presence.
DNA Constructs Allowing Homologous Recombination: Replacement Vectors
A second preferred DNA construct will comprise, from 5'-end to 3'-end: (a) a
first
nucleotide sequence comprising an sbgl polynucleotide; (b) a nucleotide
sequence comprising
a positive selection marker, such as the marker for neomycine resistance
(neo); and (c) a
second nucleotide sequence comprising a respective sbgl polynucleotide, and is
located on the
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genome downstream of the first sbgl polynucleotide sequence (a). Also
encompassed are DNA
construct prepared in an analogous manner using g34665, sbg2, g35017 or g35018
nucleotide
sequences in place of the sbgl sequences described above.
In a preferred embodiment, this DNA construct also comprises a negative
selection
marker located upstream the nucleotide sequence (a) or downstream the
nucleotide sequence
(c). Preferably, the negative selection marker comprises the thymidine kinase
(tk) gene
(Thomas et al., 1986), the hygromycine beta gene (Te Riele et al., 1990), the
hprt gene ( Van
der Lugt et al., 1991; Reid et al., 1990) or the Diphteria toxin A fragment
(Dt-A) gene (Nada et
al., 1993; Yagi et a1.1990). Preferably, the positive selection marker is
located within and exon
of an sbgl, g34665, sbg2, g35017 or g35018 polynucleotide so as to interrupt
the sequence
encoding the sbgl, g34665, sbg2, g35017 or g35018 protein. These replacement
vectors are
described, for example, by Thomas et al.( 1986; 1987), Mansour et al.( 1988)
and Koller et
al.( 1992).
The first and second nucleotide sequences (a) and (e) may be indifferently
located
within an sbgl, g34665, sbg2, g35017 or g35018 polynucleotide regulatory
sequence, an
intronic sequence, an exon sequence or a sequence containing both regulatory
and/or intronic
and/or exon sequences. The size of the nucleotide sequence of (a) and (c)
ranges from 1 to 50
kb, preferably from 1 to 10 kb, more preferably from 2 to 6 kb and most
preferably from 2 to 4
kb.
DNA Constructs Allowing Homologous Recombination: Cre-LoxP System.
These new DNA constructs make use of the site specific recombination system of
the
Pl phage. The P1 phage possesses a recombinase called Cre which interacts
specifically with a
34 base pairs loxP site. The loxP site is composed of two palindromic
sequences of 13 by
separated by a 8 by conserved sequence (Hoess et al., 1986). The recombination
by the Cre
enzyme between two loxP sites having an identical orientation leads to the
deletion of the DNA
fragment.
The Cre-loxP system used in combination with a homologous recombination
technique
has been first described by Gu et al.(1993, 1994). Briefly, a nucleotide
sequence of interest to
be inserted in a targeted location of the genome harbors at least two loxP
sites in the same
orientation and located at the respective ends of a nucleotide sequence to be
excised from the
recombinant genome. The excision event requires the presence of the
recombinase (Cre)
enzyme within the nucleus of the recombinant cell host. The recombinase enzyme
may be
brought at the desired time either by (a) incubating the recombinant cell
hosts in a culture
medium containing this enzyme, by injecting the Cre enzyme directly into the
desired cell, such
as described by Araki et al.(1995), or by lipofection of the enzyme into the
cells, such as
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described by Baubonis et al.( 1993); (b) transfecting the cell host with a
vector comprising the
Cre coding sequence operably linked to a promoter functional in the
recombinant cell host,
which promoter being optionally inducible, said vector being introduced in the
recombinant cell
host, such as described by Gu et al.( 1993) and Sauer et al.( 1988); (c)
introducing in the genome
5 of the cell host a polynucleotide comprising the Cre coding sequence
operably linked to a
promoter functional in the recombinant cell host, which promoter is optionally
inducible, and
said polynucleotide being inserted in the genome of the cell host either by a
random insertion
event or an homologous recombination event, such as described by Gu et al.(
1994).
In a specific embodiment, the vector containing the sequence to be inserted in
an sbgl,
10 g34665, sbg2, g35017 or g35018 gene sequence by homologous recombination is
constructed in
such a way that selectable markers are flanked by IoxP sites of the same
orientation, it is
possible, by treatment by the Cre enzyme, to eliminate the selectable markers
while leaving the
sbgl, g34665, sbg2, g35017 or g35018 polynucleotide sequences of interest that
have been
inserted by an homologous recombination event. Again, two selectable markers
are needed: a
15 positive selection marker to select for the recombination event and a
negative selection marker
to select for the homologous recombination event. Vectors and methods using
the Cre-loxP
system are described by Zou et al.(1994).
Thus, in one aspect, a further preferred DNA construct of the invention
comprises, from
5'-end to 3'-end: (a) a first nucleotide sequence that is comprised by an sbgl
polynucleotide; (b)
20 a nucleotide sequence comprising a polynucleotide encoding a positive
selection marker, said
nucleotide sequence comprising additionally two sequences defining a site
recognized by a
recombinase, such as a IoxP site, the two sites being placed in the same
orientation; and (c) a
second nucleotide sequence comprising an sbgl polynucleotide, and is located
on the genome
downstream ofthe first sbgl polynucleotide sequence (a). Also encompassed are
DNA
25 construct prepared in an analogous manner using g34665, sbg2, g35017 or
g35018 nucleotide
sequences in place of the sbgl sequences described above.
The sequences defining a site recognized by a recombinase, such as a loxP
site, are
preferably located within the nucleotide sequence (b) at suitable locations
bordering the
nucleotide sequence for which the conditional excision is sought. In one
specific embodiment,
30 two IoxP sites are located at each side of the positive selection marker
sequence, in order to
allow its excision at a desired time after the occurrence of the homologous
recombination event.
In a preferred embodiment of a method using the third DNA construct described
above,
the excision of the polynucleotide fragment bordered by the two sites
recognized by a
recombinase, preferably two IoxP sites, is performed at a desired time, due to
the presence
35 within the genome of the recombinant host cell of a sequence encoding the
Cre enzyme
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operably linked to a promoter sequence, preferably an inducible promoter, more
preferably a
tissue-specific promoter sequence and most preferably a promoter sequence
which is both
inducible and tissue-specific, such as described by Gu et al.(1994).
The presence of the Cre enzyme within the genome of the recombinant cell host
may
result from the breeding of two transgenic animals, the first transgenic
animal bearing the sbgl,
g34665, sbg2, g35017 or g35018 polynucleotide -derived sequence of interest
containing the
IoxP sites as described above and the second transgenic animal bearing the Cre
coding sequence
operably linked to a suitable promoter sequence, such as described by Gu et
al.(1994).
Spatio-temporal control of the Cre enzyme expression may also be achieved with
an
adenovirus based vector that contains the Cre gene thus allowing infection of
cells, or in vivo
infection of organs, for delivery of the Cre enzyme, such as described by
Anton and Graham
(1995) and Kanegae et al.(1995).
The DNA constructs described above may be used to introduce a desired
nucleotide
sequence of the invention, preferably an sbgl, g34665, sbg2, g35017 or g35018
polynucleotide,
and most preferably an altered copy an sbgl, g34665, sbg2, g35017 or g35018
polynucleotide
sequence, within a predetermined location of the targeted genome, leading
either to the
generation of an altered copy of a targeted gene (knock-out homologous
recombination) or to
the replacement of a copy of the targeted gene by another copy sufficiently
homologous to
allow an homologous recombination event to occur (knock-in homologous
recombination). In a
specific embodiment, the DNA constructs described above may be used to
introduce an sbgl,
g34665, sbg2, g35017 or g35018 polynucleotide.
Nuclear Antisense DNA Constructs
Other compositions containing a vector of the invention comprise an
oligonucleotide
fragment of the sbgl, g34665, sbg2, g35017 or g35018 polynucleotide sequences
of SEQ ID
No.l respectively, as an antisense tool that inhibits the expression of the
corresponding gene.
Preferred methods using antisense polynucleotide according to the present
invention are the
procedures described by Sczakiel et al.(1995) or those described in PCT
Application No WO
95/24223.
Preferably, the antisense tools are chosen among the polynucleotides (15-200
by long)
that are complementary to the 5'end of an sbgl, g34665, sbg2, g35017 or g35018
polynucleotide mRNA. In one embodiment, a combination of different antisense
polynucleotides complementary to different parts of the desired targeted gene
are used.
Preferably, the antisense polynucleotides of the invention have a 3'
polyadenylation
signal that has been replaced with a self cleaving ribozyme sequence, such
that RNA
polymerase II transcripts are produced without poly(A) at their 3' ends, these
antisense
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polynucleotides being incapable of export from the nucleus, such as described
by Liu et
al.(1994). In a preferred embodiment, these sbgl, g34665, sbg2, g35017 or
g35018 antisense
polynucleotides also comprise, within the ribozyme cassette, a histone stem-
loop structure to
stabilize cleaved transcripts against 3'-5' exonucleolytic degradation, such
as the structure
described by Eckner et al.( 1991 ).
Oligonucleotide Probes And Primers
The polynucleotides of the invention are useful in order to detect the
presence of at least
a copy of a nucleotide sequence of SEQ ID No. 1 or of the respective sbgl,
g34665, sbg2,
g35017 and g35018 polynucleotide or gene, or a fragment, complement, or
variant thereof in a
test sample.
Particularly preferred probes and primers of the invention include isolated,
purified, or
recombinant polynucleotides comprising a contiguous span of at least 12, 15,
18, 20, 25, 30, 35,
40, 50, 60, 70, 80, 90, 100, 150, 200, 500, 1000 or 2000 nucleotides, to the
extent that said span
is consistent with the length of the nucleotide position range, of SEQ ID No
1, wherein said
contiguous span comprises at least 1, 2, 3, 4, 5, 7 or 10 of the following
nucleotide positions of
SEQ ID No 1:
(a) nucleotide positions 31 to 292651 and 292844 to 319608;
(b) 290653 to 292652, 292653 to 296047, 292653 to 292841, 295555 to 296047,
295580 to 296047 and 296048 to 298048;
(c) 94124 to 94964;
(d) 31 to 1107, 1108 to 65853, 1108 to 1289, 14877 to 14920, 18778 to 18862,
25593 to
25740, 29388 to 29502, 29967 to 30282, 64666 to 64812, 65505 to 65853 and
65854 to 67854;
(e) 213818 to 215818, 215819 to 215941, 215819 to 215975, 216661 to 216952,
216661 to 217061, 217027 to 217061, 229647 to 229742, 230408 to 230721, 231272
to
231412, 231787 to 231880, 231870 to 231879, 234174 to 234321, 237406 to
237428, 239719
to 239807, 239719 to 239853, 240528 to 240569, 240528 to 240596, 240528 to
240617,
240528 to 240644, 240528 to 240824, 240528 to 240994, 240528 to 241685, 240800
to 240993
and 241686 to 243685;
(f) 201188 to 216915, 201188 to 201234, 214676 to 214793, 215702 to 215746 and
216836 to 216915; or
(g) a complementary sequence thereto or a fragment thereof.
Probes and primers of the invention also include isolated, purified, or
recombinant
polynucleotides having at least 70, 75, 80, 85, 90, or 95% nucleotide identity
with a contiguous
span of at least 12, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150,
200, 500, 1000 or
2000 nucleotides of nucleotide positions 31 to 292651 and 292844 to 319608 of
SEQ ID No. I.
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Preferred probes and primers of the invention also include isolated, purified,
or recombinant
polynucleotides comprising an sbgl, g34665, sbg2, g35017 or g35018 nucleotide
sequence
having at least 70, 75, 80, 85, 90, or 95% nucleotide identity with at least
one sequence selected
from the group consisting of the following nucleotide positions of SEQ ID No.
1:
(a) 290653 to 292652, 292653 to 296047, 292653 to 292841, 295555 to 296047,
295580 to 296047 and 296048 to 298048;
(b) 94124 to 94964;
(c) 31 to 1107, 1108 to 65853, 1108 to 1289, 14877 to 14920, 18778 to 18862,
25593 to
25740, 29388 to 29502, 29967 to 30282, 64666 to 64812, 65505 to 65853 and
65854 to 67854;
(d) 213818 to 215818, 215819 to 215941, 215819 to 215975, 216661 to 216952,
216661 to 217061, 217027 to 217061, 229647 to 229742, 230408 to 230721, 231272
to
231412, 231787 to 231880, 231870 to 231879, 234174 to 234321, 237406 to
237428, 239719
to 239807, 239719 to 239853, 240528 to 240569, 240528 to 240596, 240528 to
240617,
240528 to 240644, 240528 to 240824, 240528 to 240994, 240528 to 241685, 240800
to 240993
and 241686 to 243685;
(e) 201188 to 216915, 201188 to 201234, 214676 to 214793, 215702 to 215746 and
216836 to 216915; or
(f) a complementary sequence thereto or a fragment thereof.
Another set of probes and primers of the invention include isolated, purified,
or
recombinant polynucleotides comprising a contiguous span of at least 12, 15,
18, 20, 25, 30, 35,
40, 50, 60, 70, 80, 90, 100, 150, 200, 500, I 000 or 2000 nucleotides of SEQ
ID No. 1 or the
complements thereof, wherein said contiguous span comprises at least 1, 2, 3,
5, or 10
nucleotide positions of any one of the ranges of nucleotide positions,
designated posl to pos166,
of SEQ ID No. 1 listed in Table 1 above.
The invention also relates to nucleic acid probes characterized in that they
hybridize
specifically, under the stringent hybridization conditions defined above, with
a contiguous span
of at least 12, 1 S, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150,
200, 500, 1000 or 2000
nucleotides of nucleotide positions 31 to 292651 and 292844 to 319608 of SEQ
ID No. 1, or a
variant thereof or a sequence complementary thereto. Particularly preferred
are nucleic acid
probes characterized in that they hybridize specifically, under the stringent
hybridization
conditions defined above, with a nucleic acid selected from the group
consisting of nucleotide
positions:
(a) 290653 to 292652, 292653 to 296047, 292653 to 292841, 295555 to 296047,
295580 to 296047 and 296048 to 298048;
(b) 94124 to 94964;
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(c) 31 to 1107, 1108 to 65853, 1108 to 1289, 14877 to 14920, 18778 to 18862,
25593 to
25740, 29388 to 29502, 29967 to 30282, 64666 to 64812, 65505 to 65853 and
65854 to 67854;
(d) 213818 to 215818, 215819 to 215941, 215819 to 215975, 216661 to 216952,
216661 to 217061, 217027 to 217061, 229647 to 229742, 230408 to 230721, 231272
to
231412, 231787 to 231880, 231870 to 231879, 234174 to 234321, 237406 to
237428, 239719
to 239807, 239719 to 239853, 240528 to 240569, 240528 to 240596, 240528 to
240617,
240528 to 240644, 240528 to 240824, 240528 to 240994, 240528 to 241685, 240800
to 240993
and 241686 to 243685;
(e) 201188 to 216915, 201188 to 201234, 214676 to 214793, 215702 to 215746 and
216836 to 216915; or
(f) a complementary sequence thereto or a fragment thereof.
The formation of stable hybrids depends on the melting temperature (Tm) of the
DNA.
The Tm depends on the length of the primer or probe, the ionic strength of the
solution and the
G+C content. The higher the G+C content of the primer or probe, the higher is
the melting
temperature because G:C pairs are held by three H bonds whereas A:T pairs have
only two.
The GC content in the probes of the invention usually ranges between 10 and 75
%, preferably
between 35 and 60 %, and more preferably between 40 and 55 %.
A probe or a primer according to the invention may be between 8 and 2000
nucleotides
in length, or is specified to be at least 12, 15, 18, 20, 25, 35, 40, 50, 60,
70, 80, 100, 250, 500 ,
1000 nucleotides in length. More particularly, the length of these probes can
range from 8, I 0,
15, 20, or 30 to 100 nucleotides, preferably from 10 to 50, more preferably
from 15 to 30
nucleotides. Shorter probes tend to lack specificity for a target nucleic acid
sequence and
generally require cooler temperatures to form sufficiently stable hybrid
complexes with the
template. Longer probes are expensive to produce and can sometimes self
hybridize to form
hairpin structures. The appropriate length for primers and probes under a
particular set of assay
conditions may be empirically determined by one of skill in the art.
The primers and probes can be prepared by any suitable method, including, for
example, cloning and restriction of appropriate sequences and direct chemical
synthesis by a
method such as the phosphodiester method ofNarang et al.(1979), the
phosphodiester method
of Brown et al.(1979), the diethylphosphoramidite method of Beaucage et
al.(1981) and the
solid support method described in EP 0 707 592.
Detection probes are generally nucleic acid sequences or uncharged nucleic
acid
analogs such as, for example peptide nucleic acids which are disclosed in
International Patent
Application WO 92/20702, morpholino analogs which are described in U.S.
Patents Numbered
5,185,444; 5,034,506 and 5,142,047. The probe may have to be rendered "non-
extendable" in
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that additional dNTPs cannot be added to the probe. In and of themselves
analogs usually are
non-extendable and nucleic acid probes can be rendered non-extendable by
modifying the 3' end
of the probe such that the hydroxyl group is no longer capable of
participating in elongation.
For example, the 3' end of the probe can be functionalized with the capture or
detection label to
5 thereby consume or otherwise block the hydroxyl group. Alternatively, the 3'
hydroxyl group
simply can be cleaved, replaced or modified; U.S. Patent Application Serial
No. 07/049,061
filed April 19, 1993, describes modifications which can be used to render a
probe non-
extendable.
Any of the polynucleotides of the present invention can be labeled, if
desired, by
10 incorporating a label detectable by spectroscopic, photochemical,
biochemical,
immunochemical, or chemical means. For example, useful labels include
radioactive
substances (32P, 355 3H~ 1251) fluorescent dyes (5-bromodesoxyuridin,
fluorescein,
acetylaminofluorene, digoxigenin) or biotin. Preferably, polynucleotides are
labeled at their 3'
and S' ends. Examples of non-radioactive labeling of nucleic acid fragments
are described in
15 the French patent No. FR-7810975 or by Urdea et al ( 1988) or Sanchez-
Pescador et al ( 1988).
In addition, the probes according to the present invention may have structural
characteristics
such that they allow the signal amplification, such structural characteristics
being, for example,
branched DNA probes as those described by Urdea et al. in 1991 or in the
European patent No.
EP 0 225 807 (Chiron).
20 A label can also be used to capture the primer, so as to facilitate the
immobilization of
either the primer or a primer extension product, such as amplified DNA, on a
solid support. A
capture label is attached to the primers or probes and can be a specific
binding member which
forms a binding pair with the solid's phase reagent's specific binding member
(e.g. biotin and
streptavidin). Therefore depending upon the type of label carried by a
polynucleotide or a
25 probe, it may be employed to capture or to detect the target DNA. Further,
it will be understood
that the polynucleotides, primers or probes provided herein, may, themselves,
serve as the
capture label. For example, in the case where a solid phase reagent's binding
member is a
nucleic acid sequence, it may be selected such that it binds a complementary
portion of a primer
or probe to thereby immobilize the primer or probe to the solid phase. In
cases where a
30 polynucleotide probe itself serves as the binding member, those skilled in
the art will recognize
that the probe will contain a sequence or "tail" that is not complementary to
the target. In the
case where a polynucleotide primer itself serves as the capture label, at
least a portion of the
primer will be free to hybridize with a nucleic acid on a solid phase. DNA
Labeling techniques
are well known to the skilled technician.
35 The probes of the present invention are useful for a number of purposes.
They can be
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notably used in Southern hybridization to genomic DNA. The probes can also be
used to detect
PCR amplification products. They may also be used to detect mismatches in a
sequence
comprising a polynucleotide of SEQ ID Nos 1 to 26, 36 to 40 and 54 to 229, or
an sbgl,
g34665, sbg2, g35017 or g35018 polynucleotide or gene or mRNA using other
techniques.
Any of the polynucleotides, primers and probes of the present invention can be
conveniently immobilized on a solid support. Solid supports are known to those
skilled in the
art and include the walls of wells of a reaction tray, test tubes, polystyrene
beads, magnetic
beads, nitrocellulose strips, membranes, microparticles such as latex
particles, sheep (or other
animal) red blood cells, duracytes and others. The solid support is not
critical and can be
selected by one skilled in the art. Thus, latex particles, microparticles,
magnetic or non-
magnetic beads, membranes, plastic tubes, walls of microtiter wells, glass or
silicon chips,
sheep (or other suitable animal's) red blood cells and duracytes are all
suitable examples.
Suitable methods for immobilizing nucleic acids on solid phases include ionic,
hydrophobic,
covalent interactions and the like. A solid support, as used herein, refers to
any material which
is insoluble, or can be made insoluble by a subsequent reaction. The solid
support can be
chosen for its intrinsic ability to attract and immobilize the capture
reagent. Alternatively, the
solid phase can retain an additional receptor which has the ability to attract
and immobilize the
capture reagent. The additional receptor can include a charged substance that
is oppositely
charged with respect to the capture reagent itself or to a charged substance
conjugated to the
capture reagent. As yet another alternative, the receptor molecule can be any
specific binding
member which is immobilized upon (attached to) the solid support and which has
the ability to
immobilize the capture reagent through a specific binding reaction. The
receptor molecule
enables the indirect binding of the capture reagent to a solid support
material before the
performance of the assay or during the performance of the assay. The solid
phase thus can be a
plastic, derivatized plastic, magnetic or non-magnetic metal, glass or silicon
surface of a test
tube, microtiter well, sheet, bead, microparticle, chip, sheep (or other
suitable animal's) red
blood cells, duracytes and other configurations known to those of ordinary
skill in the art. The
polynucleotides of the invention can be attached to or immobilized on a solid
support
individually or in groups of at least 2, 5, 8, 10, 12, 15, 20, or 25 distinct
polynucleotides of the
invention to a single solid support. In addition, polynucleotides other than
those of the
invention may be attached to the same solid support as one or more
polynucleotides of the
invention.
Consequently, the invention also comprises a method for detecting the presence
of a
nucleic acid comprising a nucleotide sequence selected from a group consisting
of SEQ ID Nos.
1 to 26, 36 to 40 and 54 to 229, a fragment or a variant thereof or a
complementary sequence
that additional dNTPs cannot be added
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thereto in a sample, said method comprising the following steps o~
a) bringing into contact a nucleic acid probe or a plurality of nucleic acid
probes which
can hybridize with a nucleotide sequence included in a nucleic acid selected
form the group
consisting of the nucleotide sequences of SEQ ID Nos. 1 to 26, 36 to 40 and 54
to 229, a
fragment or a variant thereof or a complementary sequence thereto and the
sample to be
assayed; and
b) detecting the hybrid complex formed between the probe and a nucleic acid in
the
sample.
The invention further concerns a kit for detecting the presence of a nucleic
acid
comprising a nucleotide sequence selected from a group consisting of SEQ ID
Nos. 1 to 26, 36
to 40 and 54 to 229, a fragment or a variant thereof or a complementary
sequence thereto in a
sample, said kit comprising:
a) a nucleic acid probe or a plurality of nucleic acid probes which can
hybridize with a
nucleotide sequence included in a nucleic acid selected form the group
consisting of the
nucleotide sequences of SEQ ID Nos. 1 to 26, 36 to 40 and 54 to 229, a
fragment or a variant
thereof or a complementary sequence thereto; and
b) optionally, the reagents necessary for performing the hybridization
reaction.
In a first preferred embodiment ofthis detection method and kit, said nucleic
acid probe
or the plurality of nucleic acid probes are labeled with a detectable
molecule. In a second
preferred embodiment of said method and kit, said nucleic acid probe or the
plurality of nucleic
acid probes has been immobilized on a substrate. In a third preferred
embodiment, the nucleic
acid probe or the plurality of nucleic acid probes comprise either a sequence
which is selected
from the group consisting of the nucleotide sequences of P1 to P360 and the
complementary
sequence thereto, B I to B229, C I to C229, D 1 to D360, E 1 to E360, or a
nucleotide sequence
comprising a biallelic marker selected from the group consisting of A 1 to
A360 or a
polymorphism selected from the group consisting of A361 to A489, or the
complements thereto.
Oligoaucleotide Arrays
A substrate comprising a plurality of oligonucleotide primers or probes of the
invention
may be used either for detecting or amplifying targeted sequences in a
nucleotide sequence of
SEQ ID No. 1, more particularly in an sbgl, g34665, sbg2, g35017 or g35018
polynucleotide,
or in genes comprising an sbgl, g34665, sbg2, g35017 or g35018 polynucleotide
and may also
be used for detecting mutations in the coding or in the non-coding sequences
of an sbgl,
g34665, sbg2, g35017 or g35018 nucleic acid sequence, or genes comprising an
sbgl, g34665,
sbg2, g35017 or g35018 nucleic acid sequence.
Any polynucleotide provided herein may be attached in overlapping areas or at
random
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locations on the solid support. Alternatively the polynucleotides of the
invention may be
attached in an ordered array wherein each polynucleotide is attached to a
distinct region of the
solid support which does not overlap with the attachment site of any other
polynucleotide.
Preferably, such an ordered array of polynucleotides is designed to be
"addressable" where the
distinct locations are recorded and can be accessed as part of an assay
procedure. Addressable
polynucleotide arrays typically comprise a plurality of different
oligonucleotide probes that are
coupled to a surface of a substrate in different known locations. The
knowledge of the precise
location of each polynucleotides location makes these "addressable" arrays
particularly useful
in hybridization assays. Any addressable array technology known in the art can
be employed
with the polynucleotides of the invention. One particular embodiment of these
polynucleotide
arrays is known as GenechipsTM, and has been generally described in US Patent
5,143,854;
PCT publications WO 90/15070 and 92/10092. These arrays may generally be
produced using
mechanical synthesis methods or light directed synthesis methods which
incorporate a
combination of photolithographic methods and solid phase oligonucleotide
synthesis (Fodor et
al., 1991, incorporated herein by reference). The immobilization of arrays of
oligonucleotides
on solid supports has been rendered possible by the development of a
technology generally
identified as "Very Large Scale Immobilized Polymer Synthesis" (VLSIPSTM) in
which,
typically, probes are immobilized in a high density array on a solid surface
of a chip. Examples
of VLSIPSTM technologies are provided in US Patents 5,143,854; and 5,412,087
and. in PCT
Publications WO 90/15070, WO 92/10092 and WO 95/11995, which describe methods
for
forming oligonucleotide arrays through techniques such as light-directed
synthesis techniques.
In designing strategies aimed at providing arrays of nucleotides immobilized
on solid supports,
further presentation strategies were developed to order and display the
oligonucleotide arrays on
the chips in an attempt to maximize hybridization patterns and sequence
information. Examples
of such presentation strategies are disclosed in PCT Publications WO 94/12305,
WO 94/11530,
WO 97/29212 and WO 97/31256.
In another embodiment of the oligonucleotide arrays of the invention, an
oligonucleotide probe matrix may advantageously be used to detect mutations
occurring in an
sbgl, g34665, sbg2, g35017 or g35018 polynucleotide, including in genes
comprising an sbgl,
g34665, sbg2, g35017 or g35018 polynucleotide and preferably in an sbgl,
g34665, sbg2,
g35017 or g35018 polynucleotide regulatory region. For this particular
purpose, probes are
specifically designed to have a nucleotide sequence allowing their
hybridization to the genes
that carry known mutations (either by deletion, insertion or substitution of
one or several
nucleotides). By known mutations in an sbgl, g34665, sbg2, g35017 or g35018
polynucleotide,
it is meant, mutations in an sbgl, g34665, sbg2, g35017 or g35018
polynucleotide that have
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79
been identified according; the technique used by Huang et al.(1996) or Samson
et al.(1996), for
example, may be used to identify such mutations.
Another technique that is used to detect mutations in an sbgl, 834665, sbg2,
835017 or
835018 polynucleotide is the use of a high-density DNA array. Each
oligonucleotide probe
constituting a unit element of the high density DNA array is designed to match
a specific
subsequence of an sbgl, 834665, sbg2, 835017 or 835018 polynucleotide. Thus,
an array
consisting of oligonucleotides complementary to subsequences of the target
gene sequence is
used to determine the identity of the target sequence with the wild-type gene
sequence, measure
its amount, and detect differences between the target sequence and the
reference wild-type
nucleic acid sequence of an sbgl, 834665, sbg2, 835017 or 835018
polynucleotide. In one such
design, termed 4L tiled array, is implemented a set of four probes (A, C, G,
T), preferably 15-
nucleotide oligomers. In each set of four probes, the perfect complement will
hybridize more
strongly than mismatched probes. Consequently, a nucleic acid target of length
L is scanned for
mutations with a tiled array containing 4L probes, the whole probe set
containing all the
possible mutations in the known wild reference sequence. The hybridization
signals of the 15-
. mer probe set tiled array are perturbed by a single base change in the
target sequence. As a .
consequence, there is a characteristic loss of signal or a "footprint" for the
probes flanking a
mutation position. This technique was described by Chee et al. in 1996.
Consequently, the invention concerns an array of nucleic acid molecules
comprising at
least one polynucleotide described above as probes and primers. Preferably,
the invention
concerns an array of nucleic acid comprising at least two polynucleotides
described above as
probes and primers.
Sbgl, 834665, sbg2, 835017 and 835018 Proteins and Polypeptide Fragments: .
The terms "sb.Ql polypentides", "834665 polype tn ides", "sbg-2 polypeptides",
" 3
polypeptides", "835017 polXpeptides" are used herein to embrace all of the
proteins and
polypeptides encoded by the respective sbgl, 834665, sbg2, 835017 and 835018
polypeptides
of the present invention. Forming part of the invention are polypeptides
encoded by the
polynucleotides of the invention, as well as fusion polypeptides comprising
such polypeptides. .
The invention embodies proteins from humans, mammals, primates, non-human
primates, and
includes isolated or purified sbgl proteins consisting, consisting
essentially, or comprising the
sequence of SEQ ID Nos 27 to 35, isolated or purified 834665, 835017 and sbg2
proteins
encoded by the 834665, 835017 and sbg2 polynucleotide sequence of SEQ ID No 1,
and
isolated or purified 835018 proteins consisting, consisting essentially, or
comprising the
sequence of SEQ ID Nos 41 to 43.
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It should be noted that the sbgl, g34665, sbg2, g35017 and g35018 proteins of
the
invention also comprise naturally-occurring variants of the amino acid
sequence of the
respective human sbgl, g34665, sbg2, g35017 and g35018 proteins.
The present invention embodies isolated, purified, and recombinant
polypeptides
5 comprising a contiguous span of at least 4 amino acids, preferably at least
6, more preferably at
least 8 to 10 amino acids, more preferably at least 12, 15, 20, 25, 30, 40,
50, or 100 amino acids,
to the extent that said span is consistent with the length of a particular SEQ
ID, of SEQ ID Nos
27 to 35 and 41 to 43. In other preferred embodiments the contiguous stretch
of amino acids
comprises the site of a mutation or functional mutation, including a deletion,
addition, swap or
10 truncation of the amino acids in an sbgl, g34665, sbg2, g35017 and g35018
protein sequence.
The invention also embodies isolated, purified, and recombinant sbgl
polypeptides
comprising a contiguous span of at least 4 amino acids, preferably at least 6
or at least 8 to 10
amino acids, more preferably at least 1.2, 15, 20, 25, 30, 40, S0, or 100
amino acids of SEQ ID
Nos 27 to 35, wherein said contiguous span comprises an amino acid variation
according to
15 Table Se.
The present inventors have further identified potential cleavage sites in the
sbgl
polypeptides, and several specific sbgl peptides. An sbgl peptide has further
been tested in
behavioral studies by injection in mice, as further detailed in Example 7. In
particular, the
polypeptide of SEQ ID No 29 contains a protease cleavage site at amino acid
positions 62 to 63;
20 the polypeptide of SEQ ID No 30 contains a protease cleavage site at amino
acid positions 63 to
64 and 110 to 111; the polypeptide of SEQ ID No 32 contains a protease
cleavage site at amino
acid positions 63 to 64; the polypeptide of SEQ ID No 33 contains a protease
cleavage site at
amino acid positions 54 to 55 and 57 to 58; the polypeptide of SEQ ID No 34
contains a
protease cleavage site at amino acid positions 63 to 64 and 122 to 123; and
the polypeptide of
25 SEQ ID No 35 contains a protease cleavage site at amino acid positions 62
to 63 and 63 to 64.
Additionally, sbgl polypeptides of SEQ ID Nos 30, 32 and 34 contain cysteine
residues
predicted to be capable of forming a disulfide bridge at amino acid positions
82 and 104 of SEQ
ID No 30, amino acid positions 82 and 106 and SEQ ID No 32, and amino acid
positions 132
and 142 of SEQ ID No 34. In particularly preferred embodiment, the invention
comprises
30 isolated, purified, and recombinant sbgl peptides comprising a contiguous
span of at least 4
amino acids, preferably at least 6 or at least 8 to 10 amino acids, more
preferably at least 12 or
15 amino acids of an amino acid position range selected from the group
consisting of amino
acid positions: 1 to 63 and 64 to 102 of SEQ ID No 29; 1 to 64, 65 to 111 and
112 to I 19 of
SEQ ID No 30; 1 to 64 and 65 to 126 of SEQ ID No 32; 1 to 64, 65 to 123 and
124 to 153 of
35 SEQ ID No 34; and 1 to 61 and 65 to 106 of SEQ ID No 35.
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The invention further embodies sbgl, 834665, sbg2, 835017 and 835018
polypeptides,
including isolated and recombinant polypeptides, encoded respectively by sbgl,
834665, sbg2,
835017 and 835018 polynucleotides consisting, consisting essentially, or
comprising a
contiguous span of at least 12, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80,
90, 100, 150, 200 or
500 nucleotides, to the extent that the length of said span is consistent with
the nucleotide
position range, of SEQ ID No 1, wherein said contiguous span comprises at
least 1, 2, 3, 4, 5, 7
or 10 of the following nucleotide positions of SEQ ID No 1:
(a) 290653 to 292652, 292653 to 296047, 292653 to 292841, 295555 to 296047 and
295580 to 296047;
(b) 94144 to 94964
(c) 1108 to 65853, 1108 to 1289, 14877 to 14920, 18778 to 18862, 25593 to
25740,
29388 to 29502, 29967 to 30282, 64666 to 64812, and 65505 to 65853;
(d) 215819 to 215941, 215819 to 215975, 216661 to 216952, 216661 to 217061,
217027 to 217061, 229647 to 229742, 230408 to 230721, 231272 to 231412, 231787
to
231880, 231870 to 231879, 234174 to 234321, 237406 to 237428, 239719 to
239807, 239719
to 239853, 240528 to 240569, 240528 to 240596, 240528 to 240617, 240528 to
240644,
240528 to 240824, 240528 to 240994, 240528 to 241685 and 240800 to 240993;
(e) 201188 to 216915, 201188 to 201234, 214676 to 214793, 215702 to 215746 and
216836 to 216915; or the complements thereof.
The present invention further embodies isolated, purified, and recombinant
polypeptides encoded by an sbgl polynucleotide or gene comprising at least one
sbgl
nucleotide sequence selected from the group consisting of the following sbgl
exons: MS1, M1,
M692, M862, MS2, M1069, M1090, M1117, N , N2, Nbis, O, O1, 02, Obis, P, X, Q1,
Q, Qbis,
R and Rbis.
The invention also encompasses a purified, isolated, or recombinant
polypeptides
comprising an amino acid sequence having at least 70, 75, 80, 85, 90, 95, 98
or 99% amino acid
identity with the amino acid sequence of SEQ ID Nos 27 to 35 and 41 to 43 or a
fragment
thereof.
Sbgl, 834665, sbg2, 835017 and 835018 proteins are preferably isolated from
human or
mammalian tissue samples or expressed from human or mammalian genes. The sbgl,
834665,
sbg2, 835017 and 835018 polypeptides ofthe invention can be made using routine
expression
methods known in the art. The polynucleotide encoding the desired polypeptide,
is ligated into
an expression vector suitable for any convenient host. Both eukaryotic and
prokaryotic host
systems is used in forming recombinant polypeptides, and a summary of some of
the more
common systems. The polypeptide is then isolated from lysed cells or from the
culture medium
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and purified to the extent needed for its intended use. Purification is by any
technique known in
the art, for example, differential extraction, salt fractionation,
chromatography, centrifugation,
and the like. See, for example, Methods in Enzymology for a variety of methods
for purifying
proteins.
In addition, shorter protein fragments can be produced by chemical synthesis.
Alternatively the proteins of the invention is extracted from cells or tissues
of humans or non-
human animals. Methods for purifying proteins are known in the art, and
include the use of
detergents or chaotropic agents to disrupt particles followed by differential
extraction and
separation of the polypeptides by ion exchange chromatography, affinity
chromatography,
sedimentation according to density, and gel electrophoresis.
Any sbgl, g34665, sbg2, g35017 or g35018 eDNA or fragment thereof, including
the
respective cDNA sequences of SEQ ID Nos 2 to 26 and 36 to 40 is used to
express sbgl, g34665,
sbg2, g35017 or g35018 proteins and polypeptides. The nucleic acid encoding
the sbgl, g34665,
sbg2, g35017 or g35018 protein or polypeptide to be expressed is operably
linked to a promoter in
an expression vector using conventional cloning technology. The sbgl, g34665,
sbg2, g35017 or
g35018 insert in the expression vector may comprise the full coding sequence
for the respective
sbgl, g34665, sbg2, g35017 or g35018 protein or a portion thereof. For
example, the sbgl or
g35018 derived insert may encode a polypeptide comprising at least 10
consecutive amino acids of
the respective sbgl or g35018 protein of SEQ ID Nos 27 to 35 and 41 to 43.
The expression vector is any of the mammalian, yeast, insect or bacterial
expression
systems known in the art. Commercially available vectors and expression
systems are available
from a variety of suppliers including Genetics Institute (Cambridge, MA),
Stratagene (La Jolla,
California), Promega (Madison, Wisconsin), and Invitrogen (San Diego,
California). If desired, to
enhance expression and facilitate proper protein folding, the codon context
and codon pairing of the
sequence is optimized for the particular expression organism in which the
expression vector is
introduced, as explained by Hatfield, et al., U.S. Patent No. 5,082,767.
In one embodiment, the entire coding sequence ofthe sbgl, g34665, sbg2, g35017
or
g35018 cDNA through the poly A signal of the cDNA are operably linked to a
promoter in the
expression vector. Alternatively, ifthe nucleic acid encoding a portion ofthe
sbgl, g34665, sbg2,
g35017 or g35018 protein lacks a methionine to serve as the initiation site,
an initiating methionine
can be introduced next to the first codon of the nucleic acid using
conventional techniques.
Similarly, if the insert from the sbgl, g34665, sbg2, g35017 or g35018 cDNA
lacks a poly A
signal, this sequence can be added to the construct by, for example, splicing
out the Poly A signal
from pSGS (Stratagene) using BgII and SaII restriction endonuclease enzymes
and incorporating it
into the mammalian expression vector pXTI (Stratagene). pXTl contains the LTRs
and a portion
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of the gag gene from Moloney Murine Leukemia Virus. The position of the LTRs
in the construct
allow efficient stable transfection. The vector includes the Herpes Simplex
Thymidine Kinase
promoter and the selectable neomycin gene. The nucleic acid encoding the sbgl,
834665, sbg2,
835017 or 835018 protein or a portion thereof is obtained by PCR from a
bacterial vector
containing the a nucleotide sequence of an exon of an sbgl, 834665, sbg2,
835017 or 835018
gene as described herein and in SEQ 117 No 1, or from an sbgl or 835018 cDNA
comprising a
nucleic acid of SEQ ID No 2 to 26 and 36 to 40 using oligonucleotide primers
complementary to
the sbgl, 834665, sbg2, 835017 or 835018 nucleic acid or portion thereof and
containing
restriction endonuclease sequences for Pst I incorporated into the 5' primer
and BgllI at the 5' end
of the corresponding cDNA 3' primer, taking care to ensure that the sequence
encoding the sbgl,
834665, sbg2, 835017 or 835018 protein or a portion thereof is positioned
properly with respect to
the poly A signal. The purified fragment obtained from the resulting PCR
reaction is digested with
PstI, blunt ended with an exonuclease, digested with Bgl II, purified and
ligated to pXTI, now
containing a poly A signal and digested with BgIII.
The ligated product is transfected into mouse NIH 3T3 cells using Lipofectin
(Life
Technologies, Inc., Grand Island, New York) under conditions outlined in the
product
specification. Positive transfectants are selected after growing the
transfected cells in 600ug/ml
6418 (Sigma, St. Louis, Missouri).
Alternatively, the nucleic acids encoding the sbgl, 834665, sbg2, 835017 or
835018
protein or a portion thereof is cloned into pED6dpc2 (Genetics Institute,
Cambridge, MA). The
resulting pED6dpc2 constructs is transfected into a suitable host cell, such
as COS 1 cells.
Methotrexate resistant cells are selected and expanded.
The above procedures may also be used to express a mutant sbgl, 834665, sbg2,
835017
or 835018 protein responsible for a detectable phenotype or a portion thereof.
The expressed proteins are purified using conventional purification techniques
such as
ammonium sulfate precipitation or chromatographic separation based on size or
charge. The
protein encoded by the nucleic acid insert may also be purified using standard
immunochromatography techniques. In such procedures, a solution containing the
expressed sbgl,
834665, sbg2, 835017 or 835018 protein or portion thereof, such as a cell
extract, is applied to a
column having antibodies against the sbgl, 834665, sbg2, 835017 or 835018
protein or portion
thereof is attached to the chromatography matrix. The expressed protein is
allowed to bind the
immunochromatography column. Thereafter, the column is washed to remove non-
specifically
bound proteins. The specifically bound expressed protein is then released from
the column and
recovered using standard techniques.
To confirm expression ofthe sbgl, 834665, sbg2, 835017 or 835018 protein or a
portion
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thereof, the proteins expressed from host cells containing an expression
vector containing an insert
encoding the sbgl, 834665, sbg2, 835017 or 835018 protein or a portion thereof
can be compared
to the proteins expressed in host cells containing the expression vector
without an insert. The
presence of a band in samples from cells containing the expression vector with
an insert which is
absent in samples from cells containing the expression vector without an
insert indicates that the
sbgl, 834665, sbg2, 835017 or 835018 protein or a portion thereof is being
expressed. Generally,
the band will have the mobility expected for the sbgl, 834665, sbg2, 835017 or
835018 protein or
portion thereof. However, the band may have a mobility different than that
expected as a result of
modifications such as glycosylation, ubiquitination, or enzymatic cleavage.
Antibodies capable of specifically recognizing the expressed sbgl, 834665,
sbg2, 835017
or 835018 protein or a portion thereof are described below.
If antibody production is not possible, the nucleic acids encoding the sbgl,
834665, sbg2,
835017 or 835018 protein or a portion thereof is incorporated into expression
vectors designed for
use in purification schemes employing chimeric polypeptides. In such
strategies the nucleic acid
encoding the sbgl, 834665, sbg2, 835017 or 835018 protein or a portion thereof
is inserted in
frame with the gene encoding the other half of the chimera. The other half of
the chimera is (3-
globin or a nickel binding polypeptide encoding sequence. A chromatography
matrix having
antibody to (3-globin or nickel attached thereto is then used to purify the
chimeric protein. Protease
cleavage sites is engineered between the (3-globin gene or the nickel binding
polypeptide and the
sbgl, 834665, sbg2, 835017 or 835018 protein or portion thereof. Thus, the two
polypeptides of
the chimera is separated from one another by protease digestion.
One useful expression vector for generating (3-globin chimeric proteins is
pSGS
(Stratagene), which encodes rabbit (3-globin. Intron II of the rabbit (3-
globin gene facilitates
splicing of the expressed transcript, and the polyadenylation signal
incorporated into the construct
increases the level of expression. These techniques are well known to those
skilled in the art of
molecular biology. Standard methods are published in methods texts such as
Davis et al., (1986)
and many of the methods are available from Stratagene, Life Technologies,
Inc., or Promega.
Polypeptide may additionally be produced from the construct using in vitro
translation systems
such as the In vitro Expresses Translation Kit (Stratagene).
Antibodies That Bind sbgl, 834665, sbg2, 835017 or 835018 Polypepddes of the
Invention
Any sbgl, 834665, sbg2, 835017 or 835018 polypeptide or whole protein may be
used
to generate antibodies capable of specifically binding to an expressed sbgl,
834665, sbg2,
835017 and 835018 protein or fragments thereof.
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For an antibody composition to specifically bind to an sbgl, 834665, sbg2,
835017 or
835018 protein, it must demonstrate at least a 5%, 10%, 15%, 20%, 25%, 50%, or
100% greater
binding affinity for full length sbgl, 834665, sbg2, 835017 or 835018 protein
than for any full
length protein in an ELISA, RIA, or other antibody-based binding assay. For an
antibody
5 composition to specifically bind to a variant sbgl, 834665, sbg2, 835017 or
835018 protein, it
must demonstrate at least a 5%, 10%, 15%, 20%, 25%, 50%, or 100% greater
binding affinity
for the respective full length variant sbgl, 834665, sbg2, 835017 or 835018
protein than for the
respective reference sbgl, 834665, sbg2, 835017 or 835018 full length protein
in an ELISA,
RIA, or other antibody-based binding assay.
10 One antibody composition of the invention is capable of specifically
binding or
specifically binds to the respective sbgl org35018 proteins of SEQ ID Nos 27
to 35 and 41 to
43. Other antibody compositions of the invention are capable of specifically
binding or
specifically bind to an sbgl, sbg2 or 835018 protein variant. Optionally said
sbgl protein
variant may be a natural variant provided in Tables Sd or 5e.
15 In one embodiment, the invention concerns antibody compositions, either
polyclonal or
monoclonal, capable of selectively binding, or selectively bind to an epitope-
containing a
polypeptide comprising a contiguous span of at least 6 amino acids, preferably
at least 8 to 10
amino acids, more preferably at least 12, 15, 20, 25, 30, 40, 50, or 100 amino
acids of an sbgl,
834665, sbg2, 835017 or 835018 polypeptide.
20 The invention also concerns a purified or isolated antibody capable of
specifically
binding to a mutated sbgl, 834665, sbg2, 835017 or 835018 protein or to a
fragment or variant
thereof comprising an epitope of the mutated sbgl, 834665, sbg2, 835017 or
835018 protein. In
another preferred embodiment, the present invention concerns an antibody
capable of binding to
a polypeptide comprising at least 10 consecutive amino acids of an sbgl,
834665, sbg2, 835017
25 or 835018 protein and including at least one of the amino acids which can
be encoded by the
trait causing mutations.
In a preferred embodiment, the invention concerns the use in the manufacture
of
antibodies of a polypeptide comprising a contiguous span of at least 6 amino
acids, preferably at
least 8 to 10 amino acids, more preferably at least 12, 15, 20, 25, 30, 40,
50, or 100 amino acids
30 of any of SEQ ID Nos 27 to 35 and 41 to 43.
Non-human animals, and more particularly non-human mammals and non-human
primates, whether wild-type or transgenic, which express a different species
of sbgl, 834665,
sbg2, 835017 or 835018 than the one to which antibody binding is desired, and
animals which
do not express sbgl, 834665, sbg2, 835017 or 835018 (i.e. an sbgl, 834665,
sbg2, 835017 or
35 835018 knock out animal as described in herein) are particularly useful for
preparing antibodies.
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sbgl, 834665, sbg2, 835017 or 835018 knock out animals will recognize all or
most of the
exposed regions of an sbgl, 834665, sbg2, 835017 or 835018 protein as foreign
antigens, and
therefore produce antibodies with a wider array of sbgl, 834665, sbg2, 835017
or 835018
epitopes. Moreover, smaller polypeptides with only 10 to 30 amino acids may be
useful in
obtaining specific binding to any one ofthe sbgl, 834665, sbg2, 835017 or
835018 proteins. In
addition, the humoral immune system of animals which produce a species of
sbgl, 834665,
sbg2, 835017 or 835018 that resembles the antigenic sequence will
preferentially recognize the
differences between the animal's native sbgl, 834665, sbg2, 835017 or 835018
species and the
antigen sequence, and produce antibodies to these unique sites in the antigen
sequence.. Such a
technique will be particularly useful in obtaining antibodies that
specifically bind to any one of
the sbgl, 834665, sbg2, 835017 or 835018 proteins.
. Antibody preparations prepared according to either protocol are useful in
quantitative
immunoassays which determine concentrations of antigen-bearing substances in
biological
samples; they are also used semi-quantitatively or qualitatively to identify
the presence of antigen
in a biological sample.
The antibodies may also be used in therapeutic compositions for killing cells
expressing
the protein or reducing the levels of the protein in the body. Thus in one
embodiment, the invention
comprises the use of an antibody capable of specifically recognizing sbgl,
834665, sbg2, 835017
or 835018 for the treatment of schizophrenia or bipolar disorder.
The antibodies of the invention may be labeled by any one of the radioactive,
fluorescent
or enzymatic labels known in the art.
Consequently, the invention is also directed to a method for detecting
specifically the
presence of an sbgl, 834665, sbg2, 835017 or 835018 polypeptide according to
the invention in
a biological sample, said method comprising the following steps:
a) bringing into contact the biological sample with a polyclonal or monoclonal
antibody
that specifically binds an sbgl, 834665, sbg2, 835017 or 835018 polypeptide,
or to a peptide
fragment or variant thereof; and
b) detecting the antigen-antibody complex formed.
The invention also concerns a diagnostic kit for detecting in vitro the
presence of an
sbgl, 834665, sbg2, 835017 or 835018 polypeptide according to the present
invention in a
biological sample, wherein said kit comprises:
a) a polyclonal or monoclonal antibody that specifically binds an sbgl,
834665, sbg2,
835017 or 835018 polypeptide, or to a peptide fragment or variant thereof,
optionally labeled;
b) a reagent allowing the detection of the antigen-antibody complexes formed,
said
reagent carrying optionally a label, or being able to be recognized itself by
a labeled reagent,
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more particularly in the case when the above-mentioned monoclonal or
polyclonal antibody is
not labeled by itself.
Biallelic markers of the inventions
Advantages of the biallelic markers of the present invention
The biallelic marker of the inventions of the present invention offer a number
of
important advantages over other genetic markers such as RFLP (Restriction
fragment length
polymorphism) and VNTR (Variable Number of Tandem Repeats) markers.
The first generation of markers, were RFLPs, which are variations that modify
the
length of a restriction fragment. But methods used to identify and to type
RFLPs are relatively
wasteful of materials, effort, and time. The second generation of genetic
markers were VNTRs,
which can be categorized as either minisatellites or microsatellites.
Minisatellites are tandemly
repeated DNA sequences present in units of 5-50 repeats which are distributed
along regions of
the human chromosomes ranging from 0.1 to 20 kilobases in length. Since they
present many
possible alleles, their informative content is very high. Minisatellites are
scored by performing
Southern blots to identify the number of tandem repeats present in a nucleic
acid sample from
4
the individual being tested. However, there are only 10 potential VNTRs that
can be typed by
Southern blotting. Moreover, both RFLP and VNTR markers are costly and time-
consuming to
develop and assay in large numbers.
Single nucleotide polymorphism or biallelic markers can be used in the same
manner as
RFLPs and VNTRs but offer several advantages. Single nucleotide polymorphisms
are densely
spaced in the human genome and represent the most frequent type of variation.
An estimated
number of more than 107 sites are scattered along the 3x109 base pairs of the
human genome.
Therefore, single nucleotide polymorphism occur at a greater frequency and
with greater
uniformity than RFLP or VNTR markers which means that there is a greater
probability that
such a marker will be found in close proximity to a genetic locus of interest.
Single nucleotide
polymorphisms are less variable than VNTR markers but are mutationally more
stable.
Also, the different forms of a characterized single nucleotide polymorphism,
such as the
biallelic markers of the present invention, are often easier to distinguish
and can therefore be
typed easily on a routine basis. Biallelic markers have single nucleotide
based alleles and they
have only two common alleles, which allows highly parallel detection and
automated scoring.
The biallelic markers of the present invention offer the possibility of rapid,
high-throughput
genotyping of a large number of individuals.
Biallelic markers are densely spaced in the genome, sufficiently informative
and can be
assayed in large numbers. The combined effects of these advantages make
biallelic markers
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extremely valuable in genetic studies. Biallelic markers can be used in
linkage studies in
families, in allele sharing methods, in linkage disequilibrium studies in
populations, in
association studies of case-control populations. An important aspect of the
present invention is
that biallelic markers allow association studies to be performed to identify
genes involved in
complex traits. Association studies examine the frequency of marker alleles in
unrelated case-
and control-populations and are generally employed in the detection of
polygenic or sporadic
traits. Association studies may be conducted within the general population and
are not limited
to studies performed on related individuals in affected families (linkage
studies). Biallelic
markers in different genes can be screened in parallel for direct association
with disease or
response to a treatment. This multiple gene approach is a powerful tool for a
variety of human
genetic studies as it provides the necessary statistical power to examine the
synergistic effect of
multiple genetic factors on a particular phenotype, drug response, sporadic
trait, or disease state
with a complex genetic etiology.
Polymorphisms, Biallelic Markers And Polynucleotides Comprising Them
Polynucleotides of the present invention
In one aspect, the invention concerns biallelic markers associated with
schizophrenia.
The invention comprises chromosome 13q31-q33-related biallelic markers, region
D-related
biallelic markers, sbgl-related biallelic markers, g34665-related biallelic
markers, sbg2-related
biallelic markers, g35017-related biallelic markers and g35018-related
biallelic markers. The
markers and polymorphisms are generally referred to herein as Al, A2, A3 and
so on. The
polymorphisms and biallelic markers of the invention comprise the biallelic
markers designated
A1 to A360 in Table 6b. The polymorphisms of the invention also comprise the
polymorphisms
designated A361 to A489 in Table 6c. Also included are biallelic markers in
linkage
disequilibrium with the biallelic markers of the invention.
Details of chromosome 13q31-q33-related biallelic markers on the subregions
designated Region D including subregions thereof designated Regions Dl, D2 ,D3
and D4, and
adjacent regions referred to as Region E and Region G are shown below and in
Tables 6B and
6c. Regions D, G and E of the chromosome 13q31-q33 locus are also shown in
Figure 2.
References to the corresponding SEQ ID number, to alternative marker
designations, and
positions of the sequence features within the SEQ ID are given in Tables 6b
and 6c for biallelic
markers A1 to A242 and 361 to 489 located in Region D3 and D4. Further
biallelic markers
from the group designated A243 to A360 in Tables 6b and 6c are located in
Regions D1, D2, G
and E. The relative positions of biallelic markers on Region G and E are
further detailed below
in Table Sg; the relative positions of biallelic markers on Region D1 and D2
are further detailed
87
more particularly in the case when
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below in Table 5h.
Table Sg
BiallelicRegion E biallelicPosition BiallelicRegion G Position
marker markers on markerbiallelic on contig
contig markers
A311 99-26171-71 20778 A359 99-27912-272153458
A333 99-26173-470 22456 A322 99-26234-336210058
A308 99-26166-257 24731 A267 99-15672-166266449
A310 99-26169-211 31620 A283 99-25917-115268222
A312 99-26183-156 35869 A266 99-15668-139278427
A309 99-26167-278 43220 A282 99-25906-131291272
A78 99-20978-89 51405 A265 99-15665-398306920
A275 99-20983-48 65076 A264 99-15664-185311251
A272 99-20977-72 70519 A268 99-15682-318315770
A274 99-20981-300 94914 A271 99-20933-81 342868
A327 99-6080-99 134366 A323 99-26238-186347179
A325 99-5912-49 149345 A302 99-26146-264349864
A252 99-15229-412 154582 A321 99-26233-275362053
A276 99-22310-148 161605 A279 99-25869-182362236
A254 99-15232-291 162153 A317 99-26222-149391049
A247 99-14021-108 164660 A301 99-26138-193400078
A300 99-26126-498 170445 A318 99-26223-225405361
A329 99-7337-204 198083 A319 99-26225-148416529
A243 8-94-252 206618 A284 99-25924-215421281
A253 99-15231-219 212050 A320 99-26228-172427201
A246 8-98-68 213871 A280 99-25881-275435974
A245 8-97-98 215017 A281 99-25897-264440452
A326 99-6012-220 216597 A337 99-26769-256471739
A255 99-15239-377 223699 A338 99-26772-268483511
A244 8-95-43 236882 A339 99-26776-209494003
A328 99-7308-157 239008 A340 99-26779-437505947
A248 99-14364-415 255729 A341 99-26781-25 514635
A342 99-26782-300516212
A343 99-26783-81 519187
A344 99-26787-96 529412
A345 99-26789-201540145
A316 99-26201-267584018
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A315 99-26191-58 601044
A314 99-26190-20 602591
A313 99-26189-164603145
A277 99-25029-241727473
A336 99-26559-315740802
Table Sh
BiallelicRegion Dl biallelicPosition BiallelicRegion D2 Position
marker markers on markerbiallelic on contig
contig markers
A357 99-27365/421 48742 A304 99-26150/276168065
A356 99-27361/181 54932 A307 99-26156/290173255
A257 99-15253/382 56599 A306 99-26154/107175557
A355 99-27360/142 57371 A305 99-26153/44 177194
A251 99-15065/85 61002 A298 99-25985/194186447
A346 99-27297/280 61855 A292 99-25974/143190018
A262 99-15355/150 62749 A335 99-26284/394193065
A324 99-5873/159 64700 A303 99-26147/396196922
A261 99-15280/432 76977 A285 99-25950/121205288
A347 99-27306/108 92355 A294 99-25978/166215025
A249 99-15056/99 93854 A293 99-25977/311216394
A258 99-15256/392 98336 A291 99-25972/317224712
A349 99-27323/372 100260 A297 99-25984/312230966
A260 99-15261/202 101114 A287 99-25965/399236799
A250 99-15063/155 105587 A286 99-25961/376244955
A259 99-15258/337 110395 A288 99-25966/241254680
A348 99-27312/58 117521 A350 99-27335/19125486
A351 99-27345/189 134904 A289 99-25967/57 257662
A352 99-27349/267 138974 A290 99-25969/200261166
A353 99-27352/197 141065 A296 99-25980/173261957
A354 99-27353/105 141494 A295 99-25979/93 263848
A299 99-25989/398269515
A334 99-26267/524275710
The polynucleotide of the invention may consist of, consist essentially of, or
comprise a
contiguous span of nucleotides of a sequence from any of SEQ ID Nos. 1 to 26,
36 to 40 and 54
to 229 as well as sequences which are complementary thereto ("complements
thereof'). The
"contiguous span" may be at least 8, 10, 12, 15, 18, 20, 25, 35, 40, 50, 70,
80, 100, 250, 500,
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1000 or 2000 nucleotides in length, to the extent that a contiguous span of
these lengths is
consistent with the lengths of the particular Sequence ID.
The present invention encompasses polynucleotides for use as primers and
probes in the
methods of the invention. These polynucleotides may consist of, consist
essentially of, or
comprise a contiguous span of nucleotides of a sequence from any of SEQ ID
Nos. 1 to 26, 36
to 40 and 54 to 229 as well as sequences which are complementary thereto
("complements
thereof'). The "contiguous span" may be at least 8, 10, 12, 15, 18, 20, 25,
35, 40, 50, 70, 80,
100, 250, 500 , 1000 or 2000 nucleotides in length, to the extent that a
contiguous span of these
lengths is consistent with the lengths of the particular Sequence ID. It
should be noted that the
polynucleotides of the present invention are not limited to having the exact
flanking sequences
surrounding the polymorphic bases which, are enumerated in the Sequence
Listing. Rather, it
will be appreciated that the flanking sequences surrounding the biallelic
markers and other
polymorphisms of the invention, or any of the primers of probes of the
invention which, are
more distant from the markers, may be lengthened or shortened to any extent
compatible with
their intended use and the present invention specifically contemplates such
sequences. It will be
appreciated that the polynucleotides of SEQ ID Nos. 1 to 26, 36 to 40 and 54
to 229 may be of
any length compatible with their intended use. Also the flanking regions
outside of the
contiguous span need not be homologous to native flanking sequences which
actually occur in
human subjects. The addition of any nucleotide sequence, which is compatible
with the
nucleotides intended use is specifically contemplated. The contiguous span may
optionally
include the biallelic markers of the invention in said sequence. Biallelic
markers generally
comprise a polymorphism at one single base position. Each biallelic marker
therefore
corresponds to two forms of a polynucleotide sequence which, when compared
with one
another, present a nucleotide modification at one position. Usually, the
nucleotide modification
involves the substitution of one nucleotide for another. Optionally allele 1
or allele 2 of the
biallelic markers disclosed in Table 6b may be specified as being present at
the biallelic marker
of the invention. The contiguous span may optionally include a nucleotide at a
polymorphism
position described in Table 6c, including single nucleotide substitutions,
deletions as well as
multiple nucleotide deletions. The polymorphisms of Table 6c have not been
validated as
biallelic markers, but are expected to be mostly biallelic and may also be
referred to as biallelic
markers herein. Optionally, allele 1 or allele 2 of the polymorphisms of Table
6c may be
specified as being present at the polymorphism of the invention. Preferred
polynucleotides may
consist of, consist essentially of, or comprise a contiguous span of
nucleotides of a sequence
from SEQ ID Nos. I to 26, 36 to 40 and 54 to 229 as well as sequences which
are
complementary thereto. The "contiguous span" may be at least 8, 10, 12, 15,
18, 20, 25, 35, 40,
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50, 70, 80, 100, 250, 500, 1000 or 2000 nucleotides in length, to the extent
that a contiguous
span of these lengths is consistent with the lengths of the particular
Sequence ID.
A preferred probe or primer comprises a nucleic acid comprising a
polynucleotide
selected from the group of the nucleotide sequences of P 1 to P360 and the
complementary
sequence thereto, B 1 to B229, C 1 to C229, D 1 to D360, E 1 to E360.
The invention also relates to polynucleotides that hybridize, under conditions
of high or
intermediate stringency, to a polynucleotide of any of SEQ ID Nos. 1 to 26, 36
to 40 and 54 to
229 as well as sequences, which are complementary thereto. Preferably such
polynucleotides
are at least 20, 25, 35, 40, 50, 70, 80, 100, 250, 500 , 1000 or 2000
nucleotides in length, to the
extent that a polynucleotide of these lengths is consistent with the lengths
of the particular
Sequence 1D. Preferred polynucleotides comprise a polymorphism of the
invention. Optionally
either allele 1 or allele 2 of the polymorphism disclosed in Table 6c may be
specified as being
present at the polymorphism of the invention. Particularly preferred
polynucleotides comprise a
biallelic marker of the invention. Optionally either allele 1 or allele 2 of
the biallelic markers
disclosed in Table 6b may be specified as being present at the biallelic
marker of the invention.
Conditions of high stringency are further described herein.
The primers of the present invention may be designed from the disclosed
sequences for
any method known in the art. A preferred set of primers is fashioned such that
the 3' end of the
contiguous span of identity with the sequences of any of SEQ ID Nos. 1 to 26,
36 to 40 and 54
. to 229 is present at the 3' end of the primer. Such a configuration allows
the 3' end of the
primer to hybridize to a selected nucleic acid sequence and dramatically
increases the efficiency
of the primer for amplification or sequencing reactions. In a preferred set of
primers the
contiguous span is found in one of the sequences described in Table 6a. Allele
specific primers
may be designed such that a biallelic marker or other polymorphism of the
invention is at the 3'
end of the contiguous span and the contiguous span is present at the 3' end of
the primer. Such
allele specific primers tend to selectively prime an amplification or
sequencing reaction so long
as they are used with a nucleic acid sample that contains one of the two
alleles present at said
marker. The 3' end of primer of the invention may be located within or at
least 2, 4, 6, 8, 10,
12, 15, 18, 20, 25, 50, 100, 250, 500, or 1000 nucleotides upstream of a
biallelic marker of the
invention in said sequence or at any other location which is appropriate for
their intended use in
sequencing, amplification or the location of novel sequences or markers.
Primers with their 3'
ends located 1 nucleotide upstream of an biallelic marker of the invention
have a special utility
as microsequencing assays. Preferred microsequencing primers are described in
Table 6d.
The probes of the present invention may be designed from the disclosed
sequences for
any method known in the art, particularly methods which allow for testing if a
particular
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sequence or marker disclosed herein is present. A preferred set of probes may
be designed for
use in the hybridization assays of the invention in any manner known in the
art such that they
selectively bind to one allele of a biallelic marker or other polymorphism,
but not the other
under any particular set of assay conditions. Preferred hybridization probes
may consists of,
consist essentially of, or comprise a contiguous span which ranges in length
from 8, 10, 12, 15,
18 or 20 to 25, 35, 40, 50, 60, 70, or 80 nucleotides, or be specified as
being 12, 15, 18, 20, 25,
35, 40, or 50 nucleotides in length and including an biallelic marker or other
polymorphism of
the invention in said sequence. In a preferred embodiment, either of allele 1
or 2 disclosed in
Table 6b or 6c may be specified as being present at the biallelic marker site.
In another
preferred embodiment, said biallelic marker may be within 6, 5, 4, 3, 2, or 1
nucleotides of the
center of the hybridization probe or at the center of said probe.
In one embodiment the invention encompasses isolated, purified, and
recombinant
polynucleotides comprising, consisting of, or consisting essentially of a
contiguous span o.f 8 to
50 nucleotides of any one of SEQ ID Nos 1 to 26, 36 to 40 and 54 to 229 and
the complement
thereof, wherein said span includes a polymorphism of the invention, a
chromosome 13q31-
q33-related biallelic marker, region D-related biallelic marker, or sbgl-,
834665-, sbg2-,
835017- or 835018 -related biallelic marker in said sequence; optionally,
wherein said
polymorphism, chromosome 13q31-q33-related biallelic marker, region D-related
biallelic
marker, or sbgl-, 834665-, sbg2-, 835017- or 835018 -related biallelic marker
selected from the
group consisting of A 1 to A489, and the complements thereof, or optionally
the biallelic
markers in linkage disequilibrium therewith; optionally, wherein said
chromosome 13q31-q33-
related biallelic marker, region D-related biallelic marker, or sbgl-, 834665-
, sbg2-, 835017- or
835018 -related biallelic marker is selected from the group consisting of A1
to A69, A71 to
A74, A76 to A94, A96 to A 106, A 108 to A 112, A 114 to A 177, A 179 to A 197,
A 199 to A222,
A224 to A246, A250, A251, A253, A255, A259, A266, A268 to A232, A328 to 489;
optionally,
wherein said chromosome 13q31-q33-related biallelic marker, region D-related
biallelic marker,
sbgl-, 834665-, sbg2-, 835017- or 835018 -related biallelic marker is selected
from the group
consisting of A 1 to A69, A71 to A74, A76 to A94, A96 to A 106, A 108 to A
112, A 114 to A I 77,
A179 to A197, A199 to A222, A224 to A242 and 361 to 489, and the complements
thereof, or
optionally the biallelic markers in linkage disequilibrium therewith;
optionally, wherein said
chromosome 13q31-q33-related biallelic marker, region D-related biallelic
marker, or sbgl-,
834665-, sbg2-, 835017- or 835018 -related biallelic marker is selected from
the group
consisting of A 1 to A69, A71 to A74, A76 to A94, A96 to A 106, A 108 to A
112, A 114 to A 177,
A179 to A197, A199 to A222, A224 to A242, A250 to A251, A259 , A269 to A270,
A278,
A285 to A299, A303 to A307, A330, A334 to A335 and A346 to 357 and and 361 to
489, and
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the complements thereof, or optionally the biallelic markers in linkage
disequilibrium therewith;
optionally, wherein said contiguous span is 18 to 35 nucleotides in length and
said biallelic
marker is within 4 nucleotides of the center of said polynucleotide;
optionally, wherein said
polynucleotide consists of said contiguous span and said contiguous span is 25
nucleotides in
length and said biallelic marker is at the center of said polynucleotide;
optionally, wherein the
3' end of said contiguous span is present at the 3' end of said
polynucleotide; and optionally,
wherein the 3' end of said contiguous span is located at the 3' end of said
polynucleotide and
said biallelic marker is present at the 3' end of said polynucleotide. In a
preferred embodiment,
said probes comprise, consists of, or consists essentially of a sequence
selected from the
following sequences: P1 to P360 and the complementary sequences thereto.
In another embodiment the invention encompasses isolated, purified and
recombinant
polynucleotides comprising, consisting of, or consisting essentially of a
contiguous span of 8 to
50 nucleotides of any one of SEQ ID Nos 1 to 26, 36 to 40 and 54 to 229, or
the complement
thereof, wherein the 3' end of said contiguous span is located at the 3' end
of said
polynucleotide, and wherein the 3' end of said polynucleotide is located
within 20 nucleotides
upstream of a polymorphism of the invention, chromosome 13q31-q33-related
biallelic marker,
region D-related biallelic marker, or sbgl-, g34665-, sbg2-, g35017- or g35018
-related biallelic
marker in said sequence; optionally, wherein said chromosome 13q31-q33-related
biallelic
marker, region D-related biallelic marker, or sbgl-, g34665-, sbg2-, g35017-
or g35018 -related
biallelic marker is selected from the group consisting of A1 to A489, and the
complements
thereof, or optionally the biallelic markers in linkage disequilibrium
therewith; optionally,
wherein said a chromosome 13q31-q33-related biallelic marker, region D-related
biallelic
marker, or sbgl-, g34665-, sbg2-, g35017- or g35018 -related biallelic marker
is selected from
the group consisting of A1 to A69, A71 to A74, A76 to A94, A96 to A106, A108
to Al 12,
A114 to A177, A179 to A197, A199 to A222, A224 to A246, A250, A251, A253,
A255, A259,
A266, A268 to A232, A328 to A360, and and 361 to 489, and the complements
thereof, or
optionally the biallelic markers in linkage disequilibrium therewith;
optionally, wherein said
chromosome 13q31-q33-related biallelic marker, region D-related biallelic
marker, or sbgl-,
g34665-, sbg2-, g35017- or g35018 -related biallelic marker is selected from
the group
consisting ofAl to A69, A71 to A74, A76 to A94, A96 to A106, A108 to A112,
A114 to A177,
A179 to A197, A199 to A222, A224 to A242 and 361 to 489; optionally, wherein
said
chromosome 13q31-q33-related biallelic marker, region D-related biallelic
marker, or sbgl-,
g34665-, sbg2-, g35017- or g35018 -related biallelic marker is selected from
the group
consisting of optionally, wherein said chromosome 13q31-q33-related biallelic
marker, region
D-related biallelic marker, or sbgl-, g34665-, sbg2-, g35017- or g35018 -
related biallelic
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marker is selected from the group consisting of AI to A69, A71 to A74, A76 to
A94, A96 to
A 106, A 108 to A 1 I 2, A 114 to A 177, A 179 to A 197, A I 99 to A222, A224
to A242, A250 to
A251, A259 , A269 to A270, A278, A285 to A299, A303 to A307, A330, A334 to
A335, A346
to 357 and 361 to 489, and the complements thereof, or optionally the
biallelic markers in
5 linkage disequilibrium therewith; optionally, wherein the 3' end of said
polynucleotide is
located I nucleotide upstream of said chromosome 13q31-q33-related biallelic
marker, region
D-related biallelic marker, or sbgl-, g34665-, sbg2-, g35017- or g35018 -
related biallelic
marker; and optionally, wherein said polynucleotide comprises, consists of, or
consists
essentially of a sequence selected from the following sequences: D1 to D360
and E1 to E360.
10 In a further embodiment, the invention encompasses isolated, purified, or
recombinant
polynucleotides comprising, consisting of, or consisting essentially of a
sequence selected from
the following sequences: B 1 to B229 and C 1 to C229.
In an additional embodiment, the invention encompasses polynucleotides for use
in
hybridization assays, sequencing assays, and enzyme-based mismatch detection
assays for
1 S determining the identity of the nucleotide at a chromosome 13q31-q33-
related biallelic marker,
region D-related biallelic marker, or sbgl-, g34665-, sbg2-, g35017- or g35018
-related biallelic
marker in any of SEQ ID Nos. 1 to 26, 36 to 40 and 54 to 229 or the complement
thereof, as
well as polynucleotides for use in amplifying segments of nucleotides
comprising a
polymophism of the invention, a chromosome 13q31-q33-related biallelic marker,
region D-
20 related biallelic marker, or sbgl-, g34665-, sbg2-, g35017- or g35018 -
related biallelic marker
iri any of SEQ ID Nos 1 to 26, 36 to 40 and 54 to 229 or the complement
thereof; optionally,
wherein said chromosome 13q31-q33-related biallelic marker, region D-related
biallelic marker,
or sbgl-, g34665-, sbg2-, g35017- or g35018 -related biallelic marker is
selected from the group
consisting of AI to A489, and the complements thereof, or optionally the
biallelic markers in
25 linkage disequilibrium therewith; optionally, wherein said chromosome 13q31-
q33-related
biallelic marker, region D-related biallelic marker, or sbgl-, g34665-, sbg2-,
g35017- or g35018.
-related biallelic marker is selected from the group consisting of A1 to A69,
A71 to A74, A76 to
A94, A96 to A 106, A 108 to A 112, A 114 to A 177, A 179 to A 197, A 199 to
A222, A224 to
A246, A250, A251, A253, A255, A259, A266, A268 to A232, A328 to A360 and 361
to 489,
30 and the complements thereof, or optionally the biallelic markers in linkage
disequilibrium
therewith; optionally, wherein chromosome 13q31-q33-related biallelic marker,
region D-
related biallelic marker, or sbgl-, g34665-, sbg2-, g35017- or g35018 -related
biallelic marker is
selected from the group consisting of A1 to A69, A71 to A74, A76 to A94, A96
to A106, A108
to A112, A114 to A177, A179 to A197, A199 to A222, A224 to A242, A250 to A251,
A259 ,
35 A269 to A270, A278, A285 to A299, A303 to A307, A330, A334 to A335 and A346
to 357 and
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361 to 489, and the complements thereof, or optionally the biallelic markers
in linkage
disequilibrium therewith; and optionally, wherein chromosome 13q31-q33-related
biallelic
marker, region D-related biallelic marker, or sbgl-, g34665-, sbg2-, g35017-
or g35018 -related
biallelic marker is selected from the group consisting of A1 to A69, A71 to
A74, A76 to A94,
A96 to A 106, A 108 to A 112, A 114 to A 177, A 179 to A 197, A 199 to A222,
A224 to A242 and
361 to 489, and the complements thereof, or optionally the biallelic markers
in linkage
disequilibrium therewith.
These arrays may generally be produced using mechanical synthesis methods or
light
directed synthesis methods, which incorporate a combination of
photolithographic methods and
solid phase oligonucleotide synthesis (Fodor et al., Science, 251:767-777,
1991). The
immobilization of arrays of oligonucleotides on solid supports has been
rendered possible.by
the development of a technology generally identified as "Very Large Scale
Immobilized
Polymer Synthesis" (VLSIPSTM) in which, typically, probes are immobilized in a
high density
array on a solid surface of a chip. Examples of VLSIPSTM technologies are
provided in US
Patents 5,143,854 and 5,412,087 and in PCT Publications WO 90/15070, WO
92/10092 and
WO 95/11995, which describe methods for forming oligonucleotide arrays through
techniques
such as light-directed synthesis technique. In designing strategies aimed at
providing arrays of
nucleotides immobilized on solid supports, further presentation strategies
were developed to
order and display the oligonucleotide arrays on the chips in an attempt to
maximize
hybridization patterns and sequence information. Examples of such presentation
strategies are
disclosed in PCT Publications WO 94/12305, WO 94/11530, WO 97/29212 and WO
97/31256.
Oligonucleotide arrays may comprise at least one of the sequences selected
from the
group consisting of SEQ ID Nos. 1 to 26, 36 to 40 and 54 to 229; and the
sequences
complementary thereto or a fragment thereof of at least 8, 10, 12, 1 S, 18,
20, 25, 35, 40, 50, 70,
80, 100, 250, 500 , 1000 or 2000 consecutive nucleotides, to the extent that
fragments of these
lengths is consistent with the lengths of the particular Sequence ID, for
determining whether a
sample contains one or more alleles of the biallelic markers of the present
invention..
Oligonucleotide arrays may also comprise at least one of the sequences
selected from the group
consisting of SEQ ID Nos. 1 to 26, 36 to 40 and 54 to 229; and the sequences
complementary
thereto or a fragment thereof of at least 8, 10, 12, 15, 18, 20, 25, 35, 40,
50, 70, 80, 100, 250,
500 , 1000 or 2000 consecutive nucleotides, to the extent that fragments of
these lengths is
consistent with the lengths of the particular Sequence ID, for amplifying one
or more alleles of
the biallelic markers of Table 6b or polymorphisms of Table 6c. In other
embodiments, arrays
may also comprise at least one of the sequences selected from the group
consisting of SEQ ID
Nos. 1 to 26, 36 to 40 and 54 to 229; and the sequences complementary thereto
or a fragment
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thereof of at least 8, 10, 12, 15, 18, 20, 25, 35, 40, 50, 70, 80, 100, 250,
500 , 1000 or 2000
consecutive nucleotides, to the extent that fragments of these lengths is
consistent with the
lengths of the particular Sequence ID, for conducting microsequencing analyses
to determine
whether a sample contains one or more alleles of the biallelic markers of the
invention. In still
further embodiments, the oligonucleotide array may comprise at least one of
the sequences
selecting from the group consisting of SEQ ID Nos. 1 to 26, 36 to 40 and 54 to
229; and the
sequences complementary thereto or a fragment thereof of at least 8, 10, 12,
15, 18, 20, 25, 35,
40, 50, 70, 80, 100, 250, 500 , 1000 or 2000 nucleotides in length, to the
extent that fragments
of these lengths is consistent with the lengths of the particular Sequence ID,
for determining
whether a sample contains one or more alleles of the polymorphisms and
biallelic markers of
the present invention.
A further object of the invention relates to an array of nucleic acid
sequences
comprising either at least one of the sequences selected from the group
consisting of P1 to
P360, B1 to B229, C1 to C229, D1 to D360 E1 to E360 or the sequences
complementary thereto
or a fragment thereof of at least 8, 10, 12, 15, 18, 20, 25, 30, or 40
consecutive nucleotides
thereof, or at least one sequence comprising at least 1, 2, 3, 4, 5, 10, 20
biallelic markers
selected from the group consisting of A1 to A489 or the complements thereof.
The invention
also pertains to an array of nucleic acid sequences comprising either at least
1, 2, 3, 4, 5, 10, 20
of the sequences selected from the group consisting of P 1 to P360, B 1 to
B229, C 1 to C229, D 1
to D360, E1 to E360 or the sequences complementary thereto or a fragment
thereof of at least 8
consecutive nucleotides thereof, or at least two sequences comprising a
biallclic marker selected
from the group consisting of A 1 to A360 or the complements thereto.
The present invention also encompasses diagnostic kits comprising one or more
polynucleotides of the invention, optionally with a portion or all of the
necessary reagents and
instructions for genotyping a test subject by determining the identity of a
nucleotide at an
biallelic marker of the invention. The polynucleotides of a kit may optionally
be attached to a
solid support, or be part of an array or addressable array of polynucleotides.
The kit may
provide for the determination of the identity of the nucleotide at a marker
position by any
method known in the art including, but not limited to, a sequencing assay
method, a
microsequencing assay method, a hybridization assay method, or enzyme-based
mismatch
detection assay. Optionally such a kit may include instructions for scoring
the results of the
determination with respect to the test subjects' predisposition to
schizophrenia, or likely
response to an agent acting on schizophrenia, or chances of suffering from
side effects to an
agent acting on schizophrenia.
Finally, in any embodiments of the present invention, a biallelic marker may
may
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optionally comprise:
(a) a biallelic marker selected from the group consisting of sbgl-related
markers A85 to
A219, or more preferably a biallelic marker selected from the group consisting
of sbgl-related
markers A85 to A94, A96 to A 106, A I 08 to A 112, A 114 to A 177, A 179 to A
197 and A 199 to
A219;
(b) a biallelic marker selected from the group consisting of g34665-related
markers
A230 to A236;
(c) a biallelic marker selected from the group consisting of sbg2-related
markers A79 to
A99;
(d) the g35017-related marker A41;
(e) a biallelic marker selected from the group consisting of g35018-related
markers A1
to A39;
(f) a biallelic marker selected from the group consisting of A239, A227, A198,
A228,
A223, A 107, A218, A270, A75, A62, A65 and A70;
(g) a biallelic marker selected from the group consisting of A48, A60, A61,
A62, A65,
A70, A75, A76, A80, A107, A108, A198, A218, A221, A223, A227, A228, A239,
A285,
A286, A287, A288, A290, A292, A293, A295,A299 and A304;
(h) a biallelic marker selected from the group consisting of A304, A307, A305,
A298,
A292, A293, A291, A287, A286, A288, A289, A290, 99- A295 A299. A241, A239,
A228,
A227, A223, A221, A218, A 198, A 178, 99-24649/ 186 A 108, A 107, A80, A75,
A70, A65, and
A62; and/or
(i) a biallelic marker selected from the group consisting of A304, A307, A305,
A298,
A292, A293, A291, A287, A286, A288, A289, A290, A295 A299, A241, A239, A228,
A227,
A223, A221, A218, A198, A178, A108, A107, A80, A76, A75, A70, A65, A62, A61,
A60
A48.
Optionally, in any of the embodiments described herein, a Region D- or
chromosome
13q31-q33-related biallelic marker may be selected from the group consisting
of A1 to A69,
A71 to A74, A76 to A94, A96 to A 106, A 108 to A 112, A 114 to A 177, A 179 to
A 197, A 199 to
A222, A224 to A242, A250 to A251, A259, A269 to A270, A278, A285 to A299, A303
to
A307, A330, A334 to A335, A346 to 357 and 361 to 489. Optionally, in any of
the
embodiments described herein, a chromosome 13q31-q33-related biallelic marker
may be
selected from the group consisting of A 1 to A69, A71 to A74, A76 to A94, A96
to A106, A 108
to Al 12, A114 to A177, A179 to A197, A199 to A222, A224 to A246, A250, A251,
A253,
A255, A259, A266, A268 to A232 and A328 to A489. A set of said Region D-
related biallelic
markers or chromosome 13q31-q33-related biallelic markers may comprise at
least 1, 2, 3, 4, 5,
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10, 20, 40, 50, 100 or 200 of said biallelic markers, respectively.
Optionally, any of the compositions of methods described herein may
specifically
exclude at least 1, 2, 3, 4, 5, 10, 20 biallelic markers, or all ofthe
biallelic markers selected from
the group consisting of: A70, A75, A95, A107, A113, A178, A198, A223, A247 to
A249, A252,
A254, A256 to A258, A260 to A265, A267, A324 to A328.
Furthermore, in any of the embodiments of the present invention, a set of
chromosome
13q31-q33-related biallelic markers, Region D-related biallelic markers, or
sbgl-, g34665-,
sbg2-, g35017- or g35018 -related biallelic markers may comprise at least 1,
2, 3, 4, 5, 10, 20,
40, 50, 100 or 200 of said biallelic markers.
Methods For De Novo Identification Of Biallelic Markers
Any of a variety of methods can be used to screen a genomic fragment for
single
nucleotide polymorphisms such as differential hybridization with
oligonucleotide probes,
detection of changes in the mobility measured by gel electrophoresis or direct
sequencing of the
amplified nucleic acid. A preferred method for identifying biallelic markers
involves
comparative sequencing of genomic DNA fragments from an appropriate number of
unrelated
individuals.
In a first embodiment, DNA samples from unrelated individuals are pooled
together,
following which the genomic DNA of interest is amplified and sequenced. The
nucleotide
sequences thus obtained are then analyzed to identify significant
polymorphisms. One of the
major advantages of this method resides in the fact that the pooling of the
DNA samples
substantially reduces the number of DNA amplification reactions and sequencing
reactions,
which must be carried out. Moreover, this method is sufficiently sensitive so
that a biallelic
marker obtained thereby usually demonstrates a sufficient frequency of its
less common allele
to be useful in conducting association studies. Usually, the frequency of the
least common
allele of a biallelic marker identified by this method is at least 10%.
In a second embodiment, the DNA samples are not pooled and are therefore
amplified
and sequenced individually. This method is usually preferred when biallelic
markers need to be
identified in order to perform association studies within candidate genes.
Preferably, highly
relevant gene regions such as promoter regions or exon regions may be screened
for biallelic
markers. A biallelic marker obtained using this method may show a lower degree
of
informativeness for conducting association studies, e.g. if the frequency of
its less frequent
allele may be less than about 10%. Such a biallelic marker will however be
sufficiently
informative to conduct association studies and it will further be appreciated
that including less
informative biallelic markers in the genetic analysis studies of the present
invention, may allow
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in some cases the direct identification of causal mutations, which may,
depending on their
penetrance, be rare mutations.
The following is a description of the various parameters of a preferred method
used by
the inventors for the identification of the biallelic markers of the present
invention.
Genomic DNA samples
The genomic DNA samples from which the biallelic markers of the present
invention
are generated are preferably obtained from unrelated individuals corresponding
to a
heterogeneous population of known ethnic background. The number of individuals
from whom
DNA samples are obtained can vary substantially, preferably from about 10 to
about 1000, more
preferably from about SO to about 200 individuals. Usually, DNA samples are
collected from at
least about 100 individuals in order to have sufficient polymorphic diversity
in a given
population to identify as many markers as possible and to generate
statistically significant
results.
As for the source of the genomic DNA to be subjected to analysis, any test
sample can
be foreseen without any particular limitation. These test samples include
biological samples,
which can be tested by the methods of the present invention described herein,
and include
human and animal body fluids such as whole blood, serum, plasma, cerebrospinal
fluid, urine,
lymph fluids, and various external secretions ofthe respiratory, intestinal
and genitourinary
tracts, tears, saliva, milk, white blood cells, myelomas and the like;
biological fluids such as cell
culture supernatants; fixed tissue specimens including tumor and non-tumor
tissue and lymph
node tissues; bone marrow aspirates and fixed cell specimens. The preferred
source of genomic
DNA used in the present invention is from peripheral venous blood of each
donor. Techniques
to prepare genomic DNA from biological samples are well known to the skilled
technician.
Details of a preferred embodiment are provided in Example 1. The person
skilled in the art can
choose to amplify pooled or unpooled DNA samples.
DNA Amulification
The identification of biallelic markers in a sample of genomic DNA may be
facilitated
through the use of DNA amplification methods. DNA samples can be pooled or
unpooled for
the amplification step. DNA amplification techniques are well known to those
skilled in the art.
Various methods to amplify DNA fragments carrying biallelic markers are
further described
hereinafter herein. The PCR technology is the preferred amplification
technique used to
identify new biallelic markers.
In a first embodiment, biallelic markers are identified using genomic sequence
information generated by the inventors. Genomic DNA fragments, such as the
inserts of the
BAC clones described above, are sequenced and used to design primers for the
amplification of
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500 by fragments. These S00 by fragments are amplified from genomic DNA and
are scanned
for biallelic markers. Primers may be designed using the OSP software (Hillier
L. and Green
P., 1991 ). All primers may contain, upstream of the specific target bases, a
common
oligonucleotide tail that serves as a sequencing primer. Those skilled in the
art are familiar with
primer extensions, which can be used for these purposes.
In another embodiment of the invention, genomic sequences of candidate genes
are
available in public databases allowing direct screening for biallelic markers.
Preferred primers,
useful for the amplification of genomic sequences encoding the candidate
genes, focus on
promoters, exons and splice sites of the genes. A biallelic marker present in
these functional
regions of the gene have a higher probability to be a causal mutation.
SeQUencin~ Of Amplified Genomic DNA And Identification Of Single Nucleotide
Polymorphisms
The amplification products generated as described above, are then sequenced
using any
method known and available to the skilled technician. Methods for sequencing
DNA using
either the dideoxy-mediated method (Sanger method) or the Maxam-Gilbert method
are widely
known to those of ordinary skill in the art. Such methods are for example
disclosed in Maniatis
et al. (Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press,
Second Edition,
1989). Alternative approaches include hybridization to high-density DNA probe
arrays as
described in Chee et al. (Science 274, 610, 1996).
Preferably, the amplified DNA is subjected to automated dideoxy terminator
sequencing reactions using a dye-primer cycle sequencing protocol. The
products of the
sequencing reactions are run on sequencing gels and the sequences are
determined using gel
image analysis. The polymorphism search is based on the presence of
superimposed peaks in
the electrophoresis pattern resulting from different bases occurring at the
same position.
Because each dideoxy terminator is labeled with a different fluorescent
molecule, the two peaks
corresponding to a biallelic site present distinct colors corresponding to two
different
nucleotides at the same position on the sequence. However, the presence of two
peaks can be
an artifact due to background noise. To exclude such an artifact, the two DNA
strands are
sequenced and a comparison between the peaks is carried out. In order to be
registered as a
polymorphic sequence, the polymorphism has to be detected on both strands.
The above procedure permits those amplification products, which contain
biallelic
markers to be identified. The detection limit for the frequency of biallelic
polymorphisms
detected by sequencing pools of 100 individuals is approximately 0.1 for the
minor allele, as
verified by sequencing pools of known allelic frequencies. However, more than
90% of the
biallelic polymorphisms detected by the pooling method have a frequency for
the minor allele
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higher than 0.25. Therefore, the biallelic markers selected by this method
have a frequency of
at least 0.1 for the minor allele and less than 0.9 for the major allele.
Preferably at least 0.2 for
the minor allele and less than 0.8 for the major allele, more preferably at
least 0.3 for the minor
allele and less than 0.7 for the major allele, thus a heterozygosity rate
higher than 0.18,
preferably higher than 0.32, more preferably higher than 0.42.
In another embodiment, biallelic markers are detected by sequencing individual
DNA
samples, the frequency of the minor allele of such a biallelic marker may be
less than 0.1.
Validation of the biallelic markers of the uresent invention
The polymorphisms are evaluated for their usefulness as genetic markers by
validating
that both alleles are present in a population. Validation of the biallelic
markers is accomplished
by genotyping a group of individuals by a method of the invention and
demonstrating that both
alleles are present. Microsequencing is a preferred method of genotyping
alleles. The
validation by genotyping step may be performed on individual samples derived
from each
individual in the group or by genotyping a pooled sample derived from more
than one
individual. The group can be as small as one individual if that individual is
heterozygous for
the allele in question. Preferably the group contains at least three
individuals, more preferably
the group contains five or six individuals, so that a single validation test
will be more likely to
result in the validation of more of the biallelic markers that are being
tested. It should be noted,
however, that when the validation test is performed on a small group it may
result in a false
negative result if as a result of sampl ing error none of the individuals
tested carries one of the
two alleles. Thus, the validation process is less useful in demonstrating that
a particular initial
result is an artifact, than it is at demonstrating that there is a bona fide
biallelic marker at a
particular position in a sequence. All of the genotyping, haplotyping,
association, and
interaction study methods of the invention may optionally be performed solely
with validated
biallelic markers.
Evaluation of the freguency of the biallelic markers of the present invention
The validated biallelic markers are further evaluated for their usefulness as
genetic
markers by determining the frequency of the least common allele at the
biallelic marker site.
The determination of the least common allele is accomplished by genotyping a
group of
individuals by a method of the invention and demonstrating that both alleles
are present. This
determination of frequency by genotyping step may be performed on individual
samples derived
from each individual in the group or by genotyping a pooled sample derived
from more than
one individual. The group must be large enough to be representative of the
population as a
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whole. Preferably the group contains at least 20 individuals, more preferably
the group contains
at least 50 individuals, most preferably the group contains at least 100
individuals. Of course
the larger the group the greater the accuracy of the frequency determination
because of reduced
sampling error. A biallelic marker wherein the frequency of the less common
allele is 30% or
more is termed a "high quality biallelic marker." All of the genotyping,
haplotyping,
association, and interaction study methods of the invention may optionally be
performed solely
with high quality biallelic markers.
Another embodiment of the invention comprises methods of estimating the
frequency
of an allele in a population comprising genotyping individuals from said
population for a
13q31-q33-related biallelic marker and determining the proportional
representation of said
biallelic marker in said population. In addition, the methods of estimating
the frequency of an
allele in a population encompass methods with any further limitation described
in this
disclosure, or those following, specified alone or in any combination:
Optionally, said 13q31-
q33-related biallelic marker may be in a sequence selected individually or in
any combination
from the group consisting of SEQ Nos 1 to 26, 36 to 40 and 54 to 229; and the
complements
thereof; optionally, said 13q31-q33-related biallelic marker may be selected
from the biallelic
markers described in Table 6b or 6c; optionally, determining the frequency of
a biallelic marker
allele in a population may be accomplished by determining the identity of the
nucleotides for
both copies of said biallelic marker present in the genome of each individual
in said population
and calculating the proportional representation of said nucleotide at said
13q31-q33-related
biallelic marker for the population; optionally, determining the frequency of
a biallelic marker
allele in a population may be accomplished by performing a genotyping method
on a pooled
biological sample derived from a representative number of individuals, or each
individual, in
said population, and calculating the proportional amount of said nucleotide
compared with the
total.
Methods Of Genotypin~ An Individual For Biallelic Markers
Methods are provided to genotype a biological sample for one or more biallelic
markers
of the present invention, all of which may be performed in vitro. Such methods
of genotyping
comprise determining the identity of a nucleotide at an biallelic marker of
the invention by any
method known in the art. These methods find use in genotyping case-control
populations in
association studies as well as individuals in the context of detection of
alleles of biallelic
markers which, are known to be associated with a given trait, in which case
both copies of the
biallelic marker present in individual's genome are determined so that an
individual may be
classified as homozygous or heterozygous for a particular allele.
These genotyping methods can be performed nucleic acid samples derived from a
single
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individual or pooled DNA samples.
Genotyping can be performed using similar methods as those described above for
the
identification of the biallelic markers, or using other genotyping methods
such as those further
described below. In preferred embodiments, the comparison of sequences of
amplified genomic
fragments from different individuals is used to identify new biallelic markers
whereas
microsequencing is used for genotyping known biallelic markers in diagnostic
and association
study applications.
Another embodiment of the invention encompasses methods of genotyping a
biological
sample comprising determining the identity of a nucleotide at a 13q31-q33-
related biallelic
marker. In addition, the genotyping methods of the invention encompass methods
with any
further limitation described in this disclosure, or those following, specified
alone or in any
combination: Optionally, said 13q31-q33-related biallelic marker may be in a
sequence
selected individually or in any combination from the group consisting of SEQ
ID Nos 1 to 26,
36 to 40 and 54 to 229, and the complements thereof; optionally, said 13q31-
q33-related
biallelic marker may be selected individually or in any combination from the
biallelic markers
described in Table 6b and 6c; optionally, said method further comprises
determining the identity
of a second nucleotide at said biallelic marker, wherein said first nucleotide
and second
nucleotide are not base paired (by Watson & Crick base pairing) to one
another; optionally, said
biological sample is derived from a single individual or subject; optionally,
said method is
- performed in vitro; optionally, said biallelic marker is determined for both
copies of said
biallelic marker present in said individual's genome; optionally, said
biological sample is
derived from multiple subjects or individuals; optionally, said method further
comprises
amplifying a portion of said sequence comprising the biallelic marker prior to
said determining
step; optionally, wherein said amplifying is performed by PCR, LCR, or
replication of a
recombinant vector comprising an origin of replication and said portion in a
host cell;
optionally, wherein said determining is performed by a hybridization assay,
sequencing assay,
microsequencing assay, or an enzyme-based mismatch detection assay.
Source of DNA for ~enotyuin~
Any source of nucleic acids, in purified or non-purified form, can be utilized
as the
starting nucleic acid, provided it contains or is suspected of containing the
specific nucleic acid
sequence desired. DNA or RNA may be extracted from cells, tissues, body fluids
and the like
as described herein. While nucleic acids for use in the genotyping methods of
the invention can
be derived from any mammalian source, the test subjects and individuals from
which nucleic
acid samples are taken are generally understood to be human.
Amplification Of DNA Fragments ComprisinE Biallelic Markers
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Methods and polynucleotides are provided to amplify a segment of nucleotides
comprising one or more biallelic marker of the present invention. It will be
appreciated that
amplification of DNA fragments comprising biallelic markers may be used in
various methods
and for various purposes and is not restricted to genotyping. Nevertheless,
many genotyping
methods, although not all, require the previous amplification of the DNA
region carrying the
biallelic marker of interest. Such methods specifically increase the
concentration or total
number of sequences that span the biallelic marker or include that site and
sequences located
either distal or proximal to it. Diagnostic assays may also rely on
amplification of DNA
segments carrying a biallelic marker of the present invention.
Amplification of DNA may be achieved by any method known in the art. The
established PCR (polymerase chain reaction) method or by developments thereof
or
alternatives. Amplification methods which can be utilized herein include but
are not limited to
Ligase Chain Reaction (LCR) as described in EP A 320 308 and EP A 439 182, Gap
LCR
(Wolcott, M.J.), the so-called "NASBA" or "3SR" technique described in
Guatelli J.C. et al.
(1990) and in Compton J. (1991), Q-beta amplification as described in EP A
4544 610, strand
displacement amplification as described in Walker et al. (1996) and EP A 684
315 and, target
mediated amplification as described in PCT Publication WO 9322461.
LCR and Gap LCR are exponential amplification techniques, both depend on DNA
ligase to join adjacent primers annealed to a DNA molecule. In Ligase Chain
Reaction (LCR),
probe pairs are used which include two primary (first and second) and two
secondary (third and
fourth) probes, all of which are employed in molar excess to target. The first
probe hybridizes
to a first segment of the target strand and the second probe hybridizes to a
second segment of
the target strand, the first and second segments being contiguous so that the
primary probes abut
one another in 5' phosphate-3'hydroxyl relationship, and so that a ligase can
covalently fuse or
ligate the two probes into a fused product. In addition, a third (secondary)
probe can hybridize
to a portion of the first probe and a fourth (secondary) probe can hybridize
to a portion of the
second probe in a similar abutting fashion. Of course, if the target is
initially double stranded,
the secondary probes also will hybridize to the target complement in the first
instance. Once the
ligated strand of primary probes is separated from the target strand, it will
hybridize with the
third and fourth probes which can be ligated to form a complementary,
secondary ligated
product. It is important to realize that the ligated products are functionally
equivalent to either
the target or its complement. By repeated cycles of hybridization and
ligation, amplification of
the target sequence is achieved. A method for multiplex LCR has also been
described (WO
9320227). Gap LCR (GLCR) is a version of LCR where the probes are not adjacent
but are
separated by 2 to 3 bases.
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For amplification of mRNAs, it is within the scope of the present invention to
reverse
transcribe mRNA into cDNA followed by polymerase chain reaction (RT-PCR); or,
to use a
single enzyme for both steps as described in U.S. Patent No. 5,322,770 or, to
use Asymmetric
Gap LCR (RT-AGLCR) as described by Marshall R.L. et al. (1994). AGLCR is a
modification
of GLCR that allows the amplification of RNA.
Some of these amplification methods are particularly suited for the detection
of single
nucleotide polymorphisms and allow the simultaneous amplification of a target
sequence and
the identification of the polymorphic nucleotide as it is further described
herein.
The PCR technology is the preferred amplification technique used in the
present
invention. A variety of PCR techniques are familiar to those skilled in the
art. For a review of
PCR technology, see Molecular Cloning to Genetic Engineering White, B.A. Ed.
(1997) and
the publication entitled "PCR Methods and Applications" (1991, Cold Spring
Harbor
Laboratory Press). In each of these PCR procedures, PCR primers on either side
of the nucleic
acid sequences to be amplified are added to a suitably prepared nucleic acid
sample along with
1 S dNTPs and a thermostable polymerase such as Taq polymerase, Pfu
polymerase, or Vent
polymerase. The nucleic acid in the sample is denatured and the PCR primers
are specifically
hybridized to complementary nucleic acid sequences in the sample. The
hybridized primers are
extended. Thereafter, another cycle of denaturation, hybridization, and
extension is initiated.
The cycles are repeated multiple times to produce an amplified fragment
containing the nucleic
acid sequence between the primer sites. PCR has further been described in
several patents
including US Patents 4,683,195, 4,683,202 and 4,965,188.
Primers can be prepared by any suitable method. As for example, direct
chemical
synthesis by a method such as the phosphodiester method ofNarang S.A. et al.
(1979), the
phosphodiester method of Brown E.L. et al. (1979), the diethylphosphoramidite
method of
Beaucage et al. (1981) and the solid support method described in EP 0 707 592.
In some embodiments the present invention provides primers for amplifying a
DNA
fragment containing one or more biallelic markers of the present invention. It
will be
appreciated that the primers listed are merely exemplary and that any other
set of primers which
produce amplification products containing one or more biallelic markers of the
present
invention.
The spacing of the primers determines the length of the segment to be
amplified. In the
context of the present invention amplified segments carrying biallelic markers
can range in size
from at least about 25 by to 35 kbp. Amplification fragments from 25-3000 by
are typical,
fragments from 50-1000 by are preferred and fragments from 100-600 by are
highly preferred.
It will be appreciated that amplification primers for the biallelic markers
may be any sequence
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which allow the specific amplification of any DNA fragment carrying the
markers.
Amplification primers may be labeled or immobilized on a solid support as
described in the
section titled "Oligonucleotide Probes and Primers".
Methods of Genotypin~ DNA samples for Biallelic Markers
Any method known in the art can be used to identify the nucleotide present at
a biallelic
marker site. Since the biallelic marker allele to be detected has been
identified and specified in
the present invention, detection will prove simple for one of ordinary skill
in the art by
employing any of a number of techniques. Many genotyping methods require the
previous
amplification of the DNA region carrying the biallelic marker of interest.
While the
amplification of target or signal is often preferred at present,
ultrasensitive detection methods
which do not require amplification are also encompassed by the present
genotyping methods.
Methods well-known to those skilled in the art that can be used to detect
biallelic
polymorphisms include methods such as, conventional dot blot analyzes, single
strand
conformational polymorphism analysis (SSCP) described by Orita et al. (1989),
denaturing
gradient gel electrophoresis (DGGE), heteroduplex analysis, mismatch cleavage
detection, and
other conventional techniques as described in Sheffield, V.C. et al. (1991),
White et al. (1992),
Grompe, M. et al. (1989) and Grompe, M. (1993). Another method for determining
the
identity of the nucleotide present at a particular polymorphic site employs a
specialized
exonuclease-resistant nucleotide derivative as described in US patent
4,656,127.
Preferred methods involve directly determining the identity of the nucleotide
present at
a biallelic marker site by sequencing assay, enzyme-based mismatch detection
assay, or
hybridization assay. The following is a description of some preferred methods.
A highly
preferred method is the microsequencing technique. The term "sequencing assay"
is used
herein to refer to polymerase extension of duplex primer/template complexes
and includes both
traditional sequencing and microsequencing.
1) Sequencing assays
The nucleotide present at a polymorphic site can be determined by sequencing
methods.
In a preferred embodiment, DNA samples are subjected to PCR amplification
before
sequencing as described above. DNA sequencing methods are described in herein.
Preferably,
the amplified DNA is subjected to automated dideoxy terminator sequencing
reactions using a
dye-primer cycle sequencing protocol. Sequence analysis allows the
identification of the base
present at the biallelic marker site.
2) Microsequencing assays
In microsequencing methods, a nucleotide at the polymorphic site that is
unique to one
of the alleles in a target DNA is detected by a single nucleotide primer
extension reaction. This
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method involves appropriate microsequencing primers which, hybridize just
upstream of a
polymorphic base of interest in the target nucleic acid. A polymerase is used
to specifically
extend the 3' end of the primer with one single ddNTP (chain terminator)
complementary to the
selected nucleotide at the polymorphic site. Next the identity of the
incorporated nucleotide is
determined in any suitable way.
Typically, microsequencing reactions are carried out using fluorescent ddNTPs
and the
extended microsequencing primers are analyzed by electrophoresis on ABI 377
sequencing
machines to determine the identity of the incorporated nucleotide as described
in EP 412 883.
Alternatively capillary electrophoresis can be used in order to process a
higher number of assays
simultaneously. An example of a typical microsequencing procedure that can be
used in the
context of the present invention is provided in example 4.
Different approaches can be used to detect the nucleotide added to the
microsequencing
primer. A homogeneous phase detection method based on fluorescence resonance
energy
transfer has been described by Chen and Kwok (1997) and Chen et al. (1997). In
this method
amplified genomic DNA fragments containing po(ymorphic sites are incubated
with a 5'-
fluorescein-labeled primer in the presence of allelic dye-labeled
dideoxyribonucleoside
triphosphates and a modified Taq polymerase. The dye-labeled primer is
extended one base by
the dye-terminator specific for the allele present on the template. At the end
of the genotyping
reaction, the fluorescence intensities of the two dyes in the reaction mixture
are analyzed
directly without separation or purification. All these steps can be performed
in the same tube
and the fluorescence changes can be monitored in real time. Alternatively, the
extended primer
may be analyzed by MALDI-TOF Mass Spectrometry. The base at the polymorphic
site is
identified by the mass added onto the microsequencing primer (see Haff L.A.
and Smirnov LP.,
1997).
Microsequencing may be achieved by the established microsequencing method or
by
developments or derivatives thereof. Alternative methods include several solid-
phase
microsequencing techniques. The basic microsequencing protocol is the same as
described
previously, except that the method is conducted as a heterogenous phase assay,
in which the
primer or the target molecule is immobilized or captured onto a solid support.
To simplify the
primer separation and the terminal nucleotide addition analysis,
oligonucleotides are attached to
solid supports or are modified in such ways that permit affinity separation as
well as polymerase
extension. The 5' ends and internal nucleotides of synthetic oligonucleotides
can be modified in
a number of different ways to permit different affinity separation approaches,
e.g., biotinylation.
If a single affinity group is used on the oligonucleotides, the
oligonucleotides can be separated
from the incorporated terminator regent. This eliminates the need of physical
or size separation.
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More than one oligonucleotide can be separated from the terminator reagent and
analyzed
simultaneously if more than one affinity group is used. This permits the
analysis of several
nucleic acid species or more nucleic acid sequence information per extension
reaction. The
affinity group need not be on the priming oligonucleotide but could
alternatively be present on
the template. For example, immobilization can be carried out via an
interaction between
biotinylated DNA and streptavidin-coated microtitration wells or avidin-coated
polystyrene
particles. In the same manner oligonucleotides or templates may be attached to
a solid support
in a high-density format. In such solid phase microsequencing reactions,
incorporated ddNTPs
can be radiolabeled (Syvanen, 1994) or linked to fluorescein (Livak and
Hainer, 1994). The
detection of radiolabeled ddNTPs can be achieved through scintillation-based
techniques. The
detection of fluorescein-linked ddNTPs can be based on the binding of
antifluorescein antibody
conjugated with alkaline phosphatase, followed by incubation with a
chromogenic substrate
(such as p-nitrophenyl phosphate). Other possible reporter-detection pairs
include: ddNTP
linked to dinitrophenyl (DNP) and anti-DNP alkaline phosphatase conjugate
(Harju et al., 1993)
or biotinylated ddNTP and horseradish peroxidase-conjugated streptavidin with
o-
phenylenediamine as a substrate (WO 92/15712). As yet another alternative
solid-phase
microsequencing procedure, Nyren et al. (1993) described a method relying on
the detection of
DNA polymerase activity by an enzymatic luminometric inorganic pyrophosphate
detection
assay (ELIDA).
Pastinen et al. ( 1997), describe a method for multiplex detection of single
nucleotide
polymorphism in which the solid phase minisequencing principle is applied to
an
oligonucleotide array format. High-density arrays of DNA probes attached to a
solid support
(DNA chips) are further described in herein.
In one aspect the present invention provides polynucleotides and methods to
genotype
one or more biallelic markers of the present invention by performing a
microsequencing assay.
Preferred microsequencing primers include those being featured Table 6d. It
will be
appreciated that the microsequencing primers listed in Table 6d are merely
exemplary and that,
any primer having a 3' end immediately adjacent to a polymorphic nucleotide
may be used.
Similarly, it will be appreciated that microsequencing analysis may be
performed for any
biallelic marker or any combination of biallelic markers of the present
invention. One aspect of
the present invention is a solid support which includes one or more
microsequencing primers
listed in Table 6d, or fragments comprising at least 8, at least 12, at least
15, or at least 20
consecutive nucleotides thereof and having a 3' terminus immediately upstream
of the
corresponding biallelic marker, for determining the identity of a nucleotide
at biallelic marker
site.
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3) Mismatch detection assays based on polymerases and ligases
In one aspect the present invention provides polynucleotides and methods to
determine
the allele of one or more biallelic markers of the present invention in a
biological sample, by
mismatch detection assays based on polymerases and/or ligases. These assays
are based on the
specificity of polymerases and ligases. Polymerization reactions places
particularly stringent
requirements on correct base pairing of the 3' end of the amplification primer
and the joining of
two oligonucleotides hybridized to a target DNA sequence is quite sensitive to
mismatches
close to the ligation site, especially at the 3' end. The terms "enzyme based
mismatch detection
assay" are used herein to refer to any method of determining the allele of a
biallelic marker
based on the specificity of ligases and polymerases. Preferred methods are
described below.
Methods, primers and various parameters to amplify DNA fragments comprising
biallelic
markers of the present invention are further described herein.
Allele specific amplification
Discrimination between the two alleles of a biallelic marker can also be
achieved by
allele specific amplification, a selective strategy, whereby one of the
alleles is amplified without
amplification of the other allele. This is accomplished by placing a
polymorphic base at the 3'
end of one of the amplification primers. Because the extension forms from the
3'end of the
primer, a mismatch at or near this position has an inhibitory effect on
amplification. Therefore,
under appropriate amplification conditions, these primers only direct
amplification on their
complementary allele. Designing the appropriate allele-specific primer and the
corresponding
assay conditions are well with the ordinary skill in the art.
Ligation/amplification based methods
The "Oligonucleotide Ligation Assay" (OLA) uses two oligonucleotides which are
designed to be capable of hybridizing to abutting sequences of a single strand
of a target
molecules. One of the oligonucleotides is biotinylated, and the other is
detectably labeled. If
the precise complementary sequence is found in a target molecule, the
oligonucleotides will
hybridize such that their termini abut, and create a ligation substrate that
can be captured and
detected. OLA is capable of detecting biallelic markers and may be
advantageously combined
with PCR as described by Nickerson D.A. et al. (1990). In this method, PCR is
used to achieve
the exponential amplification of target DNA, which is then detected using OLA.
Other methods which are particularly suited for the detection of biallelic
markers
include LCR (ligase chain reaction), Gap LCR (GLCR) which are described
herein. As
mentioned above LCR uses two pairs of probes to exponentially amplify a
specific target. The
sequences of each pair of oligonucleotides, is selected to permit the pair to
hybridize to abutting
sequences of the same strand of the target. Such hybridization forms a
substrate for a template-
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dependant ligase. In accordance with the present invention, LCR can be
performed with
oligonucleotides having the proximal and distal sequences of the same strand
of a biallelic
marker site. In one embodiment, either oligonucleotide will be designed to
include the biallelic
marker site. In such an embodiment, the reaction conditions are selected such
that the
oligonucleotides can be ligated together only if the target molecule either
contains or lacks the
specific nucleotides) that is complementary to the biallelic marker on the
oligonucleotide. In
an alternative embodiment, the oligonucleotides will not include the biallelic
marker, such that
when they hybridize to the target molecule, a "gap" is created as described in
WO 90/01069.
his gap is then "filled" with complementary dNTPs (as mediated by DNA
polymerase), or by an
additional pair of oligonucleotides. Thus at the end of each cycle, each
single strand has a
complement capable of serving as a target during the next cycle and
exponential allele-specific
amplification of the desired sequence is obtained.
Ligase/Polymerase-mediated Genetic Bit AnalysisTM is another method for
determining
the identity of a nucleotide at a preselected site in a nucleic acid molecule
(WO 95/21271). This
method involves the incorporation of a nucleoside triphosphate that is
complementary to the
nucleotide present at the preselected site onto the terminus of a primer
molecule, and their
subsequent ligation to a second oligonucleotide. The reaction is monitored by
detecting a
specific label attached to the reaction's solid phase or by detection in
solution.
4) Hybridization assay methods
A preferred method of determining the identity of the nucleotide present at a
biallelic
marker site involves nucleic acid hybridization. The hybridization probes,
which can be
conveniently used in such reactions, preferably include the probes defined
herein. Any
hybridization assay may be used including Southern hybridization, Northern
hybridization, dot
blot hybridization and solid-phase hybridization (see Sambrook et al.,
Molecular Cloning-A
Laboratory Manual, Second Edition, Cold Spring Harbor Press, N.Y., 1989).
Hybridization refers to the formation of a duplex structure by two single
stranded
nucleic acids due to complementary base pairing. Hybridization can occur
between exactly
complementary nucleic acid strands or between nucleic acid strands that
contain minor regions
of mismatch. Specific probes can be designed that hybridize to one form of a
biallelic marker
and not to the other and therefore are able to discriminate between different
allelic forms.
Allele-specific probes are often used in pairs, one member of a pair showing
perfect match to a
target sequence containing the original allele and the other showing a perfect
match to the target
sequence containing the alternative allele. Hybridization conditions should be
sufficiently
stringent that there is a significant difference in hybridization intensity
between alleles, and
preferably an essentially binary response, whereby a probe hybridizes to only
one of the alleles.
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Stringent, sequence specific hybridization conditions, under which a probe
will hybridize only
to the exactly complementary target sequence are well known in the art
(Sambrook et al.,
Molecular Cloning - A Laboratory Manual, Second Edition, Cold Spring Harbor
Press, N.Y.,
1989). Stringent conditions are sequence dependent and will be different in
different
circumstances. Generally, stringent conditions are selected to be about
5°C lower than the
thermal melting point (Tm) for the specific sequence at a defined ionic
strength and pH. By
way of example and not limitation, procedures using conditions of high
stringency are as
follows: Prehybridization of filters containing DNA is carried out for 8 h to
overnight at 65°C in
buffer composed of 6X SSC, 50 mM Tris-HCI (pH 7.5), 1 mM EDTA, 0.02% PVP,
0.02%
Ficoll, 0.02% BSA, and 500 pg/ml denatured salmon sperm DNA. Filters are
hybridized for
48 h at 65°C, the preferred hybridization temperature, in
prehybridization mixture containing
100 pg/ml denatured salmon sperm DNA and 5-20 X 106 cpm of 32P-labeled probe.
Alternatively, the hybridization step can be performed at 65°C in the
presence of SSC buffer, 1
x SSC corresponding to 0.15M NaCI and 0.05 M Na citrate. Subsequently, filter
washes can be
~ done at 37°C for 1 h in a solution containing 2X SSC, 0.01% PVP,
0.01% Ficoll, and 0.01%
BSA, followed by a wash in 0.1 X SSC at 50°C for 45 min. Alternatively,
filter washes can be
performed in a solution containing 2 x SSC and 0.1% SDS, or 0.5 x SSC and 0.1%
SDS, or 0.1
x SSC and 0.1% SDS at 68°C for 15 minute intervals. Following the wash
steps, the hybridized
probes are detectable by autoradiography. By way of example and not
limitation, procedures
using conditions of intermediate stringency are as follows: Filters containing
DNA are
prehybridized, and then hybridized at a temperature of 60°C in the
presence of a 5 x SSC buffer
and labeled probe. Subsequently, filters washes are performed in a solution
containing 2x SSC
at 50°C and the hybridized probes are detectable by autoradiography.
Other conditions of high
and intermediate stringency which may be used are well known in the art and as
cited in
Sambrook et al. (Molecular Cloning - A Laboratory Manual, Second Edition, Cold
Spring
Harbor Press, N.Y., 1989) and Ausubel et al. (Current Protocols in Molecular
Biology, Green
Publishing Associates and Wiley Interscience, N.Y., 1989).
Although such hybridizations can be performed in solution, it is preferred to
employ a
solid-phase hybridization assay. The target DNA comprising a biallelic marker
of the present
invention may be amplified prior to the hybridization reaction. The presence
of a specific allele
in the sample is determined by detecting the presence or the absence of stable
hybrid duplexes
formed between the probe and the target DNA. The detection of hybrid duplexes
can be carried
out by a number of methods. Various detection assay formats are well known
which utilize
detectable labels bound to either the target or the probe to enable detection
of the hybrid
duplexes. Typically, hybridization duplexes are separated from unhybridized
nucleic acids and
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the labels bound to the duplexes are then detected. Those skilled in the art
will recognize that
wash steps may be employed to wash away excess target DNA or probe. Standard
heterogeneous assay formats are suitable for detecting the hybrids using the
labels present on
the primers and probes.
Two recently developed assays allow hybridization-based allele discrimination
with no
need for separations or washes (see Landegren U. et al.,1998). The TaqMan
assay takes
advantage of the 5' nuclease activity of Taq DNA polymerase to digest a DNA
probe annealed
specifically to the accumulating amplification product. TaqMan probes are
labeled with a
donor-acceptor dye pair that interacts via fluorescence energy transfer.
Cleavage of the
TaqMan probe by the advancing polymerase during amplification dissociates the
donor dye
from the quenching acceptor dye, greatly increasing the donor fluorescence.
All reagents
necessary to detect two allelic variants can be assembled at the beginning of
the reaction and the
results are monitored in real time (see Livak et al, 1995). In an alternative
homogeneous
hybridization-based procedure, molecular beacons are used for allele
discriminations.
Molecular beacons are hairpin-shaped oligonucleotide probes that report the
presence of
specific nucleic acids in homogeneous solutions. When they bind to their
targets they undergo a
conformational reorganization that restores the fluorescence of an internally
quenched
fluorophore (Tyagi et al., 1998).
By assaying the hybridization to an allele specific probe, one can detect the
presence or
absence of a biallelic marker allele in a given sample.
High-Throughput parallel hybridizations in array format are specifically
encompassed
within "hybridization assays" and are described below.
Hybridization to addressable arrays of oligonucleotides
Hybridization assays based on oligonucleotide arrays rely on the differences
in
hybridization stability of short oligonucleotides to perfectly matched and
mismatched target
sequence variants. Efficient access to polymorphism information is obtained
through a basic
structure comprising high-density arrays of oligonucleotide probes attached to
a solid support
(the chip) at selected positions. Each DNA chip can contain thousands to
millions of individual
synthetic DNA probes arranged in a grid-like pattern and miniaturized to the
size of a dime.
The chip technology has already been applied with success in numerous cases.
For
example, the screening of mutations has been undertaken in the BRCA1 gene, in
S. cerevisiae
mutant strains, and in the protease gene of HIV-1 virus (Hacia et al., 1996;
Shoemaker et al.,
1996 ; Kozal et al., 1996). Chips of various formats for use in detecting
biallelic
polymorphisms can be produced on a customized basis by Affymetrix
(GeneChipTM), Hyseq
(HyChip and HyGnostics), and Protogene Laboratories.
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In general, these methods employ arrays of oligonucleotide probes that are
complementary to target nucleic acid sequence segments from an individual
which, target
sequences include a polymorphic marker. EP785280, describes a tiling strategy
for the
detection of single nucleotide polymorphisms. Briefly, arrays may generally be
"tiled" for a
large number of specific polymorphisms. By "tiling" is generally meant the
synthesis of a
defined set of oligonucleotide probes which is made up of a sequence
complementary to the
target sequence of interest, as well as preselected variations of that
sequence, e.g., substitution
of one or more given positions with one or more members of the basis set of
monomers, i.e.
nucleotides. Tiling strategies are further described in PCT application No. WO
95/11995. In a
particular aspect, arrays are tiled for a number of specific, identified
biallelic marker sequences.
In particular the array is tiled to include a number of detection blocks, each
detection block
being specific for a specific biallelic marker or a set of biallelic markers.
For example, a
detection block may be tiled to include a number of probes, which span the
sequence segment
that includes a specific polymorphism. To ensure probes that are complementary
to each allele,
the probes are synthesized in pairs differing at the biallelic marker. In
addition to the probes
differing at the polymorphic base, monosubstituted probes are also generally
tiled within the
detection block. These monosubstituted probes have bases at and up to a
certain number of
bases in either direction from the polymorphism, substituted with the
remaining nucleotides
(selected from A, T, G, C and U). Typically the probes in a tiled detection
block will include
substitutions of the sequence positions up to and including those that are 5
bases away from the
bialhelic marker. The monosubstituted probes provide internal controls for the
tiled array, to
distinguish actual hybridization from artefactual cross-hybridization. Upon
completion of
hybridization with the target sequence and washing of the array, the array is
scanned to
determine the position on the array to which the target sequence hybridizes.
The hybridization
data from the scanned array is then analyzed to identify which allele or
alleles of the biallelic
marker are present in the sample. Hybridization and scanning may be carried
out as described
in PCT application No. WO 92/10092 and WO 95/11995 and US patent No.
5,424,186.
Thus, in some embodiments, the chips may comprise an array of nucleic acid
sequences
of fragments of about 15 nucleotides in length. In further embodiments, the
chip may comprise
an array including at least one of the sequences selected from the group
consisting of SEQ ID
Nos. 1 to 26, 36 to 40 and 54 to 229 and the sequences complementary thereto,
or a fragment
thereof at least about 8 consecutive nucleotides, preferably 10, 15, 20, more
preferably 25, 30,
40, 47, or 50 consecutive nucleotides. In some embodiments, the chip may
comprise an array of
at least 2, 3, 4, 5, 6, 7, 8 or more of these polynucleotides of the
invention. Solid supports and
polynucleotides of the present invention attached to solid supports are
further described in the
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section titled "Oligonucleotide probes and Primers".
5) Integrated Systems
Another technique, which may be used to analyze polymorphisms, includes
multicomponent integrated systems, which miniaturize and compartmentalize
processes such as
PCR and capillary electrophoresis reactions in a single functional device. An
example of such
technique is disclosed in US patent 5,589,136, which describes the integration
of PCR
amplification and capillary electrophoresis in chips.
Integrated systems can be envisaged mainly when microfluidic systems are used.
These
systems comprise a pattern of microchannels designed onto a glass, silicon,
quartz, or plastic
wafer included on a microchip. The movements of the samples are controlled by
electric,
electroosmotic or hydrostatic forces applied across different areas of the
microchip. For
genotyping biallelic markers, the microfluidic system may integrate nucleic
acid amplification,
microsequencing, capillary electrophoresis and a detection method such as
laser-induced
fluorescence detection.
Methods Of Genetic Analysis Using The Biallelic Markers Of The Present
Invention
Different methods are available for the genetic analysis of complex traits
(see Lander
and Schork, 1994). The search for disease-susceptibility genes is conducted
using two main
methods: the linkage approach in which evidence is sought for cosegregation
between a locus
and a putative trait locus using family studies, and the association approach
in which evidence is
sought for a statistically significant association between an allele and a
trait or a trait causing
allele (Khoury J. et al, 1993). In general, the biallelic markers of the
present invention find use
in any method known in the art to demonstrate a statistically significant
correlation between a
genotype and a phenotype. The biallelic markers may be used in parametric and
non-parametric
linkage analysis methods. Preferably, the biallelic markers of the present
invention are used to
identify genes associated with detectable traits using association studies, an
approach which
does not require the use of affected families and which permits the
identification of genes
associated with complex and sporadic traits.
The genetic analysis using the biallelic markers of the present invention may
be
conducted on any scale. The whole set of biallelic markers of the present
invention or any
subset of biallelic markers of the present invention may be used. In some
embodiments a subset
of biallelic markers corresponding to one or several candidate genes of the
present invention
may be used. Alternatively, a subset of biallelic markers of the present
invention localised on a
specific chromosome segment may be used. Further, any set of genetic markers
including a
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biallelic marker of the present invention may be used. As mentioned above, it
should be noted
that the biallelic markers of the present invention may be included in any
complete or partial
genetic map of the human genome. These different uses are specifically
contemplated in the
present invention and claims.
Linkage analysis
Linkage analysis is based upon establishing a correlation between the
transmission of
genetic markers and that of a specific trait throughout generations within a
family. Thus, the
aim of linkage analysis is to detect marker loci that show cosegregation with
a trait of interest in
pedigrees.
Parametric methods
When data are available from successive generations there is the opportunity
to study
the degree of linkage between pairs of loci. Estimates of the recombination
fraction enable loci
to be ordered and placed onto a genetic map. With loci that are genetic
markers, a genetic map
can be established, and then the strength of linkage between markers and
traits can be calculated
and used to indicate the relative positions of markers and genes affecting
those traits (Weir,
B.S., 1996). The classical method for linkage analysis is the logarithm of
odds (lod) score
method (see Morton N.E., 1955; Ott J, 1991). Calculation of lod scores
requires specification of
the mode of inheritance for the disease (parametric method). Generally, the
length of the
candidate region identified using linkage analysis is between 2 and 20Mb. Once
a candidate
region is identified as described above, analysis of recombinant individuals
using additional
markers allows further delineation of the candidate region. Linkage analysis
studies have
generally relied on the use of a maximum of 5,000 microsatellite markers, thus
limiting the
maximum theoretical attainable resolution of linkage analysis to about 600 kb
on average.
Linkage analysis has been successfully applied to map simple genetic traits
that show
clear Mendelian inheritance patterns and which have a high penetrance (i.e.,
the ratio between
the number of trait positive carriers of allele a and the total number of a
carriers in the
population). However, parametric linkage analysis suffers from a variety of
drawbacks. First, it
is limited by its reliance on the choice of a genetic model suitable for each
studied trait.
Furthermore, as already mentioned, the resolution attainable using linkage
analysis is limited,
and complementary studies are required to refine the analysis of the typical
2Mb to 20Mb
regions initially identified through linkage analysis. In addition, parametric
linkage analysis
approaches have proven difficult when applied to complex genetic traits, such
as those due to
the combined action of multiple genes and/or environmental factors. It is very
difficult to
model these factors adequately in a lod score analysis. In such cases, too
large an effort and
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cost are needed to recruit the adequate number of affected families required
for applying linkage
analysis to these situations, as recently discussed by Risch, N. and
Merikangas, K. ( 1996).
Non-parametric methods
The advantage of the so-called non-parametric methods for linkage analysis is
that they
do not require specification of the mode of inheritance for the disease, they
tend to be more
useful for the analysis of complex traits. In non-parametric methods, one
tries to prove that the
inheritance pattern of a chromosomal region is not consistent with random
Mendelian
segregation by showing that affected relatives inherit identical copies of the
region more often
than expected by chance. Affected relatives should show excess "allele
sharing" even in the
presence of incomplete penetrance and polygenic inheritance. In non-parametric
linkage
analysis the degree of agreement at a marker locus in two individuals can be
measured either by
the number of alleles identical by state (IBS) or by the number of alleles
identical by descent
(IBD). Affected sib pair analysis is a well-known special case and is the
simplest form of these
methods.
The biallelic markers of the present invention may be used in both parametric
and non-
parametric linkage analysis. Preferably biallelic markers may be used in non-
parametric
methods which allow the mapping of genes involved in complex traits. The
biallelic markers of
the present invention may be used in both IBD- and IBS- methods to map genes
affecting a
complex trait. In such studies, taking advantage of the high density of
biallelic markers, several
adjacent biallelic marker loci may be pooled to achieve the efficiency
attained by multi-allelic
markers (Zhao et al., 1998).
However, both parametric and non-parametric linkage analysis methods analyse
affected relatives, they tend to be of limited value in the genetic analysis
of drug responses or in
the analysis of side effects to treatments. This type of analysis is
impractical in such cases due
to the lack of availability of familial cases. In fact, the likelihood of
having more than one
individual in a family being exposed to the same drug at the same time is
extremely low.
Population Association Studies
The present invention comprises methods for identifying one or several genes
among a
set of candidate genes that are associated with a detectable trait using the
biallelic markers of
the present invention. In one embodiment the present invention comprises
methods to detect an
association between a biallelic marker allele or a biallelic marker haplotype
and a trait. Further,
the invention comprises methods to identify a trait causing allele in linkage
disequilibrium with
any biallelic marker allele of the present invention.
As described above, alternative approaches can be employed to perform
association
studies: genome-wide association studies, candidate region association studies
and candidate
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gene association studies. The candidate region analysis clearly provides a
short-cut approach to
the identification of genes and gene polymorphisms related to a particular
trait when some
information concerning the biology of the trait is available. Further, the
biallelic markers of the
present invention may be incorporated in any map of genetic markers of the
human genome in
order to perform genome-wide association studies. Methods to generate a high-
density map of
biallelic markers has been described in US Provisional Patent application
serial number
60/082,614. The biallelic markers of the present invention may further be
incorporated in any
map of a specific candidate region of the genome (a specific chromosome or a
specific
chromosomal segment for example).
As mentioned above, association studies may be conducted within the general
population and are not limited to studies performed on related individuals in
affected families.
Association studies are extremely valuable as they permit the analysis of
sporadic or multifactor
traits. Moreover, association studies represent a powerful method for ftne-
scale mapping
enabling much finer mapping of trait causing alleles than linkage studies.
Studies based on
pedigrees often only narrow the location of the trait causing allele.
Association studies using
the biallelic markers of the present invention can therefore be used to refine
the location of a
trait causing allele in a candidate region identified by Linkage Analysis
methods. Biallelic
markers of the present invention can be used to identify the involved gene;
such uses are
specifically contemplated in the present invention and claims.
1) Determining the frequency of a biallelic marker allele or of a biallelic
marker
haplotype in a population
Another embodiment of the present invention encompasses methods of estimating
the
frequency of a haplotype for a set of biallelic markers in a population,
comprising the steps of:
a) genotyping each individual in said population for at least one 13q31-q33-
related biallelic
marker, b) genotyping each individual in said population for a second
biallelic marker by
determining the identity of the nucleotides at said second biallelic marker
for both copies of said
second biallelic marker present in the genome; and c) applying a haplotype
determination
method to the identities of the nucleotides determined in steps a) and b) to
obtain an estimate of
said frequency. In addition, the methods of estimating the frequency of a
haplotype of the
invention encompass methods with any further limitation described in this
disclosure, or those
following, specified alone or in any combination: optionally said haplotype
determination
method is selected from the group consisting of asymmetric PCR amplification,
double PCR
amplification of specific alleles, the Clark method, or an expectation
maximization algorithm;
optionally, said second biallelic marker is a 13q31-q33-related biallelic
marker in a sequence
selected from the group consisting of SEQ ID Nos 1 to 26, 36 to 40 and 54 to
229, and the
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complements thereof; optionally, said 13q31-q33-related biallelic marker may
be selected
individually or in any combination from the biallelic markers described in
Tables 6b and 6c;
optionally, the identity of the nucleotides at the biallelic markers in
everyone of the sequences
of SEQ ID Nos 1 to 26, 36 to 40 and 54 to 229 is determined in steps a) and
b).
Association studies explore the relationships among frequencies for sets of
alleles
between loci.
Determining the frequency of an allele in a population
Allelic frequencies of the biallelic markers in a population can be determined
using one
of the methods described above under the heading "Methods for genotyping an
individual for
biallelic markers", or any genotyping procedure suitable for this intended
purpose. Genotyping
pooled samples or individual samples can determine the frequency of a
biallelic marker allele in
a population. One way to reduce the number of genotypings required is to use
pooled samples.
A major obstacle in using pooled samples is in terms of accuracy and
reproducibility for
determining accurate DNA concentrations in setting up the pools. Genotyping
individual
samples provides higher sensitivity, reproducibility and accuracy and; is the
preferred method
used in the present invention. Preferably, each individual is genotyped
separately and simple
gene counting is applied to determine the frequency of an allele of a
biallelic marker or of a
genotype in a given population.
Determining the frequency of a haplotype in a population
The gametic phase of haplotypes is unknown when diploid individuals are
heterozygous at more than one locus. Using genealogical information in
families gametic phase
can sometimes be inferred (Perlin et al., 1994). When no genealogical
information is available.
different strategies may be used. One possibility is that the multiple-site
heterozygous diploids
can be eliminated from the analysis, keeping only the homozygotes and the
single-site
heterozygote individuals, but this approach might lead to a possible bias in
the sample
composition and the underestimation of low-frequency haplotypes. Another
possibility is that
single chromosomes can be studied independently, for example, by asymmetric
PCR
amplification (see Newton et al., 1989; Wu et al., 1989) or by isolation of
single chromosome
by limit dilution followed by PCR amplification (see Ruano et al., 1990).
Further, a sample may
be haplotyped for sufficiently close biallelic markers by double PCR
amplification of specific
alleles (Sarkar, G. and Sommer S.S., 1991). These approaches are not entirely
satisfying either
because of their technical complexity, the additional cost they entail, their
lack of generalisation
at a large scale, or the possible biases they introduce. To overcome these
difficulties, an
algorithm to infer the phase of PCR-amplified DNA genotypes introduced by
Clark A.G. (1990)
may be used. Briefly, the principle is to start filling a preliminary list of
haplotypes present in
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the sample by examining unambiguous individuals, that is, the complete
homozygotes and the
single-site heterozygotes. Then other individuals in the same sample are
screened for the
possible occurrence of previously recognised haplotypes. For each positive
identification, the
complementary haplotype is added to the list of recognised haplotypes, until
the phase
information for all individuals is either resolved or identified as
unresolved. This method
assigns a single haplotype to each multiheterozygous individual, whereas
several haplotypes are
possible when there are more than one heterozygous site. Alternatively, one
can use methods
estimating haplotype frequencies in a population without assigning haplotypes
to each
individual. Preferably, a method based on an expectation-maximization (EM)
algorithm
(Dempster et al., J. R. 1977) leading to maximum-likelihood estimates of
haplotype frequencies
under the assumption of Hardy-Weinberg proportions (random mating) is used
(see Excoffier L.
and Slatkin M., 1995). The EM algorithm is a generalised iterative maximum-
likelihood
approach to estimation that is useful when data are ambiguous and/or
incomplete. The EM
algorithm is used to resolve heterozygotes into haplotypes. Haplotype
estimations are further
described below under the heading "Statistical methods. Any other method known
in the art to
determine or to estimate the frequency of a haplotype in a population may also
be used.
2) Linkage Disequilibrium analysis
Linkage disequilibrium is the non-random association of alleles at two or more
loci and
represents a powerful tool for mapping genes involved in disease traits (see
Ajioka R.S. et al.,
1997). Biallelic markers, because they are densely spaced in the human genome
and can be
genotyped in more numerous numbers than other types of genetic markers (such
as RFLP or
VNTR markers), are particularly useful in genetic analysis based on linkage
disequilibrium.
The biallelic markers of the present invention may be used in any linkage
disequilibrium
analysis method known in the art.
Briefly, when a disease mutation is first introduced into a population (by a
new
mutation or the immigration of a mutation carrier), it necessarily resides on
a single
chromosome and thus on a single "background" or "ancestral" haplotype of
linked markers.
Consequently, there is complete disequilibrium between these markers and the
disease
mutation: one finds the disease mutation only in the presence of a specific
set of marker alleles.
Through subsequent generations recombinations occur between the disease
mutation and these
marker polymorphisms, and the disequilibrium gradually dissipates. The pace of
this
dissipation is a function of the recombination frequency, so the markers
closest to the disease
gene will manifest higher levels of disequilibrium than those that are further
away. When not
broken up by recombination, "ancestral" haplotypes and linkage disequilibrium
between marker
alleles at different loci can be tracked not only through pedigrees but also
through populations.
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Linkage disequilibrium is usually seen as an association between one specific
allele at one locus
and another specific allele at a second locus.
The pattern or curve of disequilibrium between disease and marker loci is
expected to
exhibit a maximum that occurs at the disease locus. Consequently, the amount
of linkage
disequilibrium between a disease allele and closely linked genetic markers may
yield valuable
information regarding the location of the disease gene. For fine-scale mapping
of a disease
locus, it is useful to have some knowledge of the patterns of linkage
disequilibrium that exist
between markers in the studied region. As mentioned above the mapping
resolution achieved
through the analysis of linkage disequilibrium is much.higher than that of
linkage studies. The
high density of biallelic markers combined with linkage disequilibrium
analysis provides
powerful tools for fine-scale mapping. Different methods to calculate linkage
disequilibrium
are described below under the heading "Statistical Methods".
3) Population-based case-control studies of trait-marker associations
As mentioned above, the occurrence of pairs of specific alleles at different
loci on the
same chromosome is not random and the deviation from random is called linkage
disequilibrium. Association studies focus on population frequencies and rely
on the
phenomenon of linkage disequilibrium. If a specific allele in a given gene is
directly involved
in causing a particular trait, its frequency will be statistically increased
in an affected (trait
positive) population, when compared to the frequency in a trait negative
population or in a
random control population. As a consequence of the existence of linkage
disequilibrium, the
frequency of all other alleles present in the haplotype carrying the trait-
causing allele will also
be increased in trait positive individuals compared to trait negative
individuals or random
controls. Therefore, association between the trait and any allele
(specifically a biallelic marker
allele) in linkage disequilibrium with the trait-causing allele will suffice
to suggest the presence
of a trait-related gene in that particular region. Case-control populations
can be genotyped for
biallelic markers to identify associations that narrowly locate a trait
causing allele. As any
marker in linkage disequilibrium with one given marker associated with a trait
will be
associated with the trait. Linkage disequilibrium allows the relative
frequencies in case-control
populations of a limited number of genetic polymorphisms (specifically
biallelic markers) to be
analysed as an alternative to screening all possible functional polymorphisms
in order to find
trait-causing alleles. Association studies compare the frequency of marker
alleles in unrelated
case-control populations, and represent powerful tools for the dissection of
complex traits.
Case-control populations (inclusion criteria)
Population-based association studies do not concern familial inheritance but
compare
the prevalence of a particular genetic marker, or a set of markers, in case-
control populations.
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They are case-control studies based on comparison of unrelated case (affected
or trait positive)
individuals and unrelated control (unaffected or trait negative or random)
individuals.
Preferably the control group is composed of unaffected or trait negative
individuals. Further,
the control group is ethnically matched to the case population. Moreover, the
control group is
S preferably matched to the case-population for the main known confusion
factor for the trait
under study (for example age-matched for an age-dependent trait). Ideally,
individuals in the
two samples are paired in such a way that they are expected to differ only in
their disease status.
In the following "trait positive population, "case population" and "affected
population" are
used interchangeably.
An important step in the dissection of complex traits using association
studies is the
choice of case-control populations (see Lander and Schork, 1994). A major step
in the choice
of case-control populations is the clinical definition of a given trait or
phenotype. Any genetic
trait may be analysed by the association method proposed here by carefully
selecting the
individuals to be included in the trait positive and trait negative phenotypic
groups. Four
criteria are often useful: clinical phenotype, age at onset, family history
and severity. The
selection procedure for continuous or quantitative traits (such as blood
pressure for example)
involves selecting individuals at opposite ends of the phenotype distribution
of the trait under
study, so as to include in these trait positive and trait negative populations
individuals with non-
overlapping phenotypes. Preferably, case-control populations comprise
phenotypically
homogeneous populations. Trait positive and trait negative populations
comprise
phenotypically uniform populations of individuals representing each between 1
and 98%,
preferably between 1 and 80%, more preferably between 1 and 50%, and more
preferably
between 1 and 30%, most preferably between 1 and 20% of the total population
under study,
and selected among individuals exhibiting non-overlapping phenotypes. The
clearer the
difference between the two trait phenotypes, the greater the probability of
detecting an
association with biallelic markers. The selection of those drastically
different but relatively
uniform phenotypes enables efficient comparisons in association studies and
the possible
detection of marked differences at the genetic level, provided that the sample
sizes of the
populations under study are significant enough.
In preferred embodiments, a first group of between 50 and 300 trait positive
individuals, preferably about 100 individuals, are recruited according to
their phenotypes. A
similar number of trait negative individuals are included in such studies.
In the present invention, typical examples of inclusion criteria include
affection by
schizophrenia.
Association analysis
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The general strategy to perform association studies using biallelic markers
derived from
a region carrying a candidate gene is to scan two groups of individuals (case-
control
populations) in order to measure and statistically compare the allele
frequencies of the biallelic
markers of the present invention in both groups.
If a statistically significant association with a trait is identified for at
least one or more
of the analysed biallelic markers, one can assume that: either the associated
allele is directly
responsible for causing the trait (the associated allele is the trait causing
allele), or more likely
the associated allele is in linkage disequilibrium with the trait causing
allele. The specific
characteristics of the associated allele with respect to the gene function
usually gives further
insight into the relationship between the associated allele and the trait
(causal or in linkage
disequilibrium). If the evidence indicates that the associated allele within
the gene is most
probably not the trait causing allele but is in linkage disequilibrium with
the real trait causing
allele, then the trait causing allele can be found by sequencing the vicinity
of the associated
marker.
1 S Another embodiment of the present invention encompasses methods of
detecting an
association between a haplotype and a phenotype, comprising the steps of: a)
estimating the
frequency of at least one haplotype in a trait positive population according
to a method of
estimating the frequency of a haplotype of the invention; b) estimating the
frequency of said
haplotype in a control population according to the method of estimating the
frequency of a
haplotype of the invention; and c) determining whether a statistically
significant association
exists between said haplotype and said phenotype. In addition, the methods of
detecting an
association between a haplotype and a phenotype of the invention encompass
methods with any
further limitation described in this disclosure, or those following, specified
alone or in any
combination: Optionally, said 13q31-q33-related biallelic marker may be in a
sequence
selected individually or in any combination from the group consisting of SEQ
ID Nos I to 26,
36 to 40 and 54 to 229, and the complements thereof; optionally, said 13q31-
q33-related
biallelic marker may be selected individually or in any combination from the
biallelic markers
described in Tables 6b and 6c; optionally, said control population may be a
trait negative
population, or a random population; optionally, said phenotype is a disease
involving
schizophrenia, a response to an agent acting on schizophrenia, or a side
effects to an agent
acting on schizophrenia.
Haplotype analysis
As described above, when a chromosome carrying a disease allele first appears
in a
population as a result of either mutation or migration, the mutant allele
necessarily resides on a
chromosome having a set of linked markers: the ancestral haplotype. This
haplotype can be
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tracked through populations and its statistical association with a given trait
can be analysed.
Complementing single point (allelic) association studies with multi-point
association studies
also called haplotype studies increases the statistical power of association
studies. Thus, a
haplotype association study allows one to define the frequency and the type of
the ancestral
carrier haplotype. A haplotype analysis is important in that it increases the
statistical power of
an analysis involving individual markers.
In a first stage of a haplotype frequency analysis, the frequency of the
possible
haplotypes based on various combinations of the identified biallelic markers
of the invention is
determined. The haplotype frequency is then compared for distinct populations
of trait positive
and control individuals. The number of trait positive individuals, which
should be, subjected to
this analysis to obtain statistically significant results usually ranges
between 30 and 300, with a
preferred number of individuals ranging between 50 and 150. The same
considerations apply to
the number of unaffected individuals (or random control) used in the study.
The results of this
first analysis provide haplotype frequencies in case-control populations, for
each evaluated
haplotype frequency a p-value and an odd ratio are calculated. If a
statistically significant
association is found the relative risk for an individual carrying the given
haplotype of being
affected with the trait under study can be approximated.
Interaction Analysis
The biallelic markers of the present invention may also be used to identify
patterns of
biallelic markers associated with detectable traits resulting from polygenic
interactions. The
analysis of genetic interaction between alleles at unlinked loci requires
individual genotyping
using the techniques described herein. The analysis of allelic interaction
among a selected set
of biallelic markers with appropriate level of statistical significance can be
considered as a
haplotype analysis. Interaction analysis comprises stratifying the case-
control populations with
respect to a given haplotype for the first loci and performing a haplotype
analysis with the
second loci with each subpopulation.
Statistical methods used in association studies are further described herein.
4) Testing for linkage in the presence of association
The biallelic markers of the present invention may further be used in TDT
(transmission/disequilibrium test). TDT tests for both linkage and association
and is not
affected by population stratification. TDT requires data for affected
individuals and their
parents or data from unaffected sibs instead of from parents (see Spielmann S.
et al., 1993;
Schaid D.J. et al., 1996, Spielmann S. and Ewens W.J, 1998). Such combined
tests generally
reduce the false - positive errors produced by separate analyses.
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Statistical methods
In general, any method known in the art to test whether a trait and a genotype
show a
statistically significant correlation may be used.
1) Methods in linkage analysis
Statistical methods and computer programs useful for linkage analysis are well-
known
to those skilled in the art (see Terwilliger J.D. and Ott J., 1994; Ott J.,
1991).
2) Methods to estimate haplotype frequencies in a population
As described above, when genotypes are scored, it is often not possible to
distinguish
heterozygotes so that haplotype frequencies cannot be easily inferred. When
the gametic phase
is not known, haplotype frequencies can be estimated from the multilocus
genotypic data. Any
method known to person skilled in the art can be used to estimate haplotype
frequencies (see
Lange K., 1997; Weir, B.S., 1996) Preferably, maximum-likelihood haplotype
frequencies are
computed using an Expectation- Maximization (EM) algorithm (see Dempster et
al., 1977;
Excoffier L. and Slatkin M., 1995). This procedure is an iterative process
aiming at obtaining
maximum-likelihood estimates of haplotype frequencies from multi-locus
genotype data when
the gametic phase is unknown. Haplotype estimations are usually performed by
applying the
EM algorithm using for example the EM-HAPLO program (Hawley M.E. et al.,1994)
or the
Arlequin'program (Schneider.et al., 1997). The EM algorithm is a generalised
iterative
maximum likelihood approach to estimation and is briefly described below.
In the following part of this text, phenotypes will refer to multi-locus
genotypes with
unknown phase. Genotypes will refer to known-phase multi-locus genotypes.
Suppose a
sample ofN unrelated individuals typed for K markers. The data observed are
the unknown-
phase K-locus phenotypes that can categorised in F different phenotypes.
Suppose that we have
H underlying possible haplotypes (in case of K biallelic markers, H=2K).
~ For phenotype j, suppose that c~ genotypes are possible. We thus have the
following
equation
c; c;
P~ _ ~ pr(genotype; ) _ ~ pr(hk , hl ) Equation 1
i=1 i=1
where Pj is the probability of the phenotype j, hk and h, are the two
haplotypes constituent the
genotype i. Under the Hardy-Weinberg equilibrium, pr(h~,h~ becomes
pr(hg , h~ ) = pr(hk ) 2 if hk = h~ , pr(hk , hl ) = 2 pr(hk ). pr(hl ) if hk
~ h~ . Equation 2
The successive steps of the E-M algorithm can be described as follows:
Starting with initial values of the ofhaplotypes frequencies, noted
p~°~, pZ°~,....,pHO>,
these initial values serve to estimate the genotype frequencies (Expectation
step) and then
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estimate another set of haplotype frequencies (Maximisation step), noted p~'~,
pz'~,.....pH~ ,
these two steps are iterated until changes in the sets of haplotypes frequency
are very small.
A stop criterion can be that the maximum difference between haplotype
frequencies
between two iterations is less than 10-'. These values can be adjusted
according to the desired
precision of estimations. In details, at a given iteration s, the Expectation
step comprises
calculating the genotypes frequencies by the following equation:
pr(genotypel ) ~S) = pr( phenotypes ). pr(genotypel I phenotypes ) ~S)
n~ pr(hk ~ hl )~S) Eguation 3
1V . p(s)
i
where genotype i occurs in phenotype j, and where hk and h, constitute
genotype i. Each
probability is derived according to eq.l, and eq.2 described above.
Then the Maximisation step simply estimates another set of haplotype
frequencies
given the genotypes frequencies. This approach is also known as gene-counting
method (Smith,
1957).
Ci
pis+1) - 1 ~ ~ Bit -Pr(genotype; )~S) Equation 4
Where 8~r is an indicator variable which count the number of time haplotype t
in genotype i. It
takes the values of 0, 1 or 2.
To ensure that the estimation finally obtained is the maximum-likelihood
estimation
several values of departures are required. The estimations obtained are
compared and if they are
different the estimations leading to the best likelihood are kept.
3) Methods to calculate linkage disequilibrium between markers
A number of methods can be used to calculate linkage disequilibrium between
any two
genetic positions, in practice linkage disequilibrium is measured by applying
a statistical
association test to haplotype data taken from a population. Linkage
disequilibrium between any
pair of biallelic markers comprising at least one of the biallelic markers of
the present invention
(M;, M~) having alleles (a;/b;) at marker M; and alleles (a~/b~) at marker M~
can be calculated for
every allele combination (a;,a~ ; a;,b~; b;,a~ and b;,b~), according to the
Piazza formula
Da;aj= X94 - ~ (84 + 83) (84 +02), where
84= - - = frequency of genotypes not having allele a; at M; and not having
allele a~ at M~
83= - + = frequency of genotypes not having allele a; at M; and having allele
a~ at M~
82= + - = frequency of genotypes having allele a; at M; and not having allele
a~ at M~
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Linkage disequilibrium (LD) between pairs of biallelic markers (M;, M~) can
also be calculated
for every allele combination (ai,aj; ai,bj ; b;,a~ and b;,bj), according to
the maximum-likelihood
estimate (MLE) for delta (the composite genotypic disequilibrium coe~cient),
as described by
Weir (Weir B.S., 1996). The MLE for the composite linkage disequilibrium is:
Da;ate (2ni + n2 + n3 + n4/2)/N - 2(Pr(a;)~Pr(ai))
where ni = E phenotype (a;/a;, a~/a~), nz = E phenotype (a;/a;, aj/bj), n3= E
phenotype (a;/b;, aj/aj),
n4= E phenotype (a;/b;, a~/b~) and N is the number of individuals in the
sample. This formula
allows linkage disequilibrium between alleles to be estimated when only
genotype, and not
haplotype, data are available.
Another means of calculating the linkage disequilibrium between markers is as
follows.
For a couple of biallelic markers, M (alb;) and M (albs), fitting the Hardy-
Weinberg
equilibrium, one can estimate the four possible haplotype frequencies in a
given population
according to the approach described above.
The estimation of gametic disequilibrium between ai and aj is simply:
Daiaj = Pr(haplotype(al , a j )) - pr(a; ). pr(a j ).
Where pr(a~ is the probability of allele a; and pr(a~ is the probability of
allele a~ and where
pr(haplotype (a;, a~) is estimated as in Equation 3 above.
For a couple of biallelic marker only one measure of disequilibrium is
necessary to
describe the association between M and M:
Then a normalised value of the above is calculated as follows:
D'aiaj = Daiaj / max (-pr(a;).pr(aj) , -pr(b;).pr(bj)) lWlt~1 Daiaj<0
D'aiaj - Daiaj / max (pr(b;).pr(aj) , pr(a;).pr(bj)) Wlth Da;aj>O
The skilled person will readily appreciate that other LD calculation methods
can be used
without undue experimentation.
Linkage disequilibrium among a set of biallelic markers having an adequate
heterozygosity rate can be determined by genotyping between 50 and 1000
unrelated
individuals, preferably between 75 and 200, more preferably around 100.
4) Testing for association
Methods for determining the statistical significance of a correlation between
a
phenotype and a genotype, in this case an allele at a biallelic marker or a
haplotype made up of
such alleles, may be determined by any statistical test known in the art and
with any accepted
threshold of statistical significance being required. The application of
particular methods and
thresholds of significance are well with in the skill of the ordinary
practitioner of the art.
Testing for association is performed by determining the frequency of a
biallelic marker
allele in case and control populations and comparing these frequencies with a
statistical test to
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determine if their is a statistically significant difference in frequency
which would indicate a
correlation between the trait and the biallelic marker allele under study.
Similarly, a haplotype
analysis is performed by estimating the frequencies of all possible haplotypes
for a given set of
biallelic markers in case and control populations, and comparing these
frequencies with a
statistical test to determine if their is a statistically significant
correlation between the haplotype
and the phenotype (trait) under study. Any statistical tool useful to test for
a statistically
significant association between a genotype and a phenotype may be used.
Preferably the
statistical test employed is a chi-square test with one degree of freedom. A P-
value is calculated
(the P-value is the probability that a statistic as large or larger than the
observed one would
occur by chance).
Statistical significance
In preferred embodiments, significance for diagnosis purposes, either as a
positive basis
for further diagnostic tests or as a preliminary starting point for early
preventive therapy, the p
value related to a biallelic marker association is preferably about 1 x 10-Z
or less, more
preferably about 1 x 10~ or less, for a single biallelic marker analysis and
about 1 x 10-3 or less,
still more preferably 1 x 10-6 or less and most preferably of about 1 x 10-g
or less, for a
haplotype analysis involving several markers. These values are believed to be
applicable to any
association studies involving single or multiple marker combinations.
The skilled person can use the range of values set forth above as a starting
point in
order to carry out association studies with biallelic markers of the present
invention. In doing
so, significant associations between the biallelic markers of the present
invention and diseases
involving schizophrenia can be revealed and used for diagnosis and drug
screening purposes.
Phenotypic permutation
In order to confirm the statistical significance of the first stage haplotype
analysis
described above, it might be suitable to perform further analyses in which
genotyping data from
case-control individuals are pooled and randomised with respect to the trait
phenotype. Each
individual genotyping data is randomly allocated to two groups, which contain
the same number
of individuals as the case-control populations used to compile the data
obtained in the first
stage. A second stage haplotype analysis is preferably run on these artificial
groups, preferably
for the markers included in the haplotype of the first stage analysis showing
the highest relative
risk coefficient. This experiment is reiterated preferably at least between
100 and 10000 times.
The repeated iterations allow the determination of the percentage of obtained
haplotypes with a
significant p-value level.
Assessment of statistical association
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To address the problem of false positives similar analysis may be performed
with the
same case-control populations in random genomic regions. Results in random
regions and the
candidate region are compared as described in US Provisional Patent
Application entitled
"Methods, software and apparati for identifying genomic regions harbouring a
gene associated
S with a detectable trait".
5) Evaluation of risk factors
The association between a risk factor (in genetic epidemiology the risk factor
is the
presence or the absence of a certain allele or haplotype at marker loci) and a
disease is measured
by the odds ratio (OR) and by the relative risk (RR). If P(R+) is the
probability of developing
the disease for individuals with R and P(R-) is the probability for
individuals without the risk
factor, then the relative risk is simply the ratio of the two probabilities,
that is:
RR- P(R+)/P(R-)
In case-control studies, direct measures of the relative risk cannot be
obtained because of the
sampling design. However, the odds ratio allows a good approximation of the
relative risk for
low-incidence diseases and can be calculated:
OR = F+ F
I-F+ (1-F-)
F+ is the frequency of the exposure to the risk factor in cases and F- is the
frequency of the
exposure to the risk factor in controls. F+ and F~ are calculated using the
allelic or haplotype
frequencies of the study and further depend on the underlying genetic model
(dominant,
recessive, additive...).
One can further estimate the attributable risk (AR) which describes the
proportion of individuals
in a population exhibiting a trait due to a given risk factor. This measure is
important in
quantitating the role of a specific factor in disease etiology and in terms of
the public health
impact of a risk factor. The public health relevance of this measure lies in
estimating the
proportion of cases of disease in the population that could be prevented if
the exposure of
interest were absent. AR is determined as follows:
AR=PE (RR-1)/ (PE (RR-1)+1)
AR is the risk attributable to a biallelic marker allele or a biallelic marker
haplotype. PE is the
frequency of exposure to an allele or a haplotype within the population at
large; and RR is the
relative risk which, is approximated with the odds ratio when the trait under
study has a
relatively low incidence in the general population.
AR is the risk attributable to a biallelic marker allele or a biallelic marker
haplotype.
PE is the frequency of exposure to an allele or a haplotype within the
population at large; and
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RR is the relative risk which, is approximated with the odds ratio when the
trait under study has
a relatively low incidence in the general population.
Association of Biallelic Markers of the Invention with Schizophrenia
In the context of the present invention, an association between chromosome
13q31-q33-
related biallelic markers, including Region D biallelic markers, and
schizophrenia and bipolar
disorder were established. Several association studies using different
populations and screening
samples thereof, and with different sets of biallelic markers distributed on
the chromosome
13q31-q33 region and Region D thereof were carried out. Further details
concerning these
association studies and the results are provided herein in Examples Sa to Se.
This information is extremely valuable. The knowledge of a potential genetic
predisposition to schizophrenia, even if this predisposition is not absolute,
might contribute in a
very significant manner to treatment efficacy of schizophrenia and to the
development of new
therapeutic and diagnostic tools.
Identification Of Biallelic Markers In Linkage Disequilibrium With The
Biallelic
Markers of the Invention
Once a first biallelic marker has been identified in a genomic region of
interest, the
practitioner of ordinary skill in the art, using the teachings of the present
invention, can easily
identify additional biallelic markers in linkage disequilibrium with this
first marker. As
mentioned before, any marker in linkage disequilibrium with a first marker
associated with a
trait will be associated with the trait. Therefore, once an association has
been demonstrated
between a given biallelic marker and a trait, the discovery of additional
biallelic markers
associated with this trait is of great interest in order to increase the
density of biallelic markers
in this particular region. The causal gene or mutation will be found in the
vicinity of the marker
or set of markers showing the highest correlation with the trait.
Identification of additional markers in linkage disequilibrium with a given
marker
involves: (a) amplifying a genomic fragment comprising a first biallelic
marker from a plurality
of individuals; (b) identifying of second biallelic markers in the genomic
region harboring said
first biallelic marker; (c) conducting a linkage disequilibrium analysis
between said first
biallelic marker and second biallelic markers; and (d) selecting said second
biallelic markers as
being in linkage disequilibrium with said first marker. Subcombinations
comprising steps (b)
and (c) are also contemplated.
Methods to identify biallelic markers and to conduct linkage disequilibrium
analysis are
described herein and can be carried out by the skilled person without undue
experimentation.
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The present invention then also concerns biallelic markers and other
polymorphisms which are
in linkage disequilibrium with the specific biallelic markers of the invention
and which are
expected to present similar characteristics in terms of their respective
association with a given
trait. In a preferred embodiment, the invnetion concerns biallelic markers
which are in linkage
disequilibrium with the specific biallelic markers.
Identification Of Functional Mutations
Once a positive association is confirmed with a biallelic marker of the
present
invention, the associated candidate gene sequence can be scanned for mutations
by comparing
the sequences of a selected number of trait positive and trait negative
individuals. In a preferred
embodiment, functional regions such as exons and splice sites, promoters and
other regulatory
regions of the gene are scanned for mutations. Preferably, trait positive
individuals carry the
haplotype shown to be associated with the trait and trait negative individuals
do not carry the
haplotype or allele associated with the trait. The mutation detection
procedure is essentially
similar to that used for biallelic site identification.
The method used to detect such mutations generally comprises the following
steps: (a)
amplification of a region of the candidate DNA sequence comprising a biallelic
marker or a
group of biallelic markers associated with the trait from DNA samples of trait
positive patients
and trait negative controls; (b) sequencing of the amplified region; (c)
comparison of DNA
sequences from trait-positive patients and trait-negative controls; and (d)
determination of
mutations specific to trait-positive patients. Subcombinations which comprise
steps (b) and (c)
are specifically contemplated.
It is preferred that candidate polymorphisms be then verified by screening a
larger
population of cases and controls by means of any genotyping procedure such as
those described
herein, preferably using a microsequencing technique in an individual test
format.
Polymorphisms are considered as candidate mutations when present in cases and
controls at
frequencies compatible with the expected association results.
Candidate polymorphisms and mutations of the sbgl nucleic acid sequences
suspected
of being involved in a predisposition to schizophrenia can be confirmed by
screening a larger
population of affected and unaffected individuals using any of the genotyping
procedures
described herein. Preferably the microsequencing technique is used. Such
polymorphisms are
considered as candidate "trait-causing" mutations when they exhibit a
statistically significant
correlation with the detectable phenotype.
Biallelic Markers Of The Invention In Methods Of Genetic Diagnostics
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The biallelic markers and other polymorphisms of the present invention can
also be
used to develop diagnostics tests capable of identifying individuals who
express a detectable
trait as the result of a specific genotype or individuals whose genotype
places them at risk of
developing a detectable trait at a subsequent time. The trait analyzed using
the present
diagnostics may be any detectable trait, including predisposition to
schizophrenia, age of onset
of detectable symptoms, a beneficial response to or side effects related to
treatment against
schizophrenia. Such a diganosis can be useful in the monitoring, prognosis
and/or prophylactic
or curative therapy for schizophrenia.
The diagnostic techniques of the present invention may employ a variety of
methodologies to determine whether a test subject has a genotype associated
with an increased
risk of developing a detectable trait or whether the individual suffers from a
detectable trait as a
result of a particular mutation, including methods which enable the analysis
of individual
chromosomes for haplotyping, such as family studies, single sperm DNA analysis
or somatic
hybrids.
The diagnostic techniques concern the detection of specific alleles present
within the
human chromosome 13q31-q33 region; optionally within the Region D subregion;
and
optionally within an sbgl, g34665, sbg2, g35017 or g35018 nucleic acid
sequence. More
particularly, the invention concerns the detection of a nucleic acid
comprising at least one of the
nucleotide sequences of SEQ 1D Nos. 1 to 26, 36 to 40 and 54 to 229 or a
fragment thereof or a
complementary sequence thereto including the polymorphic base.
These methods involve obtaining a nucleic acid sample from the individual and,
determining, whether the nucleic acid sample contains at least one allele or
at least one biallelic
marker haplotype, indicative of a risk of developing the trait or indicative
that the individual
expresses the trait as a result of possessing a particular the human
chromosome 13q31-q33
region, Region D, sbgl, g34665, sbg2, g35017 or g35018-related polymorphism or
mutation
(trait-causing allele).
Preferably, in such diagnostic methods, a nucleic acid sample is obtained from
the
individual and this sample is genotyped using methods described above in
"Methods Of
Genotyping DNA Samples For Biallelic markers." The diagnostics may be based on
a single
biallelic marker or a on group of biallelic markers.
In each of these methods, a nucleic acid sample is obtained from the test
subject and the
biallelic marker pattern of one or more of the biallelic markers of the
invention is determined.
In one embodiment, a PCR amplification is conducted on the nucleic acid sample
to
amplify regions in which polymorphisms associated with a detectable phenotype
have been
identified. The amplification products are sequenced to determine whether the
individual
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possesses one or more human chromosome 13q31-q33 region, Region D, sbgl,
g34665, sbg2,
g35017 or g35018-related polymorphisms associated with a detectable phenotype.
The primers
used to generate amplification products may comprise the primers listed in
Table 6a.
Alternatively, the nucleic acid sample is subjected to microsequencing
reactions as described
above to determine whether the individual possesses one or more human
chromosome 13q31-
q33 region-related polymorphisms associated with a detectable phenotype
resulting from a
mutation or a polymorphism in the human chromosome 13q31-q33 region, Region D,
sbgl,
g34665, sbg2, g35017 or g35018-related biallelic marker. The primers used in
the
microsequencing reactions may include the primers listed in 6d. In another
embodiment, the
nucleic acid sample is contacted with one or more allele specific
oligonucleotide probes which,
specifically hybridize to one or more human chromosome 13q31-q33 region,
Region D, sbgl,
g34665, sbg2, g35017 or g35018-related alleles associated with a detectable
phenotype. The
probes used in the hybridization assay may include the probes listed in Table
6c. In another
embodiment, the nucleic acid sample is contacted with a second oligonucleotide
capable of
producing an amplification product when used with the allele specific
oligonucleotide in an
amplification reaction. The presence of an amplification product in the
amplification reaction
indicates that the individual possesses one or more human chromosome 13q31-q33
region,
Region D, sbgl, g34665, sbg2, g35017 or g35018-related alleles associated with
a detectable
phenotype.
In a preferred embodiment the identity of the nucleotide present at, at least
one, biallelic
marker selected from the group consisting of A1 to A69, A71 to A74, A76 to
A94, A96 to
A 106, A 108 to A 112, A 114 to A 177, A 179 to A 197, A 199 to A222, A224 to
A246, A250,
A251, A253, A255, A259, A266, A268 to A232, A328 to A360 and A361 to A489 and
the
complements thereof, is determined and the detectable trait is schizophrenia.
Diagnostic kits
comprise any of the polynucleotides of the present invention.
These diagnostic methods are extremely valuable as they can, in certain
circumstances,
be used to initiate preventive treatments or to allow an individual carrying a
significant
haplotype to foresee warning signs such as minor symptoms.
Diagnostics, which analyze and predict response to a drug or side effects to a
drug, may
be used to determine whether an individual should be treated with a particular
drug. For
example, if the diagnostic indicates a likelihood that an individual will
respond positively to
treatment with a particular drug, the drug may be administered to the
individual. Conversely, if
the diagnostic indicates that an individual is likely to respond negatively to
treatment with a
particular drug, an alternative course of treatment may be prescribed. A
negative response may
be defined as either the absence of an efficacious response or the presence of
toxic side effects.
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Clinical drug trials represent another application for the markers of the
present
invention. One or more markers indicative of response to an agent acting
against schizophrenia
or to side effects to an agent acting against schizophrenia may be identified
using the methods
described above. Thereafter, potential participants in clinical trials of such
an agent may be
screened to identify those individuals most likely to respond favorably to the
drug and exclude
those likely to experience side effects. In that way, the effectiveness of
drug treatment may be
measured in individuals who respond positively to the drug, without lowering
the measurement .
as a result of the inclusion of individuals who are unlikely to respond
positively in the study and
without risking undesirable safety problems.
PREVENTION, DIAGNOSIS AND TREATMENT OF PSYCHIATRIC DISEASE
An aspect of the present invention relates to the preparation of a medicament
for the
treatment of psychiatric disease, in particular schizophrenia and bipolar
disorder. The present
invention embodies medicaments acting on sbgl, g34665, sbg2, g35017 or g35018.
In preferred embodiments, medicaments of the invention act on sbgl, either
directly or
indirectly, by acting on the sbgl pathways. For example, the medicaments may
modulate, and
more preferably decrease the level of sbgl activity which occurs in a cell or
particular tissue, or
increase or descrease the activity ofthe sbgl protein. In certain embodiments,
the invention thus
comprises use of a compound capable of increasing or decreasing sbgl
expression or sbgl protein
activity in the preparation or manufacture of a medicament. Preferably, said
compound is used for
the treatment of a psychiatric disease, preferably for the treatment of
schizophrenia or bipolar
disorder. Preferably, said compound acts directly by binding to sbgl or an
sbgl receptor.
Such medicaments may also increase or decrease the activity of a compound
analogous to
sbgl, a compound comprising an amino acid sequence having at least 25%
homology to a
sequence selected from the group consisting of SEQ ID NOs. 27 to 35, a
compound comprising an
amino acid sequence having at least 50% homology to a sequence selected from
the group
consisting of SEQ ID NOs. 27 to 35, and a compound comprising an amino acid
sequence having
at least 80% homology to a sequence selected from the group consisting of SEQ
ID NOs. 27 to
35.
Medicaments which increase or descrease the activity of these compounds in an
individual may be used to ameliorate or prevent symptoms in individuals
suffering from or
predisposed to a psychiatric disease, as discussed above in the section
entitled "indications".
Alternatively, sbgl activity may be increased or decreasing by the expression
of the genes
encoding the identified sbgl-modulating compounds using gene therapy. Examples
of vectors
and promoters suitable for use in gene therapy are described above. Sbgl
activity may also be
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increased or decreased by preparing an antibody which binds to an sbgl
peptide, an sbgl receptor
or a protein related thereto, as well as fragments of these proteins. Such
antibodies may modulate
the interaction between sbgl and an sbgl receptor or a protein related
thereto. Antibodies and
methods of obtaining them are further described herein.
As described above, the present invention provides cellular assays for
identifying
compounds for the treatment of psychiatric disease. The assays are based on
detection of sbgl
expression, measurement of sbgl protein activity, or based on the
determination of other suitable
schizophrenia, bipolar disorder or related psychiatric disease endpoints.
Compounds for the
treatment of psychiatric disease include derivative proteins or peptides which
are capable of
inhibiting the activity of a wild type sbgl protein, which may be identified
by determining their
ability to bind a wild type sbgl protein. Compounds also include antibodies,
and small molecules
and drugs which may be obtained using a variety of synthetic approaches
familiar to those skilled
in the art, including combinatorial chemistry based techniques.
The invention further encompasses said methods for the prevention, treatment,
and
diagnosis of disease using any of the g34665, sbg2, g35017 or g35018 nucleic
acids of proteins
of the invention in analogous methods.
Sbgl in Methods of Diagnosis or Detecting Predisposition
Individuals affected by or predisposed to schizophrenia and bipolar disorder
may express
abnormal levels of sbgl, g34665, sbg2, g35017 or g35018. Individuals having
increased or
decreased sbgl, g34665, sbg2, g35017 or g35018 activity in their plasma, body
fluids, or body
tissues may be at risk of devloping schizophrenia, bipolar disorder or a
variety of potentially
related psychiatric conditions. In one aspect of the present invention is a
method for determining
whether an individual is at risk of suffering from or is currently suffering
from schizophrenia,
bipolar disorder or other psychotic disorders, mood disorders, autism,
substance dependence or
alcoholism, mental retardation, or other psychiatric diseases including
cognitive, anxiety, eating,
impulse-control, and personality disorders, as defined with the Diagnosis and
Statistical Manual of
Mental Disorders fourth edition (DSM-IV) classification, comprising
determining whether the
individual has an abnormal level of sbgl activity in plasma, body fluids, or
body tissues. The level
of sbgl or analogous compounds in plasma, body fluids, or body tissues may be
determined using
a variety approaches. In particular, the level may be determined using ELISA,
Western Blots, or
protein electrophoresis.
Biallelic Markers Of The Invention In Methods Of Genetic Diagnostics
The biallelic markers and other polymorphisms of the present invention can
also be
used to develop diagnostics tests capable of identifying individuals who
express a detectable
trait as the result of a specific genotype or individuals whose genotype
places them at risk of
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developing a detectable trait at a subsequent time. The trait analyzed using
the present
diagnostics may be used to diagnose any detectable trait, including
predisposition to
schizophrenia or bipolar disorder, age of onset of detectable symptoms, a
beneficial response to
or side effects related to treatment against schizophrenia or bipolar
disorder. Such a diagnosis
can be useful in the monitoring, prognosis and/or prophylactic or curative
therapy for
schizophrenia or bipolar disorder.
The diagnostic techniques of the present invention may employ a variety of
methodologies to determine whether a test subject has a genotype associated
with an increased
risk of developing a detectable trait or whether the individual suffers from a
detectable trait as a
result of a particular mutation, including methods which enable the analysis
of individual
chromosomes for haplotyping, such as family studies, single sperm DNA analysis
or somatic
hybrids.
The diagnostic techniques concern the detection of specific alleles present
within the
human chromosome 13q31-q33 region; optionally within the Region D subregion;
and
I S optionally within an sbgl, g34665, sbg2, g35017 or g35018 nucleic acid
sequence. More
particularly, the invention concerns the detection of a nucleic acid
comprising at least one of the
nucleotide sequences of SEQ ID Nos. 1 to 26, 36 to 40 and 54 to 229 or a
fragment thereof or a
complementary sequence thereto including the polymorphic base.
These methods involve obtaining a nucleic acid sample from the individual and,
determining, whether the nucleic acid sample contains at least one allele or
at least one biallelic
marker haplotype, indicative of a risk of developing the trait or indicative
that the individual
expresses the trait as a result of possessing a particular the human
chromosome 13q31-q33
region-related polymorphism or mutation (trait-causing allele).
Preferably, in such diagnostic methods, a nucleic acid sample is obtained from
the
individual and this sample is genotyped using methods described above in
"Methods Of
Genotyping DNA Samples For Biallelic markers." The diagnostics may be based on
a single
biallelic marker or a on group of biallelic markers.
In each of these methods, a nucleic acid sample is obtained from the test
subject and the
biallelic marker pattern of one or more of a biallelic marker of the invention
is determined.
In one embodiment, a PCR amplification is conducted on the nucleic acid sample
to
amplify regions in which polymorphisms associated with a detectable phenotype
have been
identified. The amplification products are sequenced to determine whether the
individual
possesses one or more human chromosome 13q31-q33 region, Region D, sbgl,
g34665, sbg2,
g35017 or g35018-related polymorphisms associated with a detectable phenotype.
The primers
used to generate amplification products may comprise the primers listed in
Table 6a.
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Alternatively, the nucleic acid sample is subjected to microsequencing
reactions as described
above to determine whether the individual possesses one or more human
chromosome 13q31-
q33 region, Region D, sbgl, g34665, sbg2, g35017 or g35018-related
polymorphisms
associated with a detectable phenotype resulting from a mutation or a
polymorphism in the
human chromosome 13q31-q33 region. The primers used in the microsequencing
reactions
may include the primers listed in Table 6d. In another embodiment, the nucleic
acid sample is
contacted with one or more allele specific oligonucleotide probes which,
specifically hybridize
to one or more human chromosome 13q31-q33 region, Region D, sbgl, g34665,
sbg2, g35017
or g35018-related alleles associated with a detectable phenotype. The probes
used in the
hybridization assay may include the probes listed in 6b. In another
embodiment, the nucleic
acid sample is contacted with a second oligonucleotide capable of producing an
amplification
product when used with the allele specific oligonucleotide in an amplification
reaction. The
presence of an amplification product in the amplification reaction indicates
that the individual
possesses one or more human chromosome 13q31-q33 region, Region D, sbgl,
g34665, sbg2,
g35017 or g35018-related alleles associated with a detectable phenotype. In a
preferred
embodiment, the detectable trait is schizophrenia or bipolar disorder.
Diagnostic kits comprise .
any of the polynucleotides of the present invention.
These diagnostic methods are extremely valuable as they can, in certain
circumstances,
be used to initiate preventive treatments or to allow an individual carrying a
significant
haplotype to foresee warning signs such as minor symptoms.
Diagnostics, which analyze and predict response to a drug or side effects to a
drug, may
be used to determine whether an individual should be treated with a particular
drug. For
example, if the diagnostic indicates a likelihood that an individual will
respond positively to
treatment with a particular drug, the drug may be administered to the
individual. Conversely, if
the diagnostic indicates that an individual is likely to respond negatively to
treatment with a
particular drug, an alternative course of treatment may be prescribed. A
negative response may
be defined as either the absence of an efficacious response or the presence of
toxic side effects.
Clinical drug trials represent another application for the markers of the
present
invention. One or more markers indicative of response to an agent acting
against schizophrenia
or to side effects to an agent acting against schizophrenia may be identified
using the methods
described above. Thereafter, potential participants in clinical trials of such
an agent may be
screened to identify those individuals most likely to respond favorably to the
drug and exclude
those likely to experience side effects. In that way, the effectiveness of
drug treatment may be
measured in individuals who respond positively to the drug, without lowering
the measurement
as a result of the inclusion of individuals who are unlikely to respond
positively in the study and
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without risking undesirable safety problems.
Prevention And Treatment Of Disease Using Biallelic Markers
In large part because of the risk of suicide, the detection of susceptibility
to
schizophrenia, bipolar disorder as well as other psychiatric disease in
individuals is very
important. Consequently, the invention concerns a method for the treatment of
schizophrenia or
bipolar disorder, or a related disorder comprising the following steps:
- selecting an individual whose DNA comprises alleles of a biallelic marker or
of a group of
biallelic markers ofthe human chromosome 13q31-q33 region, preferably Region D-
related
markers, and more preferably sbgl, g34665, sbg2, g35017 or g35018-related
markers associated
with schizophrenia or bipolar disorder;
- following up said individual for the appearance (and optionally the
development) of
the symptoms related to schizophrenia or bipolar disorder; and
- administering a treatment acting against schizophrenia or bipolar disorder
or against symptoms
thereof to said individual at an appropriate stage of the disease.
Another embodiment of the present invention comprises a method for the
treatment of
schizophrenia or bipolar disorder comprising the following steps:
- selecting an individual whose DNA comprises alleles of a biallelic marker or
of a
group of biallelic markers, of the human chromosome 13q31-q33 region,
preferably Region D
related markers, and more preferably sbgl, g34665, sbg2, g35017 or g35018-
related markers
associated with schizophrenia or bipolar disorder;
- administering a preventive treatment of schizophrenia or bipolar disorder to
said individual.
In a further embodiment, the present invention concerns a method for the
treatment of
schizophrenia or bipolar disorder comprising the following steps:
- selecting an individual whose DNA comprises alleles of a biallelic marker or
of a
group of biallelic markers of the human chromosome 13q31-q33, preferably
Region D-related
markers, and more preferably sbgl, g34665, sbg2, g35017 or g35018-related
markers associated
with schizophrenia or bipolar disorder;
- administering a preventive treatment of schizophrenia or bipolar disorder to
said
individual;
- following up said individual for the appearance and the development of
schizophrenia
or bipolar disorder symptoms; and optionally
- administering a treatment acting against schizophrenia or bipolar disorder
or against
symptoms thereof to said individual at the appropriate stage of the disease.
For use in the determination of the course of treatment of an individual
suffering from
disease, the present invention also concerns a method for the treatment of
schizophrenia or
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bipolar disorder comprising the following steps:
- selecting an individual suffering from schizophrenia or bipolar disorder
whose DNA
comprises alleles of a biallelic marker or of a group of biallelic markers of
the human
chromosome 13q31-q33 region, preferably Region D-related markers, and
preferably sbgl,
S g34665, sbg2, g35017 or g35018-related markers, associated with the gravity
of schizophrenia
or bipolar disorder or of the symptoms thereof; and
- administering a treatment acting against schizophrenia or bipolar disorder
or
symptoms thereof to said individual.
The invention also concerns a method for the treatment of schizophrenia or
bipolar
disorder in a selected population of individuals. The method comprises:
- selecting an individual suffering from schizophrenia or bipolar disorder and
whose
DNA comprises alleles of a biallelic marker or of a group of biallelic markers
of the human
chromosome 13q31-q33 region, preferably Region D-related markers, and more
preferably
sbgl, g34665, sbg2, g35017 or g35018-related markers associated with a
positive response to
treatment with an effective amount of a medicament acting against
schizophrenia or bipolar
disorder or symptoms thereof,
- and/or whose DNA does not comprise alleles of a biallelic marker or of a
group of
biallelic markers of the human chromosome 13q31-q33 region, preferably. Region
D-related
markers, and more preferably sbgl, g34665, sbg2, g35017 or g35018-related
markers associated
with a negative response to treatment with said medicament; and
- administering at suitable intervals an effective amount of said medicament
to said
selected individual.
In the context of the present invention, a "positive response" to a medicament
can be
defined as comprising a reduction of the symptoms related to the disease. In
the context of the
present invention, a "negative response" to a medicament can be defined as
comprising either a
lack of positive response to the medicament which does not lead to a symptom
reduction or
which leads to a side-effect observed following administration of the
medicament.
The invention also relates to a method of determining whether a subject is
likely to
respond positively to treatment with a medicament. The method comprises
identifying a first
population of individuals who respond positively to said medicament and a
second population
of individuals who respond negatively to said medicament. One or more
biallelic markers is
identified in the first population which is associated with a positive
response to said medicament
or one or more biallelic markers is identified in the second population which
is associated with a
negative response to said medicament. The biallelic markers may be identified
using the
techniques described herein.
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A DNA sample is then obtained from the subject to be tested. The DNA sample is
analyzed to determine whether it comprises alleles of one or more biallelic
markers associated
with a positive response to treatment with the medicament and/or alleles of
one or more biallelic
markers associated with a negative response to treatment with the medicament.
In some embodiments, the medicament may be administered to the subject in a
clinical
trial if the DNA sample contains alleles of one or more biallelic markers
associated with a
positive response to treatment with the medicament and/or if the DNA sample
lacks alleles of
one or more biallelic markers associated with a negative response to treatment
with the
medicament. In preferred embodiments, the medicament is a drug acting against
schizophrenia
or bipolar disorder.
Using the method of the present invention, the evaluation of drug efficacy may
be
conducted in a population of individuals likely to respond favorably to the
medicament.
Another.aspect of the invention is a method of using a medicament comprising
obtaining a DNA sample from a subject, determining whether the DNA sample
contains alleles
of one or more biallelic markers associated with a positive response to the
medicament and/or
whether the DNA sample contains alleles of one or more biallelic markers
associated with a
negative response to the medicament, and administering the medicament to the
subject if the
DNA sample contains alleles of one or more biallelic markers associated with a
positive
response to the medicament and/or if the DNA sample lacks alleles of one or
more biallelic
markers associated with a negative response to the medicament.
The invention also concerns a method for the clinical testing of a medicament,
preferably a medicament acting against schizophrenia or or bipolar disorder or
symptoms
thereof. The method comprises the following steps:
- administering a medicament, preferably a medicament susceptible of acting
against
schizophrenia or or bipolar disorder or symptoms thereof to a heterogeneous
population of
individuals,
- identifying a first population of individuals who respond positively to said
medicament and a second population of individuals who respond negatively to
said
medicament,
- identifying biallelic markers in said first population which are associated
with a
positive response to said medicament,
- selecting individuals whose DNA comprises biallelic markers associated with
a
positive response to said medicament, and
- administering said medicament to said individuals.
In any of the methods for the prevention, diagnosis and treatment of
schizophrenia and
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bipolar disorder, including methods of using a medicament, clinical testing of
a medicament,
determining whether a subject is likely to respond positively to treatment
with a medicament,
said biallelic marker may optionally comprise:
(a) a biallelic marker selected from the group consisting of biallelic markers
AI to
A489;
(b) a biallelic marker selected from the group consisting of biallelic markers
A1 to A69,
A71 to A74, A76 to A94, A96 to A 106, A 108 to A 112, A 114 to A 177, A 179 to
A 197, A 199 to
A222, A224 to A242, A250 to A251, A259 , A269 to A270, A278, A285 to A295,
A303 to
A307, A330, A334 to A335 and A346 to 357;
(c) a biallelic marker selected from the group consisting of biallelic markers
A1 to A69,
A71 to A74, A76 to A94, A96 to A 106, A 108 to A 112, A 114 to A 177, A I 79
to A 197, A 199 to
A222, A224 to A246, A250, A251, A253, A255, A259, A266, A268 to A232 and A328
to
A489;
(d) a biallelic marker selected from the group consisting of sbgl-related
markers A85 to
A219, or more preferably a biallelic marker selected from the group consisting
of sbgl-related
markers A85 to A94, A96 to A 106, A 108 to A 112, A 114 to A 177, A 179 to A
197 and A 199 to
A219;
(e) a biallelic marker selected from the group consisting of g34665-related
markers
A230 to A236;
(f) a biallelic marker selected from the group consisting of sbg2-related
markers A79 to
A99;
(g) the g35017-related biallelic marker A41;
(h) a biallelic marker selected from the group consisting of g35018-related
markers A1
to A39;
(i) a biallelic marker selected from the group consisting of A239, A227, A198,
A228,
A223, A 107, A218, A270, A75, A62, A65 and A70;
(j) a biallelic marker selected from the group consisting of A48, A60, A61,
A62, A65,
A70, A75, A76, A80, A107, A108, A198, A218, A221, A223, A227, A228, A239,
A285,
A286, A287, A288, A290, A292, A293, A295,A299 and A304;
(k) a biallelic marker selected from the group consisting of A304, A307, A305,
A298,
A292, A293, A291, A287, A286, A288, A289, A290, 99- A295 A299. A241, A239,
A228,
A227, A223, A221, A218, A 198, A 178, 99-24649/ 186 A 108, A 107, A80, A75,
A70, A65, and
A62; and/or
(1) a biallelic marker selected from the group consisting of A304, A307, A305,
A298,
A292, A293, A291, A287, A286, A288, A289, A290, A295 A299, A241, A239, A228,
A227,
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A223, A221, A218, A 198, A 178, A 108, A 107, A80, A76, A75, A70, A65, A62,
A61, A60
A48.
Such methods are deemed to be extremely useful to increase the benefibrisk
ratio
resulting from the administration of medicaments which may cause undesirable
side effects
and/or be inefficacious to a portion of the patient population to which it is
normally
administered.
Once an individual has been diagnosed as suffering from schizophrenia or
bipolar
disorder, selection tests are carried out to determine whether the DNA of this
individual
comprises alleles of a biallelic marker or of a group of biallelic markers
associated with a
positive response to treatment or with a negative response to treatment which
may include either
side effects or unresponsiveness.
The selection of the patient to be treated using the method of the present
invention can
be carried out through the detection methods described above. The individuals
which are to be
selected are preferably those whose DNA does not comprise alleles of a
biallelic marker or of a
1 S group of biallelic markers associated with a negative response to
treatment. The knowledge of
an individual's genetic predisposition to unresponsiveness or side effects to
particular
medicaments allows the clinician to direct treatment toward appropriate drugs
against
schizophrenia or bipolar disorder or symptoms thereof.
Once the patient's genetic predispositions have been determined, the clinician
can select
appropriate treatment for which negative response, particularly side effects,
has not been
reported or has been reported only marginally for the patient.
The biallelic markers of the invention have demonstrated an association with
schizophrenia and bipolar disorders. However, the present invention also
comprises any of the
prevention, diagnostic, prognosis and treatment methods described herein using
the biallelic
markers of the invention in methods of preventing, diagnosing, managing and
treating related
disorders, particularly related CNS disorders. By way of example, related
disorders may comprise
psychotic disorders, mood disorders, autism, substance dependence and
alcoholism, mental
retardation, and other psychiatric diseases including cognitive, anxiety,
eating, impulse-control,
and personality disorders, as defined with the Diagnosis and Statistical
Manual of Mental
Disorders fourth edition (DSM-IV) classification".
Recombinant Vectors
The term "vector" is used herein to designate either a circular or a linear
DNA or RNA
molecule, which is either double-stranded or single-stranded, and which
comprise at least one
polynucleotide of interest that is sought to be transferred in a cell host or
in a unicellular or
multicellular host organism.
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The present invention encompasses a family of recombinant vectors that
comprise a
polynucleotide derived from an sbgl, g34665, sbg2, g35017 or g35018 nucleic
acid sequence.
Consequently, the present invention further comprises recombinant vectors
comprising:
(a) sbgl genomic DNA or cDNAs comprised in the nucleic acids of any of
nucleotide
positions 215819 to 215941, 215819 to 215975, 216661 to 216952, 216661 to
217061, 217027
to 217061, 229647 to 229742, 230408 to 230721, 231272 to 231412, 231787 to
231880,
231870 to 231879, 234174 to 234321, 237406 to 237428, 239719 to 239807, 239719
to
239853, 240528 to 240569, 240528 to 240596, 240528 to 240617, 240528 to
240644, 240528
to 240824, 240528 to 240994, 240528 to 241685 and 240800 to 240993 of SEQ ID
No. 1, SEQ
ID Nos 2 to 26 and primate sbgl DNAs of SEQ ID Nos 54 to 111, and the
complements
thereof;
(b) g34665 genomic DNA or cDNAs comprised in the nucleic acids of any of
nucleotide positions 292653 to 292841, 295555 to 296047 and 295580 to 296047
of SEQ ID
No. 1, and the complements thereof;
(c) sbg2 genomic DNA or cDNAs comprised in the nucleic acids of any of
nucleotide
positions 201188 to 201234, 214676 to 214793, 215702 to 215746 and 216836 to
216915 of
SEQ ID No. 1, and the complements thereof;
(d) g35017 genomic DNA or cDNAs comprised in the nucleic acids of any of
nucleotide positions 94124 to 94964 of SEQ ID No. 1, and the complements
thereof;
(e) g35018 genomic DNA or cDNAs comprised in the nucleic acids of any of
nucleotide positions 1108 to 1289, 14877 to 14920, 18778 to 18862, 25593 to
25740, 29388 to
29502, 29967 to 30282, 64666 to 64812, and 65505 to 65853 of SEQ ID No. 1, and
the
complements thereof.
Generally, a recombinant vector of the invention may comprise any of the
polynucleotides described herein, as well as any sbgl, g34665, sbg2, g35017 or
g35018 primer
or probe as defined above.
In a first preferred embodiment, a recombinant vector of the invention is used
to
amplify the inserted polynucleotide derived from an sbgl, g34665, sbg2, g35017
or g35018
genomic sequence or cDNA of the invention in a suitable cell host, this
polynucleotide being
amplified at every time that the recombinant vector replicates.
A second preferred embodiment of the recombinant vectors according to the
invention
comprises expression vectors comprising either a regulatory polynucleotide or
a coding nucleic
acid of the invention, or both. Within certain embodiments, expression vectors
are employed to
express an sbgl, g34665, sbg2, g35017 or g35018 polypeptide which can be then
purified and,
for example be used in ligand screening assays or as an immunogen in order to
raise specific
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antibodies directed against an sbgl, g34665, sbg2, g35017 or g35018 protein.
In other
embodiments, the expression vectors are used for constructing transgenic
animals and also for
gene therapy. Expression requires that appropriate signals are provided in the
vectors, said
signals including various regulatory elements, such as enhancers/promoters
from both viral and
mammalian sources that drive expression of the genes of interest in host
cells. Dominant drug
selection markers for establishing permanent, stable cell clones expressing
the products are
generally included in the expression vectors of the invention, as they are
elements that link
expression of the drug selection markers to expression of the polypeptide.
More particularly, the present invention relates to expression vectors which
include
nucleic acids encoding an sbgl, g34665, sbg2, g35017 or g35018 protein or
variants or
fragments thereof, under the control of a regulatory sequence of the
respective sbgl, g34665,
sbg2, g35017 or g35018 regulatory polynucleotides, or alternatively under the
control of an
exogenous regulatory sequence.
The invention also pertains to a recombinant expression vector useful for the
expression
of a sbgl, g34665, sbg2, g35017 or g35018 cDNA sequence.
Recombinant vectors comprising a nucleic acid containing a human chromosome
13q31-33-related biallelic marker, preferably a Region D-related biallelic
marker or more
preferably an sbgl-, g34665-, sbg2-, g35017- or g35018-related biallelic
marker is also part of
the invention. In a preferred embodiment, said biallelic marker is selected
from the group
consisting of A1 to A489, and the complements thereof.
Some of the elements which can be found in the vectors of the present
invention are
described in further detail in the following sections.
1. General features of the expression vectors of the invention
A recombinant vector according to the invention comprises, but is not limited
to, a
YAC (Yeast Artificial Chromosome), a BAC (Bacterial Artificial Chromosome), a
phage, a
phagemid, a cosmid, a plasmid or even a linear DNA molecule which may comprise
a
chromosomal, non-chromosomal, semi-synthetic and synthetic DNA. Such a
recombinant
vector can comprise a transcriptional unit comprising an assembly of:
(1) a genetic element or elements having a regulatory role in gene expression,
for
example promoters or enhancers. Enhancers are cis-acting elements of DNA,
usually from
about 10 to 300 by in length that act on the promoter to increase the
transcription.
(2) a structural or coding sequence which is transcribed into mRNA and
eventually
translated into a polypeptide, said structural or coding sequence being
operably linked to the
regulatory elements described in (1); and
(3) appropriate transcription initiation and termination sequences. Structural
units
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intended for use in yeast or eukaryotic expression systems preferably include
a leader sequence
enabling extracellular secretion of translated protein by a host cell.
Alternatively, when a
recombinant protein is expressed without a leader or transport sequence, it
may include a N-
terminal residue. This residue may or may not be subsequently cleaved from the
expressed
recombinant protein to provide a final product.
Generally, recombinant expression vectors will include origins of replication,
selectable
markers permitting transformation of the host cell, and a promoter derived
from a highly
expressed gene to direct transcription of a downstream structural sequence.
The heterologous
structural sequence is assembled in appropriate phase with translation
initiation and termination
sequences, and preferably a leader sequence capable of directing secretion of
the translated
protein into the periplasmic space or the extracellular medium. In a specific
embodiment
wherein the vector is adapted for transfecting and expressing desired
sequences in mammalian
host cells, preferred vectors will comprise an origin of replication in the
desired host, a suitable
promoter and enhancer, and also any necessary ribosome binding sites,
polyadenylation site,
splice donor and acceptor sites, transcriptional termination sequences, and 5'-
flanking non-
transcribed sequences. DNA sequences derived from the SV40 viral genome, for
example
SV40 origin, early promoter, enhancer, splice and polyadenylation sites may be
used to provide
the required non-transcribed genetic elements.
The in vivo expression of an sbgl, g34665, sbg2, g35017 or g35018 polypeptide
or
fragments or variants thereof may be useful in order to correct a genetic
defect related to the
expression of the native gene in a host organism or to the production of a
biologically inactive
sbgl, g34665, sbg2, g35017 or g35018 protein.
Consequently, the present invention also comprises recombinant expression
vectors
mainly designed for the in vivo production of the sbgl, g34665, sbg2, g35017
or g35018
polypeptide by the introduction of the appropriate genetic material in the
organism of the patient
to be treated. In preferred embodiments, said genetic material comprises at
least one nucleotide
sequence selected from the group of nucleotide posittion ranges consisting of:
(a) sbgl genomic DNA or cDNAs comprised in the nucleic acids of any of
nucleotide
positions 215819 to 215941, 215819 to 215975, 216661 to 216952, 216661 to
217061, 217027
to 217061, 229647 to 229742, 230408 to 230721, 231272 to 231412, 231787 to
231880,
231870 to 231879, 234174 to 234321, 237406 to 237428, 239719 to 239807, 239719
to
239853, 240528 to 240569, 240528 to 240596, 240528 to 240617, 240528 to
240644, 240528
to 240824, 240528 to 240994, 240528 to 241685 and 240800 to 240993 of SEQ ID
No. l, SEQ
ID Nos 2 to 26 and primate sbgl DNAs of SEQ ID Nos. 54 to 11 I, and the
complements
thereof;
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(b) g34665 genomic DNA or cDNAs comprised in the nucleic acids of any of
nucleotide positions 292653 to 292841, 295555 to 296047 and 295580 to 296047
of SEQ ID
No. 1, and the complements thereof;
(c) sbg2 genomic DNA or cDNAs comprised in the nucleic acids of any of
nucleotide
positions 201188 to 201234, 214676 to 214793, 215702 to 215746 and 216836 to
216915 of
SEQ ID No. 1, and the complements thereof;
(d) g35017 genomic DNA or cDNAs comprised in the nucleic acids of any of
nucleotide positions 94124 to 94964 of SEQ ID No. 1, and the complements
thereof; and
(e) g35018 genomic DNA or cDNAs comprised in the nucleic acids of any of
nucleotide positions 1108 to 1289, 14877 to 14920, 18778 to 18862, 25593 to
25740, 29388 to
29502, 29967 to 30282, 64666 to 64812, and 65505 to 65853 of SEQ ID No. 1, and
the
complements thereof.
This genetic material may be introduced in vitro in a cell that has been
previously
extracted from the organism, the modified cell being subsequently reintroduced
in the said
I S organism, directly in vivo into the appropriate tissue.
2. Regulatory Elements
Promoters
The suitable promoter regions used in the expression vectors according to the
present
invention are chosen taking into account the cell host in which the
heterologous gene has to be
expressed. The particular promoter employed to control the expression of a
nucleic acid
sequence of interest is not believed to be important, so long as it is capable
of directing the
expression of the nucleic acid in the targeted cell. Thus, where a human cell
is targeted, it is
preferable to position the nucleic acid coding region adjacent to and under
the control of a
promoter that is capable of being expressed in a human cell, such as, for
example, a human or a
viral promoter.
A suitable promoter may be heterologous with respect to the nucleic acid for
which it
controls the expression or alternatively can be endogenous to the native
polynucleotide
containing the coding sequence to be expressed. Additionally, the promoter is
generally -
heterologous with respect to the recombinant vector sequences within which the
construct
promoter/coding sequence has been inserted.
Promoter regions can be selected from any desired gene using, for example, CAT
(chloramphenicol transferase) vectors and more preferably pKK232-8 and pCM7
vectors.
Preferred bacterial promoters are the LacI, LacZ, the T3 or T7 bacteriophage
RNA
polymerase promoters, the gpt, lambda PR, PL and trp promoters (EP 0036776),
the polyhedrin
promoter, or the p10 protein promoter from baculovirus (Kit Novagen) (Smith et
al., 1983;
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O'Reilly et al., 1992), the lambda PR promoter or also the trc promoter.
Eukaryotic promoters include CMV immediate early, HSV thymidine kinase, early
and
late SV40, LTRs from retrovirus, and mouse metallothionein-L. Selection of a
convenient
vector and promoter is well within the level of ordinary skill in the art.
The choice of a promoter is well within the ability of a person skilled in the
field of
genetic engineering. For example, one may refer to the book of Sambrook et
al.( 1989) or also
to the procedures described by Fuller et al.(1996).
Other re~ulatory elements
One will typically desire to include a polyadenylation signal to effect proper
polyadenylation of the gene transcript. The nature of the polyadenylation
signal is not believed
to be crucial to the successful practice of the invention, and any such
sequence may be '
employed such as human growth hormone and SV40 polyadenylation signals. Also
contemplated as an element of the expression cassette is a terminator. These
elements can serve
to enhance message levels and to minimize read through from the cassette into
other sequences.
The vector containing the appropriate DNA sequence as described above, more
preferably an sbgl gene regulatory polynucleotide, a polynucleotide encoding
an sbgl, g34665,
sbg2, g35017 or g35018 polypeptide comprising at least one nucleotide sequence
selected from
the group of nucleotide sequence ranges consisting of
(a) sbgl genomic DNA or cDNAs comprised in the nucleic acids of any of
nucleotide
positions 215819 to 215941, 215819 to 215975, 216661 to 216952, 216661 to
217061, 217027
to 217061, 229647 to 229742, 230408 to 230721, 231272 to 231412, 231787 to
231880,
231870 to 231879, 234174 to 234321, 237406 to 237428, 239719 to 239807, 239719
to
239853, 240528 to 240569, 240528 to 240596, 240528 to 240617, 240528 to
240644, 240528
to 240824, 240528 to 240994, 240528 to 241685 and 240800 to 240993 of SEQ ID
No. 1, SEQ
ID Nos 2 to 26 and primate sbgl DNAs or SEQ ID Nos. 54 to 11 I, and the
complements
thereof;
(b) g34665 genomic DNA or cDNAs comprised in the nucleic acids of any of
nucleotide positions 292653 to 292841, 295555 to 296047 and 295580 to 296047
of SEQ ID
No. 1, and the complements thereof;
(c) sbg2 genomic DNA or cDNAs comprised in the nucleic acids of any of
nucleotide
positions 201188 to 201234, 214676 to 214793, 215702 to 215746 and 216836 to
21691 S of
SEQ ID No. 1, and the complements thereof;
(d) g35017 genomic DNA or cDNAs comprised in the nucleic acids of any of
nucleotide positions 94124 to 94964 of SEQ ID No. 1, and the complements
thereof;
(e) g35018 genomic DNA or cDNAs comprised in the nucleic acids of any of
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nucleotide positions 1108 to 1289, 14877 to 14920, 18778 to 18862, 25593 to
25740, 29388 to
29502, 29967 to 30282, 64666 to 64812, and 65505 to 65853 of SEQ ID No. 1, and
the
complements thereof.
3. Selectable Markers
S Such markers would confer an identifiable change to the cell permitting easy
identification of cells containing the expression construct. The selectable
marker genes for
selection of transformed host cells are preferably dihydrofolate reductase or
neomycin
resistance for eukaryotic cell culture, TRPI for S. cerevisiae or
tetracycline, rifampicin or
ampicillin resistance in E. coli, or levan saccharase for mycobacteria, this
latter marker being a
negative selection marker.
4. Preferred Vectors.
Bacterial vectors
As a representative but non-limiting example, useful expression vectors for
bacterial
use can comprise a selectable marker and a bacterial origin of replication
derived from
commercially available plasmids comprising genetic elements of pBR322 (ATCC
37017). Such
commercial vectors include, for example, pKK223-3 (Pharmacia, Uppsala,
Sweden), and
GEM1 (Promega Biotec, Madison, WI, USA).
Large numbers of other suitable vectors are known to those of skill in the
art, and
commercially available, such as the following bacterial vectors: pQE70, pQE60,
pQE-9
(Qiagen), pbs, pDlO, phagescript, psiX174, pbluescript SK, pbsks, pNHBA,
pNHl6A,
pNHl8A, pNH46A (Stratagene); ptrc99a, pKK223-3, pKK233-3, pDR540, pRITS
(Pharmacia); pWLNEO, pSV2CAT, pOG44, pXTI, pSG (Stratagene); pSVK3, pBPV,
pMSG,
pSVL (Pharmacia); pQE-30 (QIAexpress).
Bacteriopha~e vectors
The P1 bacteriophage vector may contain large inserts ranging from about 80 to
about
100 kb.
The construction of Pl bacteriophage vectors such as p158 or p158/neo8 are
notably
described by Sternberg (1992, 1994). Recombinant P1 clones comprising sbgl
polynucleotide
sequences may be designed for inserting large polynucleotides of more than 40
kb (Linton et al.,
1993). To generate P1 DNA for transgenic experiments, a preferred protocol is
the protocol
described by McCormick et al.(1994). Briefly, E. coli (preferably strain
NS3529) harboring the
P1 plasmid are grown overnight in a suitable broth medium containing 25 pg/ml
of kanamycin.
The P1 DNA is prepared from the E. coli by alkaline lysis using the Qiagen
Plasmid Maxi kit
(Qiagen, Chatsworth, CA, USA), according to the manufacturer's instructions.
The P1 DNA is
purified from the bacterial lysate on two Qiagen-tip 500 columns, using the
washing and elution
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buffers contained in the kit. A phenol/chloroform extraction is then performed
before
precipitating the DNA with 70% ethanol. After solubilizing the DNA in TE (10
mM Tris-HC1,
pH 7.4, 1 mM EDTA), the concentration of the DNA is assessed by
spectrophotometry.
When the goal is to express a P1 clone comprising an sbgl polynucleotide
sequence in
a transgenic animal, typically in transgenic mice, it is desirable to remove
vector sequences
from the P1 DNA fragment, for example by cleaving the P1 DNA at rare-cutting
sites within the
P1 polylinker (SfiI, NotI or SaII). The P1 insert is then purified from vector
sequences on a
pulsed-field agarose gel, using methods similar using methods similar to those
originally
reported for the isolation of DNA from YACs (Schedl et al., 1993a; Peterson et
al., 1993, ). At
this stage, the resulting purified insert DNA can be concentrated, if
necessary, on a Millipore
Ultrafree-MC Filter Unit (Millipore, Bedford, MA, USA - 30,000 molecular
weight limit) and
then dialyzed against microinjection buffer (10 mM Tris-HC1, pH 7.4; 250 pM
EDTA)
containing 100 mM NaCI, 30 ~M spermine, 70 pM spermidine on a microdyalisis
membrane
(type VS, 0.025 pM from Millipore). The intactness of the purified Pl DNA
insert is assessed
by electrophoresis on 1% agarose (Sea Kem GTG; FMC Bio-products) pulse-field
gel and
staining with ethidium bromide.
Baculovirus vectors
A suitable vector for the expression of an sbgl polypeptide encoded by
polynucleotides
of SEQ ID No. 1 or fragments or variants thereof is a baculovirus vector that
can be propagated
in insect cells and in insect cell lines. A specific suitable host vector
system is the
pVL1392/1393 baculovirus transfer vector (Pharmingen) that is used to
transfect the SF9 cell
line (ATCC N°CRL 1711 ) which is derived from Spodoptera frugiperda.
Other suitable vectors for the expression of the sbgl polypeptide encoded by
the SEQ
ID No. 1 or fragments or variants thereof in a baculovirus expression system
include those
described by Chai et al.(1993), Vlasak et al.(1983) and Lenhard et al.(1996).
Viral vectors
In one specific embodiment, the vector is derived from an adenovirus.
Preferred
adenovirus vectors according to the invention are those described by Feldman
and Steg (1996)
or Ohno et al.(1994). Another preferred recombinant adenovirus according to
this specific
embodiment of the present invention is the human adenovirus type 2 or 5 (Ad 2
or Ad 5) or an
adenovirus of animal origin (French patent application N° FR-93.05954).
Retrovirus vectors and adeno-associated virus vectors are generally understood
to be
the recombinant gene delivery systems of choice for the transfer of exogenous
polynucleotides
in vivo, particularly to mammals, including humans. These vectors provide
efficient delivery of
genes into cells, and the transferred nucleic acids are stably integrated into
the chromosomal
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DNA of the host.
Particularly preferred retroviruses for the preparation or construction of
retroviral in
vitro or in vitro gene delivery vehicles of the present invention include
retroviruses selected
from the group consisting of Mink-Cell Focus Inducing Virus, Murine Sarcoma
Virus,
Reticuloendotheliosis virus and Rous Sarcoma virus. Particularly preferred
Murine Leukemia
V iruses include the 4070A and the 1504A viruses, Abelson (ATCC No VR-999),
Friend
(ATCC No VR-245), Gross (ATCC No VR-590), Rauscher (ATCC No VR-998) and
Moloney
Murine Leukemia Virus (ATCC No VR-190; PCT Application No WO 94/24298).
Particularly
preferred Rous Sarcoma Viruses include Bryan high titer (ATCC Nos VR-334, VR-
657, VR-
726, VR-659 and VR-728). Other preferred retroviral vectors are those
described in Roth et
al.(1996), PCT Application No WO 93/25234, PCT Application No WO 94/ 06920,
Roux et al.,
1989, Julan et al., 1992 and Neda et al., 1991.
Yet another viral vector system that is contemplated by the invention
comprises the
adeno-associated virus (AAV). The adeno-associated virus is a naturally
occurring defective
virus that requires another virus, such as an adenovirus or a herpes virus, as
a helper virus for
efficient replication and a productive life cycle (Muzyczka et al., 1992). It
is also one ofthe
few viruses that may integrate its DNA into non-dividing cells, and exhibits a
high frequency of
stable integration (Flotte et al., 1992; Samulski et al., 1989; McLaughlin et
al., 1989). One
advantageous feature of AAV derives from its reduced efficacy for transducing
primary cells
relative to transformed cells.
BAC vectors
The bacterial artificial chromosome (BAC) cloning system (Shizuya et al.,
1992) has
been developed to stably maintain large fragments of genomic DNA (100-300 kb)
in E. coli. A
preferred BAC vector comprises pBeIoBACl 1 vector that has been described by
Kim et
al.(1996). BAC libraries are prepared with this vector using size-selected
genomic DNA that
has been partially digested using enzymes that permit ligation into either the
Bam HI or HindIII
sites in the vector. Flanking these cloning sites are T7 and SP6 RNA
polymerase transcription
initiation sites that can be used to generate end probes by either RNA
transcription or PCR
methods. After the construction of a BAC library in E. coli, BAC DNA is
purified from the
host cell as a supercoiled circle. Converting these circular molecules into a
linear form precedes
both size determination and introduction of the BACs into recipient cells. The
cloning site is
flanked by two Not I sites, permitting cloned segments to be excised from the
vector by Not I
digestion. Alternatively, the DNA insert contained in the pBeIoBACl l vector
may be
linearized by treatment of the BAC vector with the commercially available
enzyme lambda
terminase that leads to the cleavage at the unique cosh site, but this
cleavage method results in a
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full length BAC clone containing both the insert DNA and the BAC sequences.
5. Delivery Of The Recombinant Vectors
In order to effect expression of the polynucleotides and polynucleotide
constructs of the
invention, these constructs must be delivered into a cell. This delivery may
be accomplished in
vitro, as in laboratory procedures for transforming cell lines, or in vivo or
ex vivo, as in the
treatment of certain diseases states.
One mechanism is viral infection where the expression construct is
encapsulated in an
infectious viral particle.
Several non-viral methods for the transfer of polynucleotides into cultured
mammalian
cells are also contemplated by the present invention, and include, without
being limited to,
calcium phosphate precipitation (Graham et al., 1973; Chen et al., 1987), DEAF-
dextran
(Gopal, 1985), electroporation (Tur-Kaspa et al., 1986; Potter et al., 1984),
direct
microinjection (Harland et al., 1985), DNA-loaded liposomes (Nicolau et al.,
1982; Fraley et
al., 1979), and receptor-mediate transfection (Wu and Wu, 1987; 1988). Some of
these
techniques may be successfully adapted for in vivo or ex vivo use.
Once the expression polynucleotide has been delivered into the cell, it may be
stably
integrated into the genome of the recipient cell. This integration may be in
the cognate location
and orientation via homologous recombination (gene replacement) or it may be
integrated in a
random, non specific location (gene augmentation). In yet further embodiments,
the nucleic
acid may be stably maintained in the cell as a separate, episomal segment of
DNA. Such
nucleic acid segments or "episomes" encode sequences sufficient to permit
maintenance and
replication independent of or in synchronization with the host cell cycle.
One specific embodiment for a method for delivering a protein or peptide to
the interior
of a cell of a vertebrate in vivo comprises the step of introducing a
preparation comprising a
physiologically acceptable carrier and a naked polynucleotide operatively
coding for the
polypeptide of interest into the interstitial space of a tissue comprising the
cell, whereby the
naked polynucleotide is taken up into the interior of the cell and has a
physiological effect. This
is particularly applicable for transfer in vitro but it may be applied to in
vivo as well.
Compositions for use in vitro and in vivo comprising a "naked" polynucleotide
are
described in PCT application N° WO 90/11092 (Vical Inc.) and also in
PCT application No.
WO 95/11307 (Institut Pasteur, INSERM, Universite d'Ottawa) as well as in the
articles of
Tacson et al.( 1996) and of Huygen et al.( 1996).
In still another embodiment of the invention, the transfer of a naked
polynucleotide of
the invention, including a polynucleotide construct of the invention, into
cells may be proceeded
with a particle bombardment (biolistic), said particles being DNA-coated
microprojectiles
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accelerated to a high velocity allowing them to pierce cell membranes and
enter cells without
killing them, such as described by Klein et al.(1987).
In a further embodiment, the polynucleotide of the invention may be entrapped
in a
liposome (Ghosh and Bacchawat, 1991; Wong et al., 1980; Nicolau et al., 1987).
In a specific embodiment, the invention provides a composition for the in vivo
production of the sbgl, g34665, sbg2, g35017 and g35018 protein or polypeptide
described
herein. It comprises a naked polynucleotide operatively coding for this
polypeptide, in solution
in a physiologically acceptable carrier, and suitable for introduction into a
tissue to cause cells
of the tissue to express the said protein or polypeptide.
The amount of vector to be injected to the desired host organism varies
according to the
site of injection. As an indicative dose, it will be injected between 0,1 and
100 pg of the vector
in an animal body, preferably a mammal body, for example a mouse body.
In another embodiment of the vector according to the invention, it may be
introduced in
vitro in a host cell, preferably in a host cell previously harvested from the
animal to be treated
and more preferably a somatic cell such as a muscle cell. In a subsequent
step, the cell that has
been transformed with the vector coding for the desired sbgl polypeptide or
the desired
fragment thereof is reintroduced into the animal body in order to deliver the
recombinant
protein within the body either locally or systemically.
Cell Hosts
Another object of the invention comprises a host cell that have been
transformed or
transfected with one of the polynucleotides described herein, and more
precisely a
polynucleotide comprising an sbgl polynucleotide selected from the group
consisting of SEQ
ID Nos. 1 to 26, 36 to 40 and 54 to 229, or a fragment or a variant thereof.
Are included host
cells that are transformed (prokaryotic cells) or that are transfected
(eukaryotic cells) with a
recombinant vector such as one of those described above.
Generally, a recombinant host cell of the invention comprises any one of the
polynucleotides or the recombinant vectors described therein.
Preferred host cells used as recipients for the expression vectors of the
invention are the
following:
a) Prokaryotic host cells: Escherichia coli strains (LE.DHS-a strain),
Bacillus subtilis,
Salmonella typhimurium, and strains from species like Pseudomonas,
Streptomyces and
Staphylococcus.
b) Eukaryotic host cells: HeLa cells (ATCC N°CCL2; N°CCL2.1;
N°CCL2.2), Cv I
cells (ATCC N°CCL70), COS cells (ATCC N°CRL1650;
N°CRL1651), Sf 9 cells (ATCC
N°CRL1711), C127 cells (ATCC N° CRL-1804), 3T3 (ATCC N°
CRL-6361), CHO (ATCC N°
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CCL-61), human kidney 293. (ATCC N° 45504; N° CRL-1573) and
BHK (ECACC N°
84100501; N° 84111301).
c) Other mammalian host cells.
Sbgl, g34665, sbg2, g35017 and g35018 gene expression in mammalian, and
typically
human, cells may be rendered defective with the replacement of an sbgl nucleic
acid
counterpart in the genome of an animal cell by an sbgl polynucleotide
according to the
invention. These genetic alterations may be generated by homologous
recombination events
using specific DNA constructs that have been previously described.
One kind of cell hosts that may be used are mammal zygotes, such as murine
zygotes.
For example, murine zygotes may undergo microinjection with a purified DNA
molecule of
interest, for example a purified DNA molecule that has previously been
adjusted to a
concentration range from 1 ng/ml -for BAC inserts- 3 ng/pl -for P1
bacteriophage inserts- in 10
mM Tris-HCI, pH 7.4, 250 pM EDTA containing 100 mM NaCI, 30 pM spermine, and70
pM
spermidine. When the DNA to be microinjected has a large size, polyamines and
high salt
concentrations can be used in order to avoid mechanical breakage of this DNA,
as described by
Schedl et al (1993b).
Any of the polynucleotides of the invention, including the DNA constructs
described
herein, may be introduced in an embryonic stem (ES) cell line, preferably a
mouse ES cell line.
ES cell lines are derived from pluripotent, uncommitted cells of the inner
cell mass of pre-
implantation blastocysts. Preferred ES cell lines are the following: ES-
E14TG2a (ATCC n°
CRL-1821), ES-D3 (ATCC n° CRL1934 and n° CRL-11632), YS001 (ATCC
n° CRL-11776),
36.5 (ATCC n° CRL-11116). To maintain ES cells in an uncommitted state,
they are cultured
in the presence of growth inhibited feeder cells which provide the appropriate
signals to
preserve this embryonic phenotype and serve as a matrix for ES cell adherence.
Preferred
feeder cells are primary embryonic fibroblasts that are established from
tissue of day 13- day 14
embryos of virtually any mouse strain, that are maintained in culture, such as
described by
Abbondanzo et al.(1993) and are inhibited in growth by irradiation, such as
described by
Robertson ( 1987), or by the presence of an inhibitory concentration of LIF,
such as described by
Pease and Williams (1990).
The constructs in the host cells can be used in a conventional manner to
produce the
gene product encoded by the recombinant sequence.
Following transformation of a suitable host and growth of the host to an
appropriate cell
density, the selected promoter is induced by appropriate means, such as
temperature shift or
chemical induction, and cells are cultivated for an additional period.
Cells are typically harvested by centrifugation, disrupted by physical or
chemical
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means, and the resulting crude extract retained for further purification.
Microbial cells employed in the expression of proteins can be disrupted by any
convenient method, including freeze-thaw cycling, sonication, mechanical
disruption, or use of
cell lysing agents. Such methods are well known by the skill artisan.
Transgenic Animals
The terms "transgenic animals" or "host animals" are used herein designate
animals that
have their genome genetically and artificially manipulated so as to include
one of the nucleic
acids according to the invention. Preferred animals are non-human mammals and
include those
belonging to a genus selected from Mus (e.g. mice), Rattus (e.g. rats) and
Oryctogalus (e.g.
rabbits) which have their genome artificially and genetically altered by the
insertion of a
nucleic acid according to the invention. 1n one embodiment, the invention
encompasses non-
human host mammals and animals comprising a recombinant vector ofthe invention
or an sbgl,
g34665, sbg2, g35017 or g35018 gene disrupted by homologous recombination with
a knock
out vector. The invention also encompasses non-human primates comprising a
recombinant
vector of the invention or an sbgl, g34665, sbg2, g35017 or g35018 gene
disrupted by
homologous recombination with a knock out vector.
The transgenic animals of the invention all include within a plurality of
their cells a
cloned recombinant or synthetic DNA sequence, more specifically one of the
purified or
isolated nucleic acids comprising an sbgl, g34665, sbg2, g35017 or g35018
polynucleotide or a
DNA sequence encoding an antisense polynucleotide such as described in the
present
specification.
Generally, a transgenic animal according the present invention comprises any
one of the
polynucleotides, the recombinant vectors and the cell hosts described in the
present invention.
In a first preferred embodiment, these transgenic animals may be good
experimental
models in order to study the diverse pathologies related to cell
differentiation, in particular
concerning the transgenic animals within the genome of which has been inserted
one or several
copies of a polynucleotide encoding a native sbgl, g34665, sbg2, g35017 or
g35018 protein, or
alternatively a mutant sbgl, g34665, sbg2, g35017 or g35018 protein.
In a second preferred embodiment, these transgenic animals may express a
desired
polypeptide of interest under the control of regulatory polynucleotides which
lead to good
yields in the synthesis of this protein of interest, and optionally a tissue
specific expression of
this protein of interest.
The design of the transgenic animals of the invention may be made according to
the
conventional techniques well known from the one skilled in the art. For more
details regarding
the production of transgenic animals, and specifically transgenic mice, it may
be referred to US
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Patents Nos 4,873,191, issued Oct. 10, 1989; 5,464,764 issued Nov 7, 1995; and
5,789,215,
issued Aug 4, 1998.
Transgenic animals of the present invention are produced by the application of
procedures which result in an animal with a genome that has incorporated
exogenous genetic
material. The procedure involves obtaining the genetic material, or a portion
thereof, which
encodes either an sbgl, g34665, sbg2, g35017 or g35018 polynucleotide or
antisense
polynucleotide such as described in the present specification.
A recombinant polynucleotide of the invention is inserted into an embryonic or
ES stem
cell line. The insertion is preferably made using electroporation, such as
described by Thomas
et al.(1987). The cells subjected to electroporation are screened (e.g. by
selection via selectable
markers, by PCR or by Southern blot analysis) to find positive cells which
have integrated the
exogenous recombinant polynucleotide into their genome, preferably via an
homologous
recombination event. An illustrative positive-negative selection procedure
that may be used
according to the invention is described by Mansour et al.(1988).
I S Then, the positive cells are isolated, cloned and injected into 3.5 days
old blastocysts
from mice, such as described by Bradley (1987). The blastocysts are then
inserted into a female
host animal and allowed to grow to term.
Alternatively, the positive ES cells are brought into contact with embryos at
the 2.5
days old 8-16 cell stage (morulae) such as described by Wood et al.(1993) or
by Nagy et
al.(1993), the ES cells being internalized to colonize extensively the
blastocyst including the
cells which will give rise to the germ line.
The offspring of the female host are tested to determine which animals are
transgenic
e.g. include the inserted exogenous DNA sequence and which are wild-type.
Thus, the present invention also concerns a transgenic animal containing a
nucleic acid,
a recombinant expression vector or a recombinant host cell according to the
invention.
Recombinant Cell Lines Derived From The Transgenic Animals Of The Invention.
A further object of the invention comprises recombinant host cells obtained
from a
transgenic animal described herein. In one embodiment the invention
encompasses cells
derived from non-human host mammals and animals comprising a recombinant
vector of the
invention or a gene comprising an sbgl, g34665, sbg2, g35017 or g35018 nucleic
acid sequence
disrupted by homologous recombination with a knock out vector.
Recombinant cell lines may be established in vitro from cells obtained from
any tissue
of a transgenic animal according to the invention, for example by transfection
of primary cell
cultures with vectors expressing onc-genes such as SV40 large T antigen, as
described by Chou
(1989) and Shay et al.(1991).
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Assays For Identification Of Compounds For Treatment Of Schizophrenia And
Bipolar Disorder
The present invention provides assays which may be used to test compounds for
their
ability to treat CNS disorders, and in particular, to ameliorate symptoms of a
CNS disorder
mediated by sbgl, g34665, sbg2, g35017 or g35018. In preferred embodiments,
compounds
tested for their ability to ameliorate syptoms of schizophrenia or bipolar
disorder mediated by
sbgl, g34665, sbg2, g35017 or g35018. Compounds may also be tested for their
ability to treat
related disorders, including among others psychotic disorders, mood disorders,
autism, substance
dependence and alcoholism, mental retardation, and other psychiatric diseases
including
cognitive, anxiety, eating, impulse-control, and personality disorders, as
defined with the
Diagnosis and Statistical Manual of Mental Disorders fourth edition (DSM-N)
classification.
The present invention also provides cell and animal, including primate and
mouse, models
of schizophrenia, bipolar disorder and related disorders.
In one aspect, provided are non-cell based, cell based and animal based assays
for the
identification of such compounds that affect sbgl activity. Sbgl activity may
be affected by
any mechanism; in certain embodiments, sbgl activity is affected by
modulating. sbgl gene
expression or the activity of the sbgl gene product.
The present methods allow the identification of compounds that affect sbgl
activity
directly or indirectly. Thus, the non-cell based, cell based and animal:
assays of the present
invention may also be used to identify compounds that act on an element of a
sbgl pathway
other than sbgl itself. These compounds can then be used as a therapeutic
treatment to
modulate sbgl and other gene products involved in schizophrenia, bipolar
disorder and related
disorders.
Cell and non-cell based assays
In one aspect, cell based assays using recombinant or non-recombinant cells
may be
used to identify compounds which modulate sbgl activity.
In one aspect, a cell based assay of the invention encompasses a method for
identifying
a test compound for the treatment of schizophrenia or bipolar disorder
comprising (a) exposing
a cell to a test compound at a concentration and time sufficient to ameliorate
an endpoint related
to schizophrenia or bipolar disorder, and (b) determining the level of sbgl
activity in a cell.
Sbgl activity can be measured, for example, by assaying a cell for mRNA
transcript level, sbgl
peptide expression, localization or protein activity. Preferably the test
compound is a
compound capable of or suspected to be capable of ameliorating a symptom of
schizophrenia,
bipolar disorder or a related disorder. Test compounds capable of modulating
sbgl activity may
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be selected for use in developing medicaments. Such cell based assays are
further described
herein in the section titled "Method For Screening Ligands That Modulate The
Expression Of
The sbgl, g34665, sbg2, g35017 and g35018 Gene."
In another aspect, a cell based assay of the invention encompasses a method
for
identifying a compound for the treatment of schizophrenia or bipolar disorder
comprising (a)
exposing a cell to a level of sbgl activity sufficient to cause a
schizophrenia-related or bipolar
disorder-related endpoint, and (b) exposing said cell to a test compound. A
test compound can
then be selected according to its ability to ameliorate said schizophrenia-
related or bipolar
disorder-related endpoints. sbgl activity may be provided by any suitable
method, including
but not limited to providing a vector containing an sbgl nucleotide sequence,
treating said cell
with a compound capable of increasing sbgl expression and treating said cell
with an sbgl
peptide. Preferably said cell is treated with an sbgl peptide comprising a
contiguous span of at
least 4 amino acids of SEQ ID Nos. 27 to 35; most preferably said sbgl peptide
comprises
amino acid positions 124 to 153 of SEQ ID No 34, as described in Example 7.
Preferably the
1 S test compound is a compound capable of or suspected to be capable of
ameliorating a symtpom
of schizophrenia, bipolar disorder or a related disorder; alternatively, the
test compound is
suspected of exacerbating an endpoint schizophrenia, bipolar disorder or a
related disorder. A
test compound capable of ameliorating any detectable symptom or endpoint of a
schizophrenia,
bipolar disorder or a related disorder may be selected for use in developing
medicaments.
In another embodiment, the invention provides cell and non-cell based assays
to sbgl to
determine whether sbg peptides bind to the cell surface, and to identify
compounds for the
treatment of schizophrenia, bipolar disorder and related disorders that
interact with an sbgl
receptor. In one such embodiment, an sbgl polynucleotide, or fragments
thereof, is cloned into
expression vectors such as those described herein. The proteins are purified
by size, charge,
immunochromatography or other techniques familiar to those skilled in the art.
Following
purification, the proteins are labeled using techniques known to those skilled
in the art. The
labeled proteins are incubated with cells or cell lines derived from a variety
of organs or tissues
to allow the proteins to bind to any receptor present on the cell surface.
Following the
incubation, the cells are washed to remove non-specifically bound protein. The
labeled proteins
are detected by autoradiography. Alternatively, unlabeled proteins may be
incubated with the
cells and detected with antibodies having a detectable label, such as a
fluorescent molecule,
attached thereto. Specificity of cell surface binding may be analyzed by
conducting a
competition analysis in which various amounts of unlabeled protein are
incubated along with
the labeled protein. The amount of labeled protein bound to the cell surface
decreases as the
amount of competitive unlabeled protein increases. As a control, various
amounts of an
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unlabeled protein unrelated to the labeled protein is included in some binding
reactions. The
amount of labeled protein bound to the cell surface does not decrease in
binding reactions
containing increasing amounts of unrelated unlabeled protein, indicating that
the protein
encoded by the nucleic acid binds specifically to the cell surface.
S In another embodiment, the present invention comprises non-cell based
binding assays,
wherein an sbgl polypeptide is prepared and purified as in cell based binding
assays described
above. Following purification, the proteins are labeled and incubated with a
cell membrane
extract or isolate derived from any desired cells from any organs, tissue or
combination of
organs or tissues of interest to allow the sbgl polypeptide to bind to any
receptor present on a
membrane. Following the incubation, the membranes are washed to remove non-
specifically
bound protein. The labeled proteins may be detected by autoradiography.
Specificity of
membrane binding of sbgl may be analyzed by conducting a competition analysis
in which
various amounts of a test compound are incubated along with the labeled
protein. Any desired
test compound, including test polypeptides, can be incubated with the cells.
The test
compounds may be detected with antibodies having a detectable label, such as a
fluorescent
molecule, attached thereto. The amount of labeled sbgl polypeptide bound to
the cell surface
decreases as the amount of competitive test compound increases. As a control,
various amounts
of an unlabeled protein or a compound unrelated to the test compound is
included in some
binding reactions. Test compounds capable of reducing the amount of sbgl bound
to cell
membranes may be selected as a candidate therapeutic compound.
In preferred embodiments ofthe cell and non-cell based assays, said sbgl
peptide
comprising a contiguous span of at least 4 amino acids of SEQ ID Nos. 27 to
35; most
preferably said sbgl peptide comprises amino acid positions 124 to 153 of SEQ
ID No 34.
Said cell based assays may comprise cells of any suitable origin; particularly
preferred
cells are human cells, primate cells, non-human primate cells and mouse cells.
If non-human
primate cells are used, the sbgl may comprise a nucleotide sequence or be
encoded by a
nucleotide sequence according to the primate nucleic acid sequences of SEQ ID
No. 54 to 111,
or a sequence complementary thereto or a fragment thereof.
Animal model based assay
Non-human animal based assays may also be used to identify compounds which
modulate sbgl activity. The invention encompasses animal models and animal
based assays
suitable, including non-transgenic or transgenic animals, including animals
containing a human
or altered form of the sbgl gene.
Thus, the present invention comprises treating an animal affected by
schizophrenia or
bipolar disorder or symptoms thereof with a test compound capable of directly
or indirectly
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modulating sbgl activity.
In one aspect, an animal based assay of the invention encompasses a method for
identifying a test compound for the treatment of schizophrenia or bipolar
disorder comprising
(a) exposing an animal to a test compound at a concentration and time
sufficient to ameliorate
an endpoint related to schizophrenia or bipolar disorder, and (b) determining
the level of sbgl
activity at a site in said animal. Sbgl activity can be measured in any
suitable cell, tissue or
site. Preferably the test compound is a compound capable of or suspected to be
capable of
ameliorating a symptom of schizophrenia, bipolar disorder or a related
disorder. Optionally.
said test compound is capable or suspected to be capable of modulating sbgl
activity. Test
compounds capable of modulating sbgl activity may be selected for use in
developing
medicaments.
In another aspect, a animal based assay of the invention encompasses a method
for
identifying a compound for the treatment of schizophrenia or bipolar disorder
comprising (a)
exposing an animal to a level of sbgl activity sufficient to cause a
schizophrenia-related or
bipolar disorder-related symptom or endpoint, and (b) exposing said animal to
a test compound.
A test compound can then be selected according to its ability to ameliorate
said schizophrenia-
related or bipolar disorder-related endpoints. sbgl activity may be provided
by any suitable
method, including but not limited to providing a vector containing. an sbgl
nucleotide sequence,
treating said animal with a compound capable of increasing sbgl expression and
treating said
cell with an sbgl peptide. Preferably, said animal is treated with an sbgl
peptide comprising a .
contiguous span of at least 4 amino acids of SEQ ID Nos. 27 to 35; most
preferably said sbgl
peptide comprises amino acid positions 124 to 153 of SEQ ID No 34, as
described in Example
7. Preferably the test compound is a compound capable of or suspected to be
capable of
ameliorating a symptom of schizophrenia, bipolar disorder or a related
disorder; alternatively,
the test compound is suspected of exacerbating a symptom of schizophrenia,
bipolar disorder or
a related disorder. A test compound capable of ameliorating any detectable
symptom or
endpoint of a schizophrenia, bipolar disorder or a related disorder may be
selected for use in
developing medicaments.
Any suitable animal may be used. Preferably, said animal is a primate, a non-
human
primate, a mammal, or a mouse.
In one embodiment, a mouse is treated with an sbgl peptide, exposed to a test
compound, and symptoms indicative of schizophrenia, bipolar disorder or a
related disorder are
assessed by observing stereotypy. In other embodiments, said symptoms are
assessed by
performing at least one test from the group consisting of home cage
observation, neurological
evaluation, stress-induced hypothermia, forced swim, PTZ seizure, locomotor
activity, tail
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suspension, elevated plus maze, novel object recognition, prepulse inhibition,
thermal pain, Y-
maze, and metabolic chamber tests (PsychoscreenT"' tests available from
Psychogenics Inc.).
Other tests are known in Crawley et al, Horm. Behav. 31(3):197-211 (1997);
Crawley, Brain
Res 835(1):18-26 (1999) for example.
In one example, the present inventors have tested sbgl peptides by injection
into mice.
An sbgl peptide comprising amino acid positions 124 to 153 of SEQ ID No 34 was
injected
peritoneally into adult mice as described herein in Example 7. Upon
observation, mice injected
with the sbgl peptide exhibited a decrease in the frequency of their movements
over the time
course of the experiment. Figure 18 demonstrates (left top panel of the
figure) a comparison of
the average number of movements in 3 separate time points (S, 10, and 15 min)
with the
average movements per min in the last period of observations (30, 35, 40, and
45 min). The
sbgl peptide also increased stereotypy - this effect was most prominent during
the last period of
observations. Because the onset of stereotypy was variable, data are presented
as the average of
stereotypy for observations over the entire time period.
The present inventors have also determined that the sbgl gene exists in
several non-
human primates. In a preferred embodiment of the animal models and drug
screening assays of
the invention, a non-human primate is treated with an sbgl peptide and exposed
to a test
compound, wherein said sbgl peptide is encoded by a nucleotide sequence
according to the
primate nucleic acid sequences of SEQ ID No. 54 to 111, or a sequence
complementary thereto
or a fragment thereof.
Any suitable test compound may be used with the screening methods of the
invention.
Examples of compounds that may be screened by the methods of the present
invention include
small organic or inorganic molecules, nucleic acids, including polynucleotides
from random and
directed polynucleotide libraries, peptides, including peptides derived from
random and directed
peptide libraries, soluble peptides, fusion peptides, and phosphopeptides,
antibodies including
polyclonal, monoclonal, chimeric, humanized, and anti-idiotypic antibodies,
and single chain
antibodies, FAb, F(ab')2 and FAb expression library fragments, and epitope-
binding fragments
thereof. In certain aspects, a compound capable of ameliorating or
exacerbating a symptom or
endpoint of schizophrenia, bipolar disorder or a related disorder may include,
by way of
example, antipsychotic drugs in general, neuroleptics, atypical neuroleptics,
antidepressants,
anti-anxiety drugs, noradrenergic agonists and antagonists, dopaminergic
agonists and
antagonists, serotonin reuptake inhibitors, benzodiazepines.
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Methods for screening substances interacting with an sbgl, 834665, sbg2,
835017
or 835018 polypeptides
For the purpose of the present invention, a ligand means a molecule, such as a
protein, a
peptide, an antibody or any synthetic chemical compound capable of binding to
the sbgl,
834665, sbg2, 835017 or 835018 protein or one of its fragments or variants or
to modulate the
expression of the polynucleotide coding for the sbgl, 834665, sbg2, 835017 or
835018 or a
fragment or variant thereof.
In the ligand screening method according to the present invention, a
biological sample
or a defined molecule to be tested as a putative ligand of the sbgl, 834665,
sbg2, 835017 or
835018 protein is brought into contact with the corresponding purified sbgl,
834665, sbg2,
835017 or 835018 protein, for example the corresponding purified recombinant
sbgl, 834665,
sbg2, 835017 or 835018 protein produced by a recombinant cell host as
described hereinbefore,
in order to form a complex between this protein and the putative ligand
molecule to be tested.
As an illustrative example, to study the interaction of the sbgl, 834665,
sbg2, 835017
and 835018 protein, or a fragment comprising a contiguous span of at least 4
amino acids,
preferably at least 6, or preferably at least 8 to 10 amino acids, more
preferably at least 12, 15,
20, 25, 30, 40, 50, or 100 amino acids of SEQ ID Nos 27 to 35 and 41 to 43,
with drugs or small
molecules, such as molecules generated through combinatorial chemistry
approaches, the
microdialysis coupled to HPLC method described by Wang et al. (1997) or the
affinity capillary
electrophoresis method described by Bush et al. (1997), can be used.
In further methods, peptides, drugs, fatty acids, lipoproteins, or small
molecules which
interact with the sbgl, 834665, sbg2, 835017 or 835018 protein, or a fragment
comprising a
contiguous span of at least 4 amino acids, preferably at least 6, or
preferably at least 8 to 10
amino acids, more preferably at least 12, 15, 20, 25, 30, 40, 50, or 100 amino
acids of SEQ 1D
Nos 27 to 35 and 41 to 43, may be identified using assays such as the
following. The molecule
to be tested for binding is labeled with a detectable label, such as a
fluorescent , radioactive, or
enzymatic tag and placed in contact with immobilized sbgl, 834665, sbg2,
835017 or 835018
protein, or a fragment thereof under conditions which permit specific binding
to occur. After
removal of non-specifically bound molecules, bound molecules are detected
using appropriate
means.
Another object of the present invention comprises methods and kits for the
screening of
candidate substances that interact with an sbgl, 834665, sbg2, 835017 or
835018 polypeptide.
The present invention pertains to methods for screening substances of interest
that
interact with an sbgl, 834665, sbg2, 835017 or 835018 protein or one fragment
or variant
thereof. By their capacity to bind covalently or non-covalently to an sbgl,
834665, sbg2,
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g35017 or g35018 protein or to a fragment or variant thereof, these substances
or molecules
may be advantageously used both in vitro and in vivo.
In vitro, said interacting molecules may be used as detection means in order
to identify
the presence of an sbgl, g34665, sbg2, g35017 or g35018 protein in a sample,
preferably a
biological sample.
A method for the screening of a candidate substance comprises the following
steps
a) providing a polypeptide comprising, consisting essentially of, or
consisting of an
sbgl, g34665, sbg2, g35017 or g35018 protein or a fragment comprising a
contiguous span of at
least 4 amino acids, preferably at least 6 amino acids, more preferably at
least 8 to 10 amino
acids, more preferably at least 12, 1 S, 20, 25, 30, 40, 50, or 100 amino
acids of SEQ ID Nos. 27
to 3 S and 41 to 43;
b) obtaining a candidate substance;
c) bringing into contact said polypeptide with said candidate substance; and
d) detecting the complexes formed between said polypeptide and said candidate
substance.
The invention further concerns a kit for the screening of a candidate
substance
interacting with the sbgl, g34665, sbg2, g35017 or g35018 polypeptide, wherein
said kit
comprises:
a) an sbgl, g34665, sbg2, g35017 or g35018 protein having an amino acid
sequence
selected from the group consisting of the amino acid sequences of SEQ ID Nos.
27 to 35 and 41
to 43 or a peptide fragment comprising a contiguous span of at least 4 amino
acids, preferably at
least 6 amino acids, more preferably at least 8 to 10 amino acids, and more
preferably at least
12, 15, 20, 25, 30, 40, 50, or 100 amino acids of SEQ ID Nos. 27 to 35 and 41
to 43; and
b) optionally means useful to detect the complex formed between the sbgl,
g34665,
sbg2, g35017 or g35018 protein or a peptide fragment or a variant thereof and
the candidate
substance.
In a preferred embodiment of the kit described above, the detection means
comprise
monoclonal or polyclonal antibodies directed against the sbgl, g34665, sbg2,
g35017 or g35018
protein or a peptide fragment or a variant thereof.
Various candidate substances or molecules can be assayed for interaction with
an sbgl,
g34665, sbg2, g35017 or g35018 polypeptide. These substances or molecules
include, without
being limited to, natural or synthetic organic compounds or molecules of
biological origin such
as polypeptides. When the candidate substance or molecule comprise a
polypeptide, this
polypeptide may be the resulting expression product of a phage clone belonging
to a phage-
based random peptide library, or alternatively the polypeptide may be the
resulting expression
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product of a cDNA library cloned in a vector suitable for performing a two-
hybrid screening
assay.
The invention also pertains to kits useful for performing the hereinbefore
described
screening method. Preferably, such kits comprise an sbgl, g34665, sbg2, g35017
or g35018
polypeptide or a fragment or a variant thereof, and optionally means useful to
detect the
complex formed between the sbgl, g34665, sbg2, g35017 or g35018 polypeptide or
its fragment
or variant and the candidate substance. In a preferred embodiment the
detection means
comprise monoclonal or polyclonal antibodies directed against the
corresponding sbgl, g34665,
sbg2, g35017 or g35018 polypeptide or a fragment or a variant thereof.
A. Candidate ligands obtained from random peptide libraries
In a particular embodiment of the screening method, the putative ligand is the
expression product of a DNA insert contained in a phage vector (Parmley and
Smith, 1988).
Specifically, random peptide phages libraries are used. The random DNA inserts
encode for
peptides of 8 to 20 amino acids in length (Oldenburg K.R. et al., 1992;
Valadon P., et al., 1996;
Lucas A.H., 1994; Westerink M.A.J., 1995; Felici F. et al., 1991). According
to this particular
embodiment, the recombinant phages expressing a protein that binds to the
immobilized sbgl,
g34665, sbg2, g35017 or g35018 protein is retained and the complex formed
between the sbgl,
g34665, sbg2, g35017 or g35018 protein and the recombinant phage may be
subsequently
immunoprecipitated by a polyclonal or a monoclonal antibody directed against
the sbgl,
g34665, sbg2, g35017 or g35018 protein.
Once the ligand library in recombinant phages has been constructed, the phage
population is brought into contact with the immobilized sbgl, g34665, sbg2,
g35017 or g35018
protein. Then the preparation of complexes is washed in order to remove the
non-specifically
bound recombinant phages. The phages that bind specifically to the sbgl,
g34665, sbg2,
g35017 or g35018 protein are then eluted by a buffer (acid pH) or
immunoprecipitated by the
monoclonal antibody produced by the hybridoma anti- sbgl, g34665, sbg2, g35017
or g35018,
and this phage population is subsequently amplified by an over-infection of
bacteria (for
example E. coli). The selection step may be repeated several times, preferably
2-4 times, in
order to select the more specific recombinant phage clones. The last step
comprises
characterizing the peptide produced by the selected recombinant phage clones
either by
expression in infected bacteria and isolation, expressing the phage insert in
another host-vector
system, or sequencing the insert contained in the selected recombinant phages.
B. Candidate ligands obtained by competition experiments.
Alternatively, peptides, drugs or small molecules which bind to the sbgl,
g34665, sbg2,
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g35017 or g35018 protein, or a fragment comprising a contiguous span of at
least 4 amino
acids, preferably at least 6 amino acids, more preferably at least 8 to 10
amino acids, and more
preferably at least 12, 15, 20, 25, 30, 40, 50, or 100 amino acids of SEQ ID
Nos. 27 to 35 and
41 to 43, may be identified in competition experiments. In such assays, the
sbgl, g34665, sbg2,
g35017 or g35018 protein, or a fragment thereof, is immobilized to a surface,
such as a plastic
plate. Increasing amounts of the peptides, drugs or small molecules are placed
in contact with
the immobilized sbgl, g34665, sbg2, g35017 or g35018 protein, or a fragment
thereof, in the
presence of a detectable labeled known sbgl, g34665, sbg2, g35017 or g35018
protein ligand.
For example, the sbgl, g34665, sbg2, g35017 or g35018 ligand may be detectably
labeled with
a fluorescent, radioactive, or enzymatic tag. The ability of the test molecule
to bind the. sbgl,
g34665, sbg2, g35017 or g35018 protein, or a fragment thereof, is determined
by measuring the
amount of detectably labeled known ligand bound in the presence of the test
molecule. A
decrease in the amount of known ligand bound to the sbgl, g34665, sbg2, g35017
or g35018
protein, or a fragment thereof, when the test molecule is present indicated
that the test molecule
is able to bind to the sbgl, g34665, sbg2, g35017 or g35018 protein, or a
fragment thereof.
C. Candidate ligands obtained by affinity chromatography.
Proteins or other molecules interacting with the sbgl, g34665, sbg2, g35017 or
g35018
protein, or a fragment comprising a contiguous span of at 4 amino acids,
preferably at least 6
amino acids, more preferably at least 8 to 10 amino acids, and more preferably
at least 12, 15,
20, 25, 30, 40, 50, or 100 amino acids of SEQ ID Nos 27 to 35 and 41 to 43,
can also be found
using affinity columns which contain the sbgl, g34665, sbg2, g35017 or g35018
protein, or a
fragment thereof. The sbgl, g34665, sbg2, g35017 or g35018 protein, or a
fragment thereof,
may be attached to the column using conventional techniques including chemical
coupling to a
suitable column matrix such as agarose, Affi Gel~ , or other matrices familiar
to those of skill
in art. In some embodiments of this method, the affinity column contains
chimeric proteins in
which the sbgl, g34665, sbg2, g35017 or g35018 protein, or a fragment thereof,
is fused to
glutathion S transferase (GST). A mixture of cellular proteins or pool of
expressed proteins as
described above is applied to the affinity column. Proteins or other molecules
interacting with
the sbgl, g34665, sbg2, g35017 or g35018 protein, or a fragment thereof,
attached to the
column can then be isolated and analyzed on 2-D electrophoresis gel as
described in Ramunsen
et al. (1997). Alternatively, the proteins retained on the affinity column can
be purified by
electrophoresis based methods and sequenced. The same method can be used to
isolate
antibodies, to screen phage display products, or to screen phage display human
antibodies.
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D. Candidate ligands obtained by optical biosensor methods
Proteins interacting with the sbgl, g34665, sbg2, g35017 or g35018 protein, or
a
fragment comprising a contiguous span of at least 4 amino acids, preferably at
least 6 amino
acids, more preferably at least 8 to 10 amino acids, and more preferably at
least 12, 15, 20, 25,
30, 40, 50, or 100 amino acids of SEQ ID Nos. 27 to 35 and 41 to 43, can also
be screened by
using an Optical Biosensor as described in Edwards and Leatherbarrow (1997)
and also in
Szabo et al. (1995). This technique permits the detection of interactions
between molecules in
real time, without the need of labeled molecules. This technique is based on
the surface
plasmon resonance (SPR) phenomenon. Briefly, the candidate ligand molecule to
be tested is
attached to a surface (such as a carboxymethyl dextran matrix). A light beam
is directed
towards the side of the surface that does not contain the sample to be tested
and is reflected by
said surface. The SPR phenomenon causes a decrease in the intensity of the
reflected light with
a specific association of angle and wavelength. The binding of candidate
ligand molecules
cause a change in the refraction index on the surface, which change is
detected as a change in
the SPR signal. For screening of candidate ligand molecules or substances that
are able to
interact with the sbgl, g34665, sbg2, g35017 or g35018 protein, or a fragment
thereof, the sbgl,
g34665, sbg2, g35017 or g35018 protein, or a fragment thereof, is immobilized
onto a surface.
This surface comprises one side of a cell through which flows the candidate
molecule to be
assayed. The binding of the candidate molecule on the sbgl, g34665, sbg2,
g35017 or g35018
protein, or a fragment thereof, is detected as a change of the SPR signal. The
candidate
molecules tested may be proteins, peptides, carbohydrates, lipids, or small
molecules generated
by combinatorial chemistry. This technique may also be performed by
immobilizing eukaryotic
or prokaryotic cells or lipid vesicles exhibiting an endogenous or a
recombinantly expressed
sbgl, g34665, sbg2, g35017 or g35018 protein at their surface.
The main advantage of the method is that it allows the determination of the
association
rate between the sbgl, g34665, sbg2, g35017 or g35018 protein and molecules
interacting with
the sbgl, g34665, sbg2, g35017 or g35018 protein. It is thus possible to
select specifically
ligand molecules interacting with the sbgl, g34665, sbg2, g35017 or g35018
protein, or a
fragment thereof, through strong or conversely weak association constants.
E. Candidate ligands obtained through a two-hybrid screening assay.
The yeast two-hybrid system is designed to study protein-protein interactions
in vivo
(Fields and Song, 1989), and relies upon the fusion of a bait protein to the
DNA binding domain
of the yeast Gal4 protein. This technique is also described in the US Patent
N° US 5,667,973
and the US Patent N° 5,283,173 (Fields et al.).
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The general procedure of library screening by the two-hybrid assay may be
performed
as described by Harper et al. (1993) or as described by Cho et al. (1998) or
also Fromont-Racine
et al. ( 1997).
The bait protein or polypeptide comprises, consists essentially of, or
consists of an
sbgl, g34665, sbg2, g35017 or g35018 polypeptide or a fragment comprising a
contiguous span
of at least 4 amino acids, preferably at least 6 amino acids, more preferably
at least 8 to 10
amino acids, and more preferably at least 12, 15, 20, 25, 30, 40, 50, or 100
amino acids of SEQ
ID Nos. 27 to 35 and 41 to 43.
More precisely, the nucleotide sequence encoding the sbgl, g34665, sbg2,
g35017 or
g35018 polypeptide or a fragment or variant thereof is fused to a
polynucleotide encoding the
DNA binding domain of the GAL4 protein, the fused nucleotide sequence being
inserted in a
suitable expression vector, for example pAS2 or pM3.
Then, a human cDNA library is constructed in a specially designed vector, such
that the
human cDNA insert is fused to a nucleotide sequence in the vector that encodes
the
transcriptional domain of the GAL4 protein. Preferably, the vector used is the
PACT vector.
The polypeptides encoded by the nucleotide inserts of the human cDNA library
are termed
"pray" polypeptides.
A third vector contains a detectable marker gene, such as beta galactosidase
gene or
CAT, gene that is placed under the control of a regulation sequence that is
responsive to the
binding of a complete Gal4 protein containing both the transcriptional
activation domain and
the DNA binding domain. For example, the vector pGSEC may be used.
Two different yeast strains are also used. As an illustrative but non limiting
example
the two different yeast strains may be the followings
- Y190, the phenotype of which is (MATa, Leu2-3, 112 ura3-12, trpl-901, his3-
D200, ade2-
101, gal4Dgal180D URA3 GAL-LacZ, LYS GAL-HIS3, cyh~;
- Y187, the phenotype of which is (MATa gal4 ga180 his3 trpl-901 ade2-101 ura3-
52 leu2-3,
-112 URA3 GAL-IacZmef), which is the opposite mating type of Y 190.
Briefly, 20 pg of pAS2/ sbgl, g34665, sbg2, g35017 or g35018 and 20 pg of pACT-
cDNA library are co-transformed into yeast strain Y190. The transformants are
selected for
growth on minimal media lacking histidine, leucine and tryptophan, but
containing the histidine
synthesis inhibitor 3-AT (50 mM). Positive colonies are screened for beta
galactosidase by
filter lift assay. The double positive colonies (His-, beta-gal+) are then
grown on plates lacking
histidine, leucine, but containing tryptophan and cycloheximide (10 mg/ml) to
select for loss of
pAS2/ sbgl, g34665, sbg2, g35017 and g35018 plasmids bu retention of pACT-cDNA
library
plasmids. The resulting Y190 strains are mated with Y187 strains expressing
sbgl, g34665,
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sbg2, g35017 and g35018 or non-related control proteins; such as cyclophilin
B, lamin, or
SNF1, as Gal4 fusions as described by Harper et al. (1993) and by Bram et al.
(Bram RJ et al.,
1993), and screened for beta galactosidase by filter lift assay. Yeast clones
that are beta gal-
after mating with the control Gal4 fusions are considered false positives.
In another embodiment of the two-hybrid method according to the invention,
interaction
between the sbgl, g34665, sbg2, g35017 or g35018 or a fragment or variant
thereof with
cellular proteins may be assessed using the Matchmaker Two Hybrid System 2
(Catalog No.
K1604-1, Clontech). As described in the manual accompanying the Matchmaker Two
Hybrid
System 2 (Catalog No. K1604-I, Clontech), nucleic acids encoding the sbgl,
g34665, sbg2,
g35017 and g35018 protein or a portion thereof, are inserted into an
expression vector such that
they are in frame with DNA encoding the DNA binding domain of the yeast
transcriptional
activator GAL4. A desired cDNA, preferably human cDNA, is inserted into a
second expression
vector such that they are in frame with DNA encoding the activation domain of
GAL4. The two
expression plasmids are transformed into yeast and the yeast are plated on
selection medium which
selects for expression of selectable markers on each of the expression vectors
as well as GAL4
dependent expression of the HIS3 gene. Transformants capable of growing on
medium lacking
histidine are screened for GAL4 dependent lacZ expression. Those cells which
are positive in both
the histidine selection and the lacZ assay contain interaction between sbgl,
g34665, sbg2, g35017
or g35018 and the protein or peptide encoded by the initially selected cDNA
insert.
Method For Screening Substances Interacting With The Regulatory Sequences Of
An sbgl, g34665, sbg2, 835017 or 835018 Gene.
The present invention also concerns a method for screening substances or
molecules
that are able to interact with the regulatory sequences of the sbgl, 834665,
sbg2, 835017 or
835018 gene, such as for example promoter or enhancer sequences.
Nucleic acids encoding proteins which are able to interact with the regulatory
sequences
of the sbgl, 834665, sbg2, 835017 or 835018 gene, more particularly a
nucleotide sequence
selected from the group consisting of the polynucleotides of the 5' and 3'
regulatory region or a
fragment or variant thereof, and preferably a variant comprising one of the
biallelic markers of
the invention, may be identified by using a one-hybrid system, such as that
described in the
booklet enclosed in the Matchmaker One-Hybrid System kit from Clontech
(Catalog Ref. n°
K1603-1). Briefly, the target nucleotide sequence is cloned upstream of a
selectable reporter
sequence and the resulting DNA construct is integrated in the yeast genome
(Saccharomyces
cerevisiae). The yeast cells containing the reporter sequence in their genome
are then
transformed with a library comprising fusion molecules between cDNAs encoding
candidate
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proteins for binding onto the regulatory sequences of the sbgl, 834665, sbg2,
835017 or 835018
gene and sequences encoding the activator domain of a yeast transcription
factor such as GAL4.
The recombinant yeast cells are plated in a culture broth for selecting cells
expressing the
reporter sequence. The recombinant yeast cells thus selected contain a fusion
protein that is
able to bind onto the target regulatory sequence of the sbgl, 834665, sbg2,
835017 or 835018
gene. Then, the cDNAs encoding the fusion proteins are sequenced and may be
cloned into
expression or transcription vectors in vitro. The binding of the encoded
polypeptides to the
target regulatory sequences of the sbgl, 834665, sbg2, 835017 or 835018 gene
may be
confirmed by techniques familiar to the one skilled in the art, such as gel
retardation assays or
DNAse protection assays.
Gel retardation assays may also be performed independently in order to screen
candidate molecules that are able to interact with the regulatory sequences of
the sbgl, 834665,
sbg2, 835017 or 835018 gene, such as described by Fried and Crothers (1981),
Garner and
Revzin (1981) and Dent and Latchman (1993). These techniques are based on the
principle
according to which a DNA fragment which is bound to a protein migrates slower
than the same
unbound DNA fragment. Briefly, the target nucleotide sequence is labeled. Then
the labeled
target nucleotide sequence is brought into contact with either a total nuclear
extract from cells
containing transcription factors, or with different candidate molecules to be
tested. The
interaction between the target regulatory sequence of the sbgl, 834665, sbg2,
835017 or 835018
gene and the candidate molecule or the transcription factor is detected after
gel or capillary
electrophoresis through a retardation in the migration.
Method For Screening Ligands That Modulate The Expression Of The sbgl,
834665, sbg2, 835017 or 835018 Gene
Another subject of the present invention is a method for screening molecules
that
modulate the expression of the sbgl, 834665, sbg2, 835017 or 835018 protein.
Such a
screening method comprises the steps of:
a) cultivating a prokaryotic or an eukaryotic cell that has been transfected
with a
nucleotide sequence encoding the sbgl, 834665, sbg2, 835017 or 835018 protein
or a variant or
a fragment thereof, placed under the control of its own promoter;
b) bringing into contact the cultivated cell with a molecule to be tested;
c) quantifying the expression of the sbgl, 834665, sbg2, 835017 or 835018
protein or a
variant or a fragment thereof.
In an embodiment, the nucleotide sequence encoding the sbgl, 834665, sbg2,
835017 or
835018 protein or a variant or a fragment thereof comprises an allele of at
least one sbgl,
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g34665, sbg2, g35017 or g35018 related biallelic marker.
Using DNA recombination techniques well known by the one skill in the art, the
sbgl,
g34665, sbg2, g35017 or g35018 protein encoding DNA sequence is inserted into
an expression
vector, downstream from its promoter sequence. As an illustrative example, the
promoter
sequence of the sbgl, g34665, sbg2, g35017 or g35018 gene is contained in the
nucleic acid of
the 5' regulatory region.
The quantification ofthe expression ofthe sbgl, g34665, sbg2, g35017 or g35018
protein may be realized either at the mRNA level or at the protein level. In
the latter case,
polyclonal or monoclonal antibodies may be used to quantify the amounts of the
sbgl, g34665,
sbg2, g35017 or g35018 protein that have been produced, for example in an
ELISA or a RIA
assay.
In a preferred embodiment, the quantification of the sbgl, g34665, sbg2,
g35017 or
g35018 mRNA is realized by a quantitative PCR amplification of the cDNA
obtained by a
reverse transcription of the total mRNA of the cultivated sbgl, g34665, sbg2,
g35017 or g35018
-transfected host cell, using a pair of primers specific for sbgl, g34665,
sbg2, g35017 or
g35018.
The present invention also concerns a method for screening substances or
molecules
that are able to increase, or in contrast to decrease, the level of expression
of the sbgl, g34665,
sbg2, g35017 or g35018 gene. Such a method may allow the one skilled in the
art to select
20. substances exerting a regulating effect on the expression level of the
sbgl, g34665, sbg2,
g35017 or g35018 gene and which may be useful as active ingredients included
in
pharmaceutical compositions for treating patients suffering from diseases.
Thus, is also part of the present invention a method for screening of a
candidate
substance or molecule that modulated the expression of the sbgl, g34665, sbg2,
g35017 or
g35018 gene, this method comprises the following steps:
- providing a recombinant cell host containing a nucleic acid, wherein said
nucleic acid
comprises a nucleotide sequence of the S' regulatory region or a biologically
active fragment or
variant thereof located upstream a polynucleotide encoding a detectable
protein;
- obtaining a candidate substance; and
- determining the ability of the candidate substance to modulate the
expression levels of
the polynucleotide encoding the detectable protein.
In a further embodiment, the nucleic acid comprising the nucleotide sequence
of the 5'
regulatory region or a biologically active fragment or variant thereof also
includes a 5'UTR
region of the sbgl cDNA of SEQ ID No 2 to 26 or the g35018 cDNA of SEQ ID No
36 to 40,
or one of its biologically active fragments or variants thereof.
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Among the preferred polynucleotides encoding a detectable protein, there may
be cited
polynucleotides encoding beta galactosidase, green fluorescent protein (GFP)
and
chloramphenicol acetyl transferase (CAT).
The invention also pertains to kits useful for performing the herein described
screening
method. Preferably, such kits comprise a recombinant vector that allows the
expression of a
nucleotide sequence of the 5' regulatory region or a biologically active
fragment or variant
thereof located upstream and operably linked to a polynucleotide encoding a
detectable protein
or the sbgl, g34665, sbg2, g35017 or g35018 protein or a fragment or a variant
thereof.
In another embodiment of a method for the screening of a candidate substance
or
molecule that modulates the expression of the sbgl, g34665, sbg2, g35017 or
g35018 gene,
wherein said method comprises the following steps:
a) providing a recombinant host cell containing a nucleic acid, wherein said
nucleic acid
comprises a 5'UTR sequence of an sbgl, g34665, sbg2, g35017 or g35018 cDNA,
preferably of
an sbgl or g35018 cDNA of SEQ ID Nos 2 to 26 or 36 to 40, or one of its
biologically active
1 S fragments or variants, the S'UTR sequence or its biologically active
fragment or variant being
operably linked to a polynucleotide encoding a detectable protein;
b) obtaining a candidate substance; and
c) determining the ability of the candidate substance to modulate the
expression levels
of the polynucleotide encoding the detectable protein.
In a specific embodiment of the above screening method, the nucleic acid that
comprises a nucleotide sequence selected from the group consisting of the
5'UTR sequence of
an sbgl, g34665, sbg2, g35017 or g35018 cDNA, preferably of an sbgl or g35018
cDNA of
SEQ ID Nos 2 to 26 or 36 to 40 or one of its biologically active fragments or
variants, includes
a promoter sequence which is endogenous with respect to the sbgl, g34665,
sbg2, g35017 or
g35018 S'UTR sequence.
In another specific embodiment of the above screening method, the nucleic acid
that
comprises a nucleotide sequence selected from the group consisting of the
5'UTR sequence of
an sbgl, g34665, sbg2, g35017 or g35018 cDNA or one of its biologically active
fragments or
variants, includes a promoter sequence which is exogenous with respect to the
sbgl, g34665,
sbg2, g35017 or g35018 5'UTR sequence defined therein.
In a further preferred embodiment, the nucleic acid comprising the 5'-UTR
sequence of
an sbgl, g34665, sbg2, g35017 or g35018 cDNA or the biologically active
fragments thereof
includes an sbgl-related biallelic marker.
The invention further comprises a kit for the screening of a candidate
substance
modulating the expression of the sbgl, g34665, sbg2, g35017 or g35018 gene,
wherein said kit
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comprises a recombinant vector that comprises a nucleic acid including a 5'UTR
sequence of
the sbgl, g34665, sbg2, g35017 or g35018 cDNA of SEQ ID Nos 2 to 26 or 36 to
40, or one of
their biologically active fragments or variants, the 5'UTR sequence or its
biologically active
fragment or variant being operably linked to a polynucleotide encoding a
detectable protein.
For the design of suitable recombinant vectors useful for performing the
screening
methods described above, it will be referred to the section of the present
specification wherein
the preferred recombinant vectors of the invention are detailed.
Expression levels and patterns of sbgl, g34665, sbg2, g35017 or g35018 may be
analyzed by solution hybridization with long probes as described in
International Patent
Application No. WO 97/05277. Briefly, the sbgl, g34665, sbg2, g35017 or g35018
cDNA or
the sbgl, g34665, sbg2, g35017 and g35018 genomic DNA described above, or
fragments
thereof, is inserted at a cloning site immediately downstream of a
bacteriophage (T3, T7 or SP6)
RNA polymerase promoter to produce antisense RNA. Preferably, the sbgl,
g34665, sbg2,
g35017 and g35018 insert comprises at least 100 or more consecutive
nucleotides of the
genomic DNA sequence or the cDNA sequences. The plasmid is linearized and
transcribed in
the presence of ribonucleotides comprising modified ribonucleotides (i.e.
biotin-UTP and DIG-
UTP). An excess of this doubly labeled RNA is hybridized in solution with mRNA
isolated
from cells or tissues of interest. The hybridization is performed under
standard stringent
conditions (40-50°C for 16 hours in an 80% formamide, 0. 4 M NaCI
buffer, pH 7-8). The
unhybridized probe is removed by digestion with ribonucleases specific for
single-stranded
RNA (i.e. RNases CL3, T1, Phy M, U2 or A). The presence of the biotin-UTP
modification
enables capture of the hybrid on a microtitration plate coated with
streptavidin. The presence of
the DIG modification enables the hybrid to be detected and quantified by ELISA
using an anti-
DIG antibody coupled to alkaline phosphatase.
Quantitative analysis of sbgl, g34665, sbg2, g35017 or g35018 gene expression
may
also be performed using arrays. As used herein, the term array means a one
dimensional, two
dimensional, or multidimensional arrangement of a plurality of nucleic acids
of sufficient length
to permit specific detection of expression of mRNAs capable of hybridizing
thereto. For
example, the arrays may contain a plurality of nucleic acids derived from
genes whose
expression levels are to be assessed. The arrays may include the sbgl, g34665,
sbg2, g35017
and g35018 genomic DNA, the sbgl, g34665, sbg2, g35017 or g35018 cDNA
sequences or the
sequences complementary thereto or fragments thereof, particularly those
comprising at least
one of the biallelic markers according the present invention. Preferably, the
fragments are at
least 15 nucleotides in length. In other embodiments, the fragments are at
least 25 nucleotides
in length. In some embodiments, the fragments are at least 50 nucleotides in
length. More
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preferably, the fragments are at least 100 nucleotides in length. In another
preferred
embodiment, the fragments are more than 100 nucleotides in length. In some
embodiments the
fragments may be more than 500 nucleotides in length.
For example, quantitative analysis of sbgl, g34665, sbg2, g35017 or g35018
gene
expression may be performed with a complementary DNA microarray as described
by Schena
et al.(1995 and 1996). Full length sbgl, g34665, sbg2, g35017 or g35018 cDNAs
or fragments
thereof are amplified by PCR and arrayed from a 96-well microtiter plate onto
silylated
microscope slides using high-speed robotics. Printed arrays are incubated in a
humid chamber
to allow rehydration of the array elements and rinsed, once in 0. 2% SDS for 1
min, twice in
water for I min and once for 5 min in sodium borohydride solution. The arrays
are submerged
in water for 2 min at 95°C, transferred into 0. 2% SDS for 1 min,
rinsed twice with water, air
dried and stored in the dark at 25°C.
Cell or tissue mRNA is isolated or commercially obtained and probes are
prepared by a
single round of reverse transcription. Probes are hybridized to 1 cmz
microarrays under a 14 x
14 mm glass coverslip for 6-12 hours at 60°C. Arrays are washed for 5
min at 25°C in low
stringency wash buffer (1 x SSC/0. 2% SDS), then for 10 min at room
temperature in high
stringency wash buffer (0. 1 x SSC/0. 2% SDS). Arrays are scanned in 0. 1 x
SSC using a
fluorescence laser scanning device fitted with a custom filter set. Accurate
differential
expression measurements are obtained by taking the average of the ratios of
two independent
hybridizations.
Quantitative analysis of sbgl, g34665, sbg2, g35017 or g35018 gene expression
may
also be performed with full length sbgl, g34665, sbg2, g35017 or g35018 cDNAs
or fragments
thereof in complementary DNA arrays as described by Pietu et al.(1996). The
full length sbgl,
g34665, sbg2, g35017 or g35018 cDNA or fragments thereof is PCR amplified and
spotted on
membranes. Then, mRNAs originating from various tissues or cells are labeled
with
radioactive nucleotides. After hybridization and washing in controlled
conditions, the
hybridized mRNAs are detected by phospho-imaging or autoradiography. Duplicate
experiments are performed and a quantitative analysis of differentially
expressed mRNAs is
then performed.
Alternatively, expression analysis using the sbgl, g34665, sbg2, g35017 or
g35018
genomic DNA, the sbgl, g34665, sbg2, g35017 or g35018 cDNA, or fragments
thereof can be
done through high density nucleotide arrays as described by Lockhart et al.(
1996) and
Sosnowsky et al.(1997). Oligonucleotides of 15-50 nucleotides from the
sequences of the sbgl,
g34665, sbg2, g35017 or g35018 genomic DNA, the sbgl, g34665, sbg2, g35017 or
g35018
cDNA sequences particularly those comprising at least one of biallelic markers
according the
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present invention, or the sequences complementary thereto, are synthesized
directly on the chip
(Lockhart et al., supra) or synthesized and then addressed to the chip
(Sosnowski et al., supra).
Preferably, the oligonucleotides are about 20 nucleotides in length.
sbgl, 834665, sbg2, 835017 or 835018 cDNA probes labeled with an appropriate
compound, such as biotin, digoxigenin or fluorescent dye, are synthesized from
the appropriate
mRNA population and then randomly fragmented to an average size of 50 to 100
nucleotides.
The said probes are then hybridized to the chip. After washing as described in
Lockhart et al.,
supra and application of different electric fields (Sosnowsky et al., 1997).,
the dyes or labeling
compounds are detected and quantified. Duplicate hybridizations are performed.
Comparative
analysis of the intensity of the signal originating from cDNA probes on the
same target
oligonucleotide in different cDNA samples indicates a differential expression
of sbgl, 834665,
sbg2, 835017 or 835018 mRNA.
Methods For Inhibiting The Expression Of An sbgl, 834665, sbg2, 835017 or
835018 Gene
Other therapeutic compositions according to the present invention comprise
advantageously an oligonucleotide fragment of the nucleic sequence of sbgl,
834665, sbg2,
835017 or 835018 as an antisense tool or a triple helix tool that inhibits the
expression of the
corresponding sbgl, 834665, sbg2, 835017 or 835018 gene. A preferred fragment
of the
nucleic sequence of sbgl, 834665, sbg2, 835017 or 835018 comprises an allele
of at least one of
the biallelic markers of the invention.
Antisense Approach
Preferred methods using antisense polynucleotide according to the present
invention are
the procedures described by Sczakiel et al.(1995).
Preferably, the antisense tools are chosen among the polynucleotides (15-200
by long)
that are complementary to the 5'end of the sbgl, 834665, sbg2, 835017 or
835018 mRNA. In
another embodiment, a combination of different antisense polynucleotides
complementary to
different parts of the desired targeted gene are used.
Preferred antisense polynucleotides according to the present invention are
complementary fo a sequence of the mRNAs of sbgl, 834665, sbg2, 835017 or
835018 that
contains either the translation initiation codon ATG or a splicing donor or
acceptor site.
The antisense nucleic acids should have a length and melting temperature
sufficient to
permit formation of an intracellular duplex having sufficient stability to
inhibit the expression of
the sbgl, 834665, sbg2, 835017 or 835018 mRNA in the duplex. Strategies for
designing
antisense nucleic acids suitable for use in gene therapy are disclosed in
Green et al., (1986) and
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Izant and Weintraub, (1984).
In some strategies, antisense molecules are obtained by reversing the
orientation of the
sbgl, 834665, sbg2, 835017 or 835018 coding region with respect to a promoter
so as to
transcribe the opposite strand from that which is normally transcribed in the
cell. The antisense
molecules may be transcribed using in vitro transcription systems such as
those which employ
T7 or SP6 polymerase to generate the transcript. Another approach involves
transcription of
sbgl, 834665, sbg2, 835017 or 835018 antisense nucleic acids in vivo by
operably linking DNA
containing the antisense sequence to a promoter in a suitable expression
vector.
Alternatively, suitable antisense strategies are those described by Rossi et
al.(1991), in
the International Applications Nos. WO 94/23026, WO 95/04141, WO 92/18522 and
in the
European Patent Application No. EP 0 572 287 A2
An alternative to the antisense technology that is used according to the
present
invention comprises using ribozymes that will bind to a target sequence via
their
complementary polynucleotide tail and that will cleave the corresponding RNA
by hydrolyzing
its target site (namely "hammerhead ribozymes"). Briefly, the simplified cycle
of a
hammerhead ribozyme comprises (1) sequence specific binding to the target RNA
via
complementary antisense sequences; (2) site-specific hydrolysis of the
cleavable motif of the
target strand; and (3) release of cleavage products, which gives rise to
another catalytic cycle.
Indeed, the use of long-chain antisense polynucleotide (at least 30 bases
long) or ribozymes
with long antisense arms are advantageous. A preferred delivery system for
antisense ribozyme
is achieved by covalently linking these antisense ribozymes to lipophilic
groups or to use
liposomes as a convenient vector. Preferred antisense ribozymes according to
the present
invention are prepared as described by Sczakiel et al.(1995).
Triple Helix Approach
The sbgl, 834665, sbg2, 835017 or 835018 genomic DNA may also be used to
inhibit
the expression of the sbgl, 834665, sbg2, 835017 or 835018 gene based on
intracellular triple
helix formation.
Triple helix oligonucleotides are used to inhibit transcription from a genome.
They are
particularly useful for studying alterations in cell activity when it is
associated with a particular
gene.
Similarly, a portion of the sbgl, 834665, sbg2, 835017 or 835018 genomic DNA
can be
used to study the effect of inhibiting sbgl, 834665, sbg2, 835017 or 835018
transcription within
a cell. Traditionally, homopurine sequences were considered the most useful
for triple helix
strategies. However, homopyrimidine sequences can also inhibit gene
expression. Such
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homopyrimidine oligonucleotides bind to the major groove at
homopurine:homopyrimidine
sequences. Thus, both types of sequences from the sbgl, g34665, sbg2, g35017
or g35018
genomic DNA are contemplated within the scope of this invention.
To carry out gene therapy strategies using the triple helix approach, the
sequences of
the sbgl, g34665, sbg2, g35017 or g35018 genomic DNA are first scanned to
identify 10-mer to
20-mer homopyrimidine or homopurine stretches which could be used in triple-
helix based
strategies for inhibiting sbgl, g34665, sbg2, g35017 or g35018 expression.
Following
identification of candidate homopyrimidine or homopurine stretches, their
efficiency in
inhibiting sbgl, g34665, sbg2, g35017 or g35018 expression is assessed by
introducing varying
amounts of oligonucleotides containing the candidate sequences into tissue
culture cells which
express the sbgl, g34665, sbg2, g35017 or g35018 gene.
The oligonucleotides can be introduced into the cells using a variety of
methods known
to those skilled in the art, including but not limited to calcium phosphate
precipitation, DEAE-
Dextran, electroporation, liposome-mediated transfection or native uptake.
Treated cells are monitored for altered cell function or reduced sbgl, g34665,
sbg2,
g35017 or g35018 expression using techniques such as Northern blotting, RNase
protection
assays, or PCR based strategies to monitor the transcription levels of the
sbgl, g34665, sbg2,
g35017 or g35018 gene in cells which have been treated with the
oligonucleotide.
The oligonucleotides which are effective in inhibiting gene expression in
tissue culture
cells may then be introduced in vivo using the techniques described above in
the antisense
approach at a dosage calculated based on the in vitro results, as described in
antisense approach.
In some embodiments, the natural (beta) anomers of the oligonucleotide units
can be
replaced with alpha anomers to render the oligonucleotide more resistant to
nucleases. Further,
an intercalating agent such as ethidium bromide, or the like, can be attached
to the 3' end of the
alpha oligonucleotide to stabilize the triple helix. For information on the
generation of
oligonucleotides suitable for triple helix formation see Griffin et al.(
1989).
Pharmaceutical Compositions And Formulations
Sb~l-modulating_Compounds
Using the methods disclosed herein, compounds that selectively modulate sbgl
activity in
vitro and in vivo may be identified. The compounds identified by the process
of the invention
include, for example, antibodies having binding specificity for the sbgl
peptide. It is also
expected that homologues of sbgl may be useful for modulating sbgl-mediated
activity and the
related physiological condition associated with schizophrenia or bipolar
disorder. Generally, it is
3 S further expected that assay methods of the present invention based on the
role of sbgl in central
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nervous system disorder may be used to identify compounds capable of
intervening in the assay
cascade of the invention.
Indications
While sbgl has demonstrated an association with schizophrenia and bipolar
disorder,
indications involving sbgl may include various central nervous system
disorders. Nervous system
disorders are expected to have complex genetic bases and often share certain
symptoms. In
particular, as described herein, indications may include schizophrenia and
other psychotic
disorders, mood disorders, autism, substance dependence and alcoholism, mental
retardation, and
other psychiatric diseases including cognitive, anxiety, eating, impulse-
control, and personality
disorders, as defined with the Diagnosis and Statistical Manual of Mental
Disorders fourth edition
(DSM-IV) classification.
Pharmaceutical Formulations and Routes of Administration
The compounds identified using the methods of the present invention can be
administered
to a mammal, including a human patient, alone or in pharmaceutical
compositions where they are
mixed with suitable carriers or excipient(s) at therapeutically effective
doses to treat or ameliorate
schizophrenia or bipolar disorder related disorders. A therapeutically
effective dose further refers
to that amount of the compound sufficient to result in amelioration of
symptoms as determined by
the methods described herein. Preferably, a therapeutically effective dosage
is suitable for
continued periodic use or administration. Techniques for formulation and
administration of the
compounds of the instant application may be found in "Remington's
Pharmaceutical Sciences,"
Mack Publishing Co., Easton, PA, latest edition.
Routes of Administration
Suitable routes of administration include oral, rectal, transmucosal, or
intestinal
administration, parenteral delivery, including intramuscular, subcutaneous,
intramedullary
injections, as well as intrathecal, direct intraventricular, intravenous,
intraperitoneal, intranasal or
intraocular injections. A particularly useful method of administering
compounds for treating
central nervous system disease involves surgical implantation of a device for
delivering the
compound over an extended period of time. Sustained release formulations of
the invented
medicaments particularly are contemplated.
Composition/Formulation
Pharmaceutical compositions and medicaments for use in accordance with the
present
invention may be formulated in a conventional manner using one or more
physiologically
acceptable carriers comprising excipients and auxiliaries. Proper formulation
is dependent upon
the route of administration chosen.
For injection, the agents ofthe invention may be formulated in aqueous
solutions,
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preferably in physiologically compatible buffers such as Hanks's solution,
Ringer's solution, or
physiological saline buffer such as a phosphate or bicarbonate buffer. For
transmucosal
administration, penetrants appropriate to the barrier to be permeated are used
in the formulation.
Such penetrants are generally known in the art.
Pharmaceutical preparations which can be used orally include push-fit capsules
made of
gelatin, as well as soft, sealed capsules made of gelatin and a plasticizes,
such as glycerol or
sorbitol. The push-fit capsules can contain the active ingredients in
admixture with fillers such as
lactose, binders such as starches, and/or lubricants such as talc or magnesium
stearate and,
optionally, stabilizers. In soft capsules, the active compounds may be
dissolved or suspended in
suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene
glycols. In addition,
stabilizers may be added. All formulations for oral administration should be
in dosages suitable
for such administration.
For buccal administration,the compositions may take the form of tablets or
lozenges
formulated in conventional manner.
For administration by inhalation, the compounds for use according to the
present
invention are conveniently delivered in the form of an aerosol spray
presentation from pressurized
packs or a nebulizer, with the use of a suitable gaseous propellant, e.g.,
carbon dioxide. In the
case of a pressurized aerosol the dosage unit may be determined by providing a
valve to deliver a
metered amount. Capsules and cartridges of, e.g., gelatin, for use in an
inhaler or insuf~lator, may
be formulated containing a powder mix of the compound and a suitable powder
base such as
lactose or starch.
The compounds may be formulated for parenteral administration by injection,
e.g., by
bolus injection or continuous infusion. Formulations for injection may be
presented in unit
dosage form, e.g., in ampoules or in multi-dose containers, with an added
preservative. The
compositions may take such forms as suspensions, solutions or emulsions in
aqueous vehicles,
and may contain formulatory agents such as suspending, stabilizing and/or
dispersing agents.
Pharmaceutical formulations for parenteral administration include aqueous
solutions of
the active compounds in water-soluble form. Aqueous suspensions may contain
substances which
increase the viscosity of the suspension, such as sodium carboxymethyl
cellulose, sorbitol, or
dextran. Optionally, the suspension may also contain suitable stabilizers or
agents which increase
the solubility of the compounds to allow for the preparation of highly
concentrated solutions.
Alternatively, the active ingredient may be in powder or lyophilized form for
constitution
with a suitable vehicle, such as sterile pyrogen-free water, before use.
In addition to the formulations described previously, the compounds may also
be
formulated as a depot preparation. Such long acting formulations may be
administered by
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implantation (for example subcutaneously or intramuscularly) or by
intramuscular injection.
Thus, for example, the compounds may be formulated with suitable polymeric or
hydrophobic
materials (for example as an emulsion in an acceptable oil) or ion exchange
resins, or as sparingly
soluble derivatives, for example, as a sparingly soluble salt.
Additionally, the compounds may be delivered using a sustained-release system,
such as
semipermeable matrices of solid hydrophobic polymers containing the
therapeutic agent. Various
sustained release materials have been established and are well known by those
skilled in the art.
Sustained-release capsules may, depending on their chemical nature, release
the compounds for a
few weeks up to over 100 days.
Depending on the chemical nature and the biological stability of the
therapeutic reagent,
additional strategies for protein stabilization may be employed.
The pharmaceutical compositions also may comprise suitable solid or gel phase
carriers
or excipients. Examples of such carriers or excipients include but are not
limited to calcium
carbonate, calcium phosphate, various sugars, starches, cellulose derivatives,
gelatin, and
polymers such as polyethylene glycols.
Effective Dosage.
Pharmaceutical compositions suitable for use in the present invention include
compositions wherein the active ingredients are contained in an effective
amount to achieve their
intended purpose. More specifically, a therapeutically effective amount means
an amount
effective to prevent development of or to alleviate the existing symptoms of
the subject being
treated. Determination of the effective amounts is well within the capability
of those skilled in the
art, especially in light of the detailed disclosure provided herein.
For any compound used in the method of the invention, the therapeutically
effective dose
can be estimated initially from cell culture assays, and a dose can be
formulated in animal.models.
Such information can be used to more accurately determine useful doses in
humans.
A therapeutically effective dose refers to that amount of the compound that
results in
amelioration of symptoms in a patient. Toxicity and therapeutic efficacy of
such compounds can
be determined by standard pharmaceutical procedures in cell cultures or
experimental animals,
e.g., for determining the LD50, (the dose lethal to 50% of the test
population) and the ED50 (the
dose therapeutically effective in 50% of the population). The dose ratio
between toxic and
therapeutic effects is the therapeutic index and it can be expressed as the
ratio between LD50 and
ED50. Compounds which exhibit high therapeutic indices are preferred.
The data obtained from these cell culture assays and animal studies can be
used in
formulating a range of dosage for use in human. The dosage of such compounds
lies preferably
within a range of circulating concentrations that include the ED50, with
little or no toxicity. The
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dosage may vary within this range depending upon the dosage form employed and
the route of
administration utilized. The exact formulation, route of administration and
dosage can be chosen
by the individual physician in view of the patient's condition. (See, e.g.,
Fingl et al., 1975, in "The
Pharmacological Basis of Therapeutics", Ch. 1 ).
Computer-Related Embodiments
As used herein the term "nucleic acid codes of the invention" encompass the
nucleotide
sequences comprising, consisting essentially of, or consisting of any one of
the following:
a) a contiguous span of at least 12, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70,
80, 90, 100,
150, 200, 500, 1000 or 2000 nucleotides of SEQ ID No. I, and the complements
thereof,
wherein said contiguous span comprises at least one of the following
nucleotide positions of
SEQ ID No 1: 31 to 292651 and 292844 to 319608.
b) a contiguous span of at least 12, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70,
80, 90, 100,
150, 200, 500, 1000 or 2000 nucleotides of any of SEQ ID Nos. 54 to 229, and
the complements
thereof, to the extent that such a length is consistent with the particular
sequence ID.
c) a contiguous span of at least 8, 12, 15, 18, 20, 25, 30, 35, 40, 45, 50,
55, 60, 65, 70,
75, 80, 90, 100 or 200 nucleotides, to the extent that such a length is
consistent with the
particular sequence ID, of SEQ ID Nos. 2 to 26, 36 to 40 or the complements
thereof.
d) a contiguous span of at least 12, 15, 18, 20, 25, 30, 35, 40, 45, 50, 55,
60, 65, 70, 75,
80, 90 or 100 nucleotides of SEQ ID No. 1 or the complements thereof wherein
said contiguous
span comprises at least one of the following nucleotide positions of SEQ ID No
1:
(i) 292653 to 296047, 292653 to 292841, 295555 to 296047 and 295580
to 296047;
(ii) 31 to 1107, 1108 to 65853, 1108 to 1289, 14877 to 14920, 18778 to
18862, 25593 to 25740, 29388 to 29502, 29967 to 30282, 64666 to 64812, 65505
to 65853 and
65854 to 67854;
(iii) 94124 to 94964;
(iv) 213818 to 215818, 215819 to 215941, 215819 to 215975, 216661 to
216952, 216661 to 217061, 217027 to 217061, 229647 to 229742, 230408 to
230721, 231272
to 231412, 231787 to 231880, 231870 to 231879, 234174 to 234321, 237406 to
237428,
239719 to 239807, 239719 to 239853, 240528 to 240569, 240528 to 240596, 240528
to
240617, 240528 to 240644, 240528 to 240824, 240528 to 240994, 240528 to
241685, 240800
to 240993 and 241686 to 243685; and
(v) 201188 to 216915, 201188 to 201234, 214676 to 214793, 215702 to
215746 and 216836 to 216915;
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e) a contiguous span according to a), b), c) or d), wherein said span includes
a biallelic
marker selected from the group consisting of A 1 to A489.
f) a contiguous span of at least 12, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70,
80, 90, 100,
150, 200, 500, 1000 or 2000 nucleotides of SEQ ID No. I or the complements
thereof, wherein
said contiguous span comprises at least 1, 2, 3, 5, or 10 nucleotide positions
of any one the
ranges of nucleotide positions designated post to pos166 of SEQ ID No. 1
listed in Table 1
above;
g) a contiguous span of at least 12, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70,
80, 90, 100,
I 50, 200, 500, 1000 or 2000 nucleotides of any of SEQ ID Nos. 2 to 26, 36 to
42, 44 to 48 and
52 to 269, and the complements thereof, wherein said span includes a
chromosome 13q31-q33-
related biallelic marker, a Region D-related biallelic marker, an sbgl-,
g34665-, sbg2-, g35017-
or g35018 -related biallelic marker;
h) a contiguous span of at least 12, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70,
80, 90, 100,
150, 200, 500, 1000 or 2000 nucleotides of any of SEQ ID Nos 2 to 26, 36 to 40
and 54 to 229,
and the complements thereof, wherein said span includes a chromosome 13q31-q33-
related
biallelic marker, a Region D-related biallelic marker, an sbgl-, g34665-, sbg2-
, g35017- or
g35018 -related biallelic marker with the alternative allele present at said
biallelic marker.
i) a contiguous span of at least 12, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70,
80, 90, 100,
150, 200, 500, 1000 or 2000 nucleotides of any of SEQ ID No I, and the
complements thereof,
wherein said span includes a polymorphism selected from the group consisting
of AI to A69,
A71 to ~A74, A76 to A94, A96 to A I 06, A 108 to A 112, A 114 to A 177, A 179
to A 1'97, A 199 to
A222, A224 to A242 and 361 to A489.
The "nucleic acid codes of the invention" further encompass nucleotide
sequences
homologous to a contiguous span of at least 30, 35, 40, 50, 60, 70, 80, 90,
100, 150, 200, 500,
1000 or 2000 nucleotides, to the extent that such a length is consistent with
the particular
sequence of SEQ ID Nos. I to 26, 36 to 40 and 54 to 229, and the complements
thereof. The
"nucleic acid codes of the invention" also encompass nucleotide sequences
homologous to a
contiguous span of at least 12, 15, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60,
65, 70, 75, 80, 90 or
100 nucleotides of SEQ ID No. 1 or the complements thereof, wherein said
contiguous span
comprises at least one of the following nucleotide positions of SEQ ID No. 1:
(i) 292653 to 296047, 292653 to 292841, 295555 to 296047 and 295580 to 296047;
(ii) 31 to 1107, 1108 to 65853, 1108 to 1289, 14877 to 14920, 18778 to 18862,
25593 to
25740, 29388 to 29502, 29967 to 30282, 64666 to 64812, 65505 to 65853 and
65854 to 67854;
(iii) 94124 to 94964;
(iv) 213818 to 215818, 215819 to 215941, 215819 to 215975, 216661 to 216952,
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216661 to 217061, 217027 to 217061, 229647 to 229742, 230408 to 230721, 231272
to
231412, 231787 to 231880, 231870 to 231879, 234174 to 234321, 237406 to
237428, 239719
to 239807, 239719 to 239853, 240528 to 240569, 240528 to 240596, 240528 to
240617,
240528 to 240644, 240528 to 240824, 240528 to 240994, 240528 to 241685, 240800
to 240993
and 241686 to 243685; and
(v) 201188 to 216915, 201188 to 201234, 214676 to 214793, 215702 to 215746 and
216836 to 216915.
Homologous sequences refer to a sequence having at least 99%, 98%, 97%, 96%,
95%, 90%, 85%, 80%, or 75% homology to these contiguous spans. Homology may be
determined using any method described herein, including BLAST2N with the
default
parameters or with any modified parameters. Homologous sequences also may
include RNA
sequences in which uridines replace the thymines in the nucleic acid codes of
the invention. It
will be appreciated that the nucleic acid codes of the invention can be
represented in the
traditional single character format (See the inside back cover of Stryer,
Lubert. Biochemistry,
3rd edition. W. H Freeman & Co., New York.) or in any other format or code
which records
the identity of the nucleotides in a sequence.
As used herein the term "polypeptide codes of SEQ ID Nos. 27 to 35 and 41 to
43"
encompasses the polypeptide sequence of SEQ B7 Nos 27 to 35 and 41 to 43,
polypeptide
sequences homologous to the polypeptides of SEQ ID Nos. 27 to 35 and 41 to 43,
or fragments of
any of the preceding sequences. Homologous polypeptide sequences refer to a
polypeptide
sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75% homology
to one of
the polypeptide sequences of SEQ ID Nos. 27 to 35 and 41 to 43. Homology may
be determined
using any of the computer programs and parameters described herein, including
FASTA with the
default parameters or with any modified parameters. The homologous sequences
may be obtained
using any of the procedures described herein or may result from the correction
of a sequencing
error as described above. The polypeptide fragments comprise at least 4, 6, 8,
10, 15, 20, 25, 30, 35,
40, 50, 75, 100, or 150 consecutive amino acids of the polypeptides of SEQ ID
Nos. 27 to 35 and
41 to 43. Preferably, the fragments are novel fragments. It will be
appreciated that the polypeptide
codes ofthe SEQ ID Nos. 27 to 35 and 41 to 43 can be represented in the
traditional single
character format or three letter format (See the inside back cover of
Starrier, Lubert. Biochemistry,
3rd edition. W. H Freeman & Co., New York.) or in any other format which
relates the identity of
the polypeptides in a sequence.
It will be appreciated by those skilled in the art that the nucleic acid codes
of SEQ ID
Nos. 1 to 26, 36 to 40 and 54 to 229 and polypeptide codes of SEQ ID Nos. 27
to 35 and 41 to
43 can be stored, recorded, and manipulated on any medium which can be read
and accessed by a
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computer. As used herein, the words "recorded" and "stored" refer to a process
for storing
information on a computer medium. A skilled artisan can readily adopt any of
the presently known
methods for recording information on a computer readable medium to generate
embodiment
comprising one or more of nucleic acid codes of SEQ ID Nos. 1 to 26, 36 to 40
and 54 to 229, or
one or more of the polypeptide codes of SEQ ID Nos. 27 to 35 and 41 to 43.
Another aspect of
the present invention is a computer readable medium having recorded thereon at
least 2, 5, 10, 15,
20, 25, 30, or SO nucleic acid codes of SEQ ID Nos 1 to 26, 36 to 40 and 54 to
229. Another
aspect of the present invention is a computer readable medium having recorded
thereon at least 2,
5, 10, 15, 20, 25, 30, or 50 polypeptide codes of SEQ ID Nos 27 to 35 and 41
to 43.
Computer readable media include magnetically readable media, optically
readable media,
electronically readable media and magnetic/optical media. For example, the
computer readable
media may be a hard disk, a floppy disk, a magnetic tape, CD-ROM, Digital
Versatile Disk (DVD), .
Random Access Memory (RAM), or Read Only Memory (ROM) as well as other types
of other
media known to those skilled in the art.
Embodiments of the present invention include systems, particularly computer
systems
which store and manipulate the sequence information described herein. One
example of a
computer system 100 is illustrated in block diagram form in Figure 19. As used
herein, "a
computer system" refers to the hardware components, software components, and
data storage
components used to analyze the nucleotide sequences of the nucleic acid codes
of SEQ ID Nos 1
to 26, 36 to 40 and 54 to 229, or the amino acid sequences of the polypeptide
codes of SEQ ID
Nos. 27 to 35 and 41 to 43. In one embodiment, the computer system 100 is a
Sun Enterprise
1000 server (Sun Microsystems, Palo Alto, CA). The computer system 100
preferably includes a
processor for processing, accessing and manipulating the sequence data. The
processor 105 can be
any well-known type of central processing unit, such as the Pentium III from
Intel Corporation, or
similar processor from Sun, Motorola, Compaq or International Business
Machines.
Preferably, the computer system 100 is a general purpose system that comprises
the
processor 105 and one or more internal data storage components 110 for storing
data, and one or
more data retrieving devices for retrieving the data stored on the data
storage components. A
skilled artisan can readily appreciate that any one of the currently available
computer systems are
suitable.
In one particular embodiment, the computer system 100 includes a processor 105
connected to a bus which is connected to a main memory 115 (preferably
implemented as RAM)
and one or more internal data storage devices 110, such as a hard drive and/or
other computer
readable media having data recorded thereon. In some embodiments, the computer
system 100
further includes one or more data retrieving device 118 for reading the data
stored on the internal
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data storage devices 110.
The data retrieving device I 18 may represent, for example, a floppy disk
drive, a compact
disk drive, a magnetic tape drive, etc. In some embodiments, the internal data
storage device 110 is
a removable computer readable medium such as a floppy disk, a compact disk, a
magnetic tape, etc.
containing control logic and/or data recorded thereon. The computer system 100
may
advantageously include or be programmed by appropriate software for reading
the control logic
and/or the data from the data storage component once inserted in the data
retrieving device.
The computer system 100 includes a display 120 which is used to display output
to a
computer user. It should also be noted that the computer system 100 can be
linked to other
computer systems 125a-c in a network or wide area network to provide
centralized access to the
computer system 100.
Software for accessing and processing the nucleotide sequences of the nucleic
acid codes
of SEQ ID Nos. 1 to 26, 36 to 40 and 54 to 229, or the amino acid sequences of
the polypeptide
codes of SEQ ID Nos. 27 to 35 and 41 to 43 (such as search tools, compare
tools, and modeling
tools etc.) may reside in main memory 115 during execution.
In some embodiments, the computer system 100 may further comprise a sequence
comparer for comparing the above-described nucleic acid codes of SEQ ID Nos. 1
to 26, 36 to 40
and 54 to 229 or polypeptide codes of SEQ ID Nos. 27 to 35 and 41 to 43 stored
on a computer
readable medium to reference nucleotide or polypeptide sequences stored on a
computer readable
medium. A "sequence comparer" refers to one or more programs which are
implemented on the
computer system 100 to compare a nucleotide or polypeptide sequence with other
nucleotide or
polypeptide sequences and/or compounds including but not limited to peptides,
peptidomimetics, .
and chemicals stored within the data storage means. For example, the sequence
comparer may
compare the nucleotide sequences of the nucleic acid codes of SEQ ID Nos. 1 to
26, 36 to 40 and
54 to 229, or the amino acid sequences of the polypeptide codes of SEQ ID Nos.
27 to 35 and 41
to 43 stored on a computer readable medium to reference sequences stored on a
computer readable
medium to identify homologies, motifs implicated in biological function, or
structural motifs. The
various sequence comparer programs identified elsewhere in this patent
specification are
particularly contemplated for use in this aspect of the invention.
Figure 20 is a flow diagram illustrating one embodiment of a process 200 for
comparing a
new nucleotide or protein sequence with a database of sequences in order to
determine the
homology levels between the new sequence and the sequences in the database.
The database of
sequences can be a private database stored within the computer system 100, or
a public database
such as GENBANK, PIR OR SWISSPROT that is available through the Internet.
The process 200 begins at a start state 201 and then moves to a state 202
wherein the new
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sequence to be compared is stored to a memory in a computer system 100. As
discussed above, the
memory could be any type of memory, including RAM or an internal storage
device.
The process 200 then moves to a state 204 wherein a database of sequences is
opened for
analysis and comparison. The process 200 then moves to a state 206 wherein the
first sequence
stored in the database is read into a memory on the computer. A comparison is
then performed at a
state 210 to determine if the first sequence is the same as the second
sequence. It is important to
note that this step is not limited to performing an exact comparison between
the new sequence and
the first sequence in the database. Well-known methods are known to those of
skill in the art for
comparing two nucleotide or protein sequences, even if they are not identical.
For example, gaps
can be introduced into one sequence in order to raise the homology level
between the two tested
sequences. The parameters that control whether gaps or other features are
introduced into a
sequence during comparison are normally entered by the user of the computer
system.
Once a comparison of the two sequences has been performed at the state 210, a
determination is made at a decision state 210 whether the two sequences are
the same. Of course,
1 S the term "same" is not limited to sequences that are absolutely identical.
Sequences that are within
the homology parameters entered by the user will be marked as "same" in the
process 200.
If a determination is made that the two sequences are the same, the process
200 moves to a
state 214 wherein the name of the sequence from the database is displayed to
the user. This state
notifies the user that the sequence with the displayed name fulfills the
homology constraints that
were entered. Once the name of the stored sequence is displayed to the user,
the process 200
moves to a decision state 218 wherein a determination is made whether more
sequences exist in the
database. If no more sequences exist in the database, then the process 200
terminates at an end
state 220. However, if more sequences do exist in the database, then the
process 200 moves to a
state 224 wherein a pointer is moved to the next sequence in the database so
that it can be
compared to the new sequence. In this manner, the new sequence is aligned and
compared with
every sequence in the database.
It should be noted that if a determination had been made at the decision state
212 that the
sequences were not homologous, then the process 200 would move immediately to
the decision .
state 218 in order to determine if any other sequences were available in the
database for
comparison.
Accordingly, one aspect of the present invention is a computer system
comprising a
processor, a data storage device having stored thereon a nucleic acid code of
SEQ ID NOs. 1 to
26, 36 to 40 and 54 to 229 or a polypeptide code of SEQ ID Nos 27 to 35 and 41
to 43, a data
storage device having retrievably stored thereon reference nucleotide
sequences or polypeptide
sequences to be compared to the nucleic acid code of SEQ ID Nos. 1 to 26, 36
to 40 and 54 to
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229 or polypeptide code of SEQ ID Nos. 27 to 35 and 41 to 43 and a sequence
comparer for
conducting the comparison. The sequence comparer may indicate a homology level
between the
sequences compared or identify structural motifs in the above described
nucleic acid code of
SEQ ID Nos. 1 to 26, 36 to 40 and 54 to 229 and polypeptide codes of SEQ ID
Nos. 27 to 35
and 41 to 43or it may identify structural motifs in sequences which are
compared to these
nucleic acid codes and polypeptide codes. In some embodiments, the data
storage device may
have stored thereon the sequences of at least 2, 5, 10, 15, 20, 25, 30, or 50
of the nucleic acid
codes of SEQ ID Nos. 1 to 26, 36 to 40 and 54 to 229 or polypeptide codes of
SEQ ID Nos. 27
to 35 and 41 to 43.
Another aspect of the present invention is a method for determining the level
of homology
between a nucleic acid code of SEQ ID Nos. 1 to 26, 36 to 40 and 54 to 229 and
a reference
nucleotide sequence, comprising the steps of reading the nucleic acid code and
the reference
nucleotide sequence through the use of a computer program which determines
homology levels and
determining homology between the nucleic acid code and the reference
nucleotide sequence with
the computer program. The computer program may be any of a number of computer
programs for
determining homology levels, including those specifically enumerated herein,
including BLAST2N
with the default parameters or with any modified parameters. The method may be
implemented
using the computer systems described above. The method may also be performed
by reading 2, 5,
10, 15, 20, 25, 30, or 50 of the above described nucleic acid codes of SEQ ID
Nos. 1 to 26, 36 to
40 and 54 to 229 through use of the computer program and determining homology
between the
nucleic acid codes and reference nucleotide sequences .
Figure 21 is a flow diagram illustrating one embodiment of a process 250 in a
computer
for determining whether two sequences are homologous. The process 250 begins
at a start state
252 and then moves to a state 254 wherein a first sequence to be compared is
stored to a
memory. The second sequence to be compared is then stored to a memory at a
state 256. The
process 250 then moves to a state 260 wherein the first character in the first
sequence is read
and then to a state 262 wherein the first character of the second sequence is
read. It should be
understood that if the sequence is a nucleotide sequence, then the character
would normally be
either A, T, C, G or U. If the sequence is a protein sequence, then it should
be in the single
letter amino acid code so that the first and sequence sequences can be easily
compared.
A determination is then made at a decision state 264 whether the two
characters are the
same. If they are the same, then the process 250 moves to a state 268 wherein
the next
characters in the first and second sequences are read. A determination is then
made whether
the next characters are the same. If they are, then the process 250 continues
this loop until two
characters are not the same. If a determination is made that the next two
characters are not the
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same, the process 250 moves to a decision state 274 to determine whether there
are any more
characters either sequence to read.
If there aren't any more characters to read, then the process 250 moves to a
state 276
wherein the level of homology between the first and second sequences is
displayed to the user.
The level of homology is determined by calculating the proportion of
characters between the
sequences that were the same out of the total number of sequences in the first
sequence. Thus,
if every character in a first 100 nucleotide sequence aligned with a every
character in a second
sequence, the homology level would be 100%.
Alternatively, the computer program may be a computer program which compares
the
nucleotide sequences of the nucleic acid codes of the present invention, to
reference nucleotide
sequences in order to determine whether the nucleic acid code of SEQ ID Nos. I
to 26, 36 to 40
and 54 to 229 differs from a reference nucleic acid sequence at one or more
positions. Optionally
such a program records the length and identity of inserted, deleted or
substituted nucleotides with
respect to the sequence of either the reference polynucleotide or the nucleic
acid code of SEQ ID
Nos. 1 to 26, 36 to 40 and 54 to 229. In one embodiment, the computer program
may be a
program which determines whether the nucleotide sequences of the nucleic acid
codes of SEQ ID
Nos. 1 to 26, 36 to 40 and 54 to 229 contain a biallelic marker or single
nucleotide polymorphism
(SNP) with respect to a reference nucleotide sequence. This single nucleotide
polymorphism may
comprise a single base substitution, insertion, or deletion, while this
biallelic marker may
comprise abour one to ten consecutive bases substituted, inserted or deleted.
Another aspect of the present invention is a method for determining the level
of homology
between a polypeptide code of SEQ ID Nos. 27 to 35 and 41 to 43 and a
reference polypeptide
sequence, comprising the steps of reading the polypeptide code of SEQ ID Nos.
27 to 35 and 41 to
43 and the reference polypeptide sequence through use of a computer program
which determines
homology levels and determining homology between the polypeptide code and the
reference
polypeptide sequence using the computer program.
Accordingly, another aspect of the present invention is a method for
determining whether a
nucleic acid code of SEQ ID Nos. I to 26, 36 to 40 and 54 to 229 differs at
one or more nucleotides
from a reference nucleotide sequence comprising the steps of reading the
nucleic acid code and the
reference nucleotide sequence through use of a computer program which
identifies differences
between nucleic acid sequences and identifying differences between the nucleic
acid code and the
reference nucleotide sequence with the computer program. In some embodiments,
the computer
program is a program which identifies single nucleotide polymorphisms. The
method may be
implemented by the computer systems described above and the method illustrated
in Figure 21.
The method may also be performed by reading at least 2, 5, 10, 15, 20, 25, 30,
or SO of the nucleic
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acid codes of SEQ ID Nos. 1 to 26, 36 to 40 and 54 to 229 and the reference
nucleotide sequences
through the use of the computer program and identifying differences between
the nucleic acid
codes and the reference nucleotide sequences with the computer program.
In other embodiments the computer based system may further comprise an
identifier for
identifying features within the nucleotide sequences of the nucleic acid codes
of SEQ ID Nos. 1 to
26, 36 to 40 and 54 to 229 or the amino acid sequences of the polypeptide
codes of SEQ ID Nos.
27 to 35 and 41 to 43.
An "identifier" refers to one or more programs which identifies certain
features within
the above-described nucleotide sequences of the nucleic acid codes of SEQ ID
Nos. 1 to 26, 36
to 40 and 54 to 229 or the amino acid sequences of the polypeptide codes of
SEQ ID Nos. 27 to
35 and 41 to 43. In one embodiment, the identifier may comprise a program
which identifies an
open reading frame in the cDNAs codes of SEQ ID Nos 2 to 26 and 36 to 40.
Figure 22 is a flow diagram illustrating one embodiment of an identifier
process 300 for
detecting the presence of a feature in a sequence. The process 300 begins at a
start state 302
and then moves to a state 304 wherein a first sequence that is to be checked
for features is
stored to a memory 115 in the computer system 100. The process 300 then moves
to a state 306
wherein a database of sequence features is opened. Such a database would
include a list of each
feature's attributes along with the name of the feature. For example, a
feature name could be
"Initiation Codon" and the attribute would be "ATG". Another example would be
the feature
name "TAATAA Box" and the feature attribute would be "TAATAA". An example of
such a
database is produced by the University of Wisconsin Genetics Computer Group
(www.gcg.com).
Once the database of features is opened at the state 306, the process 300
moves to a
state 308 wherein the first feature is read from the database. A comparison of
the attribute of
the first feature with the first sequence is then made at a state 310. A
determination is then
made at a decision state 316 whether the attribute of the feature was found in
the first sequence.
If the. attribute was found, then the process 300 moves to a state 318 wherein
the name of the
found feature is displayed to the user.
The process 300 then moves to a decision state 320 wherein a determination is
made
whether move features exist in the database. If no more features do exist,
then the process 300
terminates at an end state 324. However, if more features do exist in the
database, then the
process 300 reads the next sequence feature at a state 326 and loops back to
the state 310
wherein the attribute of the next feature is compared against the first
sequence.
It should be noted, that if the feature attribute is not found in the first
sequence at the
decision state 316, the process 300 moves directly to the decision state 320
in order to
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determine if any more features exist in the database.
In another embodiment, the identifier may comprise a molecular modeling
program
which determines the 3-dimensional structure of the polypeptides codes of SEQ
ID Nos. 27 to
35 and 41 to 43. In some embodiments, the molecular modeling program
identifies target
sequences that are most compatible with profiles representing the structural
environments of the
residues in known three-dimensional protein structures. (See, e.g., Eisenberg
et al., U.S. Patent
No. 5,436,850 issued July 25, 1995). In another technique, the known three-
dimensional
structures of proteins in a given family are superimposed to define the
structurally conserved
regions in that family. This protein modeling technique also uses the known
three-dimensional
structure of a homologous protein to approximate the structure of the
polypeptide codes of SEQ
ID Nos. 4 to 8. (See e.g., Srinivasan, et al., U.S. Patent No. 5,557,535
issued September 17,
1996). Conventional homology modeling techniques have been used routinely to
build models
of proteases and antibodies. (Sowdhamini et al., Protein Engineering 10:207,
215 (1997)).
Comparative approaches can also be used to develop three-dimensional protein
models when
the protein of interest has poor sequence identity to template proteins. In
some cases, proteins
fold into similar three-dimensional structures despite having very weak
sequence identities. For
example, the three-dimensional structures of a number of helical cytokines
fold in similar three-
dimensional topology in spite of weak sequence homology.
The recent development of threading methods now enables the identification of
likely
folding patterns in a number of situations where the structural relatedness
between target and
templates) is not detectable at the sequence level. Hybrid methods, in which
fold recognition is
performed using Multiple Sequence Threading (MST), structural equivalencies
are deduced
from the threading output using a distance geometry program DRAGON to
construct a low
resolution model, and a full-atom representation is constructed using a
molecular modeling
package such as QUANTA.
According to this 3-step approach, candidate templates are first identified by
using the
novel fold recognition algorithm MST, which is capable of performing
simultaneous threading
of multiple aligned sequences onto one or more 3-D structures. In a second
step, the structural
equivalencies obtained from the MST output are converted into interresidue
distance restraints
and fed into the distance geometry program DRAGON, together with auxiliary
information
obtained from secondary structure predictions. The program combines the
restraints in an
unbiased manner and rapidly generates a large number of low resolution model
confirmations.
In a third step, these low resolution model confirmations are converted into
full-atom models
and subjected to energy minimization using the molecular modeling package
QUANTA. (See
e.g., Aszodi et al., Proteins:Structure, Function, and Genetics, Supplement
1:38-42 (1997)).
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The results of the molecular modeling analysis may then be used in rational
drug design
techniques to identify agents which modulate the activity of the polypeptide
codes of SEQ ID
Nos. 27 to 35 and 41 to 43.
Accordingly, another aspect of the present invention is a method of
identifying a feature
within the nucleic acid codes of SEQ ID Nos. 1 to 26, 36 to 40 and 54 to 229
or the polypeptide
codes of SEQ ID Nos. 27 to 35 and 41 to 43 comprising reading the nucleic acid
codes) or the
polypeptide codes) through the use of a computer program which identifies
features therein and
identifying features within the nucleic acid codes) or polypeptide codes) with
the computer
program. In one embodiment, computer program comprises a computer program
which
identifies open reading frames. In a further embodiment, the computer program
identifies
structural motifs in a polypeptide sequence. In another embodiment, the
computer program
comprises a molecular modeling program. The method may be performed by reading
a single
sequence or at least 2, 5, 10, 15, 20, 25, 30, or 50 of the nucleic acid codes
of SEQ ID Nos. 1 to
26, 36 to 40 and 54 to 229 or the polypeptide codes of SEQ ID Nos. 27 to 35
and 41 to 43
through the use of the computer program and identifying features within the
nucleic acid codes
or polypeptide codes with the computer program.
The nucleic acid codes of SEQ ID Nos. 1 to 26, 36 to 40 and 54 to 229 or the
polypeptide codes of SEQ ID Nos. 27 to 35 and 41 to 43 may be stored and
manipulated in a
variety of data processor programs in a variety of formats. For example, the
nucleic acid codes of
SEQ ID Nos. 1 to 26, 36 to 40 and 54 to 229 or the polypeptide codes of SEQ ID
Nos. 27 to 35
and 41 to 43 may be stored as text in a word processing file, such as
MicrosoftWORD or
WORDPERFECT or as an ASCII file in a variety of database programs familiar to
those of skill in
the art, such as DB2, SYBASE, or ORACLE. In addition, many computer programs
and databases
may be used as sequence comparers, identifiers, or sources of reference
nucleotide or polypeptide
sequences to be compared to the nucleic acid codes of SEQ ID Nos. 1 to 26, 36
to 40 and 54 to
229 or the polypeptide codes of SEQ ID Nos. 27 to 35 and 41 to 43. The
following list is
intended not to limit the invention but to provide guidance to programs and
databases which are
useful with the nucleic acid codes of SEQ 1D Nos. 1 to 26, 36 to 40 and 54 to
229 or the
polypeptide codes of SEQ ID Nos. 27 to 35 and 41 to 43. The programs and
databases which
may be used include, but are not limited to: MacPattern (EMBL), DiscoveryBase
(Molecular
Applications Group), GeneMine (Molecular Applications Group), Look (Molecular
Applications
Group), MacLook (Molecular Applications Group), BLAST and BLAST2 (NCBI),
BLASTN and
BLASTX (Altschul et al, J. Mol. Biol. 215: 403 (1990)), FASTA (Pearson and
Lipman, Proc. Natl.
Acad. Sci. USA, 85: 2444 (1988)), FASTDB (Brutlag et al. Comp. App. Biosci.
6:237-245, 1990),
Catalyst (Molecular Simulations Inc.), Catalyst/SHAPE (Molecular Simulations
Inc.),
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Cerius2.DBAccess (Molecular Simulations Inc.), HypoGen (Molecular Simulations
Inc.), Insight II,
(Molecular Simulations Inc.), Discover (Molecular Simulations Inc.), CHARMm
(Molecular
Simulations Inc.), Felix (Molecular Simulations Inc.), Delphi, (Molecular
Simulations Inc.),
QuanteMM, (Molecular Simulations Inc.), Homology (Molecular Simulations Inc.),
Modeler
S (Molecular Simulations Inc.), ISIS (Molecular Simulations Inc.),
Quanta/Protein Design
(Molecular Simulations Inc.), WebLab (Molecular Simulations Inc.), WebLab
Diversity Explorer
(Molecular Simulations Inc.), Gene Explorer (Molecular Simulations Inc.),
SeqFold (Molecular
Simulations Inc.), the EMBL/Swissprotein database, the MDL Available Chemicals
Directory
database, the MDL Drug Data Report data base, the Comprehensive Medicinal
Chemistry
database, Derwents's World Drug Index database, the BioByteMasterFile
database, the Genbank
database, and the Genseqn database. Many other programs and data bases would
be apparent to
one of skill in the art given the present disclosure.
Motifs which may be detected using the above programs include sequences
encoding
leucine zippers, helix-turn-helix motifs, glycosylation sites, ubiquitination
sites, alpha helices,
and beta sheets, signal sequences encoding signal peptides which direct the
secretion of the
encoded proteins, sequences implicated in transcription regulation such as
homeoboxes, acidic
stretches, enzymatic active sites, substrate binding sites, and enzymatic
cleavage sites.
Throughout this application, various publications, patents, and published
patent
applications are cited. The disclosures of the publications, patents, and
published patent
specifications referenced in this application are all hereby incorporated by
reference in their
entireties into the present disclosure to more fully describe the state of the
art to which this
invention pertains.
EXAMPLES
Several of the methods of the present invention are described in the following
examples, which are offered by way of illustration and not by way of
limitation. Many other
modifications and variations of the invention as herein set forth can be made
without departing
from the spirit and scope thereof and therefore only such limitations should
be imposed as are
indicated by the appended claims.
Example 1
Identification Of Biallelic Markers - DNA Extraction
Donors were unrelated and healthy. They presented a sufficient diversity for
being .
representative of a heterogeneous population. The DNA from 100 individuals was
extracted
and tested for the detection of the biallelic markers.
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30 ml of peripheral venous blood were taken from each donor in the presence of
EDTA.
Cells (pellet) were collected after centrifugation for 10 minutes at 2000 rpm.
Red cells were
lysed by a lysis solution (SO ml final volume: 10 mM Tris pH7.6; 5 mM MgCl2;
10 mM NaCI).
The solution was centrifuged (10 minutes, 2000 rpm) as many times as necessary
to eliminate
the residual red cells present in the supernatant, after resuspension of the
pellet in the lysis
solution.
The pellet of white cells was lysed overnight at 42°C with 3.7 ml of
lysis solution
composed of
- 3 ml TE 10-2 (Tris-HCl 10 mM, EDTA 2 mM) / NaCI 0 4 M
- 200 pl SDS 10%
- 500 pl K-proteinase (2 mg K-proteinase in TE 10-2 / NaCI 0.4 M).
For the extraction of proteins, 1 ml saturated NaCI (6M) (1/3.5 v/v) was
added. After
vigorous agitation, the solution was centrifuged for 20 minutes at 10000 rpm.
1 S For the precipitation of DNA, 2 to 3 volumes of 100% ethanol were added to
the
previous supernatant, and the solution was centrifuged for 30 minutes at 2000
rpm. The DNA
solution was rinsed three times with 70% ethanol to eliminate salts, and
centrifuged for 20
minutes at 2000 rpm. The pellet was dried at 37°C, and resuspended in 1
ml TE 10-1 or 1 ml
water. The DNA concentration was evaluated by measuring the OD at 260 nm (1
unit OD = SO
pg/ml DNA). To determine the presence of proteins in the DNA solution, the OD
260 / OD 280
ratio was determined. Only DNA preparations having a OD 260 / OD 280 ratio
between 1.8
and 2 were used in the subsequent examples described below.
The pool was constituted by mixing equivalent quantities of DNA from each
individual.
Example 2
Identification Of Biallelic Markers: Amplification Of Genomic DNA By PCR
The amplification of specific genomic sequences of the DNA samples of Example
I
was carried out on the pool of DNA obtained previously. In addition, SO
individual samples
were similarly amplified.
PCR assays were performed using the following protocol:
Final volume 25 pl
DNA 2 ng/pl
MgCI2 2 mM
dNTP (each) 200 pM
primer (each) 2.9 ng/pl
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Ampli Taq Gold DNA polymerase 0.05 unibpl
PCR buffer (lOx = 0.1 M TrisHCl pH8.3 O.SM KCl) lx
Each pair of first primers was designed using the sequence information of
genomic
DNA sequences of SEQ ID Nos 1 to 26, 36 to 40 and 54 to 229 disclosed herein
and the OSP
software (Hillier & Green, 1991). This first pair of primers was about 20
nucleotides in length
and had the sequences disclosed in Table 6a in the columns labeled "Position
range of
amplification primer in SEQ ID No." and "Complementary position range of
amplification
primer in SEQ ID No.".
Table 6a
AmpliconSEQ PrimerPosition PrimerComplementary
ID name range name position
No of range
amplification of
primer amplification
in SEQ primer
ID in SEQ
ID
99-279431 B1 7938 7958 CI 8446 8465
8-121 1 B2 14699 14718 C2 15100 15118
99-279351 B3 21365 21385 C3 21845 21864
8-122 1 B4 25409 25426- C4 25825 25844
8-123 1 BS 29349 29366 CS 29684 29701
8-147 1 B6 29900 29919 C6 30340 30356
99-342431 B7 49219 49239 C7 49664 49684
8-127 1 B8 64639 64657 C8 64981 64999
8-128 1 B9 65453 65471 C9 65856 65874
8-129 1 B10 65547 65566 C10 65949 65966
99-342401 B11 75629 75649 C11 76140 76158
99-319591 B12 94254 94273 C12 94683 94703
99-319601 B13 95034 95053 C13 95543 95563
99-31962I B14 96707 96727 C14 97222 97242
99-442821 B15 106357 106377 C15 106805 106822
99-246561 B16 107022 107040 C16 107495 107513
99-246361 B17 107132 107152 C17 107613 107630
99-319391 B18 108425 108444 C18 108916 108935
99-442811 B19 109333 109353 C19 109848 109868
99-319411 B20 112149 112169 C20 112720 112740
99-319421 B21 115144 115162 C21 115617 115637
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99-246351 B22 155353 155373 C22 155805 155822
99-160591 B23 157860 157878 C23 158296 158316
99-24634I B24 160770 160787 C24 161240 161257
99-246391 B25 160279 160298 C25 160785 160802
99-76521 B26 168813 168830 C26 169331 169351
99-161001 B27 170666 170686 C27 171153 171173
99-58621 B28 173065 173085 C28 173495 173514
99-160831 B29 173830 173850 C29 174309 174327
99-16044I B30 175453 175470 C30 175881 175901
99-160421 B31 180464 180481 C31 180991 181008
99-59191 B32 189753 189771 C32 190187 190207
99-246581 B33 197116 197135 C33 197555 197572
99-303641 B34 198666 198684 C34 199148 199168
99-303661 B35 200145 200162 C35 200663 200683
99-160941 B36 204263 204282 C36 204643 204662
99-246441 B37 204741 204758 C37 205222 205240
99-161071 B38 206103 206120 C38 206548 206568
99-15873I B39 211454 211471 C39 211893 211910
8-124 1 B40 214564 214581 C40 214965 214983
8-125 1 B41 215506 215525 C41 215924 215942
8-132 1 B42 215628 215647 C42 215998 216016
99-139291 B43 215749 215769 C43 216210 216228
8-131 1 B44 216473 216491 C44 216883 216900
8-130 1 B45 216683 216702 C45 217091 217109
8-209 1 B46 217119 217136 C46 217521 217539
99-58971 B47 219408 219425 C47 219882 219899
99-246491 B48 220505 220522 C48 221004 221021
8-199 1 B49 221384 221402 C49 221807 221824
8-198 1 B50 221740 221759 C50 222167 222185
8-195 1 B51 222696 222713 C51 223073 223093
99-139251 B52 223499 223518 C52 224013 224033
8-192 1 B53 225103 225120 C53 225505 225524
99-160901 B54 225995 226013 C54 226510 226530
8-189 1 B55 226211 226230 C55 226615 226632
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8-188 1 B56 226569 226588 C56 226988 227005
8-187 I B57 226915 226934 C57 227319 227338
8-185 1 B58 227468 227487 C58 227888 227907
99-160511 B59 227768 227788 C59 228214 228231
8-184 1 B60 227832 227849 C60 228234 228252
8-183 1 B61 228209 228227 C61 228635 228654
8-181 1 B62 228898 228917 C62 229499 229517
8-180 I B63 229443 229462 C63 229624 229642
8-179 1 B64 229442 229459 C64 229857 229874
8-143 1 B65 229487 229506 C65 229896 229913
8-178 1 B66 229739 229756 C66 230141 230159
8-177 1 B67 230097 230115 C67 230517 230536
8-119 1 B68 230210 230227 C68 230622 230641
8-138 1 B69 230517 230536 C69 230899 230917
8-175 1 B70 230705 230724 C70 231127 231144
99-158701 B71 231278 231298 C71 231729 231747
8-142 1 B72 231084 231103 C72 231485 231503
8-145 1 B73 231588 231605 C73 231990 232007
8-171 1 B74 232147 232166 C74 232547 232566
8-170 1 B75 232405 232423 C75 232830 232849
8-169 1 B76 232744 232762 C76 233145 233163
8-168 1 B77 233056 233074 C77 233461 233479
8-235 1 B78 233314 233334 C78 233785 233801
8-137 1 B79 234039 234058 C79 234440 234458
8-165 1 B80 234516 234533 C80 234916 234935
99-16087I B81 235081 235101 C81 235515 235533
8-157 1 B82 237972 237989 C82 238381 238399
8-155 1 B83 238607 238626 C83 239029 239046
99-160381 B84 239405 239425 C84 239862 239880
8-136 1 B85 239606 239624 C85 240012 240029
8-153 1 B86 239651 239670 C86 240058 240075
8-135 1 B87 240356 240375 C87 240691 240708
99-160501 B88 240518 240538 C88 240988 241006
8-144 1 B89 240810 240828 C89 241217 241235
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8-141 1 B90 241094 241113 C90 241502 241520
99-158801 B91 241700 241717 C91 242151 242171
8-140 1 B92 241373 241392 C92 241773 241792
8-240 1 B93 242169 242188 C93 242571 242588
8-225 1 B94 244172 244191 C94 244574 244593
99-259401 B95 247513 247533 C95 248023 248043
99-160321 B96 248204 248223 C96 248588 248606
99-160551 B97 253315 253333 C97 253816 253834
99-161051 B98 255697 255715 C98 256133 256152
99-161011 B99 258138 258155 C99 258606 258623
99-160331 B100 259885 259902 C100 260324 260342
99-158751 B101 279626 279644 C101 280154 280173
99-135211 B102 287977 287995 C102 288484 288504
8-112 1 B103 292501 292519 C103 292901 292920
8-111 1 B104 295376 295395 C104 295777 295795
8-110 1 B105 295682 295701 C105 296102 296119
8-134 1 B106 295812 295830 C106 296143 296161
99-74621 B107 298946 298964 C107 299459 299476
99-160521 B108 300153 300170 C108 300660 300680
99-160471 B109 311615 311632 C109 312126 312144
99-25993I B110 315649 315668 CI10 316129 316147
99-25101I B111 316925 316943 CI11 317378 317395
AmpliconSEQ PrimerPosition PrimerComplementary
ID name range name position
No of range
amplification of
primer amplification
in SEQ primer
ID in SEQ
ID
8-94 162 B 112 1250 1267 C 1 I 651 1669
I
2
8-95 161 B 113 1125 1144 C 113 1526 1543
8-97 160 B114 1249 1268 C114 1581 1598
8-98 159 B115 1135 1154 CI15 1550 1568
99-14021151 B116 1394 1411 C116 1853 1870
99-14364152 B117 1344 1364 C117 1798 1816
99-15056115 B118 1098 1118 C118 1582 1599
99-15063116 B119 1347 1364 C119 1784 1804
99-15065117 B120 1120 1140 C120 1568 1585
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99-15229157 B121 1419 1437 C121 1893 1912
99-15231163 B 122 1189 1209 C I 1701 1719
22
99-15232155 B123 1211 1228 C123 1677 1695
99-15239164 B124 1139 1156 C124 1579 1599
99-15252118 B 125 1 I 8 C 125 434 451
99-15253119 B126 1120 1138 C126 1578 1596
99-15256120 B127 1110 1127 C127 1548 1565
99-15258121 B128 1165 1183 C128 1685 1705
99-15261122 B129 1302 1320 C129 1782 1802
99-15280123 B130 1070 1087 C130 1590 1610
99-15355124 B131 1352 1369 C131 1822 1840
99-15663175 B 132 1349 1369 C 132 1781 1798
99-15664176 B133 1184 1203 C133 1667 1685
99-15665174 B134 1423 1441 C134 1879 1898
99-15668177 B135 1363 1380 C135 1801 1821
99-15672173 B136 1120 1138 C136 1649 1666
99-15682178 B137 1184 1202 C137 1665 1683
99-16081113 B138 114 131 C138 556 575
99-16082114 B139 16 33 C139 527 547
99-20933179 B140 1130 1149 C140 1563 1581
99-20977147 B 141 1430 1447 C 141 1921 1941
99-20978148 B 142 1124 1144 C 142 1571 1589
99-20981149 B 143 1202 1219 C 143 1630 1650
99-20983150 B144 1099 1119 C144 1530 1548
99-22310154 B145 1183 1203 C145 1630 1648
99-25029180 B146 1292 1307 C146 1722 1741
99-25224125 B147 937 955 C147 1446 1466
99-25869181 B148 1320 1340 C148 1849 1868
99-25881182 B149 1227 1245 C149 1693 1713
99-25897183 B150 1242 1262 C150 1736 1756
99-25906184 BI51 1374 1392 C151 1888 1908
99-25917185 B152 1115 1135 C152 1595 1615
99-25924186 ~ B ~ 1287 ~ 1306 ~ C ~ 1717 1736
153 153
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99-25950126 B154 1381 1399 C154 1859 1879
99-25961127 B 155 1391 1411 C 155 1854 1873
99-25965128 B156 1429 1449 C156 1879 1899
99-25966129 B157 1219 1239 C157 1721 1741
99-25967130 B158 1064 1084 C158 1537 1556
99-25969I 31 B 159 1171 1191 C 159 1680 1700
99-25972132 B160 1368 1388 C160 1795 1815
99-25974133 B 161 1100 1120 C 161 1623 1643
99-25977134 B162 1191 1211 C162 1710 1730
99-25978135 B163 1155 1175 C163 1644 1663
99-25979136 B164 1409 1427 C164 1924 1944
99-25980137 B165 1332 1352 C165 1817 1837
99-25984138 B166 1293 1310 C166 1794 1812
99-25985139 B167 1308 1328 C167 1756 1776
99-25989140 B168 1346 1366 C168 1880 1898
99-26126165 B 169 1004 1022 C 169 1525 1545
99-26138187 8170 1309 1327 C170 1741 1761
99-26146188 B171 1314 1334 C171 1746 1764
99-26147141 B172 1433 1453 C172 1879 1896
99-26150142 B173 1323 1340 C173 1758 1776
99-26153143 B 174 1458 1476 C 174 1885 1905
99-26154144 B175 1396 1415 C175 1903 1920
99-26156145 B 176 1212 1229 C 176 1702 1722
99-26166166 B177 1237 1257 C177 1739 1757
99-26167167 B 178 1319 1339 C 178 1759 1778
99-26169168 B179 1262 1282 C179 1693 1711
99-26171169 B180 1431 1450 C180 1860 1880
99-26183170 B181 1348 1367 C181 1798 1818
99-26189189 B182 1215 1235 C182 1644 1664
99-26190190 B183 1071 1091 C183 1502 1520
99-26191191 B184 1095 1115 C184 1539 1558
99-26201192 B185 1304 1324 C185 1749 1767
99-26222193 B186 1354 1373 C186 1843 1863
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99-26223194 B 187 1277 1297 C 187 1842 1862
99-26225195 B188 1355 1375 C188 1805 1825
99-26228196 B189 1330 1350 C189 1792 1812
99-26233197 B 190 1254 1274 C 190 1755 1775
99-26234198 B191 1379 1399 C191 1813 1833
99-26238199 B192 1235 1255 C192 1668 1686
99-5873146 B193 1176 1194 C193 1632 1649
99-5912171 B194 1463 1483 C194 1946 1963
99-6012158 B195 1292 1310 C195 1758 1776
99-6080156 B196 1061 1081 C196 1572 1589
99-7308153 B197 1345 1362 C197 1814 1834
99-7337172 B198 1298 1318 C198 1731 1748
99-16106200 B199 32 50 C199 518 535
99-25332201 B200 1 18 C200 461 478
99-25516202 B201 1 18 C201 385 404
99-26173203 B202 1033 1052 C202 1570 1589
99-26267204 B203 983 1002 C203 1553 1573
99-26284205 B204 1460 1480 C204 1874 1894
99-26559206 B205 1187 1207 C205 1650 1670
99-26769207 B206 1249 1267 C206 1707 1727
99-26772208 B207 1235 1254 C207 1702 1722
99-26776209 B208 1294 1314 C208 1755 1775
99-26779210 B209 1072 1089 C209 1548 1568
99-26781211 B210 1477 1497 C210 1905 1925
99-26782212 B211 1202 1221 C211 1695 1715
99-26783213 B212 1421 1440 C212 1857 1877
99-26787214 B213 1406 1425 C213 1872 1892
99-26789215 B214 1301 1319 C214 1771 1791
99-27297216 B21 1206 1224 C215 1761 1779
S
99-27306217 B216 1395 1415 C216 1822 1842
99-27312218 B217 1445 1463 C217 1940 1960
99-27323219 B218 1132 1150 C218 1610 1628
99-27335220 ~ B219~ 1322 1342 ~ C219~ 1768 1788
~ ~
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99-27345221 B220 1139 1159 C220 1672 1689
99-27349222 B221 1337 1355 C221 1748 1767
99-27352223 B222 1250 1269 C222 1677 1697
99-27353224 B223 1085 1105 C223 1584 1604
99-27360225 B224 1361 1381 C224 1793 1812
99-27361226 B225 1322 1340 C225 1815 1834
99-27365227 B226 1081 1099 C226 1590 1609
99-27680228 B227 1 18 C227 509 526
99-27912229 B228 1230 1250 C228 1659 1679
99-30329112 B229 1 18 C229 496 514
Preferably, the primers contained a common oligonucleotide tail upstream of
the
specific bases targeted for amplification which was useful for sequencing.
Primers from the column labeled "Position range of amplification primer in SEQ
ID
No." contain the following additional PU 5' sequence: TGTAAAACGACGGCCAGT (SEQ
1D
No. 126); primers from the column labeled "Complementary position range of
amplification
primer in SEQ ID No." contain the following RP 5' sequence: CAGGAAACAGCTATGACC
(SEQ ID No. 127).
The synthesis of these primers was performed following the phosphoramidite
method, on a
GENSET UFPS 24.1 synthesizer.
DNA amplification was performed on a Genius II thermocyeler. After heating at
95°C
for 10 min, 40 cycles were performed. Each cycle comprised: 30 sec at
95°C, 54°C for 1 min,
and 30 sec at 72°C. For final elongation, 10 min at 72°C ended
the amplification. The
quantities of the amplification products obtained were determined on 96-well
microtiter plates,
using a fluorometer and Picogreen as intercalant agent (Molecular Probes).
Example 3
Identification of Polymorphisms
a) Identification of Biallelic Markers from Amplified Genomic DNA of Example 2
The sequencing of the amplified DNA obtained in Example 2 was carried out on
ABI
377 sequencers. The sequences of the amplification products were determined
using automated
dideoxy terminator sequencing reactions with a dye terminator cycle sequencing
protocol. The
products of the sequencing reactions were run on sequencing gels and the
sequences were
determined using gel image analysis (ABI Prism DNA Sequencing Analysis
software (2.1.2
version)).
The sequence data were further evaluated to detect the presence of biallelic
markers
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within the amplified fragments. The polymorphism search was based on the
presence of
superimposed peaks in the electrophoresis pattern resulting from different
bases occurring at the
same position as described previously.
The localization of the biallelic markers detected in the fragments of
amplification are
as shown below in Table 6b.
Table 6b
Biallelic Markers
Amplicon BM Marker Polymor- SEQ BM Position Probe
Name pbism ID positionof No.
No. probes
in
Alll in SE SE
A112 )m ID
No.
99-27943 Al 99-27943-150G C 1 8316 8304 8328 P1
8-121 A2 8-121-28 A T 1 14726 14714 14738P2
8-121 A3 8-121-36 C T 1 14734 14722 14746P3
8-121 A4 8-121-154 A T 1 14852 14840 14864P4
8-121 A5 8-121-187 A C 1 14885 14873 14897P5
8-121 A6 8-121-243 G T 1 14941 14929 14953P6
8-121 A7 8-121-281 A C 1 14979 14967 14991P7
8-121 A8 8-121-352 C T 1 15050 15038 15062P8
8-121 A9 8-121-364 C T 1 15062 15050 15074P9
8-121 A10 8-121-371 A G 1 15069 15057 15081P10
99-27935 All 99-27935-193G C 1 21672 21660 21684P11
8-122 A12 8-122-72 A T 1 25480 25468 25492P12
8-122 A13 8-122-100 C T 1 25508 25496 25520P13
8-122 A14 8-122-271 deletion 1 25679 25667 25691P14
o
CAAA
8-122 A15 8-122-272 A A 1 25680 25668 25692P15
8-122 A16 8-122-326 A A 1 25734 25722 25746P16
8-122 A17 8-122-360 C C 1 25768 25756 25780P17
8-123 A18 8-123-55 A A 1 29403 29391 29415P18
8-123 A19 8-123-189 C C 1 29537 29525 29549P19
8-123 A20 8-123-197 C C 1 29545 29533 29557P20
8-123 A21 8-123-307 G G I 29655 29643 29667P21
8-147 A22 8-147-270 A A 1 30169 30157 30181P22
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99-34243 A23 99-34243-210A A 1 49475 49463 49487P23
8-127 A24 8-127-28 A A 1 64666 64654 64678P24
8-127 A25 8-127-119 A A 1 64757 64745 64769P25
8-127 A26 8-127-159 A A 1 64797 64785 64809P26
8-127 A27 8-127-236 C C 1 64874 64862 64886P27
8-127 A28 8-127-240 A A 1 64878 64866 64890P28
8-127 A29 8-127-280 G G 1 64918 64906 64930P29
8-128 A30 8-128-33 C C 1 65485 65473 65497P30
8-128 A31 8-128-52 A A 1 65504 65492 65516P31
8-128 A32 8-128-61 G G 1 65513 65501 65525P32
8-128 A33 8-128-68 C C 1 65520 65508 65532P33
8-128 A34 8-128-69 A A 1 65521 65509 65533P34
8-128 A35 8-128-85 A A 1 65537 65525 65549P35
8-129 A36 8-129-50 C C 1 65596 65584 65608P36
8-129 A37 8-129-60 deletion 1 65607 65594 65618P37
of
A
8-129 A38 8-129-311 A G 1 65857 65845 65869P38
8-129 A39 8-129-401 C T 1 65947 65935 65959P39
99-34240 A40 99-34240-492A T 1 75667 75655 75679P40
99-31959 A41 99-31959-281C T 1 94534 94522 94546P41
99-31960 A42 99-31960-363A G 1 95396 95384 95408P42
99-31962 A43 99-31962-250C T 1 96956 96944 96968P43
99-31962 A44 99-31962-450A G 1 97156 97144 97168P44
99-44282 A45 99-44282-439A G 1 106384 106372106396P45
99-44282 A46 99-44282-54C T 1 106769 106757106781P46
99-24656 A47 99-24656-137A G I 107158 107146107170P47
99-24656 A48 99-24656-260A G 1 107281 107269107293P48
99-24636 A49 99-24636-22A G 1 107609 107597107621P49
99-31939 A50 99-31939-75A G 1 108499 108487108511P50
99-31939 A51 99-31939-273C T 1 108697 108685108709P51
99-44281 A52 99-44281-418G T 1 109451 109439109463P52
99-44281 A53 99-44281-257A G 1 109612 109600109624P53
99-44281 A54 99-44281-77A G 1 109792 109780109804P54
99-31941 A55 99-31941-320G T 1 112468 112456112480P55
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99-31942 A56 99-31942-325G T 1 115468 115456115480P56
99-24635 A57 99-24635-79A T 1 155736 155724155748P57
99-16059 A58 99-16059-313A G 1 158172 158160158184P58
99-24639 A59 99-24639-169C T 1 160634 160622160646P59
99-24639 A60 99-24639-163A C 1 160640 160628160652P60
99-24634 A61 99-24634-108A T 1 160876 160864160888P61
99-7652 A62 99-7652-162A G 1 168974 168962168986P62
99-7652 A63 99-7652-488A G 1 169300 169288169312P63
99-16100 A64 99-16100-83C T 1 170746 170734170758P64
99-16100 A65 99-16100-147A G I 170810 170798170822P65
99-16100 A66 99-16100-195G T I 170858 170846170870P66
99-16100 A67 99-16100-197C T 1 170860 170848170872P67
99-16100 A68 99-16100-244C T I 170906 170894170918P68
99-16100 A69 99-16100-381A C 1 171043 171031171055P69
99-5862 A70 99-5862-167A G 1 173358 173346173370P70
99-16083 A71 99-16083-101C T 1 174227 174215174239P71
99-16044 A72 99-16044-351C T 1 175800 175788175812P72
99-16042 A73 99-16042-420A G 1 180589 180577180601P73
99-16042 A74 99-16042-31G C 1 180978 180966180990P74
99-5919 A75 99-5919-215A G 1 189957 189945189969P75
-
99-24658 A76 99-24658-410A G 1 197163 197151197175P76
99-30364 A77 99-30364-299A G I 198964 198952198976P77
99-30366 A78 99-30366-112G T 1 200256 200244200268P78
99-16094 A79 99-16094-75G T 1 204588 204576204600P79
99-24644 A80 99-24644-194A G 1 204934 204922204946P80
99-16107 A81 99-16107-95A T 1 206197 206185206209P81
99-16107 A82 99-16107-161A G 1 206263 206251206275P82
99-16107 A83 99-16107-383C T 1 206485 206473206497P83
99-15873 A84 99-15873-303C T 1 211608 211596211620P84
8-124 A85 8-124-106 A G 1 214669 214657214681P85
8-124 A86 8-124-220 A G 1 214783 214771214795P86
8-124 A87 8-124-294 A G 1 214857 214845214869P87
8-124 A88 8-124-316 C T 1 214879 214867214891P88
8-124 A89 8-124-383 A T 1 214946 214934214958P89
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8-125 A90 8-125-33 C T 1 215538 215526215550P90
8-132 A91 8-132-312 A G 1 215705 215693215717P91
8-132 A92 8-132-179 A T 1 215838 215826215850P92
8-132 A93 8-132-164 A G 1 215853 215841215865P93
8-132 A94 8-132-97 A G 1 215920 215908215932P94
99-13929 A95 99-13929-201G T 1 216028 216016216040P95
8-131 A96 8-131-363 G T I 216538 216526216550P96
8-131 A97 8-131-199 G T 1 216702 216690216714P97
8-130 A98 8-130-236 C T 1 216874 216862216886P98
8-130 A99 8-130-220 G T 1 216890 216878216902P99
8-130 A100 8-130-144 C T 1 216966 216954216978P100
8-130 A101 8-130-143 A G 1 216967 216955216979P101
8-130 A102 8-130-102 C T I 217008 216996217020P102
8-130 A103 8-130-101 G T 1 217009 216997217021P103
8-130 A104 8-130-83 A C 1 217027 217015217039P104
8-209 A105 8-209-333 A G 1 217207 217195217219P105
8-209 A106 8-209-290 A C 1 217250 217238217262P106
99-5897 A107 99-5897-143A C 1 219540 219528219552P107
99-24649 A108 99-24649-186A G 1 220836 220824220848P108
99-24649 A109 99-24649-80G C 1 220942 220930220954P109
8-199 A110 8-199-84 G T 1 221741 221729221753P110
8-198 Alll 8-198-138 A G 1 222048 222036222060P111
8-195 A112 8-195-348 C T 1 222746 222734222758P112
99-13925 A113 99-13925-97A G 1 223595 223583223607P113
8-192 A114 8-192-82 A G I 225443 225431225455P114
99-16090 A115 99-16090-225A G 1 226219 226207226231P115
8-189 A116 8-189-340 Deletion 1 226282 226270226309P116
of 4
CTAT
8-189 A117 8-189-146 G T 1 226487 226475226499P117
8-188 A118 8-188-136 C T 1 226870 226858226882P118
8-187 A119 8-187-352 G T 1 226987 226975226999P119
8-185 A120 8-185-319 G T I 227589 227577227601P120
8-185 A121 8-185-296 A T I 227612 227600227624P121
99-16051 A122 99-16051-226C T I 228006 227994228018P122
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99-16051 A123 99-16051-164A G 1 228068 228056228080P123
8-184 A124 8-184-119 A T 1 228134 228122228146P124
8-184 A125 8-184-27 A C 1 228226 228214228238P125
8-183 A126 8-183-401 C T 1 228254 228242228266P126
8-181 A127 8-181-449 C T 1 229069 229057229081P127
8-181 A128 8-181-350 A T 1 229168 229156229180P128
8-181 A129 8-181-259 A G 1 229259 229247229271P129
8-181 A130 8-181-230 A T 1 229288 229276229300P130
8-181 A131 8-181-210 A T 1 229308 229296229320P131
8-181 A132 8-181-165 C T 1 229353 229341229365P132
8-181 A133 8-181-163 C T 1 229355 229343229367P133
8-181 A134 8-181-83 C T 1 229435 229423229447P134
8-180 A135 8-180-157 A T 1 229486 229474229498P135
8-143 A136 8-143-332 A C 1 229582 229570229594P136
8-143 A137 8-143-327 A G 1 229587 229575229599P137
8-143 A138 8-143-311 A G 1 229603 228591229615P138
8-143 A139 8-143-308 A G I 229606 229594229618P139
8-179 A140 8-179-268 A C 1 229607 229595229619P140
8-143 A141 8-143-306 A G 1 229608 229596229620P141
8-143 A142 8-143-245 G T 1 229669 229657229681P142
8-143 A143 8-143-242 A G 1 229672 229660229684P143
8-143 A144 8-143-239 C T 1 229675 229663229687P144
8-143 A145 8-143-232 G C 1 229682 229670229694P145
8-143 A146 8-143-152 G C 1 229762 229750229774P146
8-178 A147 8-178-199 G C 1 229961 229949229973P147
8-178 A148 8-178-123 Deletion 1 230037 230025230049P148
of
A
8-119 A149 8-119-404 C T 1 230238 230226230250P149
8-177 A150 8-177-281 C T 1 230256 230244230268P150
8-119 A151 8-119-377 C T I 230265 230253230277P151
8-119 A152 8-119-309 C T 1 230333 230321230345P152
8-119 A153 8-119-294 G T 1 230348 230336230360P153
8-119 A154 8-119-284 G C 1 230358 230346230370P154
8-119 A155 8-119-272 A T 1 230370 230358230382PI55
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8-119 A156 8-119-262 A T 1 230380 230368230392P156
8-119 A157 8-119-248 C T 1 230394 230382230406P157
8-119 A158 8-119-247 A G 1 230395 230383230407P158
8-119 A159 8-119-210 A C I 230432 230420230444P159
8-119 A160 8-119-204 A C 1 230438 230426230450P160
8-119 A161 8-119-200 A G 1 230442 230430230454P161
8-119 A162 8-119-195 A C 1 230447 230435230459P162
8-119 A163 8-119-125 C T 1 230517 230505230529P163
8-119 A164 8-119-120 A G 1 230522 230510230534P164
8-119 A165 8-119-97 C T 1 230545 230533230557P165
8-119 A166 8-119-93 G T 1 230549 230537230561P166
8-119 A167 8-119-38 A T I 230604 230592230616P167
8-138 A168 8-138-234 C T 1 230684 230672230696P168
8-138 A169 8-138-218 A G 1 230700 230688230712P169
8-138 A170 8-138-163 C T 1 230755 230743230767P170
8-138 A171 8-138-54 insertion 1 230864 230852230876P171
TA
8-175 A172 8-175-75 G T 1 231070 231058231082P172
8-142 A173 8-142-386 C T 1 231118 231106231130P173
8-142 A174 8-142-370 C T 1 231134 231122231146P174
8-142 A175 8-142-211 deletion 1 231290 231278231302P175
CAAA
8-142 A176 8-142-132 A G I 231372 231360231384P176
8-145 A177 8-145-339 C T 1 231669 231657231681P177
99-15870 A178 99-15870-400A G 1 231677 231665231689P178
8-145 A179 8-145-231 A T 1 231777 231765231789P179
8-145 A180 8-145-197 C T 1 231811 231799231823P180
8-145 A181 8-145-154 C T 1 231854 231842231866P181
8-145 A182 8-145-138 A C 1 231870 231858231882P182
8-145 A183 8-145-78 G C 1 231930 231918231942P183
8-171 A184 8-171-247 C T 1 232320 232308232332P184
8-170 A185 8-170-373 C T 1 232477 232465232489P185
8-169 A186 8-169-266 A G 1 232898 232886232910P186
8-169 A187 8-169-166 G T 1 232998 232986233010P187
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8-168 A188 8-168-380 A G 1 233100 233088233112P188
8-235 A189 8-235-349 C T 1 233453 233441233465P189
8-235 A190 8-235-182 G T 1 233620 233608233632P190
8-137 A191 8-137-340 G C 1 234120 234108234132P191
8-137 A192 8-137-182 C T 1 234277 234265234289P192
8-137 A193 8-137-152 A C 1 234307 234295234319P193
8-165 A194 8-165-185 G C 1 234751 234739234763P194
99-16087 A195 99-16087-219G C 1 235315 235303235327P195
8-157 A196 8-157-177 A C 1 238223 238211238235P196
8-155 A197 8-155-258 C T 1 238789 238777238801P197
99-16038 A198 99-16038-118C T 1 239763 239751239775P198
8-136 A199 8-136-166 A G 1 239864 239852239876P199
8-136 A200 8-136-145 A G 1 239885 239873239897P200
8-136 A201 8-136-80 C T 1 239950 239938239962P201
8-153 A202 8-153-32 A G 1 240044 240032240056P202
8-135 A203 8-135-212 A G 1 240497 240485240509P203
8-135 A204 8-135-166 G T 1 240543 240531240555P204
8-135 A205 8-135-112 A G 1 240597 240585240609P205
99-16050 A206 99-16050-235G C I 240772 240760240784P206
8-144 A207 8-144-378 C T 1 240858 240846240870P207
8-144 A208 8-144-234 C T 1 241002 240990241014P208
8-144 A209 8-144-196 A T 1 241040 241028241052P209
8-144 A210 8-144-127 deletion 1 241002 240090241014P210
TGGATA
C
8-141 A211 8-141-304 C T 1 241217 241205241229P211
8-141 A212 8-141-260 C T 1 241261 241249241273P212
8-141 A213 8-141-161 G T 1 241360 241348241372P213
8-140 A214 8-140-286 A G 1 241507 241495241519P214
8-140 A215 8-140-173 A C 1 241620 241608241632P215
8-140 A216 8-140-108 G C 1 241685 241673241697P216
8-140 A217 8-140-41 A G 1 241752 241740241764P217
99-15880 A218 99-15880-162A G 1 241861 241849241873P218
8-240 A219 8-240-187 G T 1 242402 242390242414P219
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8-225 A220 8-225-281 A T 1 244313 244301244325P220
99-25940 A221 99-25940-186A G 1 247860 247848247872P221
99-25940 A222 99-25940-182C T 1 247864 247852247876P222
99-16032 A223 99-16032-292G T 1 248315 248303248327P223
99-16055 A224 99-16055-216A G 1 253619 253607253631P224
99-16105 A225 99-16105-152A G 1 255848 255836255860P225
99-16101 A226 99-16101-436C T 1 258573 258561258585P226
99-16033 A227 99-16033-244A G 1 260099 260087260111P227
99-15875 A228 99-15875-165C T 1 279789 279777279801P228
99-13521 A229 99-13521-31A G 1 288007 287995288019P229
8-112 A230 8-112-241 C T 1 292680 292668292692P230
8-112 A231 8-112-155 A C 1 292766 292754292778P231
8-112 A232 8-112-45 A T 1 292876 292864292888P232
8-111 A233 8-111-301 deletion 1 295491 295479295503P233
AGAT
8-110 A234 8-110-404 G C 1 295716 295704295728P234
8-110 A235 8-110-89 A G 1 296031 296019296043P235
8-134 A236 8-134-94 C T I 296068 296056296080P236
99-7462 A237 99-7462-508C T 1 298969 298957298981P237
99-16052 A238 99-16052-214A G 1 300365 300353300377P238
99-16047 A239 99-16047-115A G 1 312030 312018312042P239
99-25993 A240 99-25993-280G C 1 315928 315916315940P240
99-25993 A241 99-25993-367A G 1 316014 316002316026P241
99-25101 A242 99-25101-151A G 1 317245 317233317257P242
Amplicon BM Marker Polymor- SEQ BM Position Probe
Name pbism ID positionof s
No. probes
in
allla112 SE
ID
No.
8-94 A243 8-94-252 A G 162 1501 1489 1513 P243
8-95 A244 8-95-43 T C 161 1501 1489 1513 P244
8-97 A245 8-97-98 G A 160 1501 1489 1513 P245
8-98 A246 8-98-68 T C 159 1501 1489 1513 P246
99-14021 A247 99-14021-108A G 151 1501 1489 1513 P247
99-14364 A248 99-14364-415G A 152 1501 1489 1513 P248
99-15056 A249 99-15056-99G A 115 1501 1489 1513 P249
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99-15063 A250 99-15063-155A C 116 1501 1489 1513 P250
99-15065 A251 99-15065-85C G 117 1501 1489 1513 P251
99-15229 A252 99-15229-412T C 157 1501 1489 1513 P252
99-15231 A253 99-15231-219T G 163 1501 1489 1513 P253
99-15232 A254 99-15232-291G T 155 1501 1489 1513 P254
99-15239 A255 99-15239-377G C 164 1501 1489 1513 P255
99-15252 A256 99-15252-404C T 118 404 392 416 P256
99-15253 A257 99-15253-382C T 119 1501 1489 1513 P257
99-15256 A258 99-15256-392C T 120 1501 1489 1513 P258
99-15258 A259 99-15258-337G T 121 1501 1489 1513 P259
99-15261 A260 99-15261-202A G 122 1501 1489 1513 P260
99-15280 A261 99-15280-432C T 123 1501 1489 1513 P261
99-15355 A262 99-15355-150C T 124 1501 1489 1513 P262
99-15663 A263 99-15663-298G A 175 1501 1489 1513 P263
99-15664 A264 99-15664-185C A 176 1501 1489 1513 P264
99-15665 A265 99-15665-398T C 174 1501 1489 1513 P265
99-15668 A266 99-15668-139C T 177 1501 1489 1513 P266
99-15672 A267 99-15672-166G A 173 1501 1489 1513 P267
99-15682 A268 99-15682-318A T 178 1501 1489 1513 P268
99-16081 A269 99-16081-217C T 113 330 318 342 P269
99-16082 A270 99-16082-218A G 114 233 221 245 P270
99-20933 A271 99-20933-81T G 179 1501 1489 1513 P271
99-20977 A272 99-20977-72A C 147 1501 1489 1513 P272
99-20978 A273 99-20978-89C G 148 1501 1489 1513 P273
99-20981 A274 99-20981-300A G 149 1501 1489 1513 P274
99-20983 A275 99-20983-48T C 150 1501 1489 1513 P275
99-22310 A276 99-22310-148G A 154 1501 1489 1513 P276
99-25029 A277 99-25029-241G A 180 1501 1489 1513 P277
99-25224 A278 99-25224-189A G 125 1126 1114 1138 P278
99-25869 A279 99-25869-182A C 181 1501 1489 1513 P279
99-25881 A280 99-25881-275G T 182 1501 1489 1513 P280
99-25897 A281 99-25897-264A T 183 1501 1489 1513 P281
99-25906 A282 99-25906-131G T 184 1501 1489 1513 P282
99-25917 A283 99-25917-115G A 185 1501 1489 1513 P283
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209
99-25924 A284 99-25924-215G C 186 1501 1489 1513 P284
99-25950 A285 99-25950-121G C 126 1501 1489 1513 P285
99-25961 A286 99-25961-376T G 127 1501 1489 1513 P286
99-25965 A287 99-25965-399T C 128 1501 1489 1513 P287
99-25966 A288 99-25966-241T C 129 1501 1489 1513 P288
99-25967 A289 99-25967-57T C 130 1501 1489 1513 P289
99-25969 A290 99-25969-200C A 131 1501 1489 1513 P290
99-25972 A291 99-25972-317G A 132 1501 1489 1513 P291
99-25974 A292 99-25974-143T C 133 1501 1489 1513 P292
99-25977 A293 99-25977-311A G 134 1501 1489 1513 P293
99-25978 A294 99-25978-166T C 135 1501 1489 1513 P294
99-25979 A295 99-25979-93A G 136 1501 1489 1513 P295
99-25980 A296 99-25980-173A T 137 1501 1489 1513 P296
99-25984 A297 99-25984-312G A 138 1501 1489 1513 P297
99-25985 A298 99-25985-194C T 139 1501 1489 1513 P298
99-25989 A299 99-25989-398T C 140 1501 1489 1513 P299
99-26126 A300 99-26126-498A G 165 1501 1489 1513 P300
99-26138 A301 99-26138-193C T 187 1501 1489 1513 P301
99-26146 A302 99-26146-264C A 188 1501 1489 1513 P302
99-26147 A303 99-26147-396G A 141 1501 1489 1513 P303
99-26150 A304 99-26150-276T C 142 1501 1489 1513 P304
99-26153 A305 99-26153-44A C 143 1501 1489 1513 P305
99-26154 A306 99-26154-107G T 144 1501 1489 1513 P306
99-26156 A307 99-26156-290A C 145 1501 1489 1513 P307
99-26166 A308 99-26166-257G A 166 1501 1489 1513 P308
99-26167 A309 99-26167-278T C 167 1501 1489 1513 P309
99-26169 A310 99-26169-211T C 168 1501 1489 1513 P310
99-26171 A311 99-26171-71A G 169 1501 1489 1513 P311
99-26183 A312 99-26183-156C T 170 1501 1489 1513 P312
99-26189 A313 99-26189-164C A 189 1501 1489 1513 P313
99-26190 A314 99-26190-20C A 190 1501 1489 1513 P314
99-26191 A315 99-26191-58G A 191 1501 1489 1513 P315
99-26201 A316 99-26201-267C G 192 1501 1489 1513 P316
99-26222 A317 99-26222-149A G 193 1501 1489 1513 P317
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99-26223 A318 99-26223-225G T 194 1501 1489 1513 P318
99-26225 A319 99-26225-148G T 195 1501 1489 1513 P319
99-26228 A320 99-26228-172G C 196 1501 1489 1513 P320
99-26233 A321 99-26233-275T C 197 1501 1489 1513 P321
99-26234 A322 99-26234-336C G 198 1501 1489 1513 P322
99-26238 A323 99-26238-186T A 199 1501 1489 1513 P323
99-5873 A324 99-5873-159G A 146 1501 1489 1513 P324
99-5912 A325 99-5912-49A G 171 1501 1489 1513 P325
99-6012 A326 99-6012-220G T 158 1501 1489 1513 P326
99-6080 A327 99-6080-99G A 156 1501 1489 1513 P327
99-7308 A328 99-7308-157C T 153 1501 1489 1513 P328
99-7337 A329 99-7337-204A C 172 1501 1489 1513 P329
99-16106 A330 99-16106-48G T 200 79 67 91 P330
99-25332 A331 99-25332-125A G 201 125 113 137 P331
99-25516 A332 99-25516-307C T 202 306 294 318 P332
99-26173 A333 99-26173-470C T 203 1501 1489 1513 P333
99-26267 A334 99-26267-524C T 204 1501 1489 1513 P334
99-26284 A335 99-26284-394G A 205 1501 1489 1513 P335
99-26559 A336 99-26559-315A G 206 1501 1489 1513 P336
99-26769 A337 99-26769-256A T 207 1501 1489- 1513 P337
99-26772 A338 99-26772-268C T 208 1501 1489 1513 P338
99-26776 A339 99-26776-209G T 209 1501 1489 1513 P339
99-26779 A340 99-26779-437G C 210 1497 1485 1509 P340
99-26781 A341 99-26781-25G T 211 1501 1489 1513 P341
99-26782 A342 99-26782-300A G 212 1501 1489 1513 P342
99-26783 A343 99-26783-81A T 213 1501 1489 1513 P343
99-26787 A344 99-26787-96A G 214 1501 1489 15'13P344
99-26789 A345 99-26789-201C T 215 1501 1489 1513 P345
99-27297 A346 99-27297-280T C 216 1501 1489 1513 P346
99-27306 A347 99-27306-108C T 217 1501 1489 1513 P347
99-27312 A348 99-27312-58A C 218 1501 1489 1513 P348
99-27323 A349 99-27323-372G C 219 1501 1489 1513 P349
99-27335 A350 99-27335-191A C 220 1501 1489 1513 P350
99-27345 A351 99-27345-189C G 221 1501 1489 1513 P351
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99-27349 A352 99-27349-267G A 222 1501 1489 1513 P352
99-27352 A353 99-27352-197C G 223 1501 1489 1513 P353
99-27353 A354 99-27353-105T C 224 1501 1489 1513 P354
99-27360 A355 99-27360-142G T 225 1501 1489 1513 P355
99-27361 A356 99-27361-181A G 226 1501 1489 1513 P356
99-27365 A357 99-27365-421C T 227 1501 1489 1513 P357
99-27680 A358 99-27680-484G T 228 484 472 496 P358
99-27912 A359 99-27912-272C T 229 1501 1489 1513 P359
99-30329 A360 99-30329-380C T 112 380 368 392 P360
Certain biallelic markers of the invention are insertions or deletions, as
indicated above.
In particular, the deletion of the nucleotides AGAT (A223, biallelic marker 8-
I 11-301 ) in Table
6b above may comprise a single deletion of the AGAT motif, or deletions of two
or more
AGAT motifs. This marker (A223) may thus also serve as a microsatellite
marker.
BM refers to "biallelic marker". All l and all2 refer respectively to allele 1
and allele 2
of the biallelic marker.
b) Identification of Polymorphisms by Comparison of Genomic DNA from
Overlapping BACs
Genomic DNA from multiple BACs derived from the same DNA donor sample and
overlapping in regions of genomic DNA of SEQ ID No. 1 was sequenced.
Sequencing was
carried out on ABI 377 sequencers. The sequences of the amplification products
were
determined using automated dideoxy terminator sequencing reactions with a dye
terminator
cycle sequencing protocol. The products of the sequencing reactions were run
on sequencing
1 S gels and the sequences were determined using gel image analysis (ABI Prism
DNA Sequencing
Analysis software (2.1.2 version)).
The sequence data from the overlapping regions of SEQ ID No. 1 were evaluated
to
detect the presence of sequence polymorphisms. The comparison of sequences
identified
sequence polymorphisms including single nucleotide substitutions and
deletions, and multiple
nucleotide deletions. The localization of these polymorphisms within SEQ ID
No. 1 is shown
below in Table 6c.
Table 6c
Polymorphisms
Ref. PolymorphismAllele 1 Allele Position in
No. 2 SEQ ID
t a No.l
A361 Deletion AAGG 61595 to 61598
362 Deletion ATTTT ~ 75217 to 75221
~
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A363 Pol mo hic C T 75367
base
A364 Deletion CACA 88634 to 88637
A365 Pol mo hic A G 90113
base
A366 Deletion ACAC 93698 to 93701
A367 Pol mo hic C T 94209
base
A368 Deletion AATG 94331 to 94334
A369 Pol mo hic A G 95396
base
A370 Pol mo hic C T 95810
base
A371 Pol mo hic C T 96956
base
A372 Pol mo hic A G 97156
base
A373 Deletion CTTTCTTTCT 98749 to 98758
A374 Deletion TA 104314 to
104315
A375 Pol mo hic A C 104455
base
A376 Pol mo hic A G 104699
base
A377 Pol mo hic C T 106253
base
A378 Pol mo hic A T 106272
base
A379 Pol mo hic A C 106350
base
A380 Pol mo hic A G 106384
base
A381 Pol mo hic A G 107158
base
A382 Deletion AT 107168 to
107169
A383 Pol mo hic A G 107609
base
A384 Pol mo hic A G 108032
base
A385 Deletion ATGGAGATGGC 108668 to
AACACCTACAT 108816
GTGACCTTTCC
AGCATGGCAGT
CTCAGAGTGGA
TATGGCAACAG
CTGCACATGAC
CTCTCCAGCAT
GGCAGTCTCAG
AGTGGATATGG
CAACAGCTGCA
CATGACCTCTC
CGGCATGGCAG
TCTCAG
A386 Pol mo hic G T 110222
base
A387 Polymo hic A G 111978
base
A388 Pol mo hic G T 112468
base
A389 Deletion ACTT 117324 to
117327
A390 Pol mo hic C T 118972
base
A391 Deletion TT 119160 to
119161
A392 Pol mo hic C T 119316
base
A393 Pol mo hic A G 119321
base
A394 Pol mo hic A G 119526
base
A395 Pol mo hic A G 120573
base
A396 Polymo hic A C 121527
base
A397 Polymo hic C T 126105
base
A398 Pol mo hic C G 129789
base
A399 Pol mo hic A G 130777
base
A400 Deletion ATT 136942 to
136944
A401 Pol mo hic A T 143839
base
A402 Pol mo hic C T 146668
base
A403 Pol mo hic C T 147281
base
A404 Pol mo hic G T 147505
base
__
A405 Deletion T ~ 148183
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A406 Pol mo hic A C 148372
base
A407 Pol mo hic A G 149012
base
A408 Pol mo hic C T 149113
base
A409 Pol mo hic A G 151637
base
A410 Deletion G 151748
A411 Pol mo hic A G 151769
base
A412 Pol mo hic C T 151847
base
A413 Pol mo hic A C 152691
base
A414 Pol mo hic A G 152766
base
A415 Pol mo hic C T 153046
base
A416 Pol mo hic A G 153123
base
A417 Pol mo hic C T 153925
base
A418 Pol mo hic G T 153977
base
A419 Pol mo hic C T 154502
base
A420 Pol mo hic A G 154677
base
A421 Pol mo hic C T 154879
base
A422 Pol mo hic G T 154918
base
A423 Pol mo hic C T 155802
base
A424 Pol mo hic A G 156448
base
A425 Pol mo hic A C 157238
base
A426 Pol mo hic A G 157897
base
A427 Pol mo hic A G 158172
base
A428 Pol mo hic A G 158302
base
A429 Deletion TT 158510 to
158511
A430 Pol mo hic C T 158803
base
A431 Pol mo hic C T 160172
base
A432 Pol mo hic C T 160634
base
A433 Pol mo hic C T 161236
base
A434 Pol mo hic A G 162810
base
A435 Pol mo hic A G 163007
base
A436 Pol mo hic A G 164877
base
A437 Pol mo hic C T 166844
base
A438 Deletion TCTC 166911 to
166914
A439 Pol mo hic A G 167754
base
A440 Pol mo hic C T 167787
base
A441 Pol rrio G T 167894
hic base
A442 Pol mo hic C T 168346
base
A443 Pol mo hic A G 168414
base
A444 Pol mo hic A C 168453
base
A445 Pol mo hic A G 169300
base
A446 Pol mo hic C T 169451
base
A447 Pol mo hic A G 169627
base
A448 Pol mo hic C T 169984
base
A449 Pol mo hic C T 170199
base
A450 Pol mo hic C T 170746
base
A451 Pol mo hic G T 170858
base
A452 Pol mo hic C T 170860
base
A453 Pol mo hic C T 170906
base
A454 Pol mo hic A G 171309
base
A455 Pol mo hic A G 171413
base
A456 Pol mo hic C T 171504
base
A457 Polymo hic C T 171539
base
A458 Pol mo hic C T 171728
base
A459 Pol mo hic A G 171898
base
A460 Deletion AA 172125 to
172126
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A461 Pol mo hic A G 172295
base
A462 Pol mo hic A G 172298
base
A463 Pol mo hic A G 172336
base
A464 Pol mo hic A G 173145
base
A465 Pol mo hic C T 173304
base
A466 Pol mo hic C T 174227
base
A467 Pol mo hic A G 174397
base
A468 Pol mo hic C T 179154
base
A469 Pol mo hic C G 180233
base
A470 Pol mo hic A G 182552
base
A471 Pol mo hic C T 182733
base
A472 Deletion A 182773
A473 Pol mo hic A G 185759
base
A474 Deletion T 186307
A475 Deletion TATC 186976 to 186979
A476 Pol mo hic A T 188755
base
A477 Pol mo hic A C 188991
base
A478 Pol mo hic C T 189002
base
A479 Pol mo hic A G 189154
base
A480 Pol mo hic A G 189177
base
A481 Pol mo hic A G 189604
base
A482 Pol mo hic C T 190063
base
A483 Deletion T 191164
A484 Deletion A 193880
A485 Pol mo hic A G 193897
base
A486 Pol mo hic A T 194441
base
A487 Deletion T 194459
A488 Pol mo hic A T 1953
base 06
A489 Deletion TATC _
~ 226323 to
226326
Example 4
Validation Of The Polymorphisms Through Microsequencing
The biallelic markers identified in Example 3a were further confirmed and
their
respective frequencies were determined through microsequencing.
Microsequencing was
carried out for each individual DNA sample described in Example 1.
Amplification from genomic DNA of individuals was performed by PCR as
described
above for the detection of the biallelic markers with the same set of PCR
primers (Table 6a).
The preferred primers used in microsequencing were about 19 nucleotides in
length and
hybridized just upstream of the considered polymorphic base. According to the
invention, the
primers used in microsequencing are detailed in Table 6d.
Table 6d
Marker NameBiallelicSEQ Mis. Position Mis. Complementary
1 range 2
of
MarkerID microsequencing position
No. range
of
primer microsequencing
mis.
1 in
SEQ primer
ID mis.
No. 2 in
SE ID
No.
99-27943-150A1 1 D1 8297 8315 E1 8317 8335
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8-121-28 A2 1 D2 14707 14725 E2 14727 14745
8-121-36 A3 1 D3 14715 14733 E3 14735 14753
8-121-154 A4 1 D4 14833 14851 E4 14853 14871
8-121-187 A5 1 D5 14866 14884 E5 14886 14904
8-121-243 A6 1 D6 14922 14940 E6 14942 14960
8-121-281 A7 1 D7 14960 14978 E7 14980 14998
8-121-352 A8 1 D8 15031 15049 ES 15051 15069
8-121-364 A9 1 D9 15043 15061 E9 15063 15081
8-121-371 A10 1 D10 15050 15068 E10 15070 15088
99-27935-193All 1 D11 21653 21671 E11 21673 21691
8-122-72 A12 1 D12 25461 25479 E12 25481 25499
8-122-100 A13 I D13 25489 25507 E13 25509 25527
8-122-271 A14 I D14 25660 25678 E14 25680 25698
8-122-272 A15 1 D15 25661 25679 E15 25681 25699
8-122-326 A16 1 D16 25715 25733 E16 25735 25753
8-122-360 A17 1 D17 25749 25767 E17 25769 25787
8-123-55 A18 1 D18 29384 29402 E18 29404 29422
8-123-189 A19 1 D19 29518 29536 E19 29538 29556
8-123-197 A20 1 D20 29526 29544 E20 29546 29564
8-123-307 A21 1 D21 29636 29654 E21 29656 29674
8-147-270 A22 1 D22 29780 29798 E22 29800 29818
99-34243-210A23 I D23 49456 49474 E23 49476 49494
8-127-28 A24 1 D24 64647 64665 E24 64667 64685
8-127-119 A25 1 D25 64738 64756 E25 64758 64776
8-127-159 A26 1 D26 64778 64796 E26 64798 64816
8-127-236 A27 1 D27 64855 64873 E27 64875 64893
8-127-240 A28 1 D28 64859 64877 E28 64879 64897
8-127-280 A29 1 D29 64899 64917 E29 64919 64937
8-128-33 A30 1 D30 65466 65484 E30 65486 65504
8-128-52 A31 1 D31 65485 65503 E31 65505 65523
8-128-61 A32 1 D32 65494 65512 E32 65514 65532
8-128-68 A33 1 D33 65501 65519 E33 65521 65539
8-128-69 A34 1 D34 65502 65520 E34 65522 65540
8-128-85 A35 1 D35 65518 65536 E35 65538 65556
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8-129-50 A36 1 D36 65577 65595 E36 65597 65615
8-129-60 A37 1 D37 65587 65605 E37 65607 65625
8-129-311 A38 1 D38 65838 65856 E38 65858 65876
8-129-401 A39 1 D39 65928 65946 E39 65948 65966
99-34240-492A40 1 D40 75648 75666 E40 75668 75686
99-31959-281A41 1 D41 94515 94533 E41 94535 94553
99-31960-363A42 1 D42 95377 95395 E42 95397 95415
99-31962-250A43 1 D43 96937 96955 E43 96957 96975
99-31962-450A44 I D44 97137 97155 E44 97157 97175
99-44282-439A45 1 D45 106365 106383 E45 106385 106403
99-44282-54A46 I D46 106750 106768 E46 106770 106788
99-24656-137A47 I D47 107139 107157 E47 107159 107177
99-24656-260A48 1 D48 107262 107280 E48 107282 107300
99-24636-22A49 1 D49 107590 107608 E49 107610 107628
99-31939-75A50 1 D50 108480 108498 E50 108500 108518
99-31939-273A51 1 D51 108778 108796 E51 108798.108816
99-44281-418A52 1 D52 109432 109450 E52 109452 109470
99-44281-257A53 1 D53 109593 109611 E53 109613 109631
99-44281-77A54 1 D54 109773 109791 E54 109793 109811
99-31941-320A55 1 D55 112449 112467 E55 112469 112487
99-31942-325A56 1 D56 115449 115467 E56 115469 115487
99-24635-79A57 1 D57 155717 155735 E57 155737 155755
99-16059-313A58 1 D58 158153 158171 E58 158173 158191
99-24639-169A59 1 D59 160615 160633 E59 160635 160653
99-24639-163A60 1 D60 160621 160639 E60 160641 160659
99-24634-108A61 1 D61 160857 160875 E61 160877 160895
99-7652-162A62 1 D62 168955 168973 E62 168975 168993
99-7652-488A63 1 D63 169281 169299 E63 169301 169319
99-16100-83A64 1 D64 170727 170745 E64 170747 170765
99-16100-147A65 1 D65 170791 170809 E65 170811 170829
99-16100-195A66 1 D66 170839 170857 E66 170859 170877
99-16100-197A67 1 D67 170841 170859 E67 170861 170879
99-16100-244A68 1 D68 170887 170905 E68 170907 170925
99-16100-381A69 1 D69 171024 171042 E69 171044 171062
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99-5862-167 A70 1 D70 173339 173357 E70 173359 173377
99-16083-101A71 1 D71 174208 174226 E71 174228 174246
99-16044-351A72 1 D72 175781 175799 E72 175801 175819
99-16042-420A73 1 D73 180570 180588 E73 180590 180608
99-16042-31 A74 1 D74 180959 180977 E74 180979 180997
99-5919-215 A75 1 D75 189938 189956 E75 189958 189976
99-24658-410A76 I D76 197144 197162 E76 197164 197182
99-30364-299A77 I D77 198945 198963 E77 198965 198983
99-30366-112A78 1 D78 200237 200255 E78 200257 200275
99-16094-75 A79 I D79 204569 204587 E79 204589 204607
99-24644-194A80 1 D80 204915 204933 E80 204935 204953
99-16107-95 A81 1 D81 206178 206196 E81 206198 206216
99-16107-161A82 I D82 206244 206262 E82 206264 206282
99-16107-383A83 1 D83 206466 206484 E83 206486 206504
99-15873-303A84 1 D84 211589 211607 E84 211609 211627
8-124-106 A85 1 D85 214650 214668 E85 214670 214688
8-124-220 A86 1 D86 214764 214782 E86 214784 214802
8-124-294 A87 1 D87 214838 214856 E87 214858 214876
8-124-316 A88 1 D88 214860 214878 E88 214880 214898
8-124-383 A89 1 D89 214927 214945 E89 214947 214965
8-125-33 A90 1 D90 215519 215537 E90 215539 215557
8-132-312 A91 1 D91 215686 215704 E91 215706 215724
8-132-179 A92 1 D92 215819 215837 E92 215839 215857
8-132-164 A93 1 D93 215834 215852 E93 215854 215872
8-132-97 A94 1 D94 215901 215919 E94 215921 215939
99-13929-201A95 1 D95 216009 216027 E95 216029 216047
8-131-363 A96 1 D96 216519 216537 E96 216539 216557
8-131-199 A97 1 D97 216683 216701 E97 216703 216721
8-130-236 A98 1 D98 216855 216873 E98 216875 216893
8-130-220 A99 1 D99 216871 216889 E99 216891 216909
8-130-144 A100 1 D100 216947 216965 E100 216967 216985
8-130-143 A101 1 D101 216948 216966 E101 216968 216986
8-130-102 A102 1 D102 216989 217007 E102 217009 217027
8-130-101 A103 I D103 216990 217008 E103 217010 217028
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8-130-83 A104 1 D104 217008 217026 E104 217028 217046
8-209-333 A105 1 D105 217188 217206 E105 217208 217226
8-209-290 A 106 1 D 106 217231 217249 E 106 217251 217269
99-5897-143 A107 1 D107 219521 219539 E107 219541 219559
99-24649-186A108 1 D108 220817 220835 E108 220837 220855
99-24649-80 A109 1 D109 220923 220941 E109 220943 220961
8-199-84 A110 1 D110 221722 221740 EI10 221742 221760
8-198-138 Alll 1 D111 222029 222047 E111 222049 222067
8-195-348 A112 1 D112 222727 222745 E112 222747 222765
99-13925-97 A113 1 D113 223576 223594 E113 223596 223614
8-192-82 A114 1 D114 225424 225442 E114 225444 225462
99-16090-225A115 1 D115 226200 226218 E115 226220 226238
8-189-340 A116 1 D116 226274 226292 E116 226294 226312
8-189-146 A117 1 D117 226468 226486 E117 226488 226506
8-188-136 A118 1 D118 226851 226869 E118 226871 226889
8-187-352 A119 1 D119 226968 226986 E119 226988 227006
8-185-319 A120 1 D120 227570 227588 E120 227590 227608
8-185-296 A121 1 D121 227593 227611 E121 227613 227631
99-16051-226A122 1 D122 227987 228005 E122 228007 228025
99-16051-164A123 1 D123 228049 228067 E123 228069 228087
8-184-119 A124 1 D124 228115 228133 E124 228135 228153
8-184-27 A125 1 D125 228207 228225 E125 228227 228245
8-183-401 A126 1 D126 228235 228253 E126 228255 228273
8-181-449 A127 1 D127 229050 229068 E127 229070 229088
8-181-350 A128 1 D128 229149 229167 E128 229169 229187
8-181-259 A129 1 D129 229240 229258 E129 229260 229278
8-181-230 A130 1 D130 229269 229287 E130 229289 229307
8-181-210 A131 1 D131 229289 229307 E131 229309 229327
8-181-165 A132 l D132 229334 229352 E132 229354 229372
8-181-163 A133 1 D133 229336 229354 E133 229356 229374
8-181-83 A134 1 D134 229416 229434 E134 229436 229454
8-180-157 A135 1 D135 229467 229485 E135 229487 229505
8-143-332 A136 1 D136 229563 229581 E136 229583 229601
8-143-327 A137 1 D137 229568 229586 E137 229588 229606
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8-143-311 A138 1 D138 229584 229602 E138 229604229622
8-143-308 A139 1 D139 229587 229605 E139 229607229625
8-179-268 A140 1 D140 229588 229606 E140 229608229626
8-143-306 A141 I D141 229589 229607 E141 229609229627
8-143-245 A142 1 D142 229650 229668 E142 229670229688
8-143-242 A143 1 D143 229653 229671 E143 229673229691
8-143-239 A144 1 D144 229656 229674 E144 229676229694
8-143-232 A145 1 D145 229663 229681 E145 229683229701
8-143-152 A146 1 D146 229743 229761 E146 229763229781
8-178-199 A147 1 D147 229942 229960 E147 229962229980
8-178-123 A148 1 D148 230018 230036 E148 230038230056
8-119-404 A149 1 D149 230219 230237 E149 230239230257
8-177-281 A150 1 D150 230237 230255 E150 230257230275
8-119-377 A151 1 D151 230246 230264 E151 230266230284
8-119-309 A152 I D152 230314 230332 E152 230334230352
8-119-294 A153 1 D153 230329 230347 E153 230349230367
8-119-284 A154 1 D154 230339 230357 E154 230359230377
8-119-272 A155 1 D155 230351 230369 E155 230371230389
8-119-262 A156 1 D156 230361 230379 E156 230381230399
8-119-248 A157 I D157 230375 230393 E157 230395230413
8-119-247 A158 I D158 230376 230394 E158 230396230414
8-119-210 A159 1 D159 230413 230431 E159 230433230451
8-119-204 A160 1 D160 230419 230437 E160 230439230457
8-119-200 A161 1 D161 230423 230441 E161 230443230461
8-119-195 A162 1 D162 230428 230446 E162 230448230466
8-119-125 A163 1 D163 230498 230516 E163 230518230536
8-119-120 A164 1 D164 230503 230521 E164 230523230541
8-119-97 A165 1 D165 230526 230544 E165 230546230564
8-119-93 A166 I D166 230530 230548 E166 230550230568
8-119-38 A167 1 D167 230585 230603 E167 230605230623
8-138-234 A168 1 D168 230665 230683 E168 230685230703
8-138-218 A169 1 D169 230681 230699 E169 230701230719
8-138-163 A170 1 D170 230736 230754 E170 230756230774
8-138-54 A171 1 D171 230845 230863 E171 230865230883
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8-175-75 A172 1 D172 231051 231069 E172 231071 231089
8-142-386 A173 1 D173 231099 231117 E173 231119 231137
8-142-370 A174 1 D174 231115 231133 E174 231135 231153
8-142-211 A175 1 D175 231274 231292 E175 231294 231312
8-142-132 A176 1 D176 231353 231371 E176 231373 231391
8-145-339 A177 1 D177 231650 231668 E177 231670 231688
99-15870-400A178 1 D178 231658 231676 E178 231678 231696
8-145-231 A179 1 D179 231758 231776 E179 231778 231796
8-145-197 A180 1 D180 231792 231810 E180 231812 231830
8-145-154 A181 1 D181 231835 231853 E181 231855 231873
8-145-138 A182 1 D182 231851 231869 E182 231871 231889
8-145-78 A183 1 D183 231911 231929 E183 231931 231949
8-171-247 A184 1 D184 232301 232319 E184 232321 232339
8-170-373 A185 1 D185 232458 232476 E185 232478 232496
8-169-266 A186 1 D186 232879 232897 E186 232899 232917
8-169-166 A187 I D187 232979 232997 E187 232999 233017
8-168-380 A188 1 D188 233081 233099 E188 233101 233119
8-235-349 A189 1 D189 233434 233452 E189 233454 233472
8-235-182 A190 1 D190 233601 233619 E190 233621 233639
8-137-340 A191 1 D191 234101 234119 E191 234121 234139
8-137-182 A192 1 D192 234258 234276 E192 234278 234296
8-137-152 A193 1 D193 234288 234306 E193 234308 234326
8-165-185 A194 I D194 234732 234750 E194 234752 234770
99-16087-219A195 I D195 235296 235314 E195 235316 235334
8-157-177 A196 1 D196 238204 238222 E196 238224 238242
8-155-258 A197 1 D197 238770 238788 E197 238790 238808
99-16038-118A198 1 D198 239744 239762 E198 239764 239782
8-136-166 A199 1 D199 239845 239863 E199 239865 239883
8-136-145 A200 1 D200 239866 239884 E200 239886 239904
8-136-80 A201 I D201 239931 239949 E201 239951 239969
8-153-32 A202 I D202 240025 240043 E202 240045 240063
8-135-212 A203 1 D203 240478 240496 E203 240498 240516
8-135-166 A204 1 D204 240524 240542 E204 240544 240562
8-135-112 A205 1 D205 240578 240596 E205 240598 240616
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99-16050-235A206 1 D206 240753 240771 E206 240773 240791
8-144-378 A207 1 D207 240839 240857 E207 240859 240877
8-144-234 A208 1 D208 240983 241001 E208 241003 241021
8-144-196 A209 1 D209 241021 241039 E209 241041 241059
8-144-127 A210 1 D210 241090 241108 E210 241110 241128
8-141-304 A211 1 D211 241198 241216 E211 241218 241236
8-141-260 A212 1 D212 241242 241260 E212 241262 241280
8-141-161 A213 1 D213 241341 241359 E213 241361 241379
8-140-286 A214 1 D214 241488 241506 E214 241508 241526
8-140-173 A215 I D215 241601 241619 E215 241621 241639
8-140-108 A216 1 D216 241666 241684 E216 241686 241704
8-140-41 A217 1 D217 241733 241751 E217 241753 241771
99-15880-162A218 1 D218 241842 241860 E218 241862 241880
8-240-187 A219 1 D219 242383 242401 E219 242403 242421
8-225-281 A220 1 D220 244294 244312 E220 244314 244332
99-25940-186A221 1 D221 247841 247859 E221 247861 247879
99-25940-182A222 1 D222 247845 247863 E222 247865 247883
99-16032-292A223 1 D223 248296 248314 E223 248316 248334
99-16055-216A224 1 D224 253600 253618 E224 253620 253638
99-16105-152A225 1 D225 255829 255847 E225 255849 255867
99-16101-436A226 1 D226 258554 258572 E226 258574 258592
99-16033-244A227 1 D227 260080 260098 E227 260100 260118
99-15875-165A228 1 D228 279770 279788 E228 279790 279808
99-13521-31A229 1 D229 287988 288006 E229 288008 288026
8-112-241 A230 1 D230 292661 292679 E230 292681 292699
8-112-155 A231 1 D231 292747 292765 E231 292767 292785
8-112-45 A232 I D232 292857 292875 E232 292877 292895
8-111-301 A233 I D233 295476 295494 E233 295496 295514
8-110-404 A234 1 D234 295697 295715 E234 295717 295735
8-110-89 A235 1 D235 296012 296030 E235 296032 296050
8-134-94 A236 1 D236 296049 296067 E236 296069 296087
99-7462-508A237 1 D237 298950 298968 E237 298970 298988
99-16052-214A238 1 D238 300346 300364 E238 300366 300384
99-16047-115A239 1 D239 312011 312029 E239 312031 312049
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99-25993-280A240 1 D240 315909 315927 E240 315929 315947
99-25993-367A241 1 D241 315995 316013 E241 316015 316033
99-25101-151A242 1 D242 317226 317244 E242 317246 317264
Marker Name BiallelicSEQ1 Mis. Position Mis. Complementary
MarkerID 1 range 2 position
No. of range
microsequencing of
primer microsequencing
mis. primer
1 in mis.
SEQ 2 in
ID SEQ
No. ID
No.
8-94-252 A243 162 D243 1482 1500* E243 1502 1521
8-95-43 A244 161 D244 1481 1500 E244 1502 1520*
8-97-98 A245 160 D245 1482 1500* E245 1502 1521
8-98-68 A246 159 D246 1481 1500 E246 1502 1520*
99-14021-108A247 151 D247 1482 1500* E247 1502 1521
99-14364-415A248 152 D248 1482 1500* E248 1502 1521
99-15056-99 A249 115 D249 1482 1500* E249 1502 1521
99-15063-155A250 116 D250 1482 1500* E250 1502 1521
99-15065-85 A251 117 D251 1481 1500 E251 1502 1520*
99-15229-412A252 157 D252 1481 1500 E252 1502 1520*
99-15231-219A253 163 D253 1481 1500 E253 1502 1520*
99-15232-291A254 155 D254 1481 1500 E254 1502 1520*
99-15239-377A255 164 D255 1482 1500* E255 1502 1521
99-15252-404A256 118 D256 384 403 E256 405 423*
99-15253-382A257 119 D257 1481 1500 E257 1502 1520*
99-15256-392A258 120 D258 1481 1500 E258 1502 1520*
99-15258-337A259 121 D259 1481 1500 E259 1502 1520*
99-15261-202A260 122 D260 1482 1500* E260 1502 1521
99-15280-432A261 123 D261 1481 1500 E261 1502 1520*
99-15355-150A262 124 D262 1482 1500* E262 1502 1521
99-15663-298A263 175 D263 1482 1500* E263 1502 1521
99-15664-185A264 176 D264 1482 1500* E264 1502 1521
99-15665-398A265 174 D265 1481 1500 E265 1502 1520*
99-15668-139A266 177 D266 1482 1500* E266 1502 1521
99-15672-166A267 173 D267 1482 1500* E267 1502 1521
99-15682-318A268 178 D268 1482 1500* E268 1502 1521
99-16081-217A269 113 D269 310 329 E269 331 349*
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99-16082-218A270 114 D270 214 232* E270 234 253
99-20933-81 A271 179 D271 1481 1500 E271 1502 1520*
99-20977-72 A272 147 D272 1482 1500* E272 1502 1521
99-20978-89 A273 148 D273 1481 1500 E273 1502 1520*
99-20981-300A274 149 D274 1481 1500 E274 1502 1520*
99-20983-48 A275 150 D275 1482 1500* E275 1502 1521
99-22310-148A276 154 D276 1481 1500 E276 1502 1520*
99-25029-241A277 180 D277 1482 1500* E277 1502 1521
99-25224-189A278 125 D278 1107 1125* E278 1127 1146
99-25869-182A279 181 D279 1482 1500* E279 1502 1521
99-25881-275A280 182 D280 1481 1500 E280 1502 1520*
99-25897-264A281 183 D281 1482 1500* E281 1502 1521
99-25906-131A282 184 D282 1481 1500 E282 1502 1520*
99-25917-115A283 185 D283 1481 1500 E283 1502 1520*
99-25924-215A284 186 D284 1482 1500* E284 1502 1521
99-25950-121A285 126 D285 1482 1500* E285 1502 1521
99-25961-376A286 127 D286 1481 1500 E286 1502 1520*
99-25965-399A287 128 D287 1481 1500 E287 1502 1520*
99-25966-241A288 129 D288 1481 1500 E288 1502 1520*
99-25967-57 A289 130 D289 1481 1500 E289 1502 1520*
99-25969-200A290 131 D290 1482 1500* E290 1502 1521
99-25972-317A291 132 D291 1482 1500* E291 1502 1521
99-25974-143A292 133 D292 1481 1500 E292 1502 1520*
99-25977-311A293 134 D293 1482 1500* E293 1502 1521
99-25978-166A294 135 D294 1481 1500 E294 1502 1520*
99-25979-93 A295 136 D295 1482 1500* E295 1502 1521
99-25980-173A296 137 D296 1482 1500* E296 1502 1521
99-25984-312A297 138 D297 1482 1500* E297 1502 1521
99-25985-194A298 139 D298 1481 1500 E298 1502 1520*
99-25989-398A299 140 D299 1481 1500 E299 1502 1520*
99-26126-498A300 165 D300 1482 1500* E300 1502 1521
99-26138-193A301 187 D301 1481 1500 E301 1502 1520*
99-26146-264A302 188 D302 1482 1500* E302 1502 1521
99-26147-396A303 141 D303 1482 1500* E303 1502 1521
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99-26150-276A304 142 D304 1481 1500 E304 1502 1520*
99-26153-44A305 143 D305 1482 1500* E305 1502 1521
99-26154-107A306 144 D306 1481 1500 E306 1502 1520*
99-26156-290A307 145 D307 1482 1500* E307 1502 1521
99-26166-257A308 166 D308 1481 1500 E308 1502 1520*
99-26167-278A309 167 D309 1482 1500* E309 1502 1521
99-26169-211A310 168 D310 1482 1500* E310 1502 1521
99-26171-71A311 169 D311 1481 1500 E311 1502 1520*
99-26183-156A312 170 D312 1482 1500* E312 1502 1521
99-26189-164A313 189 D313 1482 1500* E313 1502 1521
99-26190-20A314 190 D314 1482 1500* E314 1502 1521
99-26191-58A315 191 D315 1481 1500 E315 1502 1520*
99-26201-267A316 192 D316 1481 1500 E316 1502 1520*
99-26222-149A317 193 D317 1481 1500 E317 1502 1520*
99-26223-225A318 194 D318 1481 1500 E318 1502 1520*
99-26225-148A319 195 D319 1481 1500 E319 1502 1520*
99-26228-172A320 196 D320 1482 1500* E320 1502 1521
99-26233-275A321 197 D321 1482 1500* E321 1502 1521
99-26234-336A322 198 D322 1481 1500 E322 1502 1520*
99-26238-186A323 199 D323 1481 1500 E323 1502 1520*
99-5873-159A324 146 D324 1481 1500 E324 1502 1520*
99-5912-49 A325 171 D325 1481 1500 E325 1502 1520*
99-6012-220A326 158 D326 1481 1500 E326 1502 1520*
99-6080-99 A327 156 D327 1481 1500 E327 1502 1520*
99-7308-157A328 153 D328 1482 1500* E328 1502 1521
99-7337-204A329 172 D329 1482 1500* E329 1502 1521
99-16106-48A330 200 D330 59 78 E330 80 99
99-25332-125A331 201 D331 105 124 E331 126 145
99-25516-307A332 202 D332 286 305 E332 307 326
99-26173-470A333 203 D333 1481 1500 E333 1502 1521
99-26267-524A334 204 D334 1481 1500 E334 1502 1521
99-26284-394A335 205 D335 1481 1500 E335 1502 1521
99-26559-315A336 206 D336 1481 1500 E336 1502 1521
99-26769-256A337 207 D337 1481 1500 E337 1502 1521
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99-26772-268A338 208 D338 1481 1500 E338 1502 1520*
99-26776-209A339 209 D339 1481 1500 E339 1502 1521
99-26779-437A340 210 D340 1477 1496 E340 1498 1517
99-26781-25A341 211 D341 1482 1500* E341 1502 1521
99-26782-300A342 212 D342 1482 1500* E342 1502 1521
99-26783-81A343 213 D343 1481 1500 E343 1502 1521
99-26787-96A344 214 D344 1482 1500* E344 1502 1521
99-26789-201A345 215 D345 1482 1500* E345 1502 1521
99-27297-280A346 216 D346 1481 1500 E346 1502 1521
99-27306-108A347 217 D347 1481 1500 E347 1502 1521
99-27312-58A348 218 D348 1481 1500 E348 1502 1521
99-27323-372A349 219 D349 1481 1500 E349 1502 1521
99-27335-191A350 220 D350 1481 1500 E350 1502 1521
99-27345-189A351 221 D351 1481 1500 E351 1502 1521
99-27349-267A352 222 D352 1482 1500* E352 1502 1521
99-27352-197A353 223 D353 1481 1500 E353 1502 1520*
99-27353-105A354 224 D354 1482 1500* E354 1502 1521
99-27360-142A355 225 D355 1482 1500* E355 1502 1521
99-27361-181A356 226 D356 1482 1500* E356 1502 1521
99-27365-421A357 227 D357 1482 1500* E357 1502 1521
99-27680-484A358 228 D358 464 483 E358 485 504
99-27912-272A359 229 D359 1481 1500 E359 1502 1521
99-30329-380A360 112 D360 361 379 E360 381 399
Mis 1 and Mis 2 respectively refer to microsequencing primers which hybridized
with
the coding strand or with the non-coding strand of the nuceotide sequences of
the invention.
The microsequencing reaction was performed as follows
After purification of the amplification products, the microsequencing reaction
mixture
was prepared by adding, in a 20p1 final volume: 10 pmol microsequencing
oligonucleotide, 1 U
Thermosequenase (Amersham E79000G), 1.25 pl Thermosequenase buffer (260 mM
Tris HCl
pH 9.5, 65 mM MgCl2), and the two appropriate fluorescent ddNTPs (Perkin
Elmer, Dye
Terminator Set 401095) complementary to the nucleotides at the polymorphic
site of each
biallelic marker tested, following the manufacturer's recommendations. After 4
minutes at
94°C, 20 PCR cycles of 15 sec at 55°C, S sec at 72°C, and
10 sec at 94°C were carried out in a
Tetrad PTC-225 thermocycler (MJ Research). The unincorporated dye terminators
were then
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removed by ethanol precipitation. Samples were finally resuspended in
formamide-EDTA
loading buffer and heated for 2 min at 95°C before being loaded on a
polyacrylamide
sequencing gel. The data were collected by an ABI PRISM 377 DNA sequencer and
processed
using the GENESCAN software (Perkin Elmer).
Following gel analysis, data were automatically processed with software that
allows the
determination of the alleles of biallelic markers present in each amplified
fragment.
The software evaluates such factors as whether the intensities of the signals
resulting
from the above microsequencing procedures are weak, normal, or saturated, or
whether the
signals are ambiguous. In addition, the software identifies significant peaks
(according to shape
and height criteria). Among the significant peaks, peaks corresponding to the
targeted site are
identified based on their position.. When two significant peaks are detected
for the same
position, each sample is categorized classification as homozygous or
heterozygous type based
on the height ratio.
Example Sa
Association Study Between Schizophrenia And The Biallelic Markers Of The
Invention:
Collection Of DNA Samples From Affected And Non-Affected Individuals
A) Affected population
All the samples were collected from a large epidemiological study of
schizophrenia
undertaken in hospital centers of Quebec from October 1995 to April 1997. The
population was
composed of French Caucasian individuals. The study design consisted in the
ascertainment of
cases and two of their first degree relatives (parents or siblings).
As a whole, 956 schizophrenic cases were ascertained according to the
following
inclusion criteria:
- the diagnosis had been done by a psychiatrist;
- the diagnosis had been done at least 3 years before recruitment time, in
order to
exclude individuals suffering from transient manic-depressive psychosis or
depressive
disorders;
- the patient ancestors had been living in Quebec for at least 6 generations;
- it was possible to get a blood sample from 2 close relatives.
Among the 956 schizophrenic ascertained cases, 834 individuals were included
in the
study for the following reasons:
- for the included individual cases, the diagnosis of schizophrenia was
established
according to the DSM-IV (Diagnostic and Statistical Manual, Fourth edition,
Revised 1994,
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American Psychiatric Press);
- samples from individuals suffering from schizoaffective disorder were
discarded;
- individuals suffering from catatonic schizophrenia were also excluded from
the
population of schizophrenic cases;
- were also excluded the individuals having a first degree relative or 2 or
more second
degree relatives suffering from depression or mood disorder;
- individuals having had severe head trauma, severe obstretical complications,
encephalitis, or meningitis before onset of symptoms were also excluded;
- has also been excluded from the population of schizophrenic cases a patient
suffering
from epilepsy and treated with anticonvulsants.
The age at onset was not added as an inclusion criteria.
B) Unaffected population
Control cases were respectively ascertained based on the following cumulative
criteria:
- the individual must not be affected by schizophrenia or any other
psychiatric disorder;
- the individual must have 35 years old or more;
- the individual must belong to the French-Canadian population;
- the individual must have one or two first degree relative available for
blood sampling.
Controls were matched with cases sex when possible.
C) Cases and Control Populations Selected for the Association Study
The unaffected population retained for the study was composed of 241
individuals. The
initial sample of the clinical study was composed of 215 cases and 214
controls. The controls
were composed of 116 males and 98 females while the cases were composed of 154
males and
64 females. For each control, two first degree relatives (father, mother,
sisters and brothers)
were available. In order to match the sex of cases and controls, the parents
of female controls
were substituted for the female controls where possible and where the parents
were known to be
unaffected by schizophrenia or other psychosis. The parents of 27 female
controls were thus
substituted for the respective females, resulting in a total control sample
size of 241 individuals.
The composition of the control sample is detailed below in Table 7.
Table 7
Description of control samples
Probands 187
Male 116
Female 71
Parents of probands 54
Fathers ~ 27
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Mothers I 27
Total I 241
The association data that are presented below were obtained on a population
size
detailed in Table 8 below, wherein the individuals have been randomly selected
from the
populations detailed above.
Table 8
Cases and Control
Populations
Selected for
the Association
Study
sample type Cases Controls
sample size 215 241
Gender
Male 151 143
Female 64 98
Familial history
of psychosis
(FH)*
positive (FH+) 82 0
none (FH-) 133 241
* : close relatives
(first or second
degree)
Both case and control populations form two groups, each group consisting of
unrelated
individuals that do not share a known common ancestor. Additionally, the
individuals of the
control population were selected among those having no family history of
schizophrenia or
schizophrenic disorder.
Genotyping of affected and control individuals
A) Results from the genotypin~
The general strategy to perform.the association studies was to individually
scan the
DNA samples from all individuals in each of the populations described above in
order to
establish the allele frequencies of biallelic markers, and among them the
biallelic markers of the
invention, in the diploid genome of the tested individuals belonging to each
of these
populations.
Allelic frequencies of every biallelic marker in each population (cases and
controls)
were determined by performing microsequencing reactions on amplified fragments
obtained by
genomic PCR performed on the DNA samples from each individual. Genomic PCR and
microsequencing were performed as detailed above in Examples 1 to 3 using the
described PCR
and microsequencing primers.
Single biallelic marker frequency analysis
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For each allele of the biallelic markers included in this study, the
difference between the
allelic frequency in the unaffected population and in the population affected
by schizophrenia
was calculated and the absolute value of the difference was determined. The
more the
difference in allelic frequency for a particular biallelic marker or a
particular set of biallelic
markers, the more probable an association between the genomic region harboring
this particular
biallelic marker or set of biallelic markers and schizophrenia. Allelic
frequencies were also
useful to check that the markers used in the haplotype studies meet the Hardy-
Weinberg
proportions (random mating).
The allelic frequencies of biallelic markers in the chromosome 13q31-q33
region
between the affected and the unaffected population, using the sample
population described
above, is set forth in Table 9.
Table 9
Allelic frequencies of markers in different sub-samples
marker alleles all sample
cases controls
all HF+ HF-
99-20978/89C/G 0.51 0.47 0.51 0.55
99-20983/48A/G 0.30 0.28 0.33 0.29
99-20981/300A/G 0.54 0.51 0.55 0.56
99-20977/72A/C 0.40 0.41 0.38 0.35
99-6080/99 C/T 0.58 0.57 0.57 0.55
99-15229/412A/G 0.54 0.52 0.55 0.53
99-22310/148C/T 0.46 0.48 0.44 0.47
99-15232/291C/T 0.46 0.48 0.43 0.47
99-14021/108A/G 0.46 0.48 0.44 0.47
8-98/68 A/G 0.20 0.18 0.23 0.19
8-97/98 C/T 0.78 0.75 0.81 0.80
99-6012/220C/T 0.20 0.19 0.23 0.19
8-95/43 A/G 0.18 0.20 0.18 0.21
99-7308/157C/T 0.39 0.42 0.36 0.39
99-14364/415C/T 0.38 0.40 0.36 0.39
99-15672/166C/T 0.51 0.47 0.54 0.54
99-15668/139C/T 0.58 0.56 0.62 0.65
99-15665/398A/G 0.72 0.67 0.72 0.76
99-15663/298C/T 0.72 0.67 0.72 0.76
99-15664/185C/T 0.69 0.62 0.72 0.72
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99-15682/318A/T 0.35 0.40 0.34 0.32
99-20933/81A/C 0.43 0.41 0.42 0.40
99-16081/217C/T 0.43 0.38 0.46 0.39
99-16082/218A/G 0.33 0.31 0.35 0.32
99-5862/167C/T 0.47 0.43 0.44 0.51
99-16100/147A/G 0.48 0.44 0.45 0.50
99-7652/ A/G 0.49 0.46 0.46 0.52
162
99-5919/215A/G 0.66 0.71 0.69 0.60
99-5897/143A/C 0.58 0.61 0.53 0.59
99-15870/400A/G 0.32 0.38 0.27 0.33
99-16032/292A/C 0.61 0.62 0.64 0.58
99-15880/162A/G 0.62 0.63 0.65 0.58
99-16038/118A/G 0.38 0.36 0.35 0.42
99-15875/165C/T 0.58 0.57 0.57 0.63
99-16033/244C/T 0.55 0.57 0.49 0.54
99-16047/115C/T 0.73 0.75 0.68 0.73
In the association study described herein, several individual biallelic
markers were
shown to be significantly associated with schizophrenia. In particular,
several of the
chromosome 13q31-q33 region biallelic markers (99-16038/118 (A198), 99-
15880/162 (A218),
99-5919/215 (A75), 99-15875/165 (A228), 99-16032/292 (A223)) showed
significant
association with schizophrenia in both familial and sporadic schizophrenia
cases. The
significance of the absolute value of the difference of allelic frequency of
the individual biallelic
markers in the affected and the unaffected population is set forth in Figure
2, with several
biallelic marker having allelic frequency differences with p-values
approaching or less than
0.05, biallelic marker 99-5919/215 (A75) having a p-value of less than 0.01.
Figure 2 also
shows the physical order of certain specific biallelic markers. These results
show that several
biallelic markers individually associated with schizophrenia are physically
located in a
particular region of significance, the subregion of the chromosome 13q31-q33
region referred to
herein as Region D.
Haplotype frequency analysis
Analysis of markers Haplotype analysis for association of chromosome 13q31-q33-
related biallelic markers and schizophrenia was performed by estimating the
frequencies of all
possible 2, 3 and 4 marker haplotypes in the affected and control populations
described above.
Haplotype estimations were performed by applying the Expectation-Maximization
(EM)
algorithm (Excoffier and Slatkin, 1995), using the EM-HAPLO program (Hawley et
al., 1994)
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as described above. Estimated haplotype frequencies in the affected and
control population
were compared by means of a chi-square statistical test (one degree of
freedom).
Haplotype association results in schizophrenia cases
The results of the haplotype analysis using the chromosome 13q31-q33-related
biallelic
markers biallelic markers is shown in Figure 3. In particular, the figures
show the most
significant haplotypes using the biallelic markers: 99-16047/115 (A239), 99-
16033/244 (A227),
99-16038/118 (A198), 99-15875/165 (A228), 99-16032/292 (A223), 99-5897/143
(A107), 99-
15880/162 (A218), 99-16082/218 (A270), 99-5919/215 (A75), 99-7652/162 (A62),
99-
16100/147 (A65), 99-5862/167 (A70).
A number of biallelic marker haplotypes were shown to be significantly
associated with
schizophrenia. A first preferred haplotype (HAP287 of Figure 3) consisting of
four biallelic
markers (99-16038/118 (A198), 99-16082/218 (A270), (99-7652/162 (A62) and 99-
16100/147
(A65)) is highly significantly associated with schizophrenia in both total
cases and sporadic
cases. Figure 4 shows the characteristics of this haplotype. This haplotype
presented a p-value
of 3.1x10 7 and an odd-ratio of 4.01 for total cases and a p-value of 3.9x10 6
and an odd-ratio
of 3.88 for sporadic cases. Phenotypic permutation tests confirmed the
statistical significance
of these results. Estimated haplotype frequencies were 13.8% in total cases,
13.5% in the
sporadic cases, and 3.8 % in the controls.
Several other significant haplotypes are listed in Figure 3, including several
2-, 3- and
4-marker haplotypes. Considered to be highly significantly associated with
schizophrenia are
the most significant 2-marker haplotype (HAP1 consisting of biallelic markers
99-15875/165
(A228) and 99-5919/215 (A75)) and the most significant 3-marker haplotype
(HAP67
consisting of biallelic markers 99-16038/118 (A198), 99-16082/218 (A270) and
99-7652/162
(A218)).
Further preferrred significant haplotypes considered associated with
schizophrenia are
haplotypes having p-values above a desired threshold level are also; all the
haplotypes listed in
Figure 3 present p-values below 1.0x10-2 for 2-marker haplotypes, I.OxIO~ for
3-marker
haplotypes, and 1.Ox 10-5 for 4-marker haplotypes. All of the biallelic
markers presented in
Figure 4 except for 1 (99-16047/115 (A239)) are involved in haplotypes having
a p-value above
these threshold levels. Figure 3 shows several 2-marker haplotypes, HAP1 to
HAPB, having p-
values ranging from 1.0x10-2 to 1.2x10-3, several 3-marker haplotypes, HAP67
to HAP76,
having p-values ranging from 1.3x10-5 to 1.0x1 O~ and several 4-marker
haplotypes, HAP287 to
HAP291, having p-values ranging from 8.2x10-' to 3.1x10-'. Figure 4 shows
biallelic markers
involved in significant haplotypes having significance thresholds of 1.0x10-Z,
l.OxlO~, and
1.0x10-5 for 2-, 3- and 4-marker haplotypes, respectively.
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Several 2-, 3- and 4-marker haplotypes, HAP l, HAPB, HAP70, HAP71, HAP75,
HAP76, HAP288, HAP290 and HAP291, often comprised the biallelic marker 99-
5919/215
(A75) allele A. Furthermore, several 2-, 3- and 4-marker haplotypes, HAP7,
HAP67, HAP69,
HAP75, HAP287 AND HAP288, often comprised the biallelic marker 99-16038/118
(?.198)
allele G.
Example Sb
Association Study Between Schizophrenia And The Biallelic Markers Of The
Invention
Collection Of DNA Samples From Affected And Non-Affected Individuals
Biallelic markers of the invention were further analyzed in the French
Canadian
population described above. For this analysis, the proband case population
under- study
consisted of 139 individuals, the control population consisted of 141
individuals, as described in
Table 10 below.
Table 10
Cases and Control
Populations
Selected for
the Association
Stud
Sample type Cases Controls
Sample size 139 141
Gender
Male 94 96
Female 45 45
Familial history
of psychosis
(FH)*
positive (FH+) 76 0
none (FH-) 63 141
* : close relatives
(first or second
degree)
Genotyping of affected and control individuals
A) Results from the ~enotypin~
The general strategy for performing the association studies was to
individually scan the
DNA samples from all individuals in each of the populations described above in
order to
establish the allele frequencies of biallelic markers, and among them the
biallelic markers of the
invention, in the diploid genome of the tested individuals belonging to each
of these
populations.
Allelic frequencies of every biallelic marker in each population (cases and
controls)
were determined by performing microsequencing reactions on amplified fragments
obtained by
genomic PCR performed on the DNA samples from each individual. Genomic PCR and
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microsequencing were performed as detailed above in Examples 1 to 3 using the
described PCR
and microsequencing primers.
Single biallelic marker frequency analysis
For each allele of the biallelic markers included in this study, the
difference between the
allelic frequency in the unaffected population and in the population affected
by schizophrenia
was calculated and the absolute value of the difference was determined. The
allelic frequencies
of between the affected and the unaffected population in the regions is set
forth in Table 11,
using the sample population described above and in Table 10. The more the
difference in allelic
frequency for a particular biallelic marker or a particular set of biallelic
markers, the more
probable an association between the genomic region harboring this particular
biallelic marker or
set of biallelic markers and schizophrenia. Allelic frequencies were also
useful to check that the
markers used in the haplotype studies meet the Hardy-Weinberg proportions
(random mating).
Table 11
Allelic frequencies of markers in differents sub-samples (%)
Marker polymorphismCases All controls
All casesHF+ HF-
99-20978/89 C/G 50,37 47,26 54,03 55;43
99-20983/48 A/G 30,37 28,67 32,5 26,52
99-20977/72 A/C 41,01 42,11 39,68 34,4
99-20981/300A/G 52,17 51,33 53,17 60
99-6080/99 C/T 58,82 58 59,84 54,85
99-15229/412A/G 54,92 52,86 57,26 51,88
99-22310/148C/T 44,2 46,71 41,13 48,57
99-15232/291G/T 43,85 46,43 40,83 49,28
99-14021/108A/G 44,85 47,26 42,06 48,54
8-94/252 A/G 2,22 1,97 2,54 2,52
8-98/68 A/G 19,06 17,76 20,63 19,06
8-97/98 C/T 76,26 74,34 78,57 77,3
99-6012/220 G/T 20 18,49 21,77 18,79
99-7308/157 C/T 40,31 41,89 38,18 39,36
99-14364/415C/T 39,93 40,79 38,89 40
8-95/43 A/G 20,29 20,39 20,16 22,14
99-15672/166C/T 49,28 47,37 51,59 56,74
99-15668/139C/T 58,21 56,16 60,66 66,67
99-15665/398A/G 70,5 67,76 73,81 76,79
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99-15663/298C/T 70,5 67,76 73,81 76,95
99-15664/185G/T 66,54 62,33 71,43 72,5
99-15682/318A/T 35,27 39,58 29,82 32,66
99-20933/81 A/C 43,12 42,76 43,55 42,45
99-26146/264G/T 39,62 38,67 40,91 38,85
99-25922/147G/T 44,19 39,58 50 40,94
99-16081/217C/T 42,28 38,82 46,67 36,74
99-16082/218A/G 34,73 31,94 38,14 33,81
99-24656/260A/G 48,87 49,32 48,31 54,04
99-24639/163G/T 38,52 33,33 45 40,51
99-24634/108A/T 44,85 42,67 47,54 50
99-7652/162 A/G 45,29 44,08 46,77 50,36
99-16100/147A/G 44,66 42,75 46,77 48,89
99-5862/167 C/T 43,53 41,45 46,03 49,29
99-5919/215 A/G 69,42 71,05 67,46 60,28
99-24658/410C/T 64,13 69,08 58,06 61,07
99-24644/194A/G 39,42 41,22 37,3 40,51
99-5897/143 A/C 57,61 60,67 53,97 61,07
99-24649/186C/T 67,75 67,33 68,25 62,95
99-15870/400A/G 33,46 36,67 29,51 30,29
99-16038/118A/G 34,53 36,18 32,54 43,62
99-15880/162A/G 65,11 63,16 67,46 56,43
99-25940/182A/G 59,42 56,67 62,7 52,59
99-16032/292A/C 64,03 61,84 66,67 55,67
99-16033/244C/T 54,51 56,76 51,69 56,44
99-15875/165C/T 56,88 57,89 55,65 66,3
99-16047/115C/T 71,69 74,67 68,03 75,19
99-25993/367A/G 44,53 40,79 49,18 40,51
99-25989/398A/G 32,81 33,33 32,2 27,86
99-25979/93 A/G 68,12 69,08 66,94 69,32
99-25969/200G/T 36,67 38,67 34,17 38,85
99-25966/241A/G 66,3 67,11 65,32 63,21
99-25961/376A/C 39,63 42,57 36,07 37,31
99-25965/399A/G 50,36 51,97 48,39 49,64
99-25977/311A/G 72,01 67,76 77,59 73,72
99-25950/121C/G 31,75 36 26,61 27,54
99-25974/143A/G 25,55 28,29 22,13 22,7
99-26150/276A/G 46,54 51,43 40,83 47,76
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99-15258/337G/T 25,55 26,97 23,77 24,1
99-15261/202A/G 63,06 59,46 67,5 65,15
99-15256/392C/T 64,96 61,33 69,35 65,3
99-15056/99 C/T 32,72 36,49 28,23 31,11
99-15280/432C/T 42,28 44 40,16 38,97
99-15355/150C/T 72,3 70,39 74,6 68,79
99-15253/382C/T 63,04 62,67 63,49 62,95
99-5873/159 C/T 78,1 79,05 76,98 77,34
Haplotype frequency analysis
Analysis of markers Haplotype analysis for association of chromosome 13q31-q33-
related biallelic markers and schizophrenia was performed by estimating the
frequencies of all
possible 2, 3 and 4 marker haplotypes in the affected and control populations
described above.
Haplotype estimations were performed by applying the Expectation-Maximization
(EM)
algorithm (Excoffier and Slatkin, 1995), using the EM-HAPLO program (Hawley et
al., 1994)
as described above. Estimated haplotype frequencies in the affected and
control population
were compared by means of a chi-square statistical test (one degree of
freedom).
Haulotype association results in schizophrenia cases
Haplotype studies yielded significant results indicating an association of the
nucleotide
sequences of the invention with schizophrenia. Significant results are shown
in Figures 5 and 6,
including descriptions of the frequency of the haplotype leading to the
maximum chi square test
(reference no. ( 1 ) in figures), the test of the frequency of a particular
haplotype in cases vs in
1 S controls (reference no. (2) in figures) and the p- value assuming that the
test has a chi-square
distribution with 1 degree of freedom (ddl) (reference no. (3) in figures).
The results of the
haplotype analysis using 28 preferred biallelic markers of the invention, 99-
24656-260 (A48),
99-24639-163 (A60), 99-24634-108 (A61), 99-7652-162 (A62), 99-16100-147 (A65),
99-5862-
167 (A70), 99-5919-215 (A75), 99-24658-410 (A76), 99-24644-194 (A80), 99-5897-
143
(A107), 99-24649-186 (A108), 99-16038-118 (A198), 99-15880-162 (A218), 99-
25940-182
(A221), 99-16032-292 (A223), 99-16033-244 (A227), 99-15875-165 (A228), 99-
16047-115
(A239), 99-25950-121 (A285), 99-25961-376 (A286), 99-25965-399 (A287), 99-
25966-241
(A288), 99-25969-200 (A290), 99-25974-143 (A292), 99-25977-31 I (A293), 99-
25979-93
(A295), 99-25989-398 (A299), and 99-26150-276 (A304) are shown in Figures S
and 6.
Figures 5 and 6 also show the physical order of the biallelic markers
comprising the haplotypes.
Figure 5 shows the results of the haplotype analysis using the following
biallelic
markers located on the approximately 319kb sequence of SEQ ID No. 1: 99-24656-
260 (A48),
99-24639-163 (A60), 99-24634-108 (A61), 99-7652-162 (A62), 99-16100-147 (A65),
99-5862-
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167 (A70), 99-5919-215 (A75), 99-24658-410 (A76), 99-24644-194 (A80), 99-5897-
143
(A107), 99-24649-186 (A108), 99-16038-118 (A198), 99-15880-162 (A218), 99-
25940-182
(A221 ), 99-16032-292 (A223), 99-16033-244 (A227), 99-15875-165 (A228), and 99-
16047-
115 (A239).
Figure 6 shows the results of the haplotype analysis using the following
biallelic
markers located on the approximately 3 l9kb of SEQ ID No. 1 as well as
additional biallelic
markers located on the human chromosome 13q31-q33 locus: 199-16038-118 (A198),
99-
15880-162 (A218), 99-25940-182 (A221 ), 99-16032-292 (A223), 99-16033-244
(A227), 99-
15875-165 (A228), 99-16047-115 (A239), 99-25950-121 (A285), 99-25961-376
(A286), 99-
25965-399 (A287), 99-25966-241 (A288), 99-25969-200 (A290), 99-25974-143
(A292), 99-
25977-31 I (A293), 99-25979-93 (A295), 99-25989-398 (A299), and 99-26150-276
(A304).
A number of biallelic marker haplotypes were shown to be significantly
associated with
schizophrenia.
Several preferred haplotype all showing highly significant association with
schizophrenia and including various 2-, 3- and 4- marker haplotypes are
haplotypes 817, 818
and 819, 137, 138, 1 and 2 of Figure 6, and haplotypes 970, 154 and 1 of
Figure 5. The p-
values, odd-ratios and estimated haplotype frequencies are further described
in Figures 5 and 6.
In particular, the two marker haplotype 1 of Figure 5 consisting of biallelic
markers 99-5862-
167 (A70) and 99-15875-165 (A228) showed a highly significant p-value of
7.8x10 5 and an
odd-ratio of 1.61. Haplotype 818 of Figure 6 consisting of four biallelic
markers (99-16032-292
(A223), 99-25969-200 (A290), 99-25977-31 I (A293), and 99-25989-398 (A299))
presented a
p-value of 3.1x10 7 and an odd-ratio of 9.08. Another example showing
significance is
haplotype 817 of Figure 6 consisting of four biallelic markers (99-16033-244
(A227), 99-
15875-165 (A228), 99-25950-121 (A285) and 99-25979-93 (A295)), presented a p-
value of
2.4x10 7 and an odd-ratio of 100. Phenotypic permutation tests confirmed the
statistical
significance of these results. Estimated haplotype frequencies were 10.5% in
cases and 0 % in
the controls. Haplotype 970 of Figure 5 consisting of four biallelic markers
(99-5919-215 .
(A75), 99-24658-410 (A76), 99-15875-165 (A228), and 99-16047-115 (A239))
presented a p-
value of 7.8x10 7 and an odd-ratio of 2.41. Phenotypic permutation tests
confirmed the
statistical significance of these results. Estimated haplotype frequencies
were 25.7% in cases
and 12.5 % in the controls.
Several other significant haplotypes are listed in Figures 5 and 6, including
several 2-,
3- and 4-marker haplotypes. Considered to be highly significantly associated
with
schizophrenia are the most significant 2-marker haplotypes (for example
haplotype I of Figure
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noted above and the most significant 3-marker haplotypes (for example
haplotype 137 of
Figure 6 consisting of biallelic markers (99-15875-165 (A228), 99-16047-115
(A239) and 99-
25950-121 (A285)).
Further preferrred significant haplotypes considered associated with
schizophrenia are
haplotypes having p-values above a desired threshold level; all the haplotypes
listed in Figures 5
and 6 present p-values below 1.0x10-2 for 2-marker haplotypes, 1.0x10-4 for 3-
marker
haplotypes, and 1.0x10-5 for 4-marker haplotypes. Figures S and 6 show several
2-marker
haplotypes, haplotypes 1 to 9 and haplotypes 1 to 5 of Figures 5 and 6
respectively, having p-
values ranging from 7.8x10-5 to 8.6x103, several 3-marker haplotypes,
haplotypes 154 to 163
and 137 to 141 of Figures 5 and 6 respectively, having p-values ranging from
3.9x10-6 to
1.1x10 and several 4-marker haplotypes, haplotypes 970 to 973 and 817 to 836
of Figures 5
and 6 respectively, having p-values ranging from 2.4x10' to 7.3x10-6.
Additionally, a particularly large number of the significant 2-, 3- and 4-
marker
haplotypes often comprised the biallelic markers A223, A76, A227, A239, A286,
A290, A299
and most commonly A228 (99-15875-165), allele T.
The statistical significance of the results obtained for the haplotype
analysis was
evaluated by a phenotypic permutation test reiterated 100 times on a computer.
For this
computer simulation, data from the affected and control individuals were
pooled and randomly
allocated to two groups which contained the same number of individuals as the
case-control
populations used to produce the data summarized in figures 5 and 6. A
haplotype analysis was
then run on these artificial groups for the markers included in the haplotypes
showing strong
association with schizophrenia. This experiment was reiterated 100 times and
the results are
shown in the columns of Figures 5 and 6 labelled "Haplotype test by
permutation procedure".
For a given haplotype, these results demonstrate the number of obtained
(simulated) haplotypes
having a p-value comparable to the one obtained for the given haplotype among
100 iterations.
These results, set forth in Figures 5 and 6 validate the statistical
significance of the association
between the haplotypes and schizophrenia .
Example Sc
Association Study Between Schizophrenia and the Biallelic Markers of the
Invention in
French Canadian Samples
Collection Of DNA Samples From Affected And Non-Affected Individuals
Biallelic markers of the present invention were further genotyped in French
Canadian
samples as described above in order to compare the association of the 1 st and
the 2nd portion of
Region D with schizophrenia. The population used in the study was the same as
described
above with the exception that 2 male FH+ cases were not included.
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The biallelic markers analyzed in the study include 34 preferred biallelic
markers of the
invention located in Region D of the chromosome 13q31-33 region. Included in
the analysis
were the 14 following biallelic markers from the first of two portions of
Region D: 99-
26150/276 (A304), 99-26156/290 (A307), 99-26153/44 (A305), 99-25985/194
(A298), 99-
25974/143 (A292), 99-25977/311 (A293), 99-25972/317 (A291), 99-25965/399
(A287), 99-
25961/376 (A286), 99-25966/241 (A288), 25967/57 (A289), 99-25969/200 (A290),
99-
25979/93 (A295) and 99-25989/398 (A299). Included in the analysis were also
the 20
following biallelic markers from the second of two portions of Region D: 99-
25993/367 (A241),
99-16047/115 (A239), 99-15875/165 (A228), 99-16033/244 (A227), 99-16032/292
(A223), 99-
25940/182 (A221), 99-15880/162 (A218), 99-16038/118 (A198), 99-15870/400
(A178), 99-
24649/186 (A108), 99-5897/143 (A107), 99-24644/194 (A80), 99-24658/410 (A76),
99-
5919/215 (A75), 99-5862/167 (A70), 99-16100/147 (A65), 99-7652/162 (A62), 99-
24634/108
(A61), 99-24639/163 (A60) and 99-24656/260 (A48).
Single biallelic marker association results in schizophrenia cases
Single biallelic marker studies yielded significant results, indicating an
association of
the nucleotide sequences of the invention with schizophrenia. Biallelic
markers used in the
analysis included the set of 34 biallelic markers shown in Table 11 below, 14
biallelic markers
of which were located on the first of two portions of Region D, and 20 of
which were located on
the second portion. The distribution of markers in shown in Table 12 below. As
summarized in
Table 13 , analyses using these biallelic markers demonstrated a significant
association with
schizophrenia for 5 markers on the second portion of Region D.
Table 11
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99-16032/292 A/C 58
99-25940/ 182 A/G 53
99-15880/ 162 A/G 58
99-16038/ 118 A/G 42
99-15870/400 A/G 33
99-24649/186 C/T 65
99-5897/ 143 A/C 59
99-24644/ 194 A/G 39
99-24658/410 C/T 58
99-5919/215 A/G 60
99-5862/167 C/T 51
99-16100/147 A/G 50
99-7652/162 A/G 52
99-24634/108 A/T 53
99-24639/163 G/T 44
99-24656/260 A/G 54
Table 12
Region No. of BiallelicMean frequencyMean
markers (a) inter-marker
(a) distance
(a)
D ls'half 14 (14) 0.34 (0.07)7 (6.3)
D 2" half 20 (8) 0.42 (0.06)11 (13)
D 1 S' and 34 (22) 0.39 (0.07)10.3 ( 11
2" half )
Haplotype frequency analysis
Analysis of markers Haplotype analysis for association of chromosome 13q31-q33-
related biallelic markers and schizophrenia was performed by estimating the
frequencies of all
possible 2, 3 and 4 marker haplotypes in the affected and control populations
described above.
Haplotype estimations were performed by applying the Expectation-Maximization
(EM)
algorithm (Excoffier and Slatkin, 1995), using the EM-HAPLO program (Hawley et
al., 1994)
as described above.
Haplotype association results in schizophrenia cases
Significant results were also obtained in haplotype studies indicating an
association of
the nucleotide sequences of the invention with schizophrenia.
The present inventors having previously demonstrated highly significant
association of
biallelic markers located on the Region D subregion of the human chromosome
13q31-q33
locus with disease. Using the Omnibus LR test which compares the profile of
haplotype
frequencies, and Haplo-maxM test which is based on haplotype differences for
each haplotype
in two groups, Figures 7 and 8 describe the results of an analysis of the
first and second portions
of Region D which demonstrated an association of the second portion of Region
D with
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schizophrenia.
For combinations of 2 and 3 biallelic markers, one likelihood ratio test is
obtained based
on the haplotype frequency values calculated using the E-M algorithm. A
permutation
procedure was used, where data from the affected and control individuals was
pooled and
randomly allocated to two groups which contained the same number of
individuals as the case-
control populations used to produce the data. A haplotype analysis was then
run on these
artificial groups for the markers included in the haplotypes showing strong
association with
schizophrenia. This experiment was reiterated 100 times. For a given
haplotype, these results
demonstrate the number of obtained (simulated) haplotypes having a p-value
comparable to the
one obtained for the given haplotype among 100 iterations.
Figure 7 shows a comparison of the LR test value distributions of haplotype
frequencies in the two portions of Region D. This association of the second
portion of Region
D with schizophrenia is shown using both 2-marker and 3-marker combinations.
The
distribution of LR test values in the different regions was analyzed using a
Kruskal-Wallis rank
test, a chi-square test with r-1 degrees of freedom, where r represents the
number of value sets
compared. As shown, the significance of the association is demonstrated by a
chi-square value
(one degree of freedom) of 74.405 and a p-value of less than 1x10 10 for 2
marker
combinations, and a chi-square value (one degree of freedom) of 228.72 and a p-
value of 1x10
10 for 3- marker combinations.
Another association analysis approach based on haplotype frequency
differences,
referred to as the Haplo-maxM test, was conducted using region D biallelic
markers. For one
combination of markers having h haplotypes, h differences of haplotype
frequencies can be
compared via a Pearson chi-square statistic (one degree of freedom). The haplo-
max test selects
the difference showing the maximum positive test value between cases versus
controls
(rejecting test values based on rare haplotype frequencies, i.e, with an
estimated number of
haplotypes inferior to 10); for one combination of markers there is therefore
one Max-M test
value. The results of the Haplo-maxM test using Region D biallelic markers are
shown in
Figure 8.
Figure 8 shows the distribution of haplo-maxM test values obtained for both 2-
marker
and 3-marker combinations in the two portions of Region D, demonstrating an
association of
the second portion of Region D with schizophrenia. The comparison of the
distribution of
Haplo-maxM test values oin the two regions was analyzed using a Kruskal-Wallis
rank test, a
chi-square test with r-1 degrees of freedom, where r represents the number of
value sets
compared. As shown, the significance of the association is demonstrated by a
chi-square value
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(one degree of freedom) of 34.839 and a p-value of less than 3.58x10 9 for 2
marker
combinations, and a chi-square value (one degree of freedom) of 13.773 and a p-
value of
2.6x10 4 for 3- marker combinations.
The results from the haplo-maxM tests further confirms the association shown
using the
Omnibus LR test results.
Results of association studies discussed above using biallelic markers of the
invention
are further summarized in Table 13 below, showing a significant association of
the biallelic
markers with schizophrenia in both single biallelic marker and haplotype
analysis.
Table 13
Single-point Analysis ~ Multi-point analysis
(Haplotype-based analysis)
No. of allelic freq ~ No. Significant ~ Omnibus LR TEST
differences > 10% allelic tests
2-mks 3-mks 4-mks
D, 1 st 0 0 0,03 0,05 0,06
D, 2nd ~ 0 ~ 5 ~ 0,30 ~ 0,30 ~ 0,31
* percentage of significant tests (5% level of significance)
Cases (N=213) / Controls (N=241)
Example Sd
Association Study Between Bipolar Disorder and the Biallelic Markers of the
Invention
Description of study design
Biallelic markers of the invention were analyzed in bipolar disorder cases. As
in
examples above, single and multi-point analyses showed a significant
association of the markers
of the invention, of Region D of the chromosome 13q33 locus, and more
particularly of a sub-
region of Region D with bipolar disorder.
A1 Description of the Affected pouulation
All the samples were collected from a study of bipolar disorder undertaken in
a hospital
located south of Buenos Aires, Argentina, generally representing a population
estimated at
about 400,000 inhabitants. Patients were evaluated by four doctors in 1994 and
1995. The
study design involved in the ascertainment of cases and their first degree
relatives (parents or
siblings). 514 individuals were available for the study. This group consisted
of 158 subjects
from 51 different families, and 356 independent subjects.
As a whole, bipolar disorder cases were ascertained according to the diagnosis
of
bipolar disorder established by the DSM-IV (Diagnostic and Statistical Manual,
Fourth edition,
Revised 1994, American Psychiatric Press);
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Available for consideration for each coded case were also age, sex,
nationality of
parents and grand parents, ethnic origin, familial composition, marital state,
socio-economic
level, educational level, professional situation, employment, receational
activities, age of onset
of phychiatric symptoms, age of first consultation, occurrences of obstetric
or prenatal
incidents, suicide attempts, other medical conditions, treatment for or
occurrence of a
neurological condition, familial occurrence of symptoms, previous or
concurrent use of
psychotropic drugs, other admissions to a hospital or medical treatments, and
diagnostic reason
for admission including (a) DSM-IV diagnosis and (b) symptoms first presented
on admission
to hospital.
Available for study were 226 bipolar disorder ascertained cases of which 203
were
independent cases. This group consisted of 51 cases from S 1 families, 20
cases in relatives
thereof, and 155 independent cases. Upon elimination of 3 cases from the
initial independent
155 cases due to discovery of a familial relation, the total number of
independent cases was 203.
Cases were classified according to bipolar disorder type. The cases included
115
bipolar disorder type I individuals (including 1 rapid cycling case), 67
bipolar disorder type II
individuals (including 1 rapid cycling case), 18 unclassified bipolar disorder
cases, and 3 cases
which remained unclassified due to lack of or inconsistent information.
The 203 independent cases were examined for a familial history of psychosis.
53 of
these cases reported an occurrence of psychosis (characterized as
schizophrenia or bipolar
disorder) among first degree relatives (father, mother, brothers, sisters or
children).
Bl Decription of the Unaffected population
Available for study were 201 controls which had not been affected by any
psychiatric
difficulties or reported any familial history of psychiatric difficulties.
Available for
consideration were also age, sex and ethnic origin of the unaffected
population.
C) Case and Control Populations Selected for the Association Study
For the association study, the case population under study consisted of 201
individuals
selected from the 226 total cases above; the control population consisted of
198 individuals
selected from the 201 controls described above.
The association data that are presented in the Example Sd below were obtained
on a
population size detailed in Table 14 below.
Table 14
Cases and Control
Populations
Selected for
the Association
Stud
Sample type Cases Controls
Sample size 201 198
Gender
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Male 68 81
Female 124 117
Missing 9
Ethnic origin
Causasian 182 177
Non Caucasian 5 21
Missing 14
Familial history
of psychosis
(FH)*
positive (FH+) 54 0
none (FH-) 147 198
* : close relatives
(first degree)
Both case and control populations form two groups, each group consisting of
unrelated
individuals that do not share a known common ancestor.
Genotyuing of affected and control individuals
The general strategy was to individually scan the DNA samples from all
individuals in
each of the populations described above in order to establish the allele
frequencies of biallelic
markers, and among them the biallelic markers of the invention, in the diploid
genome of the
tested individuals belonging to each of these populations.
Allelic frequencies of every biallelic marker in each population (cases and
controls)
were determined by performing microsequencing reactions on amplified fragments
obtained by
genomic PCR performed on the DNA samples from each individual. Genomic PCR and
microsequencing were performed as detailed above in Examples 1 to 3 using the
described PCR
and microsequencing primers.
Association analysis
The association analysis included 30 preferred biallelic markers of the
invention located
in Region D of the chromosome 13q31-33 region. Included in the analysis were
the 14
following biallelic markers from the first of two subjective portions of
Region D: 99-26150/276
(A304), 99-26156/290 (A307), 99-26153/44 (A305), 99-25985/194 (A298), 99-
25974/143
(A292), 99-25977/311 (A293), 99-25972/317 (A291), 99-25965/399 (A287), 99-
25961/376
(A286), 99-25966/241 (A288), 25967/57 (A289), 99-25969/200 (A290), 99-25979/93
(A295)
and 99-25989/398 (A299). Included in the analysis were also the 16 following
biallelic markers
from the second oftwo portions of Region D: 99-25993/367 (A241), 99-16047/115
(A239), 99-
15875/165 (A228), 99-16033/244 (A227), 99-16032/292 (A223), 99-25940/182 (A221
), 99-
15880/162 (A218), 99-16038/118 (A198), 99-15870/400 (A178), 99-24649/186
(A108), 99-
5897/143 (A107), 99-24644/194 (A80), 99-5919/215 (A75), 99-5862/167 (A70), 99-
16100/147
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(A65), and 99-7652/162 (A62).
A) Single biallelic marker association results in bipolar disorder cases
For each allele of the biallelic markers included in this study, the
difference between the
allelic frequency in the unaffected population and in the population affected
by bipolar disorder
was calculated and the absolute value of the difference was determined. The
set of biallelic
markers and their allelic frequencies included in this study are set forth in
Table 15. The more
the difference in allelic frequency for a particular biallelic marker or a
particular set of biallelic
markers, the more probable an association between the genomic region harboring
this particular
biallelic marker or set of biallelic markers and bipolar disorder. Allelic
frequencies were also
useful to check that the markers used in the haplotype studies meet the Hardy-
Weinberg
proportions (under random mating assumptions)
Table 15
REGION CONTIG POSITIONSNPS GENOTYPEDPOLYMORPHISM FREQUENCY
ON CONTIG IN CONTROLS
168,02 99-26150/276 A/G 62,93
173,29 99-26156/290 A/C 72,42
177,01 99-26153/44 A/C 52,66
186,41 99-25985/194 C/T 28,87
190,15 99-25974/143 A/G 31,79
216,43 99-25977/311 A/G 63,82
224,62 99-25972/317 C/T 72,32
Region 236,64 99-25965/399 A/G 58,24
D
first 244,82 99-25961/376 A/C 44,35
Half
254,70 99-25966/241 A/G 66,18
257,85 99-25967/57 A/G 42,44
261,23 99-25969/200 G/T 35,76
263,67 99-25979/93 A/G 67,15
269,39 99-25989/398 A/G 35,88
299,02 99-25993/367 A/G 47,38
Region 303,04 99-16047/115 C/T 69,01
D
second 335,02 99-15875/165 C/T 61,3
Half
354,81 99-16033/244 C/T 50,3
366,51 99-16032/292 A/C 62,87
367,14 99-25940/182 A/G 54;39
372,98 99-15880/162 A/G 62,72
375,28 99-16038/118 A/G ~ 37,29
~ ~
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383,41 99-15870/400 A/G 29,65
394,16 99-24649/186 C/T 66,57
395,27 99-5897/143 A/C 52,6
409,93 99-24644/194 A/G 38,29
424,95 99-5919/215 A/G 60,63
441,62 99-5862/167 C/T 46,53
444,00 99-16100/147 A/G 48,84
445,84 99-7652/162 A/G 49,7
TOTAL 30
(1) : frequency (%) in Caucasian controls (N=177) of the first allele
(alphabetic order)
Region D was arbitrarily split in two halves (D ls' half and D 2"d half) for
purpose of the
analysis.
The present inventors have previously demonstrated significant association of
biallelic
markers located on the Region D subregion ofthe human chromosome 13q31-33
region with
disease. Using a set of 30 biallelic markers shown in Table 15, D 15' half
contained 14 markers
and D 2"d half contained 16 markers.
Table 15 also shows the physical order of the biallelic markers on Region D of
the
human chromosome 13q31-q33 region. The mean intermarker distances ofthe
biallelic markers
on the first and the second subjective portions of Region D were as listed
below in Table 16.
Table 16
Region Mean
Inter-marker distance
(std)
D ls'half 7.80(6.33)
D 2" half 9.79 (8.78)
D 1 S' and 9.58 (8.46)
2" half
The analysis using selected Region D biallelic markers of the invention
demonstrated a
significant association with bipolar disorder for the second portion of Region
D. The analysis
was conducted using the sample population described above with 182 Caucasian
cases and 177
Caucasian controls selected from the total case and control group.
One biallelic marker in particular, 99-15875/165(A228), located on the second
half of
Region D, demonstrated a significant association with disease at a
significance level of better
than 5% (corresponding to an absolute logarithm (p-value) of 1.3).
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B) Haplotype association results in bipolar disorder cases
Haplotype analysis for association of chromosome 13q31-q33-related biallelic
markers and
bipolar disorder was performed by estimating the frequencies of all possible
2, 3 and 4 marker
haplotypes in the affected and control populations described above. Haplotype
frequencies
estimations were performed by applying the Expectation-Maximization (EM)
algorithm (Excoffier
and Slatkin, 1995), modified by Nicholas Schork.
Significant results were obtained in haplotype studies indicating an
association of the
nucleotide sequences of the invention with bipolar disorder. The haplotype
analysis as shown in
the Figures 9A, 9B, 10A, l OB, 1 lA and 11B was conducted using the sample
population
described above, using 182 Caucasian cases and 177 Caucasian controls selected
from the total
case and control group.
Using the Omnibus LR test which compares the profile of haplotype frequencies,
and
Haplo-maxM test which is based on haplotype frequencies differences for each
haplotype in
two groups, Figures 9A, 9B, 1 OA, l OB, 11 A and 11 B show the results of a
comparison of the
first and second portions of Region D which demonstrated an association of the
second portion
of Region D with bipolar disorder.
a - Omnibus LR tests values
For a given combination of 2, 3 or 4 biallelic markers, one likelihood ratio
test (LR test)
is obtained based on the haplotype frequencies values calculated using the E-M
algorithm.
Figures 9A and 9B show a comparison of the LR test value distributions of
haplotype
frequencies in the two portions of Region D. This association of the second
portion of Region
D with bipolar disorder is shown using both 2-marker and 3-marker
combinations. A Kruskall
Wallis rank test was used to compare LR test values distributions in the two
subjective portions
of Region D. This test has an asymptotic Chi-square distribution, under the
null hypothesis of
no difference between the sets compared, with (r-1 ) degrees of freeedom,
where r represents the
number of sets compared. Here, we compare the 2 portions of region D, so ~=2,
and the
asymptotic Chi-square distribution has 1 degree of freedom. As shown, the
significance of the
association is demonstrated by a chi-square value (one degree of freedom) of
46.62 and a p-
value of 8.62x10 12 for 2 marker combinations, and a chi-square value (one
degree of freedom)
of 124.72 and a p-value of 5.86x10 29 for 3- marker combinations.
b - Haplo-max tests values
Another association analysis approach based on haplotype frequencies
differences,
referred to as the Haplo-max test, was conducted using region D biallelic
markers. The haplo-
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max test selects the difference showing the maximum positive (maxM) or
negative (maxS) test
value between cases versus controls (rejecting test values based on rare
haplotype frequencies,
i.e, with an estimated number of haplotypes carriers inferior to 10) ; for one
combination of
markers there is therefore one Max-M and one Max-S test values.
Figures I OA and l OB show the distribution of haplo-maxM test values obtained
for both
2-marker and 3-marker combinations in the two portions of Region D,
demonstrating an
association of the second portion of Region D with bipolar disorder. The
comparison of the
distribution of Haplo-maxM test values in the two regions was analyzed using a
Kruskal-Wallis
rank test, a chi-square test with 1 degree of freedom. As shown, the
significance of the
association is demonstrated by a chi-square value of 29.07 and a p-value
6.98x10 8 for 2 marker
combinations, and a chi-square value of 98.63 and a p-value of 3.04x10 23 for
3- marker
combinations.
Figures 1 IA and 11B show the distribution of Haplo-maxS test values again
obtained
for all 2-marker and 3-marker combinations in the two portions ofRegion D,
demonstrating an
association of the second portion of Region D with bipolar disorder. The
comparison of the
distributions of Haplo-maxS test values in the two portions was analyzed using
a Kruskal-
Wallis rank test with one degree of freedom. As shown, the significance of the
association is
demonstrated by a chi-square value of 34.6 and a p-value of 4.05x10 9 for 2
marker
combinations, and a chi-square value of 98.31 and a p-value of 3.58x10 23 for
3- marker
combinations.
The results from the haplo-maxM and haplo-maxS tests thus further confirm the
association shown using the Omnibus LR test results.
Example Se
Confirmation of Associations With Schizophrenia and Bipolar Disorder
("SCREENING
II")
Results obtained above using French Canadian schizophrenia samples and
Argentinian
bipolar disorder cases were confirmed in larger screening samples and in
several different
populations using markers spanning Region D of the chromosome 13q31-q33
region.
In the confirmation studies, French Canadian schizophrenia samples (Algene)
described
above, additional United States schizophrenia samples and Argentinian bipolar
disorder
(Labimo) samples were analyzed in sub-regions of Region D referred to as sub-
regions D1 to
D4. The schizophrenia sample referred to as the Algene (or French Canadian)
and the bipolar
disorder sample referred to as the Labimo sample (Argentinian) are as
described above. The
United States schizophrenia samples are described in Table 17 below.
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Table 17
United
States
Schizophrenia
Cases
and Control
Populations
United
States
Caucasians
Sample Cases Random
type US
Controls
Sample 131 188
size
Ethnic
origin
European Causasians 92
(26 female, 66 male)
Ashkenazi Caucasians 24
(7 female, 17 female)
Other Caucasians 15
(7 female, 8 male)
Familial
history
of psychosis
(FH)
positive (FH+) 133
none (FH-) 147 198
A set of 32 SNPs covering sub-regions D 1 to D4 (mean density of 1 SNP/25kb)
was
genotyped on the two different schizophrenia samples and one bipolar disorder
sample. The 32
biallelic markers genotyped are shown in Table 18.
Table 18
SNPs Polymorphism% Frequency in Algene
Controls(141)
99-5873/159 C/T 22
99-30329/380 C/T 48
99-15253/382 C/T 37
99-15280/432 C/T 39
99-15256/392 C/T 35
99-15258/337 G/T 24
99-27345/189 G/C 26
99-26150/276 A/G 48
99-25974/143 A/G 23
99-25950/121 G/C 28
99-25972/317 C/T 28
99-25965/399 A/G 50
99-25966/241 A/G 37
99-25989/398 A/G 28
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99-16047/115 C/T 25
99-16052/214 A/G 37
99-15875/165 C/T 34
99-16105/152 A/G 46
99-16032/292 A/C 44
99-15880/162 A/G 44
99-15870/400 A/G 30
99-5897/143 A/C 39
99-24644/194 A/G 41
99-24658/410 C/T 39
99-5919/215 A/G 40
99-5862/167 C/T 49
99-24634/108 A/T 50
99-24656/260 A/G 46
99-31960/363 A/G 39
8-128/33 C/T 23
99-27935/193 G/C 21
99-27943/150 G/C 35
For each of the three populations, the number of significant tests in each sub-
region of
Region D based on single and multiple point biallelic marker analyses were
compared among
cases and controls. For single point analyses, excess of heterozygotes and
deficiency of
heterozygotes (Hardy-Weinberg disequilibrium coefficient), allelic and
genotypic association
analyses and logistic regression analyses were compared. For multipoint
analyses, the
haplotypic frequency differences between case and controls were examined,
reported as MaxM
for the maximum positive difference, and MaxS as the maximum negative
difference, and the
Omnibus LR test. The HaploMax tests giving MaxS and MaxM results and the
Omnibus LR
test are known and otherwise described herein. As noted in Figures 12 to 17,
the tests containing
the footnote ( 1 ) involved significance thresholds which were assessed from
observed
distributions, inferred taking into account the D1, D2, D3 and D4 subregions
for each sub-
population studied relative to the number of tests performed; for tests
containing the footnote
(2) in Figures 12 to 17, significant tests were defined as those having a
significance level of 5%
1 S or better.
The present inventors have found that samples from three different populations
all show
a significant association to the schizophrenia trait with biallelic markers
located in region D,
thus confirming previous association studies with different samples and
markers. Furthermore,
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the inventors have found in all three populations that the association is most
significant in the
sub-region D3. Thus, it is likely that a gene associated with schizophrenia
and bipolar disorder
resides in the region. The sbgl and g35030 nucleic acid sequences described
herein reside in
the region D3.
In addition to results using markers in previous analyses, analyses with the
32 biallelic
markers listed in Table 18 demonstrated significant results in single point
analyses for several
newly analyzed biallelic markers. In particular, markers 99-25974-143 (A292),
99-25972-317
(A291), 99-15870-400 (A178), 99-24656-260 (A48) demonstrated a statistically
significant
excess or deficiency of heterozygotes.
Schizophrenia: Algene (French Canadian)
The analysis using Algene samples compared (1) the total patients cluster of
patients
selected for analysis (2) cases of the cluster showing a familial history of
psychosis (FH+), and
(3) cases of the cluster with an absence of familial history of psychosis (FH-
) to Algene control
samples. Additionally, for further comparison, the number of significant tests
in Region D and
1 S each of the sub-regions of Region D were compared among total cases and
total controls from
the screening sample of example Sb above is listed in Figure 12 under "first
screening sample".
As previously reported, the original French Canadian (Algene) samples show a
significant
association to the schizophrenia trait with biallelic markers located in
region D, both in single and
multi-point analyses. Furthermore, results show that the association is
clearly confined to sub-
region D3 and does not extend to D2 and D4. In single point analyses, a
significant concentration
of biallelic markers containing the sbgl gene presented an excess of
heterozygotes for familial
cases. Five of 13 (5/13) markers around sbgl were significant for allelic
association analysis.
Figure 12 provides the results from a single and multi-point biallelic marker
analysis
comparing regions D1, D2, D3, and D4 located in the chromosome 13q31-q33
region.
Figure 13 shows the sum of the results shown in Figure 12 over the larger
Region D
span tested (ie. D1, D2, D3 and D4).
Figures 12 and 13 thus demonstrate that there is a significant association
with Region D
and schizophrenia in the Algene sample. Furthermore, these figures show that
the number and
percentage of significant tests was highest in sub-region D3 consistently
across comparisons
among controls and FH+, FH- and total cases. In comparing the number of
significant tests in
sub-region D3 among FH+ and FH- cases, the figures show that the association
is more clearly
observed in cases having a familial history of psychosis; single point
analyses suggested a
higher number of significant tests in the FH+ cases than multiple point
analyses.
Figures 12 and 13 also show that a larger screening sample confirms the
results of the
smaller sample from the first screening of Algene samples, both for the larger
Region D and for
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the sub-region D3.
Schizophrenia: United States Schizophrenia samples
As in the French Canadian samples, the present inventors have found Region D,
and
more specifically sub-region D3, to be significantly associated with
schizophrenia in a first,
smaller screening sample of the United States Schizophrenia samples. Further
analysis in the
United States Schizophrenia population using a set of biallelic markers
covering Region D
confirms that the association of sub-region D3 with schizophrenia is of high
statistical
significance.
The United States Schizophrenia samples selected for the analysis consisted of
the 92
European Caucasians. Two analyses were performed, a first analysis using
controls consisting
of 188.random US controls, and a second analysis where controls consisted of
241 controls
from the French Canadian samples described above.
Figure 14 provides the results from a single and multi-point biallelic marker
analysis
comparing regions D1, D2, D3, and D4 located in the chromosome 13q31-q33
region. Figure
15 shows the sum of the results shown in Figure 14 over the larger Region D
span tested (ie.
D1, D2, D3 and D4).
As shown in the figures, the analysis in United States Schizophrenia samples
also
suggests a significant association of sub-region D2 with schizophrenia, when
considering multi-
point analyses. However, this association of the D2 region with schizophrenia
is of lesser
statistical significance than the association of schizophrenia with sub-region
D3 because a lower
number of tests were carried out in the D2 region. Additionally, one marker
(99-5897/143) in
particuar, localized in the sbgl gene showed a significant excess of
heterozygotes in
schizophrenia familial cases.
In general, the number of significant tests in United States Schizophrenia
samples were
lower that in French Canadian population. This may be attributed to the higher
heterogeneity of
the United States Schizophrenia sample in comparison to the French Canadian
samples.
Analyses using the United States Schizophrenia samples were done using either
Caucasian
controls from the French Canadian samples, or US random controls.
Bipolar disorder: Labimo (Argentinean)
As in the French Canadian and United States Schizophrenia samples, the present
inventors have found Region D, and more specifically sub-region D3, to be
significantly
associated with bipolar disorder in Labimo samples from Argentina. Further
analysis using a
more extensive set of biallelic markers covering Region D confirms that the
association of sub-
region D3 with bipolar disorder is of high statistical significance.
Figure 16 provides the results from a single and multi-point biallelic marker
analysis
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comparing regions D1, D2, D3, and D4 located in the chromosome 13q31-q33
region. Figure
17 shows the sum of the results shown in Figure 16 over the larger Region D
span tested (ie.
D1, D2, D3 and D4). While results showed the most significant association for
D3 in Labimo
samples, some background signal was seen for D2. It is possible that this
variance in the
percentage of significant tests reflects the higher relative heterogeneity of
the Labimo samples
in comparison to the French Canadian samples.
Figures 16 and 17 thus demonstrate that there is a significant association
with Region D
and bipolar disorder in the Labimo sample.
Analyses of Labimo samples were also conducted separately in bipolar disorder
I and
bipolar disorder II cases, as shown in Figure 16. In comparisons of results
obtained with bipolar
disorder I and II types, the association of sub-region D3 with schizophrenia
tended to be more
clearly found in bipolar disorder I cases.
Example 6
Preparation of Antibody Compositions to the sbgl protein
Substantially pure protein or polypeptide is isolated from transfected or
transformed cells
containing an expression vector encoding the sbgl protein or a portion
thereof. The concentration
of protein in the final preparation is adjusted, for example, by concentration
on an Amicon filter
device, to the level of a few micrograms/ml. Monoclonal or polyclonal antibody
to the protein can
then be prepared as follows:
A. Monoclonal Antibody Production b,~ybridoma Fusion
Monoclonal antibody to epitopes in the sbgl protein or a portion thereof can
be prepared
from murine hybridomas according to the classical method of Kohler, G. and
Milstein, C., Nature .
256:495 (1975) or derivative methods thereof. Also see Harlow, E., and D.
Lane. 1988.
Antibodies A Laboratory Manual. Cold Spring Harbor Laboratory. pp. 53-242.
Briefly, a mouse is repetitively inoculated with a few micrograms of the sbgl
protein or a
portion thereof over a period of a few weeks. The mouse is then sacrificed,
and the antibody
producing cells of the spleen isolated. The spleen cells are fused by means of
polyethylene glycol
with mouse myeloma cells, and the excess unfused cells destroyed by growth of
the system on
selective media comprising aminopterin (HAT media). The successfully fused
cells are diluted and
aliquots of the dilution placed in wells of a microtiter plate where growth of
the culture is
continued. Antibody-producing clones are identified by detection of antibody
in the supernatant
fluid of the wells by immunoassay procedures, such as ELISA, as originally
described by Engvall,
(1980), and derivative methods thereof. Selected positive clones can be
expanded and their
monoclonal antibody product harvested for use. Detailed procedures for
monoclonal antibody
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253
production are described in Davis, L. et al. Basic Methods in Molecular
Biology Elsevier, New
York. Section 21-2.
B. Po~clonal Antibody Production by Immunization
Polyclonal antiserum containing antibodies to heterogeneous epitopes in the
sbgl protein
or a portion thereof can be prepared by immunizing suitable non-human animal
with the sbgl
protein or a portion thereof, which can be unmodified or modified to enhance
immunogenicity. A
suitable non-human animal is preferably a non-human mammal is selected,
usually a mouse, rat,
rabbit, goat, or horse. Alternatively, a crude preparation which has been
enriched for sbgl
concentration can be used to generate antibodies. Such proteins, fragments or
preparations are
introduced into the non-human mammal in the presence of an appropriate
adjuvant (e.g..
aluminum hydroxide, RIBI, etc.) which is known in the art. In addition the
protein, fragment or
preparation can be pretreated with an agent which will increase antigenicity,
such agents are
known in the art and include, for example, methylated bovine serum albumin
(mBSA), bovine
serum albumin (BSA), Hepatitis B surface antigen, and keyhole limpet
hemocyanin (KLH).
Serum from the immunized animal is collected, treated and tested according to
known
procedures. If the serum contains polyclonal antibodies to undesired epitopes,
the polyclonal
antibodies can be purified by immunoaffinity chromatography.
Effective polyclonal antibody production is affected by many factors related
both to the
antigen and the host species. Also, host animals vary in response to site of
inoculations and
dose, with both inadequate or excessive doses of antigen resulting in low
titer antisera. Small
doses (ng level) of antigen administered at multiple intradermal sites appears
to be most
reliable. Techniques for producing and processing polyclonal antisera are
known in the art, see
for example, Mayer and Walker (1987). An effective immunization protocol for
rabbits can be
found in Vaitukaitis, J. et al. J. Clin. Endocrinol. Metab. 33:988-991 (1971).
Booster injections can be given at regular intervals, and antiserum harvested
when
antibody titer thereof, as determined semi-quantitatively, for example, by
double immunodiffusion
in agar against known concentrations of the antigen, begins to fall. See, for
example, Ouchterlony,
O. et al., (1973). Plateau concentration of antibody is usually in the range
of 0.1 to 0.2 mg/ml of
serum (about 12 p,M). Affinity of the antisera for the antigen is determined
by preparing
competitive binding curves, as described, for example, by Fisher, D., Chap. 42
in: Manual of
Clinical Immunology, 2d Ed. (Rose and Friedman, Eds.) Amer. Soc. For
Microbiol., Washington,
D.C. ( 1980).
Antibody preparations prepared according to either the monoclonal or the
polyclonal
protocol are useful in quantitative immunoassays which determine
concentrations of antigen-
bearing substances in biological samples; they are also used semi-
quantitatively or qualitatively to
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identify the presence of antigen in a biological sample. The antibodies may
also be used in
therapeutic compositions for killing cells expressing the protein or reducing
the levels of the protein
in the body.
S
Example 7
Study of effect of sbgl peptides on behavior of mice
Animals: Male C57BL6 adult mice (approximately 6 weeks old)
Peptides: sbg 1 peptide:
NH2-QPLERMWTCNYNQQKDQSCNHKEITSTKAE-COOH
Control 1: NH2-REAHKSETISSKLQKEKQIKKQ-COOH
Control 2: NH2-MHMKTILGPRLGLGE-COOH
Protocol:
1. Inject mice intraperitoneally with 50 pg peptide in 200 pl sterile
physiological saline (n = 4 / peptide).
2. Place mice in clean empty cages containing no litter, and only a small test
tube rack. The cages are covered with a plastic sheet to enable taking
photographs and video-tracking.
3. Observe behavior for one minute from t = 5 min up to t = 45 min, as
indicated. Any locomoter or stereotypy movements were recorded as
positive over 1 min intervals. Locomoter movements include climbing, and
rearing while stereotypy movements include grooming and scratching. At
the end of the experiment, the number of movements were added up for
each animal.
Results:
1. Mice injected with the sbgl peptide exhibited a decrease in the frequency
of their movements over the time course of the experiment, shown in
Figure 18. This is illustrated in the left top panel of Figure 18, where we
compare the average number of movements in 3 separate time points (5, 10,
and 15 min) with the average movements per min in the last period of
observations (30, 35, 40, and 45 min). The sbgl peptide also increased
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stereotypy - this effect was most prominent during the last period of
observations. However, because the onset of stereotype was variable, we
presented the data as the average of stereotypy for observations over the
entire time period.
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The disclosures of all issued patents, published PCT applications, scientific
references or
other publications cited herein are incorporated herein by reference in their
entireties.
Although this invention has been described in terms of certain preferred
embodiments,
other embodiments which will be apparent to those of ordinary skill in the art
of view of the
disclosure herein are also within the scope of this invention. Accordingly,
the scope of the
invention is intended to be defined only by reference to the appended claims.
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Seguence listinE free text
The following free text appears in the accompanying Sequence Listing:
Schizophrenia
Associated
Protein
Biallelic
marker
regulatory
region
gene
exon
complement
polymorphic
base
or
allele
deletion
of
basic
protease
cleavage
site
probe
primer
downstream
upstream
amplification
sequencing
oligonucleotide
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258
The disclosures of the following references are incorporated herein by
reference in their
entireties:
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SEQUENCE LISTING
<110> GENSET
<120> SCHIZOPHRENIA ASSOCIATED GENES, PROTEINS AND BIALLELIC MARKERS
<130> 53.W01
<150> US 60/126,903
<151> 1999-03-30
<150> US 60/131,971
<151> 1999-04-30
<150> US 60/132,065
<151> 1999-04-30
<150> US 60/143,928
<151> 1999-07-14
<150> US 60/145,915
<151> 1999-07-27
<150> US 60/146,453
<151> 1999-07-29
<150> US 60/146,452
<151> 1999-07-29
<150> US 60/162,288
<151> 1999-10-28
<160> 231
<170> Patent.pm
<210> 1
<211> 319608
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<222> 31..1107
<223> 5'regulatory region 835018 gene
<220>
<221> exon
<222> 1108..1289
<223> exon A 835018 gene
<220>
<221> exon
<222> 14877..14920
<223> exon B 835018 gene
<220>
<221> exon
<222> 18778..18862
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<223> exon Bbis 835018 gene
2
<220>
<221> exon
<222> 25593..25740
<223> exon C 835018 gene
<220>
<221> exon
<222> 29388..29502
<223> exon D 835018 gene
<220>
<221> exon
<222> 29967..30282
<223> exon E 835018 gene
<220>
<221> exon
<222> 64666..64812
<223> exon F 835018 gene
<220>
<221> exon
<222> 65505..65853
<223> exon G 835018 gene
<220>
<221> misc_feature
<222> 65854..67854
<223> 3'regulatory region 835018 gene
<220>
<221> exon
<222> 94124..94964
<223> exon 835017
<220>
<221> exon
<222> 201188..201234
<223> exon S 835030 gene
<220>
<221> exon
<222> 214676..214793
<223> exon T 835030 gene
<220>
<221> exon
<222> 215702..215746
<223> exon U 835030 gene
<220>
<221> exon
<222> 216836..216915
<223> exon V 835030 gene
<220>
<221> misc_feature
<222> 213818..215818
<223> 3'regulatory region 834872 gene
<220>
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<221> exon
<222> 215819..215941
<223> exon R complement 834872 gene
<220>
<221> exon
<222> 215819..215975
<223> exon Rbis complement 834872 gene
<220>
<221> exon
<222> 216661..216952
<223> exon Qbis complement 834872 gene
<220>
<221> exon
<222> 216661..217061
<223> exon Q complement 834872 gene
<220>
<221> exon
<222> 217027..217061
<223> exon Q1 complement 834872 gene
<220>
<221> exon
<222> 229647..229742
<223> exon X complement 834872 gene
<220>
<221> exon
<222> 230408..230721
<223> exon P complement 834872 gene
<220>
<221> exon
<222> 231272..231412
<223> exon Obis complement 834872 gene
<220>
<221> exon
<222> 231787..231880
<223> exon 02 complement 834872 gene
<220>
<221> exon
<222> 231870..231879
<223> exon O1 complement 834872 gene
<220>
<221> exon
<222> 234174..234321
<223> exon 0 complement 834872 gene
<220>
<221> exon
<222> 237406..237428
<223> exon Nbis complement 834872 gene
<220>
<221> exon
<222> 239719..239807
<223> exon N2 complement 834872 gene
3
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
4
<220>
<221> exon
<222> 239719..239853
<223> exon N complement 834872 gene
<220>
<221> exon
<222> 240528..240569
<223> exon M1117 complement 834872 gene
<220>
<221> exon
<222> 240528..240596
<223> exon M1090 complement 834872 gene
<220>
<221> exon
<222> 240528..240617
<223> exon M1069 complement 834872 gene
<220>
<221> exon
<222> 240528..240644
<223> exon MS2 complement 834872 gene
<220>
<221> exon
<222> 240528..240824
<223> exon M862 complement 834872 gene
<220>
<221> exon
<222> 240528..240994
<223> exon M692 complement 834872 gene
<220>
<221> exon
<222> 240528..241685
<223> exon Ml complement 834872 gene
<220>
<221> exon
<222> 240800..240993
<223> exon MS1 complement 834872 gene
<220>
<221> misc_feature
<222> 241686..243685
<223> 5'regulatory region 834872 gene
<220>
<221> misc_feature
<222> 290652..292652
<223> 3'regulatory region 834665 gene
<220>
<221> exon
<222> 292653..292841
<223> exon B complement 834665 gene
<220>
<221> exon
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222>295555..296047
<223>exon Ab complement 834665
gene
<220>
<221>exon
<222>295980..296047
<223>exon A complement 834665 gene
<220>
<221>misc
feature
<222>_
296048..298048
<223>5'regulatory region 834665
gene
<220>
<221>allele
<222>8316
<223>99-27943-150 . polymorphic or
base G C
<220>
<221>allele
<222>14726
<223>8-121-28 . polymorphic base
A or T
<220>
<221>allele
<222>14734
<223>8-121-36 . polymorphic base
C or T
<220>
<221>allele
<222>14852
<223>8-121-154 . polymorphic base T
A or
<220>
<221>allele
<222>14885
<223>8-121-187 . polymorphic base C
A or
<220>
<221>allele
<222>14941
<223>8-121-243 . polymorphic base T
G or
<220>
<221>allele
<222>14979
<223>8-121-281 . polymorphic base C
A or
<220>
<221>allele
<222>15050
<223>8-121-352 . polymorphic base T
C or
<220>
<221>allele
<222>15062
<223>8-121-364 . polymorphic base T
C or
<220>
<221>allele
<222>15069
<223>8-121-371 . polymorphic base G
A or
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
6
<220>
<221>allele
<222>21672
<223>99-27935-193 . polymorphic
base G or
C
<220>
<221>allele
<222>25480
<223>8-122-72. polymorphic
base A or
T
<220>
<221>allele
<222>25508
<223>8-122-100. polymorphicbaseC or
T
<220>
<221>allele
<222>25679
<223>8-122-271. deletion CAAA
of
<220>
<221>allele
<222>25680
<223>8-122-272. polymorphicbaseA or
G
<220>
<221>allele
<222>25734
<223>8-122-326. polymorphicbaseA or
C
<220>
<221>allele
<222>25768
<223>8-122-360. polymorphicbaseC or
T
<220>
<221>allele
<222>29403
<223>8-123-55. polymorphic
base A or
T
<220>
<221>allele
<222>29537
<223>8-123-189. polymorphicbaseC or
T
<220>
<221>allele
<222>29545
<223>8-123-197. polymorphicbaseC or
T
<220>
<221>allele
<222>29655
<223>8-123-307. polymorphicbaseG or
C
<220>
<221>allele
<222>30169
<223>8-147-270. polymorphicbaseA or
G
<220>
<221>allele
<222>49475
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
7
<223> 99-34243-210 . polymorphic base A or T
<220>
<221>allele
<222>64666
<223>8-127-28 . polymorphic base
A or G
<220>
<221>allele
<222>64757
<223>8-127-119. polymorphic base
A or G
<220>
<221>allele
<222>64797
<223>8-127-159. polymorphic base
A or C
<220>
<221>allele
<222>64874
<223>8-127-236. polymorphic base
C or T
<220>
<221>allele
<222>64878
<223>8-127-240. polymorphic base
A or G
<220>
<221>allele
<222>64918
<223>8-127-280. polymorphic base
G or T
<220>
<221>allele
<222>65485
<223>8-128-33 . polymorphic base
C or T
<220>
<221>allele
<222>65504
<223>8-128-52 polymorphic base A
. or G
<220>
<221>allele
<222>65513
<223>8-128-61 polymorphic base G
. or C
<220>
<221>allele
<222>65520
<223>8-128-68 polymorphic base C
. or T
<220>
<221>allele
<222>65521
<223>8-128-69 polymorphic base A
. or G
<220>
<221>allele
<222>65537
<223>8-128-85 polymorphic base A
. or C
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
8
<221>allele
<222>65596
<223>8-129-50 polymorphic base r T
. C o
<220>
<221>allele
<222>65607
<223>8-129-60 deletion of A
.
<220>
<221>allele
<222>65857
<223>8-129-311 polymorphic base or
. A G
<220>
<221>allele
<222>65947
<223>8-129-401 polymorphic base or
. C T
<220>
<221>allele
<222>75667
<223>99-34240-492. polymorphic A or
base T
<220>
<221>allele
<222>94534
<223>99-31959-281. polymorphic C or
base T
<220>
<221>allele
<222>95396
<223>99-31960-363. polymorphic A or
base G
<220>
<221>allele
<222>96956
<223>99-31962-250. polymorphic C or
base T
<220>
<221>allele
<222>97156
<223>99-31962-450. polymorphic A or
base G
<220>
<221>allele
<222>106384
<223>99-44282-439. polymorphic A or
base G
<220>
<221>allele
<222>106769
<223>99-44282-54. polymorphic C or
base T
<220>
<221>allele
<222>107158
<223>99-24656-137. polymorphic A or
base G
<220>
<221>allele
<222>107281
<223>99-24656-260. polymorphic A or
base G
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
9
<220>
<221>allele
<222>107609
<223>99-24636-22polymorphic base A
. or G
<220>
<221>allele
<222>108499
<223>99-31939-75polymorphic base A
. or G
<220>
<221>allele
<222>108697
<223>99-31939-273. polymorphicbase C
or T
<220>
<221>allele
<222>109451
<223>99-44281-418. polymorphicbase G
or T
<220>
<221>allele
<222>109612
<223>99-44281-257. polymorphicbase A
or G
<220>
<221>allele
<222>109792
<223>99-44281-77polymorphic base A
. or G
<220>
<221>allele
<222>112468
<223>99-31941-320. polymorphicbase G
or T
<220>
<221>allele
<222>115468
<223>99-31942-325. polymorphicbase G
or T
<220>
<221>allele
<222>155736
<223>99-24635-79. polymorphicbase A
or T
<220>
<221>allele
<222>158172
<223>99-16059-313. polymorphicbase A
or G
<220>
<221>allele
<222>160634
<223>99-24639-169. polymorphicbase C
or T
<220>
<221>allele
<222>160640
<223>99-24639-163. polymorphicbase A
or C
<220>
<221>allele
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222>160876
<223>99-24634-108. polymorphicbase A
or T
<220>
<221>allele
<222>168974
<223>99-7652-162. polymorphic
base A or
G
<220>
<221>allele
<222>169300
<223>99-7652-488. polymorphic
base A or
G
<220>
<221>allele
<222>170746
<223>99-16100-83. polymorphic
base C or
T
<220>
<221>allele
<222>170810
<223>99-16100-147. polymorphicbase A
or G
<220>
<221>allele
<222>170858
<223>99-16100-195. polymorphicbase G
or T
<220>
<221>allele
<222>170860
<223>99-16100-197. polymorphicbase C
or T
<220>
<221>allele
<222>170906
<223>99-16100-244. polymorphicbase C
or T
<220>
<221>allele
<222>171043
<223>99-16100-381. polymorphicbase A
or C
<220>
<221>allele
<222>173358
<223>99-5862-167. polymorphicbase A
or G
<220>
<221>allele
<222>174227
<223>99-16083-101. polymorphicbase C
or T
<220>
<221>allele
<222>175800
<223>99-16044-351. polymorphicbase C
or T
<220>
<221>allele
<222>180589
<223>99-16042-420. polymorphicbase A
or G
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<220>
<221>allele
<222>180978
<223>99-16042-31. polymorphic G or
base C
<220>
<221>allele
<222>189957
<223>99-5919-215. polymorphic A or
base G
<220>
<221>allele
<222>197163
<223>99-24658-410. polymorphic A or
base G
<220>
<221>allele
<222>198964
<223>99-30364-299. polymorphic A or
base G
<220>
<221>allele
<222>200256
<223>99-30366-112. polymorphic G or
base T
<220>
<221>allele
<222>204588
<223>99-16094-75. polymorphic G or
base T
<220>
<221>allele
<222>204934
<223>99-24644-194. polymorphic A or
base G
<220>
<221>allele
<222>206197
<223>99-16107-95. polymorphic A or
base T
<220>
<221>allele
<222>206263
<223>99-16107-161. polymorphic A or
base G
<220>
<221>allele
<222>206485
<223>99-16107-383. polymorphic C or
base T
<220>
<221>allele
<222>211608
<223>99-15873-303. polymorphic C or
base T
<220>
<221>allele
<222>214669
<223>8-124-106 polymorphic baseor
. A G
<220>
<221>allele
<222>214783
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
12
<223>8-124-220 polymorphicbase A or
. G
<220>
<221>allele
<222>214857
<223>8-124-294 polymorphicbase A or
. G
<220>
<221>allele
<222>214879
<223>8-124-316 polymorphicbase C or
. T
<220>
<221>allele
<222>214946
<223>8-124-383 polymorphicbase A or
. T
<220>
<221>allele
<222>215538
<223>8-125-33 polymorphicbase C or
. T
<220>
<221>allele
<222>215705
<223>8-132-312 polymorphicbase A or
. G
<220>
<221>allele
<222>215838
<223>8-132-179 polymorphicbase A or
. T
<220>
<221>allele
<222>215853
<223>8-132-164 polymorphicbase A or
. G
<220>
<221>allele
<222>215920
<223>8-132-97 polymorphicbase
. A
or
G
<220>
<221>allele
<222>216028
<223>99-13929-201. polymorphic ase G
b or T
<220>
<221>allele
<222>216538
<223>8-131-363 polymorphicbase G or
. T
<220>
<221>allele
<222>216702
<223>8-131-199 polymorphicbase G or
. T
<220>
<221>allele
<222>216874
<223>8-130-236 polymorphicbase C or
. T
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
13
<221>allele
<222>216890
<223>8-130-220 polymorphic base or
. G T
<220>
<221>allele
<222>216966
<223>8-130-144 polymorphic base or
. C T
<220>
<221>allele
<222>216967
<223>8-130-143 polymorphic base or
. A G
<220>
<221>allele
<222>217008
<223>8-130-102 polymorphic base or
. C T
<220>
<221>allele
<222>217009
<223>8-130-101 polymorphic base or
. G T
<220>
<221>allele
<222>217027
<223>8-130-83 polymorphic base r C
. A o
<220>
<221>allele
<222>217207
<223>8-209-333 polymorphic base.Aor'G
.
<220>
<221>allele
<222>217250
<223>8-209-290 polymorphic base or
. A C
<220>
<221>allele
<222>219540
<223>99-5897-143. polymorphic A or
base C
<220>
<221>allele
<222>220836
<223>99-24649-186. polymorphic A or
base G
<220>
<221>allele
<222>220942
<223>99-24649-80. polymorphic G or
base C
<220>
<221>allele
<222>221741
<223>8-199-84 polymorphic base
. G or T
<220>
<221>allele
<222>222048
<223>8-198-138 polymorphic base or
. A G
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
14
<220>
<221> allele
<222> 222746
<223> 8-195-348 . polymorphic base C or T
<220>
<221> allele
<222> 223595
<223> 99-13925-97 . polymorphic base A or G
<220>
<221>allele
<222>225443
<223>8-192-82 polymorphic base r G
. A o
<220>
<221>allele
<222>226219
<223>99-16090-225. polymorphic A or
base G
<220>
<221>allele
<222>226282
<223>8-189-340 deletion of CTAT
.
<220>
<221>allele
<222>226487
<223>8-189-146 polymorphic base or
. G T
<220>
<221>allele
<222>226870
<223>8-188-136 polymorphic base or
. C T
<220>
<221>allele
<222>226987
<223>8-187-352 polymorphic base or
. G T
<220>
<221>allele
<222>227589
<223>8-185-319 polymorphic base or
. G T
<220>
<221>allele
<222>227612
<223>8-185-296 polymorphic base or
. A T
<220>
<221>allele
<222>228006
<223>99-16051-226. polymorphic C or
base T
<220>
<221>allele
<222>228068
<223>99-16051-164. polymorphic A or
base G
<220>
<221>allele
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222>228134
<223>8-184-119. polymorphicbase A
or T
<220>
<221>allele
<222>228226
<223>8-184-27 polymorphic
, base A or
C
<220>
<221>allele
<222>228254
<223>8-183-401. polymorphicbase C
or T
<220>
<221>allele
<222>229069
<223>8-181-449. polymorphicbase C
or T
<220>
<221>allele
<222>229168
<223>8-181-350. polymorphicbase A
or T
<220>
<221>allele
<222>229259
<223>8-181-259. polymorphicbase A
or G
<220>
<221>allele
<222>229288
<223>8-181-230. polymorphicbase A
or T
<220>
<221>allele
<222>229308
<223>8-181-210. polymorphicbase A
or T
<220>
<221>allele
<222>229353
<223>8-181-165. polymorphicbase C
or T
<220>
<221>allele
<222>229355
<223>8-181-163. polymorphicbase C
or T
<220>
<221>allele
<222>229435
<223>8-181-83 . polymorphic
base C or
T
<220>
<221>allele
<222>229486
<223>8-180-157. polymorphicbase A
or T
<220>
<221>allele
<222>229582
<223>8-143-332. polymorphicbase A
or C
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
16
<220>
<221>allele
<222>229587
<223>8-143-327. polymorphicbase A
or G
<220>
<221>allele
<222>229603
<223>8-143-311. polymorphicbase A
or G
<220>
<221>allele
<222>229606
<223>8-143-308. polymorphicbase A
or G
<220>
<221>allele
<222>229607
<223>8-179-268. polymorphicbase A
or C
<220>
<221>allele
<222>229608
<223>8-143-306. polymorphicbase A
or G
<220>
<221>allele
<222>229669
<223>8-143-245. polymorphicbase G
or T
<220>
<221>allele
<222>229672
<223>8-143-242. polymorphicbase A
or G
<220>
<221>allele
<222>229675
<223>8-143-239. polymorphicbase C
or T
<220>
<221>allele
<222>229682
<223>8-143-232. polymorphicbase G
or C
<220>
<221>allele
<222>229762
<223>8-143-152. polymorphicbase G
or C
<220>
<221>allele
<222>229961
<223>8-178-199. polymorphicbase G
or C
<220>
<221>allele
<222>230037
<223>8-178-123. deletion A
of
<220>
<221>allele
<222>230238
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
17
<223>8-119-404. polymorphicbase C
or T
<220>
<221>allele
<222>230256
<223>8-177-281. polymorphicbase C
or T
<220>
<221>allele
<222>230265
<223>8-119-377. polymorphicbase C
or T
<220>
<221>allele
<222>230333
<223>8-119-309. polymorphicbase C
or T
<220>
<221>allele
<222>230348
<223>8-119-294. polymorphicbase G
or T
<220>
<221>allele
<222>230358
<223>8-119-284. polymorphicbase G
or C
<220>
<221>allele
<222>230370
<223>8-119-272. polymorphicbase A
or T
<220>
<221>allele
<222>230380
<223>8-119-262. polymorphicbase A
or T
<220>
<221>allele
<222>230394
<223>8-119-248. polymorphicbase C
or T
<220>
<221>allele
<222>230395
<223>8-119-247. polymorphicbase A
or G
<220>
<221>allele
<222>230432
<223>8-119-210. polymorphicbase A
or C
<220>
<221>allele
<222>230438
<223>8-119-204. polymorphicbase A
or C
<220>
<221>allele
<222>230442
<223>8-119-200. polymorphicbase A
or G
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
18
<221>allele
<222>230447
<223>8-119-195. polymorphicbase A
or C
<220>
<221>allele
<222>230517
<223>8-119-125. polymorphicbase C
or T
<220>
<221>allele
<222>230522
<223>8-119-120. polymorphicbase A
or G
<220>
<221>allele
<222>230545
<223>8-119-97 . polymorphicbase C
or T
<220>
<221>allele
<222>230549
<223>8-119-93 . polymorphicbase G
or T
<220>
<221>allele
<222>230604
<223>8-119-38 . polymorphicbase A
or T
<220>
<221>allele
<222>230684
<223>8-138-234. polymorphicbase C
or T
<220>
<221>allele
<222>230700
<223>8-138-218. polymorphicbase A
or G
<220>
<221>allele
<222>230755
<223>8-138-163. polymorphicbase C
or T
<220>
<221>allele
<222>230864
<223>8-138-54 . insertionTA
of
<220>
<221>allele
<222>231070
<223>8-175-75 . polymorphicbase G
or T
<220>
<221>allele
<222>231118
<223>8-142-386. polymorphicbase C
or T
<220>
<221>allele
<222>231134
<223>8-142-370. polymorphicbase C
or T
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
19
<220>
<221>allele
<222>231290
<223>8-142-211 deletion CAAA
. of
<220>
<221>allele
<222>231372
<223>8-142-132 polymorphicbaseA or
. G
<220>
<221>allele
<222>231669
<223>8-145-339 polymorphicbaseC or
. T
<220>
<221>allele
<222>231677
<223>99-15870-400. polymorphic
base A
or G
<220>
<221>allele
<222>231777
<223>8-145-231 polymorphicbaseA or
. T
<220>
<221>allele
<222>231811
<223>8-145-197 polymorphicbaseC or
. T
<220>
<221>allele
<222>231854
<223>8-145-154 polymorphicbaseC or
. T
<220>
<221>allele
<222>231870
<223>8-145-138 polymorphicbaseA or
. C
<220>
<221>allele
<222>231930
<223>8-145-78 polymorphic
. base G
or C
<220>
<221>allele
<222>232320
<223>8-171-247 polymorphicbaseC or
, T
<220>
<221>allele
<222>232477
<223>8-170-373 polymorphicbaseC or
. T
<220>
<221>allele
<222>232898
<223>8-169-266 polymorphicbaseA or
. G
<220>
<221>allele
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222>232998
<223>8-169-166 polymorphicbaseG or
. T
<220>
<221>allele
<222>233100
<223>8-168-380 polymorphicbaseA or
. G
<220>
<221>allele
<222>233453
<223>8-235-349 polymorphicbaseC or
. T
<220>
<221>allele
<222>233620
<223>8-235-182 polymorphicbaseG or
. T
<220>
<221>allele
<222>234120
<223>8-137-340 polymorphicbaseG or
. C
<220>
<221>allele
<222>234277
<223>8-137-182 polymorphicbaseC or
. T
<220>
<221>allele
<222>234307
<223>8-137-152 polymorphicbaseA or
. C
<220>
<221>allele
<222>234751
<223>8-165-185 polymorphicbaseG or
. C
<220>
<221>allele
<222>235315
<223>99-16087-219. polymorphic
base G
or C
<220>
<221>allele
<222>238223
<223>8-157-177 polymorphicbaseA or
. C
<220>
<221>allele
<222>238789
<223>8-155-258 polymorphicbaseC or
. T
<220>
<221>allele
<222>239763
<223>99-16038-118. polymorphic
base C
or T
<220>
<221>allele
<222>239864
<223>8-136-166 polymorphicbaseA or
. G
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
21
<220>
<221>allele
<222>239885
<223>8-136-145. polymorphicbase G
A or
<220>
<221>allele
<222>239950
<223>8-136-80 . polymorphic
base C or
T
<220>
<221>allele
<222>240044
<223>8-153-32 . polymorphic
base A or
G
<220>
<221>allele
<222>240497
<223>8-135-212. polymorphicbase G
A or
<220>
<221>allele
<222>240543
<223>8-135-166. polymorphicbase T
G or
<220>
<221>allele
<222>240597
<223>8-135-112. polymorphicbase G
A or
<220>
<221>allele
<222>240772
<223>99-16050-235 ic base or
. polymorph G C
<220>
<221>allele
<222>240858
<223>8-144-378. polymorphicbase T
C or
<220>
<221>allele
<222>241002
<223>8-144-239. polymorphicbase T
C or
<220>
<221>allele
<222>241040
<223>8-144-196. polymorphicbase T
A or
<220>
<221>allele
<222>241002
<223>8-144-127. deletion TGGATAC
of
<220>
<221>allele
<222>241217
<223>8-141-304. polymorphicbase T
C or
<220>
<221>allele
<222>241261
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
22
<223>8-141-260. polymorphic base
C or T
<220>
<221>allele
<222>241360
<223>8-141-161. polymorphic base
G or T
<220>
<221>allele
<222>241507
<223>8-140-286. polymorphic base
A or G
<220>
<221>allele
<222>241620
<223>8-140-173 polymorphic base or
. A C
<220>
<221>allele
<222>241685
<223>8-140-108 polymorphic base or
. G C
<220>
<221>allele
<222>241752
<223>8-140-41 polymorphic base r G
. A o
<220>
<221>allele
<222>241861
<223>99-15880-162. polymorphic A or
base G
<220>
<221>allele
<222>242402
<223>8-240-187 polymorphic base or
. G T
<220>
<221>allele
<222>244313
<223>8-225-281 polymorphic base or
. A T
<220>
<221>allele
<222>247860
<223>99-25940-186. polymorphic A or
base G
<220>
<221>allele
<222>247864
<223>99-25940-182. polymorphic C or
base T
<220>
<221>allele
<222>248315
<223>99-16032-292. polymorphic G or
base T
<220>
<221>allele
<222>253619
<223>99-16055-216. polymorphic A or
base G
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
23
<221>allele
<222>255848
<223>99-16105-152. polymorphic base or
A G
<220>
<221>allele
<222>258573
<223>99-16101-436. polymorphic base or
C T
<220>
<221>allele
<222>260099
<223>99-16033-244. polymorphic base or
A G
<220>
<221>allele
<222>279789
<223>99-15875-165. polymorphic base or
C T
<220>
<221>allele
<222>288007
<223>99-13521-31. polymorphic base or
A G
<220>
<221>allele
<222>292680
<223>8-112-241 polymorphic base T
. C or
<220>
<221>allele
<222>292766
<223>8-112-155 polymorphic base C
. A or
<220>
<221>allele
<222>292876
<223>8-112-45 polymorphic base T
. A or
<220>
<221>allele
<222>295491
<223>8-111-301 deletion of AGAT
.
<220>
<221>allele
<222>295716
<223>8-110-404 polymorphic base C
. G or
<220>
<221>allele
<222>296031
<223>8-110-89 polymorphic base G
. A or
<220>
<221>allele
<222>296068
<223>8-134-94 polymorphic base T
. C or
<220>
<221>allele
<222>298969
<223>99-7462-508. polymorphic base or
C T
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
24
<220>
<221>allele
<222>300365
<223>99-16052-214. polymorphic base A
or G
<220>
<221>allele
<222>312030
<223>99-16047-115. polymorphic base A
or G
<220>
<221>allele
<222>315928
<223>99-25993-280. polymorphic base G
or C
<220>
<221>allele
<222>316014
<223>99-25993-367. polymorphic base A
or G
<220>
<221>allele
<222>317245
<223>99-25101-151. polymorphic base A
or G
<220>
<221>primer
bind
<222>7938..7958
<223>99-27943.rp
<220>
<221>primer
bind
<222>8446..8465
<223>99-27943.pucomplement
<220>
<221>primer
bind
<222>14699.
14718
<223>8-121.pu
<220>
<221>primer
bind
<222>15100.
15118
<223>8-121.rp
complement
<220>
<221>primer
bind
<222>21365.
21385
<223>99-27935.rp
<220>
<221>primer
bind
<222>21845.
21864
<223>99-27935.pucomplement
<220>
<221>primer
bind
<222>25409..25426
<223>8-122.pu
<220>
<221>primer
bind
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 25825..25844
<223> 8-122.rp complement
<220>
<221> primer bind
<222> 29349. 29366
<223> 8-123.pu
<220>
<221> primer bind
<222> 29684..29701
<223> 8-123.rp complement
<220>
<221> primer bind
<222> 29900. 29919
<223> 8-147.pu
<220>
<221> primer bind
<222> 30340..30356
<223> 8-147.rp complement
<220>
<221> primer bind
<222> 49219..49239
<223> 99-34243.rp
<220>
<221> primer bind
<222> 49664. 49684
<223> 99-34243.pu complement
<220>
<221> primer bind
<222> 64639. 64657
<223> 8-127.pu
<220>
<221> primer bind
<222> 64981..64999
<223> 8-127.rp complement
<220>
<221> primer bind
<222> 65453..65471
<223> 8-128.pu
<220>
<221> primer bind
<222> 65547. 65566
<223> 8-129.pu
<220>
<221> primer bind
<222> 65856..65874
<223> 8-128.rp complement
<220>
<221> primer bind
<222> 65949. 65966
<223> 8-129.rp complement
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
26
<220>
<221> primer bind
<222> 75629..75649
<223> 99-34240.rp
<220>
<221> primer bind
<222> 76140..76158
<223> 99-34240.pu complement
<220>
<221> primer bind
<222> 94254..94273
<223> 99-31959.pu
<220>
<221> primer bind
<222> 94683. 94703
<223> 99-31959.rp complement
<220>
<221> primer bind
<222> 95034..95053
<223> 99-31960.pu
<220>
<221> primer bind
<222> 95543..95563
<223> 99-31960.rp complement
<220>
<221> primer bind
<222> 96707. 96727
<223> 99-31962.pu
<220>
<221> primer bind
<222> 97222. 97242
<223> 99-31962.rp complement
<220>
<221> primer bind
<222> 106357 .106377
<223> 99-44282.rp
<220>
<221> primer bind
<222> 106805 .106822
<223> 99-44282.pu complement
<220>
<221> primer bind
<222> 107022..107040
<223> 99-24656.pu
<220>
<221> primer bind
<222> 107132..107152
<223> 99-24636.rp
<220>
<221> primer bind
<222> 107495 .107513
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> 99-24656.rp complement
27
<220>
<221> primer bind
<222> 107613 .107630
<223> 99-24636.pu complement
<220>
<221> primer bind
<222> 108425 .108444
<223> 99-31939.pu
<220>
<221> primer bind
<222> 108916 .108935
<223> 99-31939.rp complement
<220>
<221> primer bind
<222> 109333 .109353
<223> 99-44281.rp
<220>
<221> primer bind
<222> 109848..109868
<223> 99-44281.pu complement
<220>
<221> primer bind
<222> 112149 .112169
<223> 99-31941.pu
<220>
<221> primer bind
<222> 112720 .112740
<223> 99-31941.rp complement
<220>
<221> primer bind
<222> 115144 .115162
<223> 99-31942.pu
<220>
<221> primer bind
<222> 115617 .115637
<223> 99-31942.rp complement
<220>
<221> primer bind
<222> 155353..155373
<223> 99-24635.rp
<220>
<221> primer bind
<222> 155805 .155822
<223> 99-24635.pu complement
<220>
<221> primer bind
<222> 157860 .157878
<223> 99-16059.pu
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<221> primer bind
<222> 158296 .158316
<223> 99-16059.rp complement
<220>
<221> primer bind
<222> 160279 .160298
<223> 99-24639.rp
<220>
<221> primer bind
<222> 160770 .160787
<223> 99-24634.pu
<220>
<221> primer bind
<222> 160785..160802
<223> 99-24639.pu complement
<220>
<221> primer bind
<222> 161240..161257
<223> 99-24634.rp complement
<220>
<221> primer bind
<222> 168813..168830
<223> 99-7652.pu
<220>
<221> primer bind
<222> 169331 .169351
<223> 99-7652.rp complement
<220>
<221> primer bind
<222> 170666..170686
<223> 99-16100.pu
<220>
<221> primer bind
<222> 171153 .171173
<223> 99-16100.rp complement
<220>
<221> primer bind
<222> 173065..173085
<223> 99-5862.rp
<220>
<221> primer bind
<222> 173495 .173514
<223> 99-5862.pu complement
<220>
<221> primer bind
<222> 173830..173850
<223> 99-16083.rp
<220>
<221> primer bind
<222> 174309 .174327
<223> 99-16083.pu complement
28
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
29
<220>
<221> primer bind
<222> 175453 .175470
<223> 99-16044.pu
<220>
<221> primer bind
<222> 175881 .175901
<223> 99-16044.rp complement
<220>
<221> primer bind
<222> 180464 .180481
<223> 99-16042.rp
<220>
<221> primer bind
<222> 180991 .181008
<223> 99-16042.pu complement
<220>
<221> primer bind
<222> 189753 .189771
<223> 99-5919.pu
<220>
<221> primer bind
<222> 190187 .190207
<223> 99-5919.rp complement
<220>
<221> primer bind
<222> 197116..197135
<223> 99-24658.rp
<220>
<221> primer bind
<222> 197555 .197572
<223> 99-24658.pu complement
<220>
<221> primer bind
<222> 198666 .198684
<223> 99-30364.pu
<220>
<221> primer bind
<222> 199148 .199168
<223> 99-30364.rp complement
<220>
<221> primer bind
<222> 200145 .200162
<223> 99-30366.pu
<220>
<221> primer bind
<222> 200663..200683
<223> 99-30366.rp complement
<220>
<221> primer bind
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 204263..204282
<223> 99-16094.rp
<220>
<221> primer bind
<222> 204643..204662
<223> 99-16094.pu complement
<220>
<221> primer bind
<222> 204741 .204758
<223> 99-24644.pu
<220>
<221> primer bind
<222> 205222 .205240
<223> 99-24644.rp complement
<220>
<221> primer bind
<222> 206103..206120
<223> 99-16107.pu
<220>
<221> primer bind
<222> 206548 .206568
<223> 99-16107.rp complement
<220>
<221> primer bind
<222> 211454 .211471
<223> 99-15873.rp
<220>
<221> primer bind
<222> 211893 .211910
<223> 99-15873.pu complement
<220>
<221> primer bind
<222> 214564..214581
<223> 8-124.pu
<220>
<221> primer bind
<222> 214965..214983
<223> 8-124.rp complement
<220>
<221> primer bind
<222> 215506..215525
<223> 8-125.pu
<220>
<221> primer bind
<222> 215628 .215647
<223> 8-132.rp
<220>
<221> primer bind
<222> 215799..215769
<223> 99-13929.rp
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<220>
<221> primer bind
<222> 215924 .215942
<223> 8-125.rp complement
<220>
<221> primer bind
<222> 215998 .216016
<223> 8-132.pu complement
<220>
<221> primer bind
<222> 216210 .216228
<223> 99-13929.pu complement
<220>
<221> primer bind
<222> 216473 .216491
<223> 8-131.rp
<220>
<221> primer bind
<222> 216683 .216702
<223> 8-130.rp
<220>
<221> primer bind
<222> 216883 .216900
<223> 8-131.pu complement
<220>
<221> primer bind ,
<222> 217091 .217109
<223> 8-130.pu complement
<220>
<221> primer bind
<222> 217119 .217136
<223> 8-209.rp
<220>
<221> primer bind
<222> 217521 .217539
<223> 8-209.pu complement
<220>
<221> primer bind
<222> 219408 .219425
<223> 99-5897.pu
<220>
<221> primer bind
<222> 219882 .219899
<223> 99-5897.rp complement
<220>
<221> primer bind
<222> 220505 .220522
<223> 99-24649.rp
<220>
<221> primer bind
<222> 221004 .221021
31
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> 99-24649.pu complement
32
<220>
<221> primer bind
<222> 221384 .221402
<223> 8-199.rp
<220>
<221> primer bind
<222> 221740 .221759
<223> 8-198.rp
<220>
<221> primer bind
<222> 221807 .221824
<223> 8-199.pu complement
<220>
<221> primer bind
<222> 222167 .222185
<223> 8-198.pu complement
<220>
<221> primer bind
<222> 222696 .222713
<223> 8-195.rp
<220>
<221> primer bind
<222> 223073 .223093
<223> 8-195.pu complement
<220>
<221> primer bind
<222> 223499..223518
<223> 99-13925.pu
<220>
<221> primer bind
<222> 224013 .224033
<223> 99-13925.rp complement
<220>
<221> primer bind
<222> 225103..225120
<223> 8-192.rp
<220>
<221> primer bind
<222> 225505 .225524
<223> 8-192.pu complement
<220>
<221> primer bind
<222> 225995 .226013
<223> 99-16090.pu
<220>
<221> primer bind
<222> 226211..226230
<223> 8-189.rp
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<221> primer bind
<222> 226510 .226530
<223> 99-16090.rp complement
<220>
<221> primer bind
<222> 226569 .226588
<223> 8-188.rp
<220>
<221> primer bind
<222> 226615 .226632
<223> 8-189.pu complement
<220>
<221> primer bind
<222> 226915 .226934
<223> 8-187.rp
<220>
<221> primer bind
<222> 226988..227005
<223> 8-188.pu complement
<220>
<221> primer bind
<222> 227319..227338
<223> 8-187.pu complement
<220>
<221> primer bind
<222> 227468 .227487
<223> 8-185.rp
<220>
<221> primer bind
<222> 227768 .227788
<223> 99-16051.rp
<220>
<221> primer bind
<222> 227832 .227849
<223> 8-184.rp
<220>
<221> primer bind
<222> 227888 .227907
<223> 8-185.pu complement
<220>
<221> primer bind
<222> 228209 .228227
<223> 8-183.rp
<220>
<221> primer bind
<222> 228214..228231
<223> 99-16051.pu complement
<220>
<221> primer bind
<222> 228234..228252
<223> 8-184.pu complement
33
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
34
<220>
<221> primer bind
<222> 228635 .228654
<223> 8-183.pu complement
<220>
<221> primer bind
<222> 228898 .228917
<223> 8-181.rp
<220>
<221> primer bind
<222> 229442 .229459
<223> 8-179.rp
<220>
<221> primer bind
<222> 229443 .229462
<223> 8-180.rp
<220>
<221> primer bind
<222> 229487 .229506
<223> 8-143.rp
<220>
<221> primer bind
<222> 229499..229517
<223> 8-181.pu complement
<220>
<221> primer bind
<222> 229624 .229642
<223> 8-180.pu complement
<220>
<221> primer bind
<222> 229739 .229756
<223> 8-178.rp
<220>
<221> primer bind
<222> 229857 .229874
<223> 8-179.pu complement
<220>
<221> primer bind
<222> 229896 .229913
<223> 8-143.pu complement
<220>
<221> primer bind
<222> 230097 .230115
<223> 8-177.rp
<220>
<221> primer bind
<222> 230141 .230159
<223> 8-178.pu complement
<220>
<221> primer bind
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 230210..230227
<223> 8-119.rp
<220>
<221> primer bind
<222> 230517 .230536
<223> 8-138.rp
<220>
<221> primer bind
<222> 230517 .230536
<223> 8-177.pu complement
<220>
<221> primer bind
<222> 230622 .230641
<223> 8-119.pu complement
<220>
<221> primer bind
<222> 230705 .230724
<223> 8-175.rp
<220>
<221> primer bind
<222> 230899 .230917
<223> 8-138.pu complement
<220>
<221> primer bind
<222> 231084 .231103
<223> 8-142.rp
<220>
<221> primer bind
<222> 231127 .231144
<223> 8-175.pu complement
<220>
<221> primer bind
<222> 231278..231298
<223> 99-15870.pu
<220>
<221> primer bind
<222> 231485 .231503
<223> 8-142.pu complement
<220>
<221> primer bind
<222> 231588 .231605
<223> 8-145.rp
<220>
<221> primer bind
<222> 231729 .231747
<223> 99-15870.rp complement
<220>
<221> primer bind
<222> 231990 .232007
<223> 8-145.pu complement
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
36
<220>
<221> primer bind
<222> 232147 .232166
<223> 8-171.rp
<220>
<221> primer bind
<222> 232405 .232423
<223> 8-170.rp
<220>
<221> primer bind
<222> 232547 .232566
<223> 8-171.pu complement
<220>
<221> primer bind
<222> 232744 .232762
<223> 8-169.rp
<220>
<221> primer bind
<222> 232830..232849
<223> 8-170.pu complement
<220>
<221> primer bind
<222> 233056..233074
<223> 8-168.rp
<220>
<221> primer bind
<222> 233145 .233163
<223> 8-169.pu complement
<220>
<221> primer bind
<222> 233314..233334
<223> 8-235.rp
<220>
<221> primer bind
<222> 233461 .233479
<223> 8-168.pu complement
<220>
<221> primer bind
<222> 233785..233801
<223> 8-235.pu complement
<220>
<221> primer bind
<222> 234039 .234058
<223> 8-137.rp
<220>
<221> primer bind
<222> 234440 .234458
<223> 8-137.pu complement
<220>
<221> primer bind
<222> 234516..234533
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
37
<223> 8-165.rp
<220>
<221> primer bind
<222> 234916 .234935
<223> 8-165.pu complement
<220>
<221> primer bind
<222> 235081 .235101
<223> 99-16087.rp
<220>
<221> primer bind
<222> 235515 .235533
<223> 99-16087.pu complement
<220>
<221> primer bind
<222> 237972 .237989
<223> 8-157.rp
<220>
<221> primer bind
<222> 238381..238399
<223> 8-157.pu complement
<220>
<221> primer bind
<222> 238607 .238626
<223> 8-155.rp
<220>
<221> primer bind
<222> 239029..239046
<223> 8-155.pu complement
<220>
<221> primer bind
<222> 239405 .239425
<223> 99-16038.rp
<220>
<221> primer bind
<222> 239606 .239624
<223> 8-136.rp
<220>
<221> primer bind
<222> 239651 .239670
<223> 8-153.rp
<220>
<221> primer bind
<222> 239862 .239880
<223> 99-16038.pu complement
<220>
<221> primer bind
<222> 240012 .240029
<223> 8-136.pu complement
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<221> primer bind
<222> 240058 .240075
<223> 8-153.pu complement
<220>
<221> primer bind
<222> 240356 .240375
<223> 8-135.rp
<220>
<221> primer bind
<222> 240518 .240538
<223> 99-16050.rp
<220>
<221> primer bind
<222> 240691 .240708
<223> 8-135.pu complement
<220>
<221> primer bind
<222> 240810 .240828
<223> 8-144.rp
<220>
<221> primer bind
<222> 240988 .241006
<223> 99-16050.pu complement
<220>
<221> primer bind
<222> 291094 .241113
<223> 8-141.rp
<220>
<221> primer bind
<222> 241217 .241235
<223> 8-144.pu complement
<220>
<221> primer bind
<222> 241373 .241392
<223> 8-140.rp
<220>
<221> primer bind
<222> 241502 .241520
<223> 8-141.pu complement
<220>
<221> primer bind
<222> 241700..241717
<223> 99-15880.pu
<220>
<221> primer bind
<222> 241773 .241792
<223> 8-140.pu complement
<220>
<221> primer bind
<222> 242151 .242171
<223> 99-15880.rp complement
38
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
39
<220>
<221> primer bind
<222> 242169..242188
<223> 8-240.rp
<220>
<221> primer bind
<222> 242571 .242588
<223> 8-240.pu complement
<220>
<221> primer bind
<222> 244172 .244191
<223> 8-225.rp
<220>
<221> primer bind
<222> 244574 .244593
<223> 8-225.pu complement
<220>
<221> primer bind
<222> 247513..247533
<223> 99-25940.rp
<220>
<221> primer bind
<222> 248023..248043
<223> 99-25940.pu complement
<220>
<221> primer bind
<222> 248204..248223
<223> 99-16032.rp
<220>
<221> primer bind
<222> 248588 .248606
<223> 99-16032.pu complement
<220>
<221> primer bind
<222> 253315 .253333
<223> 99-16055.rp
<220>
<221> primer bind
<222> 253816 .253834
<223> 99-16055.pu complement
<220>
<221> primer bind
<222> 255697..255715
<223> 99-16105.pu
<220>
<221> primer bind
<222> 256133 .256152
<223> 99-16105.rp complement
<220>
<221> primer bind
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 258138..258155
<223> 99-16101.pu
<220>
<221> primer bind
<222> 258606 .258623
<223> 99-16101.rp complement
<220>
<221> primer bind
<222> 259885..259902
<223> 99-16033.rp
<220>
<221> primer bind
<222> 260324 .260342
<223> 99-16033.pu complement
<220>
<221> primer bind
<222> 279626 .279644
<223> 99-15875.pu
<220>
<221> primer bind
<222> 280154..280173
<223> 99-15875.rp complement
<220>
<221> primer bind
<222> 287977 .287995
<223> 99-13521.pu
<220>
<221> primer bind
<222> 288484 .288504
<223> 99-13521.rp complement
<220>
<221> primer bind
<222> 292501 .292519
<223> 8-112.rp
<220>
<221> primer bind
<222> 292901 .292920
<223> 8-112.pu complement
<220>
<221> primer bind
<222> 295376 .295395
<223> 8-111.rp
<220>
<221> primer bind
<222> 295682 .295701
<223> 8-110.rp
<220>
<221> primer bind
<222> 295777 .295795
<223> 8-lll.pu complement
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<220>
<221> primer bind
<222> 295812 .295830
<223> 8-134.rp
<220>
<221> primer bind
<222> 296102 .296119
<223> 8-110.pu complement
<220>
<221> primer bind
<222> 296143 .296161
<223> 8-134.pu complement
<220>
<221> primer bind
<222> 298946 .298964
<223> 99-7462.rp
<220>
<221> primer bind
<222> 299459 .299476
<223> 99-7462.pu complement
<220>
<221> primer bind
<222> 300153 .300170
<223> 99-16052.pu
<220>
<221> primer bind
<222> 300660 .300680
<223> 99-16052.rp complement
<220>
<221> primer bind
<222> 311615 .311632
<223> 99-16047.rp
<220>
<221> primer bind
<222> 312126..312144
<223> 99-16047.pu complement
<220>
<221> primer bind
<222> 315649 .315668
<223> 99-25993.pu
<220>
<221> primer bind
<222> 316129 .316147
<223> 99-25993.rp complement
<220>
<221> primer bind
<222> 316925 .316943
<223> 99-25101.rp
<220>
<221> primer bind
<222> 317378 .317395
41
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> 99-25101.pu complement
42
<220>
<221> primer bind
<222> 8297..8315
<223> 99-27943-150.mis
<220>
<221> primer bind
<222> 8317..8335
<223> 99-27943-150.mis complement
<220>
<221> primer bind
<222> 14707. 14725
<223> 8-121-28.mis
<220>
<221> primer bind
<222> 14715. 14733
<223> 8-121-36.mis
<220>
<221> primer bind
<222> 14727. 14745
<223> 8-121-28.mis complement
<220>
<221> primer bind
<222> 14735. 14753
<223> 8-121-36.mis complement
<220>
<221> primer bind
<222> 14833. 14851
<223> 8-121-154.mis
<220>
<221> primer bind
<222> 14853..14871
<223> 8-121-154.mis complement
<220>
<221> primer bind
<222> 14866. 14884
<223> 8-121-187.mis
<220>
<221> primer bind
<222> 14886..14904
<223> 8-121-187.mis complement
<220>
<221> primer bind
<222> 14922..14940
<223> 8-121-243.mis
<220>
<221> primer bind
<222> 14942. 14960
<223> 8-121-243.mis complement
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
43
<221> primer bind
<222> 14960. 14978
<223> 8-121-281.mis
<220>
<221> primer bind
<222> 14980. 14998
<223> 8-121-281.mis complement
<220>
<221> primer bind
<222> 15031. 15049
<223> 8-121-352.mis
<220>
<221> primer bind
<222> 15043. 15061
<223> 8-121-364.mis
<220>
<221> primer bind
<222> 15050. 15068
<223> 8-121-371.mis
<220>
<221> primer bind
<222> 15051. 15069
<223> 8-121-352.mis complement
<220>
<221> primer bind
<222> 15063. 15081
<223> 8-121-364.mis complement
<220>
<221> primer bind
<222> 15070. 15088
<223> 8-121-371.mis complement
<220>
<221> primer bind
<222> 21653. 21671
<223> 99-27935-193.mis
<220>
<221> primer bind
<222> 21673. 21691
<223> 99-27935-193.mis complement
<220>
<221> primer bind
<222> 25461..25479
<223> 8-122-72.mis
<220>
<221> primer bind
<222> 25481..25499
<223> 8-122-72.mis complement
<220>
<221> primer bind
<222> 25489..25507
<223> 8-122-100.mis
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
44
<220>
<221> primer bind
<222> 25509..25527
<223> 8-122-100.mis complement
<220>
<221> primer bind
<222> 25661. 25679
<223> 8-122-272.mis
<220>
<221> primer bind
<222> 25681. 25699
<223> 8-122-272.mis complement
<220>
<221> primer bind
<222> 25715..25733
<223> 8-122-326.mis
<220>
<221> primer bind
<222> 25735. 25753
<223> 8-122-326.mis complement
<220>
<221> primer bind
<222> 25749..25767
<223> 8-122-360.mis
<220>
<221> primer bind
<222> 25769..25787
<223> 8-122-360.mis complement
<220>
<221> primer bind
<222> 29384..29402
<223> 8-123-55.mis
<220>
<221> primer bind
<222> 29404. 29422
<223> 8-123-55.mis complement
<220>
<221> primer bind
<222> 29518..29536
<223> 8-123-189.mis
<220>
<221> primer bind
<222> 29526..29544
<223> 8-123-197.mis
<220>
<221> primer bind
<222> 29538..29556
<223> 8-123-189.mis complement
<220>
<221> primer bind
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 29546..29564
<223> 8-123-197.mis complement
<220>
<221> primer bind
<222> 29636. 29654
<223> 8-123-307.mis
<220>
<221> primer bind
<222> 29656. 29674
<223> 8-123-307.mis complement
<220>
<221> primer bind
<222> 30150. 30168
<223> 8-147-270.mis
<220>
<221> primer bind
<222> 30170. 30188
<223> 8-147-270.mis complement
<220>
<221> primer bind
<222> 49456. 49474
<223> 99-34243-210.mis
<220>
<221> primer bind
<222> 49976. 49494
<223> 99-34243-210.mis complement
<220>
<221> primer bind
<222> 64647. 64665
<223> 8-127-28.mis
<220>
<221> primer bind
<222> 64667..64685
<223> 8-127-28.mis complement
<220>
<221> primer bind
<222> 69738. 64756
<223> 8-127-119.mis
<220>
<221> primer bind
<222> 64758. 64776
<223> 8-127-119.mis complement
<220>
<221> primer bind
<222> 64778..64796
<223> 8-127-159.mis
<220>
<221> primer bind
<222> 64798. 64816
<223> 8-127-159.mis complement
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
46
<220>
<221> primer bind
<222> 64855. 64873
<223> 8-127-236.mis
<220>
<221> primer bind
<222> 64859. 64877
<223> 8-127-240.mis
<220>
<221> primer bind
<222> 64875..64893
<223> 8-127-236.mis complement
<220>
<221> primer bind
<222> 64879..64897
<223> 8-127-240.mis complement
<220>
<221> primer bind
<222> 64899..64917
<223> 8-127-280.mis
<220>
<221> primer bind
<222> 64919. 64937
<223> 8-127-280.mis complement
<220>
<221> primer bind
<222> 65466. 65484
<223> 8-128-33.mis
<220>
<221> primer bind
<222> 65485..65503
<223> 8-128-52.mis
<220>
<221> primer bind
<222> 65486..65504
<223> 8-128-33.mis complement
<220>
<221> primer bind
<222> 65494. 65512
<223> 8-128-6l.mis
<220>
<221> primer bind
<222> 65501. 65519
<223> 8-128-68.mis
<220>
<221> primer bind
<222> 65502. 65520
<223> 8-128-69.mis
<220>
<221> primer bind
<222> 65505..65523
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
47
<223> 8-128-52.mis complement
<220>
<221> primer bind
<222> 65514. 65532
<223> 8-128-6l.mis complement
<220>
<221> primer bind
<222> 65518. 65536
<223> 8-128-85.mis
<220>
<221>primer bind
<222>65521. 65539
<223>8-128-68.miscomplement
<220>
<221>primer bind
<222>65522. 65540
<223>8-128-69.miscomplement
<220>
<221>primer bind
<222>65538. 65556
<223>8-128-85.miscomplement
<220>
<221>primer bind
<222>65577. 65595
<223>8-129-50.mis
<220>
<221> primer bind
<222> 65597..65615
<223> 8-129-50.mis complement
<220>
<221> primer bind
<222> 65838..65856
<223> 8-129-311.mis
<220>
<221> primer bind
<222> 65858. 65876
<223> 8-129-311.mis complement
<220>
<221> primer bind
<222> 65928..65946
<223> 8-129-401.mis
<220>
<221> primer bind
<222> 65948. 65966
<223> 8-129-401.mis complement
<220>
<221> primer bind
<222> 75648. 75666
<223> 99-34240-492.mis
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<221> primer bind
<222> 75668..75686
<223> 99-34240-492.mis complement
48
<220>
<221> primer bind
<222> 94515. 94533
<223> 99-31959-281.mis
<220>
<221> primer bind
<222> 94535..94553
<223> 99-31959-281.mis complement
<220>
<221> primer bind
<222> 95377. 95395
<223> 99-31960-363.mis
<220>
<221> primer bind
<222> 95397. 95415
<223> 99-31960-363.mis complement
<220>
<221> primer bind
<222> 96937. 96955
<223> 99-31962-250.mis
<220>
<221> primer bind
<222> 96957. 96975
<223> 99-31962-250.mis complement
<220>
<221> primer bind
<222> 97137..97155
<223> 99-31962-450.mis
<220>
<221> primer bind
<222> 97157. 97175
<223> 99-31962-450.mis complement
<220>
<221> primer bind
<222> 106365..106383
<223> 99-44282-439.mis
<220>
<221> primer bind
<222> 106385..106403
<223> 99-44282-439.mis complement
<220>
<221> primer bind
<222> 106750 .106768
<223> 99-44282-54.mis
<220>
<221> primer bind
<222> 106770..106788
<223> 99-44282-54.mis complement
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
49
<220>
<221> primer bind
<222> 107139 .107157
<223> 99-24656-137.mis
<220>
<221> primer bind
<222> 107159 .107177
<223> 99-24656-137.mis complement
<220>
<221> primer bind
<222> 107262 .107280
<223> 99-24656-260.mis
<220>
<221> primer bind
<222> 107282 .107300
<223> 99-24656-260.mis complement
<220>
<221> primer bind
<222> 107590..107608
<223> 99-24636-22.mis
<220>
<221> primer bind
<222> 107610 .107628
<223> 99-24636-22.mis complement
<220>
<221> primer bind
<222> 108480..108498
<223> 99-31939-75.mis
<220>
<221> primer_bind
<222> 108500 .108518
<223> 99-31939-75.mis complement
<220>
<221> primer bind
<222> 108678..108696
<223> 99-31939-273.mis
<220>
<221> primer bind
<222> 108698..108716
<223> 99-31939-273.mis complement
<220>
<221> primer bind
<222> 109932..109450
<223> 99-44281-418.mis
<220>
<221> primer bind
<222> 109452 .109470
<223> 99-44281-418.mis complement
<220>
<221> primer bind
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 109593..109611
<223> 99-44281-257.mis
<220>
<221> primer bind
<222> 109613..109631
<223> 99-44281-257.mis complement
<220>
<221> primer bind
<222> 109773 .109791
<223> 99-44281-77.mis
<220>
<221> primer bind
<222> 109793..109811
<223> 99-44281-77.mis complement
<220>
<221> primer bind
<222> 112449 .112467
<223> 99-31941-320.mis
<220>
<221> primer bind
<222> 112469 .112487
<223> 99-31941-320.mis complement
<220>
<221> primer bind
<222> 115449..115467
<223> 99-31942-325.mis
<220>
<221> primer bind
<222> 115469..115487
<223> 99-31942-325.mis complement
<220>
<221> primer bind
<222> 155717 .155735
<223> 99-24635-79.mis
<220>
<221> primer bind
<222> 155737..155755
<223> 99-24635-79.mis complement
<220>
<221> primer bind
<222> 158153 .158171
<223> 99-16059-313.mis
<220>
<221> primer bind
<222> 158173 .158191
<223> 99-16059-313.mis complement
<220>
<221> primer bind
<222> 160615 .160633
<223> 99-24639-169.mis
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<220>
<221> primer bind
<222> 160621 .160639
<223> 99-24639-163.mis
S1
<220>
<221> primer bind
<222> 160635..160653
<223> 99-24639-169.mis complement
<220>
<221> primer bind
<222> 160641 .160659
<223> 99-24639-163.mis complement
<220>
<221> primer bind
<222> 160857..160875
<223> 99-24634-108.mis
<220>
<221> primer bind
<222> 160877..160895
<223> 99-24634-108.mis complement
<220>
<221> primer bind
<222> 168955 .168973
<223> 99-7652-162.mis
<220>
<221> primer bind
<222> 168975..168993
<223> 99-7652-162.mis complement
' <220>
<221> primer bind
<222> 169281..169299
<223> 99-7652-488.mis
<220>
<221> primer bind
<222> 169301..169319
<223> 99-7652-488.mis complement
<220>
<221> primer bind
<222> 170727..170745
<223> 99-16100-83.mis
<220>
<221> primer bind
<222> 170747 .170765
<223> 99-16100-83.mis complement
<220>
<221> primer bind
<222> 170791..170809
<223> 99-16100-147.mis
<220>
<221> primer bind
<222> 170811..170829
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> 99-16100-147.mis complement
52
<220>
<221> primer bind
<222> 170839 .170857
<223> 99-16100-195.mis
<220>
<221> primer bind
<222> 170841 .170859
<223> 99-16100-197.mis
<220>
<221> primer bind
<222> 170859 .170877
<223> 99-16100-195.mis complement
<220>
<221> primer bind
<222> 170861 .170879
<223> 99-16100-197.mis complement
<220>
<221> primer bind
<222> 170887 .170905
<223> 99-16100-244.mis
<220>
<221> primer bind
<222> 170907 .170925
<223> 99-16100-244.mis complement
<220>
<221> primer bind
<222> 171024 .171042
<223> 99-16100-381.mis
<220>
<221> primer bind
<222> 171044..171062
<223> 99-16100-381.mis complement
<220>
<221> primer bind
<222> 173339 .173357
<223> 99-5862-167.mis
<220>
<221> primer bind
<222> 173359 .173377
<223> 99-5862-167.mis complement
<220>
<221> primer bind
<222> 174208 .174226
<223> 99-16083-lOl.mis
<220>
<221> primer bind
<222> 174228..174246
<223> 99-16083-lOl.mis complement
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<221> primer bind
<222> 175781 .175799
<223> 99-16044-351.mis
53
<220>
<221> primer bind
<222> 175801 .175819
<223> 99-16044-351.mis complement
<220>
<221> primer bind
<222> 180570 .180588
<223> 99-16042-420.mis
<220>
<221> primer bind
<222> 180590 .180608
<223> 99-16042-420.mis complement
<220>
<221> primer bind
<222> 180959 .180977
<223> 99-16042-3l.mis
<220>
<221> primer bind
<222> 180979 .180997
<223> 99-16042-3l.mis complement
<220>
<221> primer bind
<222> 189938..189956
<223> 99-5919-215.mis
<220>
<221> primer bind
<222> 189958 .189976
<223> 99-5919-215.mis complement
<220>
<221> primer bind
<222> 197144 .197162
<223> 99-24658-410.mis
<220>
<221> primer bind
<222> 197164 .197182
<223> 99-24658-410.mis complement
<220>
<221> primer bind
<222> 198945 .198963
<223> 99-30364-299.mis
<220>
<221> primer bind
<222> 198965..198983
<223> 99-30364-299.mis complement
<220>
<221> primer bind
<222> 200237 .200255
<223> 99-30366-112.mis
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
54
<220>
<221> primer bind
<222> 200257 .200275
<223> 99-30366-112.mis complement
<220>
<221> primer bind
<222> 204569 .204587
<223> 99-16094-75.mis
<220>
<221> primer bind
<222> 204589..204607
<223> 99-16094-75.mis complement
<220>
<221> primer bind
<222> 204915 .204933
<223> 99-24644-194.mis
<220>
<221> primer bind
<222> 204935 .204953
<223> 99-24649-194.mis complement
<220>
<221> primer bind
<222> 206178..206196
<223> 99-16107-95.mis
<220>
<221> primer bind
<222> 206198 .206216
<223> 99-16107-95.mis complement
<220>
<221> primer bind
<222> 206244 .206262
<223> 99-16107-161.mis
<220>
<221> primer bind
<222> 206264 .206282
<223> 99-16107-161.mis complement
<220>
<221> primer bind
<222> 206466 .206484
<223> 99-16107-383.mis
<220>
<221> primer bind
<222> 206486 .206504
<223> 99-16107-383.mis complement
<220>
<221> primer bind
<222> 211589..211607
<223> 99-15873-303.mis
<220>
<221> primer bind
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 211609..211627
<223> 99-15873-303.mis complement
<220>
<221> primer bind
<222> 214650 .214668
<223> 8-124-106.mis
<220>
<221> primer bind
<222> 214670 .214688
<223> 8-124-106.mis complement
<220>
<221> primer bind
<222> 214764 .214782
<223> 8-124-220.mis
<220>
<221> primer bind
<222> 214784 .214802
<223> 8-124-220.mis complement
<220>
<221> primer bind
<222> 214838 .214856
<223> 8-124-294.mis
<220>
<221> primer bind
<222> 214858 .214876
<223> 8-124-294.mis complement
<220>
<221> primer bind
<222> 214860 .214878
<223> 8-124-316.mis
<220>
<221> primer bind
<222> 214880 .219898
<223> 8-124-316.mis complement
<220>
<221> primer bind
<222> 214927 .214945
<223> 8-124-383.mis
<220>
<221> primer bind
<222> 214947..214965
<223> 8-124-383.mis complement
<220>
<221> primer bind
<222> 215519..215537
<223> 8-125-33.mis
<220>
<221> primer bind
<222> 215539 .215557
<223> 8-125-33.mis complement
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<220>
<221> primer bind
<222> 215686..215704
<223> 8-132-312.mis
<220>
<221> primer bind
<222> 215706 .215724
<223> 8-132-312.mis complement
<220>
<221> primer bind
<222> 215819 .215837
<223> 8-132-179.mis
<220>
<221> primer bind
<222> 215834 .215852
<223> 8-132-164.mis
<220>
<221> primer bind
<222> 215839 .215857
<223> 8-132-179.mis complement
<220>
<221> primer bind
<222> 215854 .215872
<223> 8-132-164.mis complement
<220>
<221> primer bind
<222> 215901..215919
<223> 8-132-97.mis
<220>
<221> primer bind
<222> 215921..215939
<223> 8-132-97.mis complement
<220>
<221> primer bind
<222> 216009..216027
<223> 99-13929-201.mis
<220>
<221> primer bind
<222> 216029..216047
<223> 99-13929-201.mis complement
<220>
<221> primer bind
<222> 216519 .216537
<223> 8-131-363.mis
<220>
<221> primer bind
<222> 216539 .216557
<223> 8-131-363.mis complement
<220>
<221> primer bind
<222> 216683 .216701
56
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> 8-131-199.mis
57
<220>
<221> primer bind
<222> 216703..216721
<223> 8-131-199.mis complement
<220>
<221> primer bind
<222> 216855 .216873
<223> 8-130-236.mis
<220>
<221> primer bind
<222> 216871 .216889
<223> 8-130-220.mis
<220>
<221> primer bind
<222> 216875 .216893
<223> 8-130-236.mis complement
<220>
<221> primer bind
<222> 216891 .216909
<223> 8-130-220.mis complement
<220>
<221> primer bind
<222> 216947 .216965
<223> 8-130-144.mis
<220>
<221> primer bind
<222> 216948..216966
<223> 8-130-143.mis
<220>
<221> primer bind
<222> 216967..216985
<223> 8-130-144.mis complement
<220>
<221> primer bind
<222> 216968 .216986
<223> 8-130-143.mis complement
<220>
<221> primer bind
<222> 216989 .217007
<223> 8-130-102.mis
<220>
<221> primer bind
<222> 216990 .217008
<223> 8-130-lOl.mis
<220>
<221> primer bind
<222> 217008 .217026
<223> 8-130-83.mis
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
58
<221> primer bind
<222> 217009..217027
<223> 8-130-102.mis complement
<220>
<221> primer bind
<222> 217010 .217028
<223> 8-130-lOl.mis complement
<220>
<221> primer bind
<222> 217028..217046
<223> 8-130-83.mis complement
<220>
<221> primer bind
<222> 217188 .217206
<223> 8-209-333.mis
<220>
<221> primer bind
<222> 217208 .217226
<223> 8-209-333.mis complement
<220>
<221> primer bind
<222> 217231 .217249
<223> 8-209-290.mis
<220>
<221> primer bind
<222> 217251..217269
<223> 8-209-290.mis complement
<220>
<221> primer bind
<222> 219521 .219539
<223> 99-5897-143.mis
<220>
<221> primer bind
<222> 219541 .219559
<223> 99-5897-193.mis complement
<220>
<221> primer bind
<222> 220817 .220835
<223> 99-24649-186.mis
<220>
<221> primer bind
<222> 220837 .220855
<223> 99-24649-186.mis complement
<220>
<221> primer bind
<222> 220923 .220941
<223> 99-24649-80.mis
<220>
<221> primer bind
<222> 220943..220961
<223> 99-24649-80.mis complement
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
59
<220>
<221> primer bind
<222> 221722..221790
<223> 8-199-84.mis
<220>
<221> primer bind
<222> 221742 .221760
<223> 8-199-84.mis complement
<220>
<221> primer bind
<222> 222029 .222047
<223> 8-198-138.mis
<220>
<221> primer bind
<222> 222049 .222067
<223> 8-198-138.mis complement
<220>
<221> primer bind
<222> 222727 .222745
<223> 8-195-348.mis
<220>
<221> primer bind
<222> 222747..222765
<223> 8-195-348.mis complement
<220>
<221> primer bind
<222> 223576..223594
<223> 99-13925-97.mis
<220>
<221> primer bind
<222> 223596 .223614
<223> 99-13925-97.mis complement
<220>
<221> primer bind
<222> 225424 .225442
<223> 8-192-82.mis
<220>
<221> primer bind
<222> 225444..225462
<223> 8-192-82.mis complement
<220>
<221> primer bind
<222> 226200 .226218
<223> 99-16090-225.mis
<220>
<221> primer bind
<222> 226220 .226238
<223> 99-16090-225.mis complement
<220>
<221> primer bind
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 226468..226486
<223> 8-189-146.mis
<220>
<221> primer bind
<222> 226488 .226506
<223> 8-189-146.mis complement
<220>
<221> primer bind
<222> 226851..226869
<223> 8-188-136.mis
<220>
<221> primer bind
<222> 226871 .226889
<223> 8-188-136.mis complement
<220>
<221> primer bind
<222> 226968..226986
<223> 8-187-352.mis
<220>
<221> primer bind
<222> 226988..227006
<223> 8-187-352.mis complement
<220>
<221> primer bind
<222> 227570..227588
<223> 8-185-319.mis
<220>
<221> primer bind
<222> 227590 .227608
<223> 8-185-319.mis complement
<220>
<221> primer bind
<222> 227593 .227611
<223> 8-185-296.mis
<220>
<221> primer bind
<222> 227613 .227631
<223> 8-185-296.mis complement
<220>
<221> primer bind
<222> 227987..228005
<223> 99-16051-226.mis
<220>
<221> primer bind
<222> 228007 .228025
<223> 99-16051-226.mis complement
<220>
<221> primer bind
<222> 228049 .228067
<223> 99-16051-164.mis
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
61
<220>
<221> primer bind
<222> 228069 .228087
<223> 99-16051-164.mis complement
<220>
<221> primer bind
<222> 228115..228133
<223> 8-184-119.mis
<220>
<221> primer bind
<222> 228135 .228153
<223> 8-184-119.mis complement
<220>
<221> primer bind
<222> 228207 .228225
<223> 8-184-27.mis
<220>
<221> primer bind
<222> 228227 .228245
<223> 8-184-27.mis complement
<220>
<221> primer bind
<222> 228235 .228253
<223> 8-183-401.mis
<220>
<221> primer bind
<222> 228255..228273
<223> 8-183-401.mis complement
<220>
<221> primer bind
<222> 229050 .229068
<223> 8-181-449.mis
<220>
<221> primer bind
<222> 229070..229088
<223> 8-181-449.mis complement
<220>
<221> primer bind
<222> 229149..229167
<223> 8-181-350.mis
<220>
<221> primer bind
<222> 229169..229187
<223> 8-181-350.mis complement
<220>
<221> primer bind
<222> 229240 .229258
<223> 8-181-259.mis
<220>
<221> primer bind
<222> 229260 .229278
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> 8-181-259.mis complement
62
<220>
<221> primer bind
<222> 229269..229287
<223> 8-181-230.mis
<220>
<221> primer bind
<222> 229289..229307
<223> 8-181-210.mis
<220>
<221> primer bind
<222> 229289..229307
<223> 8-181-230.mis complement
<220>
<221> primer bind
<222> 229309..229327
<223> 8-181-210.mis complement
<220>
<221> primer bind
<222> 229334..229352
<223> 8-181-165.mis
<220>
<221> primer bind
<222> 229336..229354
<223> 8-181-163.mis
<220>
<221> primer bind
<222> 229354 .229372
<223> 8-181-165.mis complement
<220>
<221> primer bind
<222> 229356 .229374
<223> 8-181-163.mis complement
<220>
<221> primer bind
<222> 229416..229434
<223> 8-181-83.mis
<220>
<221> primer bind
<222> 229436..229454
<223> 8-181-83.mis complement
<220>
<221> primer bind
<222> 229467 .229485
<223> 8-180-157.mis
<220>
<221> primer bind
<222> 229487 .229505
<223> 8-180-157.mis complement
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<221> primer bind
<222> 229563 .229581
<223> 8-143-332.mis
<220>
<221> primer bind
<222> 229568 .229586
<223> 8-143-327.mis
<220>
<221> primer bind
<222> 229583..229601
<223> 8-143-332.mis complement
<220>
<221> primer bind
<222> 229584 .229602
<223> 8-143-311.mis
<220>
<221> primer bind
<222> 229587..229605
<223> 8-143-308.mis
<220>
<221> primer bind
<222> 229588..229606
<223> 8-143-327.mis complement
<220>
<221> primer bind
<222> 229588 .229606
<223> 8-179-268.mis
63
<220>
<221> primer bind
<222> 229589..229607
<223> 8-143-306.mis
<220>
<221> primer bind
<222> 229604 .229622
<223> 8-143-311.mis complement
<220>
<221> primer bind
<222> 229607 .229625
<223> 8-143-308.mis complement
<220>
<221> primer bind
<222> 229608..229626
<223> 8-179-268.mis complement
<220>
<221> primer bind
<222> 229609 .229627
<223> 8-143-306.mis complement
<220>
<221> primer bind
<222> 229650..229668
<223> 8-143-245.mis
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
64
<220>
<221> primer bind
<222> 229653..229671
<223> 8-143-242.mis
<220>
<221> primer bind
<222> 229656..229674
<223> 8-143-239.mis
<220>
<221> primer bind
<222> 229663..229681
<223> 8-143-232.mis
<220>
<221> primer bind
<222> 229670 .229688
<223> 8-143-245.mis complement
<220>
<221> primer bind
<222> 229673 .229691
<223> 8-143-242.mis complement
<220>
<221> primer bind
<222> 229676..229694
<223> 8-143-239.mis complement
<220>
<221> primer bind
<222> 229683 .229701
<223> 8-143-232.mis complement
<220>
<221> primer bind
<222> 229743 .229761
<223> 8-143-152.mis
<220>
<221> primer bind
<222> 229763 .229781
<223> 8-143-152.mis complement
<220>
<221> primer bind
<222> 229942 .229960
<223> 8-178-199.mis
<220>
<221> primer bind
<222> 229962 .229980
<223> 8-178-199.mis complement
<220>
<221> primer bind
<222> 230219 .230237
<223> 8-119-404.mis
<220>
<221> primer bind
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 230237..230255
<223> 8-177-281.mis
<220>
<221> primer bind
<222> 230239 .230257
<223> 8-119-404.mis complement
<220>
<221> primer bind
<222> 230246 .230264
<223> 8-119-377.mis
<220>
<221> primer bind
<222> 230257 .230275
<223> 8-177-281.mis complement
<220>
<221> primer bind
<222> 230266 .230284
<223> 8-119-377.mis complement
<220>
<221> primer bind
<222> 230314..230332
<223> 8-119-309.mis
<220>
<221> primer bind
<222> 230329..230347
<223> 8-119-294.mis
<220>
<221> primer bind
<222> 230334 .230352
<223> 8-119-309.mis complement
<220>
<221> primer bind
<222> 230339..230357
<223> 8-119-284.mis
<220>
<221> primer bind
<222> 230349..230367
<223> 8-119-294.mis complement
<220>
<221> primer bind
<222> 230351 .230369
<223> 8-119-272.mis
<220>
<221> primer bind
<222> 230359 .230377
<223> 8-119-284.mis complement
<220>
<221> primer bind
<222> 230361 .230379
<223> 8-119-262.mis
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
66
<220>
<221> primer bind
<222> 230371 .230389
<223> 8-119-272.mis complement
<220>
<221> primer bind
<222> 230375 .230393
<223> 8-119-248.mis
<220>
<221> primer bind
<222> 230376 .230394
<223> 8-119-247.mis
<220>
<221> primer bind
<222> 230381 .230399
<223> 8-119-262.mis complement
<220>
<221> primer bind
<222> 230395 .230413
<223> 8-119-248.mis complement
<220>
<221> primer bind
<222> 230396 .230414
<223> 8-119-247.mis complement
<220>
<221> primer bind
<222> 230413 .230431
<223> 8-119-210.mis
<220>
<221> primer bind
<222> 230419 .230437
<223> 8-119-204.mis
<220>
<221> primer bind
<222> 230423 .230441
<223> 8-119-200.mis
<220>
<221> primer bind
<222> 230428 .230446
<223> 8-119-195.mis
<220>
<221> primer_bind
<222> 230433 .230451
<223> 8-119-210.mis complement
<220>
<221> primer bind
<222> 230439 .230457
<223> 8-119-204.mis complement
<220>
<221> primer bind
<222> 230443 .230461
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> 8-119-200.mis complement
67
<220>
<221> primer bind
<222> 230448 .230466
<223> 8-119-195.mis complement
<220>
<221> primer bind
<222> 230498 .230516
<223> 8-119-125.mis
<220>
<221> primer bind
<222> 230503..230521
<223> 8-119-120.mis
<220>
<221> primer bind
<222> 230518 .230536
<223> 8-119-125.mis complement
<220>
<221> primer bind
<222> 230523..230541
<223> 8-119-120.mis complement
<220>
<221> primer bind
<222> 230526 .230544
<223> 8-119-97.mis
<220>
<221> primer bind
<222> 230530 .230548
<223> 8-119-93.mis
<220>
<221> primer bind
<222> 230546..230564
<223> 8-119-97.mis complement
<220>
<221> primer bind
<222> 230550 .230568
<223> 8-119-93.mis complement
<220>
<221> primer bind
<222> 230585..230603
<223> 8-119-38.mis
<220>
<221> primer bind
<222> 230605 .230623
<223> 8-119-38.mis complement
<220>
<221> primer bind
<222> 230665..230683
<223> 8-138-234.mis
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
68
<221> primer bind
<222> 230681 .230699
<223> 8-138-218.mis
<220>
<221> primer bind
<222> 230685 .230703
<223> 8-138-234.mis complement
<220>
<221> primer bind
<222> 230701 .230719
<223> 8-138-218.mis complement
<220>
<221> primer bind
<222> 230736 .230754
<223> 8-138-163.mis
<220>
<221> primer bind
<222> 230756 .230774
<223> 8-138-163.mis complement
<220>
<221> primer bind
<222> 231051 .231069
<223> 8-175-75.mis
<220>
<221> primer bind
<222> 231071 .231089
<223> 8-175-75.mis complement
<220>
<221> primer bind
<222> 231099 .231117
<223> 8-142-386.mis
<220>
<221> primer bind
<222> 231115..231133
<223> 8-142-370.mis
<220>
<221> primer bind
<222> 231119..231137
<223> 8-142-386.mis complement
<220>
<221> primer bind
<222> 231135 .231153
<223> 8-142-370.mis complement
<220>
<221> primer bind
<222> 231353 .231371
<223> 8-142-132.mis
<220>
<221> primer bind
<222> 231373 .231391
<223> 8-142-132.mis complement
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
69
<220>
<221> primer bind
<222> 231650 .231668
<223> 8-145-339.mis
<220>
<221> primer bind
<222> 231658 .231676
<223> 99-15870-400.mis
<220>
<221> primer bind
<222> 231670 .231688
<223> 8-145-339.mis complement
<220>
<221> primer bind
<222> 231678..231696
<223> 99-15870-400.mis complement
<220>
<221> primer bind
<222> 231758 .231776
<223> 8-145-231.mis
<220>
<221> primer bind
<222> 231778 .231796
<223> 8-145-231.mis complement
<220>
<221> primer bind
<222> 231792 .231810
<223> 8-145-197.mis
<220>
<221> primer bind
<222> 231812 .231830
<223> 8-145-197.mis complement
<220>
<221> primer bind
<222> 231835 .231853
<223> 8-145-154.mis
<220>
<221> primer bind
<222> 231851 .231869
<223> 8-145-138.mis
<220>
<221> primer bind
<222> 231855 .231873
<223> 8-145-154.mis complement
<220>
<221> primer bind
<222> 231871 .231889
<223> 8-145-138.mis complement
<220>
<221> primer bind
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 231911..231929
<223> 8-145-78.mis
<220>
<221> primer bind
<222> 231931 .231949
<223> 8-145-78.mis complement
<220>
<221> primer bind
<222> 232301 .232319
<223> 8-171-247.mis
<220>
<221> primer bind
<222> 232321 .232339
<223> 8-171-247.mis complement
<220>
<221> primer bind
<222> 232458 .232476
<223> 8-170-373.mis
<220>
<221> primer bind
<222> 232478 .232496
<223> 8-170-373.mis complement
<220>
<221> primer bind
<222> 232879 .232897
<223> 8-169-266.mis
<220>
<221> primer bind
<222> 232899..232917
<223> 8-169-266.mis complement
<220>
<221> primer bind
<222> 232979 .232997
<223> 8-169-166.mis
<220>
<221> primer bind
<222> 232999 .233017
<223> 8-169-166.mis complement
<220>
<221> primer bind
<222> 233081 .233099
<223> 8-168-380.mis
<220>
<221> primer bind
<222> 233101 .233119
<223> 8-168-380.mis complement
<220>
<221> primer bind
<222> 233434 .233452
<223> 8-235-349.mis
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<220>
<221> primer bind
<222> 233454 .233472
<223> 8-235-349.mis complement
71
<220>
<221> primer bind
<222> 233601..233619
<223> 8-235-182.mis
<220>
<221> primer bind
<222> 233621 .233639
<223> 8-235-182.mis complement
<220>
<221> primer bind
<222> 234101..234119
<223> 8-137-340.mis
<220>
<221> primer bind
<222> 234121..234139
<223> 8-137-340.mis complement
<220>
<221> primer bind
<222> 234258..234276
<223> 8-137-182.mis
<220>
<221> primer bind
<222> 234278 .234296
<223> 8-137-182.mis complement
<220>
<221> primer bind
<222> 234288..234306
<223> 8-137-152.mis
<220>
<221> primer bind
<222> 234308 .234326
<223> 8-137-152.mis complement
<220>
<221> primer bind
<222> 234732 .234750
<223> 8-165-185.mis
<220>
<221> primer bind
<222> 234752 .234770
<223> 8-165-185.mis complement
<220>
<221> primer bind
<222> 235296..235314
<223> 99-16087-219.mis
<220>
<221> primer bind
<222> 235316..235334
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
72
<223> 99-16087-219.mis complement
<220>
<221> primer bind
<222> 238204 .238222
<223> 8-157-177.mis
<220>
<221> primer bind
<222> 238224 .238242
<223> 8-157-177.mis complement
<220>
<221> primer bind
<222> 238770 .238788
<223> 8-155-258.mis
<220>
<221> primer bind
<222> 238790 .238808
<223> 8-155-258.mis complement
<220>
<221> primer bind
<222> 239744 .239762
<223> 99-16038-118.mis
<220>
<221> primer bind
<222> 239764 .239782
<223> 99-16038-118.mis complement
<220>
<221> primer bind
<222> 239845 .239863
<223> 8-136-166.mis
<220>
<221> primer bind
<222> 239865 .239883
<223> 8-136-166.mis complement
<220>
<221> primer bind
<222> 239866 .239884
<223> 8-136-145.mis
<220>
<221> primer bind
<222> 239886 .239904
<223> 8-136-145.mis complement
<220>
<221> primer bind
<222> 239931 .239949
<223> 8-136-80.mis
<220>
<221> primer bind
<222> 239951 .239969
<223> 8-136-80.mis complement
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
73
<221> primer bind
<222> 240025 .240043
<223> 8-153-32.mis
<220>
<221> primer bind
<222> 240045 .240063
<223> 8-153-32.mis complement
<220>
<221> primer bind
<222> 240478 .240496
<223> 8-135-212.mis
<220>
<221> primer bind
<222> 240498 .240516
<223> 8-135-212.mis complement
<220>
<221> primer bind
<222> 240524 .240542
<223> 8-135-166.mis
<220>
<221> primer bind
<222> 240544 .240562
<223> 8-135-166.mis complement
<220>
<221> primer bind
<222> 240578 .240596
<223> 8-135-112.mis
<220>
<221> primer bind
<222> 240598 .240616
<223> 8-135-112.mis complement
<220>
<221> primer bind
<222> 240753 .240771
<223> 99-16050-235.mis
<220>
<221> primer bind
<222> 240773 .240791
<223> 99-16050-235.mis complement
<220>
<221> primer bind
<222> 240839 .240857
<223> 8-144-378.mis
<220>
<221> primer bind
<222> 240859 .240877
<223> 8-144-378.mis complement
<220>
<221> primer bind
<222> 240983 .241001
<223> 8-144-234.mis
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
74
<220>
<221> primer bind
<222> 241003 .241021
<223> 8-144-234.mis complement
<220>
<221> primer bind
<222> 241021..241039
<223> 8-144-196.mis
<220>
<221> primer bind
<222> 241041 .241059
<223> 8-144-196.mis complement
<220>
<221> primer bind
<222> 241198 .241216
<223> 8-141-304.mis
<220>
<221> primer bind
<222> 241218..241236
<223> 8-141-304.mis complement
<220>
<221> primer bind
<222> 241242..241260
<223> 8-141-260.mis
<220>
<221> primer bind
<222> 241262 .241280
<223>~8-141-260.mis complement
<220>
<221> primer bind
<222> 241341..291359
<223> 8-141-161.mis
<220>
<221> primer bind
<222> 241361 .241379
<223> 8-141-161.mis complement
<220>
<221> primer bind
<222> 241488 .291506
<223> 8-140-286.mis
<220>
<221> primer bind
<222> 241508..241526
<223> 8-140-286.mis complement
<220>
<221> primer bind
<222> 241601 .241619
<223> 8-140-173.mis
<220>
<221> primer bind
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 241621..241639
<223> 8-140-173.mis complement
<220>
<221> primer bind
<222> 241666 .241684
<223> 8-140-108.mis
<220>
<221> primer bind
<222> 241686..241704
<223> 8-140-108.mis complement
<220>
<221> primer bind
<222> 241733..241751
<223> 8-140-4l.mis
<220>
<221> primer bind
<222> 241753..241771
<223> 8-140-4l.mis complement
<220>
<221> primer bind
<222> 241842 .241860
<223> 99-15880-162.mis
<220>
<221> primer bind
<222> 241862..241880
<223> 99-15880-162.mis complement
<220>
<221> primer bind
<222> 242383 .242401
<223> 8-240-187.mis
<220>
<221> primer bind
<222> 242403 .242421
<223> 8-240-187.mis complement
<220>
<221> primer bind
<222> 244294..244312
<223> 8-225-281.mis
<220>
<221> primer bind
<222> 244314..244332
<223> 8-225-281.mis complement
<220>
<221> primer bind
<222> 247841..247859
<223> 99-25940-186.mis
<220>
<221> primer bind
<222> 247845 .247863
<223> 99-25940-182.mis
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
76
<220>
<221> primer bind
<222> 247861..247879
<223> 99-25940-186.mis complement
<220>
<221> primer bind
<222> 247865 .247883
<223> 99-25940-182.mis complement
<220>
<221> primer bind
<222> 248296 .248314
<223> 99-16032-292.mis
<220>
<221> primer bind
<222> 248316 .248334
<223> 99-16032-292.mis complement
<220>
<221> primer bind
<222> 253600..253618
<223> 99-16055-216.mis
<220>
<221> primer bind
<222> 253620 .253638
<223> 99-16055-216.mis complement
<220>
<221> primer bind
<222> 255829..255847
<223> 99-16105-152.mis
<220>
<221> primer bind
<222> 255849..255867
<223> 99-16105-152.mis complement
<220>
<221> primer bind
<222> 258554 .258572
<223> 99-16101-436.mis
<220>
<221> primer bind
<222> 258574 .258592
<223> 99-16101-436.mis complement
<220>
<221> primer bind
<222> 260080..260098
<223> 99-16033-244.mis
<220>
<221> primer bind
<222> 260100..260118
<223> 99-16033-244.mis complement
<220>
<221> primer bind
<222> 279770 .279788
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
77
<223> 99-15875-165.mis
<220>
<221> primer bind
<222> 279790 .279808
<223> 99-15875-165.mis complement
<220>
<221> primer bind
<222> 287988 .288006
<223> 99-13521-3l.mis
<220>
<221> primer bind
<222> 288008 .288026
<223> 99-13521-3l.mis complement
<220>
<221> primer bind
<222> 292661 .292679
<223> 8-112-241.mis
<220>
<221> primer bind
<222> 292681..292699
<223> 8-112-241.mis complement
<220>
<221> primer bind
<222> 292747..292765
<223> 8-112-155.mis
<220>
<221> primer bind
<222> 292767 .292785
<223> 8-112-155.mis complement
<220>
<221> primer bind
<222> 292857..292875
<223> 8-112-45.mis
<220>
<221> primer bind
<222> 292877..292895
<223> 8-112-45.mis complement
<220>
<221> primer bind
<222> 295697..295715
<223> 8-110-404.mis
<220>
<221> primer bind
<222> 295717..295735
<223> 8-110-404.mis complement
<220>
<221> primer bind
<222> 296012 .296030
<223> 8-110-89.mis
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
78
<221> primer bind
<222> 296032..296050
<223> 8-110-89.mis complement
<220>
<221> primer bind
<222> 296049..296067
<223> 8-134-94.mis
<220>
<221> primer bind
<222> 296069..296087
<223> 8-134-94.mis complement
<220>
<221> primer bind
<222> 298950..298968
<223> 99-7462-508.mis
<220>
<221> primer bind
<222> 298970 .298988
<223> 99-7462-508.mis complement
<220>
<221> primer bind
<222> 300346 .300364
<223> 99-16052-214.mis
<220>
<221> primer bind
<222> 300366 .300384
<223> 99-16052-214.mis complement
<220>
<221> primer bind
<222> 312011..312029
<223> 99-16047-115.mis
<220>
<221> primer bind
<222> 312031..312049
<223> 99-16047-115.mis complement
<220>
<221> primer bind
<222> 315909 .315927
<223> 99-25993-280.mis
<220>
<221> primer bind
<222> 315929 .315947
<223> 99-25993-280.mis complement
<220>
<221> primer bind
<222> 315995 .316013
<223> 99-25993-367.mis
<220>
<221> primer bind
<222> 316015 .316033
<223> 99-25993-367.mis complement
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
79
<220>
<221> primer bind
<222> 317226..317244
<223> 99-25101-151.mis
<220>
<221> primer bind
<222> 317246..317264
<223> 99-25101-151.mis complement
<220>
<221> misc_binding
<222> 8304 .8328
<223> 99-27943-150. probe
<220>
<221> misc_binding
<222> 14714..19738
<223> 8-121-28. probe
<220>
<221> misc_binding
<222> 14722..14746
<223> 8-121-36. probe
<220>
<221> misc_binding
<222> 14840..14864
<223> 8-121-154. probe
<220>
<221> misc_binding
<222> 14873..14897
<223> 8-121-187. probe
<220>
<221> misc_binding
<222> 14929..14953
<223> 8-121-243. probe
<220>
<221> misc_binding
<222> 14967..14991
<223> 8-121-281. probe
<220>
<221> misc_binding
<222> 15038..15062
<223> 8-121-352. probe
<220>
<221> misc_binding
<222> 15050..15074
<223> 8-121-364. probe
<220>
<221> misc_binding
<222> 15057..15081
<223> 8-121-371. probe
<220>
<221> misc binding
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 21660..21684
<223> 99-27935-193. probe
<220>
<221> misc_binding
<222> 25468..25492
<223> 8-122-72. probe
<220>
<221> misc_binding
<222> 25496..25520
<223> 8-122-100. probe
<220>
<221> misc_binding
<222> 25668..25692
<223> 8-122-272. probe
<220>
<221> misc_binding
<222> 25722..25746
<223> 8-122-326. probe
<220>
<221> misc_binding
<222> 25756..25780
<223> 8-122-360. probe
<220>
<221> misc_binding
<222> 29391..29415
<223> 8-123-55. probe
<220>
<221> misc_binding
<222> 29525..29549
<223> 8-123-189. probe
<220>
<221> misc_binding
<222> 29533..29557
<223> 8-123-197. probe
<220>
<221> misc_binding
<222> 29643..29667
<223> 8-123-307. probe
<220>
<221> misc_binding
<222> 30157..30181
<223> 8-147-270. probe
<220>
<221> misc_binding
<222> 49463..49487
<223> 99-34293-210. probe
<220>
<221> misc_binding
<222> 64654..64678
<223> 8-127-28. probe
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
81
<220>
<221> misc_binding
<222> 64745..64769
<223> 8-127-119. probe
<220>
<221> misc_binding
<222> 64785..64809
<223> 8-127-159. probe
<220>
<221> misc_binding
<222> 64862..64886
<223> 8-127-236. probe
<220>
<221> misc_binding
<222> 64866..64890
<223> 8-127-240. probe
<220>
<221> misc_binding
<222> 64906..64930
<223> 8-127-280. probe
<220>
<221> misc_binding
<222> 65473..65497
<223> 8-128-33. probe
<220>
<221> misc_binding
<222> 65492..65516
<223> 8-128-52. probe
<220>
<221> misc_binding
<222> 65501..65525
<223> 8-128-6l. probe
<220>
<221> misc_binding
<222> 65508..65532
<223> 8-128-68. probe
<220>
<221> misc_binding
<222> 65509..65533
<223> 8-128-69. probe
<220>
<221> misc_binding
<222> 65525..65549
<223> 8-128-85. probe
<220>
<221> misc_binding
<222> 65584..65608
<223> 8-129-50. probe
<220>
<221> misc_binding
<222> 65845..65869
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
82
<223> 8-129-311. probe
<220>
<221> misc_binding
<222> 65935..65959
<223> 8-129-401. probe
<220>
<221> misc_binding
<222> 75655..75679
<223> 99-34240-492. probe
<220>
<221> misc_binding
<222> 94522..94546
<223> 99-31959-281. probe
<220>
<221> misc_binding
<222> 95384..95408
<223> 99-31960-363. probe
<220>
<221> misc_binding
<222> 96944..96968
<223> 99-31962-250. probe
<220>
<221> misc_binding
<222> 97144..97168
<223> 99-31962-450. probe
<220>
<221> misc_binding
<222> 106372..106396
<223> 99-44282-439. probe
<220>
<221> misc_binding
<222> 106757..106781
<223> 99-44282-54. probe
<220>
<221> misc_binding
<222> 107146..107170
<223> 99-24656-137. probe
<220>
<221> misc_binding
<222> 107269..107293
<223> 99-24656-260. probe
<220>
<221> misc_binding
<222> 107597..107621
<223> 99-24636-22. probe
<220>
<221> misc_binding
<222> 108487..108511
<223> 99-31939-75. probe
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
83
<221> misc_binding
<222> 108685..108709
<223> 99-31939-273. probe
<220>
<221> misc_binding
<222> 109439..109463
<223> 99-44281-418. probe
<220>
<221> misc_binding
<222> 109600..109624
<223> 99-44281-257. probe
<220>
<221> misc_binding
<222> 109780..109804
<223> 99-44281-77. probe
<220>
<221> misc_binding
<222> 112456..112480
<223> 99-31941-320. probe
<220>
<221> misc_binding
<222> 115456..115480
<223> 99-31942-325. probe
<220>
<221> misc_binding
<222> 155724..155748
<223> 99-24635-79. probe
<220>
<221> misc_binding
<222> 158160..158184
<223> 99-16059-313. probe
<220>
<221> misc_binding
<222> 160622..160646
<223> 99-24639-169. probe
<220>
<221> misc_binding
<222> 160628..160652
<223> 99-24639-163. probe
<220>
<221> misc_binding
<222> 160864..160888
<223> 99-24634-108. probe
<220>
<221> misc_binding
<222> 168962..168986
<223> 99-7652-162. probe
<220>
<221> misc_binding
<222> 169288..169312
<223> 99-7652-488. probe
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
84
<220>
<221> misc_binding
<222> 170734..170758
<223> 99-16100-83. probe
<220>
<221> misc_binding
<222> 170798..170822
<223> 99-16100-147. probe
<220>
<221> misc_binding
<222> 170846..170870
<223> 99-16100-195. probe
<220>
<221> misc_binding
<222> 170848..170872
<223> 99-16100-197. probe
<220>
<221> misc_binding
<222> 170894..170918
<223> 99-16100-244. probe
<220>
<221> misc_binding
<222> 171031..171055
<223> 99-16100-381. probe
<220>
<221> misc_binding
<222> 173346..173370
<223> 99-5862-167. probe
<220>
<221> misc_binding
<222> 174215..174239
<223> 99-16083-lOl.probe
<220>
<221> misc_binding
<222> 175788..175812
<223> 99-16044-351. probe
<220>
<221> misc_binding
<222> 180577..180601
<223> 99-16042-420. probe
<220>
<221> misc_binding
<222> 180966..180990
<223> 99-16042-3l. probe
<220>
<221> misc_binding
<222> 189945..189969
<223> 99-5919-215. probe
<220>
<221> misc binding
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 197151..197175
<223> 99-24658-410. probe
<220>
<221> misc_binding
<222> 198952..198976
<223> 99-30364-299. probe
<220>
<221> misc_binding
<222> 200244..200268
<223> 99-30366-112. probe
<220>
<221> misc_binding
<222> 204576..204600
<223> 99-16094-75. probe
<220>
<221> misc_binding
<222> 204922..204946
<223> 99-24644-194. probe
<220>
<221> misc_binding
<222> 206185..206209
<223> 99-16107-95. probe
<220>
<221> misc_binding
<222> 206251..206275
<223> 99-16107-161. probe
<220>
<221> misc_binding
<222> 206473..206497
<223> 99-16107-383. probe
<220>
<221> misc_binding
<222> 211596..211620
<223> 99-15873-303. probe
<220>
<221> misc_binding
<222> 214657..214681
<223> 8-124-106. probe
<220>
<221> misc_binding
<222> 214771..214795
<223> 8-124-220. probe
<220>
<221> misc_binding
<222> 214845..214869
<223> 8-124-294. probe
<220>
<221> misc_binding
<222> 214867..214891
<223> 8-124-316. probe
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
86
<220>
<221> misc_binding
<222> 214934..214958
<223> 8-124-383. probe
<220>
<221> misc_binding
<222> 215526..215550
<223> 8-125-33. probe
<220>
<221> misc_binding
<222> 215693..215717
<223> 8-132-312. probe
<220>
<221> misc_binding
<222> 215826..215850
<223> 8-132-179. probe
<220>
<221> misc_binding
<222> 215841..215865
<223> 8-132-164. probe
<220>
<221> misc_binding
<222> 215908..215932
<223> 8-132-97. probe
<220>
<221> misc_binding
<222> 216016..216040
<223> 99-13929-201. probe
<220>
<221> misc_binding
<222> 216526..216550
<223> 8-131-363. probe
<220>
<221> misc_binding
<222> 216690..216714
<223> 8-131-199. probe
<220>
<221> misc_binding
<222> 216862..216886
<223> 8-130-236. probe
<220>
<221> misc_binding
<222> 216878..216902
<223> 8-130-220. probe
<220>
<221> misc_binding
<222> 216954..216978
<223> 8-130-144. probe
<220>
<221> misc_binding
<222> 216955..216979
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> 8-130-143. probe
87
<220>
<221> misc_binding
<222> 216996..217020
<223> 8-130-102. probe
<220>
<221> misc_binding
<222> 216997..217021
<223> 8-130-lOl.probe
<220>
<221> misc_binding
<222> 217015..217039
<223> 8-130-83. probe
<220>
<221> misc_binding
<222> 217195..217219
<223> 8-209-333. probe
<220>
<221> misc_binding
<222> 217238..217262
<223> 8-209-290. probe
<220>
<221> misc_binding
<222> 219528..219552
<223> 99-5897-143. probe
<220>
<221> misc_binding
<222> 220824..220848
<223> 99-24649-186. probe
<220>
<221> misc_binding
<222> 220930..220954
<223> 99-24649-80. probe
<220>
<221> misc_binding
<222> 221729..221753
<223> 8-199-84. probe
<220>
<221> misc_binding
<222> 222036..222060
<223> 8-198-138. probe
<220>
<221> misc_binding
<222> 222734..222758
<223> 8-195-348. probe
<220>
<221> misc_binding
<222> 223583..223607
<223> 99-13925-97. probe
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
88
<221> misc_binding
<222> 225431..225455
<223> 8-192-82. probe
<220>
<221> misc_binding
<222> 226207..226231
<223> 99-16090-225. probe
<220>
<221> misc_binding
<222> 226975..226499
<223> 8-189-146. probe
<220>
<221> misc_binding
<222> 226858..226882
<223> 8-188-136. probe
<220>
<221> misc_binding
<222> 226975..226999
<223> 8-187-352. probe
<220>
<221> misc_binding
<222> 227577..227601
<223> 8-185-319. probe
<220>
<221> misc_binding
<222> 227600..227624
<223> 8-185-296. probe
<220>
<221> misc_binding
<222> 227994..228018
<223> 99-16051-226. probe
<220>
<221> misc_binding
<222> 228056..228080
<223> 99-16051-164. probe
<220>
<221> misc_binding
<222> 228122..228146
<223> 8-184-119. probe
<220>
<221> misc_binding
<222> 228214..228238
<223> 8-184-27. probe
<220>
<221> misc_binding
<222> 228242..228266
<223> 8-183-401. probe
<220>
<221> misc_binding
<222> 229057..229081
<223> 8-181-449. probe
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
89
<220>
<221> misc_binding
<222> 229156..229180
<223> 8-181-350. probe
<220>
<221> misc_binding
<222> 229247..229271
<223> 8-181-259. probe
<220>
<221> misc_binding
<222> 229276..229300
<223> 8-181-230. probe
<220>
<221> misc_binding
<222> 229296..229320
<223> 8-181-210. probe
<220>
<221> misc_binding
<222> 229341..229365
<223> 8-181-165. probe
<220>
<221> misc_binding
<222> 229343..229367
<223> 8-181-163. probe
<220>
<221> misc_binding
<222> 229423..229447
<223> 8-181-83. probe
<220>
<221> misc_binding
<222> 229474..229498
<223> 8-180-157. probe
<220>
<221> misc_binding
<222> 229570..229594
<223> 8-143-332. probe
<220>
<221> misc_binding
<222> 229575..229599
<223> 8-143-327. probe
<220>
<221> misc_binding
<222> 229591..229615
<223> 8-143-311. probe
<220>
<221> misc_binding
<222> 229599..229618
<223> 8-143-308. probe
<220>
<221> misc binding
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 229595..229619
<223> 8-179-268. probe
<220>
<221> misc_binding
<222> 229596..229620
<223> 8-143-306. probe
<220>
<221> misc_binding
<222> 229657..229681
<223> 8-143-245. probe
<220>
<221> misc_binding
<222> 229660..229684
<223> 8-143-242. probe
<220>
<221> misc_binding
<222> 229663..229687
<223> 8-143-239. probe
<220>
<221> misc_binding
<222> 229670..229694
<223> 8-143-232. probe
<220>
<221> misc_binding
<222> 229750..229774
<223> 8-143-152. probe
<220>
<221> misc_binding
<222> 229949..229973
<223> 8-178-199. probe
<220>
<221> misc_binding
<222> 230226..230250
<223> 8-119-404. probe
<220>
<221> misc_binding
<222> 230244..230268
<223> 8-177-281. probe
<220>
<221> misc_binding
<222> 230253..230277
<223> 8-119-377. probe
<220>
<221> misc_binding
<222> 230321..230345
<223> 8-119-309. probe
<220>
<221> misc_binding
<222> 230336..230360
<223> 8-119-294. probe
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
91
<220>
<221> misc_binding
<222> 230346..230370
<223> 8-119-284. probe
<220>
<221> misc_binding
<222> 230358..230382
<223> 8-119-272. probe
<220>
<221> misc_binding
<222> 230368..230392
<223> 8-119-262. probe
<220>
<221> misc_binding
<222> 230382..230406
<223> 8-119-248. probe
<220>
<221> misc_binding
<222> 230383..230407
<223> 8-119-247. probe
<220>
<221> misc_binding
<222> 230420..230444
<223> 8-119-210. probe
<220>
<221> misc_binding
<222> 230426..230450
<223> 8-119-204. probe
<220>
<221> misc_binding
<222> 230430..230454
<223> 8-119-200. probe
<220>
<221> misc_binding
<222> 230435..230459
<223> 8-119-195. probe
<220>
<221> misc_binding
<222> 230505..230529
<223> 8-119-125. probe
<220>
<221> misc_binding
<222> 230510..230534
<223> 8-119-120. probe
<220>
<221> misc_binding
<222> 230533..230557
<223> 8-119-97. probe
<220>
<221> misc_binding
<222> 230537..230561
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> 8-119-93. probe
92
<220>
<221> misc_binding
<222> 230592..230616
<223> 8-119-38. probe
<220>
<221> misc_binding
<222> 230672..230696
<223> 8-138-234. probe
<220>
<221> misc_binding
<222> 230688..230712
<223> 8-138-218. probe
<220>
<221> misc_binding
<222> 230743..230767
<223> 8-138-163. probe
<220>
<221> misc_binding
<222> 231058..231082
<223> 8-175-75. probe
<220>
<221> misc_binding
<222> 231106..231130
<223> 8-142-386. probe
<220>
<221> misc_binding
<222> 231122..231146
<223> 8-142-370. probe
<220>
<221> misc_binding
<222> 231360..231384
<223> 8-142-132. probe
<220>
<221> misc_binding
<222> 231657..231681
<223> 8-145-339. probe
<220>
<221> misc_binding
<222> 231665..231689
<223> 99-15870-400. probe
<220>
<221> misc_binding
<222> 231765..231789
<223> 8-145-231. probe
<220>
<221> misc_binding
<222> 231799..231823
<223> 8-145-197. probe
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
93
<221> misc_binding
<222> 231842..231866
<223> 8-145-154. probe
<220>
<221> misc_binding
<222> 231858..231882
<223> 8-145-138. probe
<220>
<221> misc_binding
<222> 231918..231942
<223> 8-145-78. probe
<220>
<221> misc_binding
<222> 232308..232332
<223> 8-171-247. probe
<220>
<221> misc_binding
<222> 232465..232489
<223> 8-170-373. probe
<220>
<221> misc_binding
<222> 232886..232910
<223> 8-169-266. probe
<220>
<221> misc_binding
<222> 232986..233010
<223> 8-169-166. probe
<220>
<221> misc_binding
<222> 233088..233112
<223> 8-168-380. probe
<220>
<221> misc_binding
<222> 233441..233465
<223> 8-235-349. probe
<220>
<221> misc_binding
<222> 233608..233632
<223> 8-235-182. probe
<220>
<221> misc_binding
<222> 234108..234132
<223> 8-137-340. probe
<220>
<221> misc_binding
<222> 234265..234289
<223> 8-137-182. probe
<220>
<221> misc_binding
<222> 234295..234319
<223> 8-137-152. probe
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
94
<220>
<221> misc_binding
<222> 234739..234763
<223> 8-165-185. probe
<220>
<221> misc_binding
<222> 235303..235327
<223> 99-16087-219. probe
<220>
<221> misc_binding
<222> 238211..238235
<223> 8-157-177. probe
<220>
<221> misc_binding
<222> 238777..238801
<223> 8-155-258. probe
<220>
<221> misc_binding
<222> 239751..239775
<223> 99-16038-118. probe
<220>
<221> misc_binding
<222> 239852..239876
<223> 8-136-166. probe
<220>
<221> misc_binding
<222> 239873..239897
<223> 8-136-145. probe
<220>
<221> misc_binding
<222> 239938..239962
<223> 8-136-80. probe
<220>
<221> misc_binding
<222> 240032..240056
<223> 8-153-32. probe
<220>
<221> misc_binding
<222> 240485..240509
<223> 8-135-212. probe
<220>
<221> misc_binding
<222> 240531..240555
<223> 8-135-166. probe
<220>
<221> misc_binding
<222> 240585..240609
<223> 8-135-112. probe
<220>
<221> mist binding
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 240760..240784
<223> 99-16050-235. probe
<220>
<221> misc_binding
<222> 240846..240870
<223> 8-144-378. probe
<220>
<221> misc_binding
<222> 240990..241014
<223> 8-144-239. probe
<220>
<221> misc_binding
<222> 241028..241052
<223> 8-144-196. probe
<220>
<221> misc_binding
<222> 241205..241229
<223> 8-141-309. probe
<220>
<221> misc_binding
<222> 241249..241273
<223> 8-141-260. probe
<220>
<221> misc_binding
<222> 241348..241372
<223> 8-141-161. probe
<220>
<221> misc_binding
<222> 241495..241519
<223> 8-140-286. probe
<220>
<221> misc_binding
<222> 241608..291632
<223> 8-140-173. probe
<220>
<221> misc_binding
<222> 241673..241697
<223> 8-140-108. probe
<220>
<221> misc_binding
<222> 241740..241764
<223> 8-140-4l. probe
<220>
<221> misc_binding
<222> 241849..241873
<223> 99-15880-162. probe
<220>
<221> misc_binding
<222> 242390..242414
<223> 8-240-187. probe
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
96
<220>
<221> misc_binding
<222> 244301..244325
<223> 8-225-281. probe
<220>
<221> misc_binding
<222> 297848..247872
<223> 99-25940-186. probe
<220>
<221> misc_binding
<222> 247852..247876
<223> 99-25940-182. probe
<220>
<221> misc_binding
<222> 248303..248327
<223> 99-16032-292. probe
<220>
<221> misc_binding
<222> 253607..253631
<223> 99-16055-216. probe
<220>
<221> misc_binding
<222> 255836..255860
<223> 99-16105-152. probe
<220>
<221> misc_binding
<222> 258561..258585
<223> 99-16101-436. probe
<220>
<221> misc_binding
<222> 260087..260111
<223> 99-16033-244. probe
<220>
<221> misc_binding
<222> 279777..279801
<223> 99-15875-165. probe
<220>
<221> misc_binding
<222> 287995..288019
<223> 99-13521-3l. probe
<220>
<221> misc_binding
<222> 292668..292692
<223> 8-112-241. probe
<220>
<221> misc_binding
<222> 292754..292778
<223> 8-112-155. probe
<220>
<221> misc_binding
<222> 292864..292888
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
97
<223> 8-112-45. probe
<220>
<221> misc_binding
<222> 295704..295728
<223> 8-110-404. probe
<220>
<221> misc_binding
<222> 296019..296043
<223> 8-110-89. probe
<220>
<221> misc_binding
<222> 296056..296080
<223> 8-134-94. probe
<220>
<221> misc_binding
<222> 298957..298981
<223> 99-7462-508. probe
<220>
<221> misc_binding
<222> 300353..300377
<223> 99-16052-214. probe
<220>
<221> misc_binding
<222> 312018..312042
<223> 99-16047-115. probe
<220>
<221> misc_binding
<222> 315916..315940
<223> 99-25993-280. probe
<220>
<221> misc_binding
<222> 316002..316026
<223> 99-25993-367. probe
<220>
<221> misc_binding
<222> 317233..317257
<223> 99-25101-151. probe
<220>
<221> allele
<222> 61595..61598
<223> deletion AAGG
<220>
<221> allele
<222> 75217..75221
<223> deletion ATTTT
<220>
<221> allele
<222> 75367
<223> polymorphic base C or T
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
98
<221> allele
<222> 88634..88637
<223> deletion CACA
<220>
<221> allele
<222> 90113
<223> polymorphic base A or G
<220>
<221> allele
<222> 93698..93701
<223> deletion ACAC
<220>
<221>allele
<222>94209
<223>polymorphic C
base or
T
<220>
<221>allele
<222>94331..94334
<223>deletion AATG
<220>
<221>allele
<222>95396
<223>polymorphic A
base or
G
<220>
<221>allele
<222>95810
<223>polymorphic C
base or
T
<220>
<221>allele
<222>96956
<223>polymorphic C
base or
T
<220>
<221>allele
<222>97156
<223>polymorphic A
base or
G
<220>
<221>allele
<222>98748..98757
<223>deletion CTTTCTTTCT
<220>
<221>allele
<222>104314..104315
<223>deletion TA
<220>
<221>allele
<222>104455
<223>polymorphic A
base or
C
<220>
<221>allele
<222>104699
<223>polymorphic A
base or
G
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
99
<220>
<221> allele
<222> 106253
<223> polymorphic base C or T
<220>
<221> allele
<222> 106272
<223> polymorphic base A or T
<220>
<221> allele
<222> 106350
<223> polymorphic base A or C
<220>
<221> allele
<222> 106384
<223> polymorphic base A or G
<220>
<221> allele
<222> 107158
<223> polymorphic base A or G
<220>
<221> allele
<222> 107168..107169
<223> deletion AT
<220>
<221> allele
<222> 107609
<223> polymorphic base A or G
<220>
<221> allele
<222> 108032
<223> polymorphic base A or G
<220>
<221> allele
<222> 108668..108816
<223> deletion
ATGGAGATGGCAACACCTACATGTGACCTTTCCAGCATGGCAGTCTCAGAGTGGATATGGCAACAGCTGCACATGAC
CTCTCCAGCATGGCAGTCTCAGAGTGGATATGGCAACAGCTGCACATGACCTCTCCGGCATGGCAGTCTCAG
<220>
<221> allele
<222> 110222
<223> polymorphic base G or T
<220>
<221> allele
<222> 111978
<223> polymorphic base A or G
<220>
<221> allele
<222> 112468
<223> polymorphic base G or T
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
100
<220>
<221> allele
<222> 117324..117327
<223> deletion ACTT
<220>
<221> allele
<222> 118972
<223> polymorphic base C or T
<220>
<221> allele
<222> 119160..119161
<223> deletion TT
<220>
<221> allele
<222> 119316
<223> polymorphic base C or T
<220>
<221> allele
<222> 119321
<223> polymorphic base A or G
<220>
<221> allele
<222> 119526
<223> polymorphic base A or G
<220>
<221> allele
<222> 120573
<223> polymorphic base A or G
<220>
<221> allele
<222> 121527
<223> polymorphic base A or C
<220>
<221> allele
<222> 126105
<223> polymorphic base C or T
<220>
<221> allele
<222> 129789
<223> polymorphic base C or G
<220>
<221> allele
<222> 130777
<223> polymorphic base A or G
<220>
<221> allele
<222> 136942..136944
<223> deletion ATT
<220>
<221> allele
<222> 143839
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> polymorphic base A or T
101
<220>
<221> allele
<222> 146668
<223> polymorphic base C or T
<220>
<221> allele
<222> 147281
<223> polymorphic base C or T
<220>
<221> allele
<222> 147505
<223> polymorphic base G or T
<220>
<221> allele
<222> 148183
<223> deletion T
<220>
<221> allele
<222> 148372
<223> polymorphic base A or C
<220>
<221> allele
<222> 149012
<223> polymorphic base A or G
<220>
<221> allele
<222> 149113
<223> polymorphic base C or T
<220>
<221> allele
<222> 151637
<223> polymorphic base A or G
<220>
<221> allele
<222> 151748
<223> deletion G
<220>
<221> allele
<222> 151769
<223> polymorphic base A or G
<220>
<221> allele
<222> 151847
<223> polymorphic base C or T
<220>
<221> allele
<222> 152691
<223> polymorphic base A or C
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
102
<221> allele
<222> 152766
<223> polymorphic base A or G
<220>
<221> allele
<222> 153046
<223> polymorphic base C or T
<220>
<221> allele
<222> 153123
<223> polymorphic base A or G
<220>
<221> allele
<222> 153925
<223> polymorphic base C or T
<220>
<221> allele
<222> 153977
<223> polymorphic base G or T
<220>
<221> allele
<222> 154502
<223> polymorphic base C or T
<220>
<221> allele
<222> 154677
<223> polymorphic base A or G
<220>
<221> allele
<222> 154879
<223> polymorphic base C or T
<220>
<221> allele
<222> 154918
<223> polymorphic base G or T
<220>
<221> allele
<222> 155802
<223> polymorphic base C or T
<220>
<221> allele
<222> 156448
<223> polymorphic base A or G
<220>
<221> allele
<222> 157238
<223> polymorphic base A or C
<220>
<221> allele
<222> 157897
<223> polymorphic base A or G
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
103
<220>
<221> allele
<222> 158172
<223> polymorphic base A or G
<220>
<221> allele
<222> 158302
<223> polymorphic base A or G
<220>
<221> allele
<222> 158512..158513
<223> deletion TT
<220>
<221> allele
<222> 158803
<223> polymorphic base C or T
<220>
<221> allele
<222> 160172
<223> polymorphic base C or T
<220>
<221> allele
<222> 160634
<223> polymorphic base C or T
<220>
<221> allele
<222> 16123'6
<223> polymorphic base C or T
<220>
<221> allele
<222> 162810
<223> polymorphic base A or G
<220>
<221> allele
<222> 163007
<223> polymorphic base A or G
<220>
<221> allele
<222> 164877
<223> polymorphic base A or G
<220>
<221> allele
<222> 166844
<223> polymorphic base C or T
<220>
<221> allele
<222> 166911..166914
<223> deletion TCTC
<220>
<221> allele
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 167754
<223> polymorphic base A or G
<220>
<221> allele
<222> 167787
<223> polymorphic base C or T
<220>
<221> allele
<222> 167894
<223> polymorphic base G or T
<220>
<221> allele
<222> 168346
<223> polymorphic base C or T
<220>
<221> allele
<222> 168414
<223> polymorphic base A or G
<220>
<221> allele
<222> 168453
<223> polymorphic base A or C
<220>
<221> allele
<222> 169300
<223> polymorphic base A or G
<220>
<221> allele
<222> 169451
<223> polymorphic base C or T
<220>
<221> allele
<222> 169627
<223> polymorphic base A or G
104
<220>
<221> allele
<222> 169984
<223> polymorphic base C or T
<220>
<221> allele
<222> 170199
<223> polymorphic base C or T
<220>
<221> allele
<222> 170746
<223> polymorphic base C or T
<220>
<221> allele
<222> 170858
<223> polymorphic base G or T
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<220>
<221> allele
<222> 170860
<223> polymorphic base C or T
<220>
<221> allele
<222> 170906
<223> polymorphic base C or T
<220>
<221> allele
<222> 171309
<223> polymorphic base A or G
<220>
<221> allele
<222> 171413
<223> polymorphic base A or G
<220>
<221> allele
<222> 171504
<223> polymorphic base C or T
<220>
<221> allele
<222> 171539
<223> polymorphic base C or T
<220>
<221> allele
<222> 171728
<223> polymorphic base C or T
<220>
<221> allele
<222> 171898
<223> polymorphic base A or G
<220>
<221> allele
<222> 172125..172126
<223> deletion AA
105
<220>
<221> allele
<222> 172295
<223> polymorphic base A or G
<220>
<221> allele
<222> 172298
<223> polymorphic base A or G
<220>
<221> allele
<222> 172336
<223> polymorphic base A or G
<220>
<221> allele
<222> 173145
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> polymorphic base A or G
106
<220>
<221> allele
<222> 173304
<223> polymorphic base C or T
<220>
<221> allele
<222> 174227
<223> polymorphic base C or T
<220>
<221> allele
<222> 174397
<223> polymorphic base A or G
<220>
<221> allele
<222> 179154
<223> polymorphic base C or T
<220>
<221> allele
<222> 180233
<223> polymorphic base C or G
<220>
<221> allele
<222> 182552
<223> polymorphic base A or G
<220>
<221> allele
<222> 182733
<223> polymorphic base C or T
<220>
<221> allele
<222> 182773
<223> deletion A
<220>
<221> allele
<222> 185759
<223> polymorphic base A or G
<220>
<221> allele
<222> 186307
<223> deletion T
<220>
<221> allele
<222> 186976..186979
<223> deletion TATC
<220>
<221> allele
<222> 188755
<223> polymorphic base A or T
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
107
<221>allele
<222>188991
<223>polymorphicbase A
or C
<220>
<221>allele
<222>189002
<223>polymorphicbase C
or T
<220>
<221>allele
<222>189154
<223>polymorphicbase A
or G
<220>
<221>allele
<222>189177
<223>polymorphicbase A
or G
<220>
<221>allele
<222>189604
<223>polymorphicbase A
or G
<220>
<221>allele
<222>190063
<223>polymorphicbase C
or T
<220>
<221>allele
<222>191164
<223>deletion
T
<220>
<221>allele
<222>193880
<223>deletion
A
<220>
<221> allele
<222> 193897
<223> polymorphic base A or G
<220>
<221> allele
<222> 194441
<223> polymorphic base A or T
<220>
<221> allele
<222> 195306
<223> polymorphic base A or T
<220>
<221> allele
<222> 226323..226326
<223> deletion TATC
<220>
<221> misc_feature
<222> 4222,11245,27205..27206,27212..27213,27240,27347,27378,28258
108818,128283,137062..137063,164757,172148..172150,180820,184929
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
108
194460,200104,207061..207062,207949,239085,249787,249806,250156
250189,250841,251114,264938,265019,265078,274640,277770,314308
318680,318731
<223> n=a, g, c or t
<400> 1
cgggcgaattcgagctcggtacccggggatcatctttgtcatagattgtagtaaaaataa60
tctgtgaaaagtgactgattattgacaggtagccttgggtatgcagctcaagtaggcatt120
ataaaataaaaaacatcacattccatgtattttcaaaaaaagcttctggcttactcaaaa180
ggtaagtgttctttaaacaacttcaatggaaaaggagtttcttccaaatgcttggagaac240
tccttctcaagtccggaataaagcaaggtctacagagacaaagtataaataaaaccatgg300
tgctgagctggtaccactattgggctgctaagcactgctaagcattgccttcagatgagt360
tacctagcctttgtaaagctcagattccacagctataaactgagatgaataataatacac420
aaaacactaagctgttgagtagattaaatgaaattatttatgtagagcaaatagaacagt480
actgtaccttataaaatttaaaaccaaaatgtaaattctgatttttacccaagggtcaac540
tccgcacaattttgcaatggacccttccccggccctccagaagctgaatatcgttgtgta600
tcatatccaaattcagtatcaccagggcatagagtaagtgccaactgtgaggccatagct660
atgcgtccactcccctgaaacacattgtgtaccttcattcttggagttgagtctttgcat720
ttcatcctccagagtgagaatagactgcgtgttggagaggtcagggaaattatgtctttc780
tatgtctagccctttataggtcgattatttgaatgcttgacagcatctgtccacttatct840
atccctgcaataataaaatacgggactaaagtagctcgtatctctagtgggagagtgcat900
atattttatacgtcaattctttaaaaggggaaattctttcagagcttcagaaaatatcac960
ggaagagttaaaagaatgtttgagaagaacatgtctgagtattacctactagcattacaa1020
ttttactgctttaaagtaattataattttcattgcaggatctattaaaaaggcttttacc1080
tgacggtaattcttcttgtacttacaggtcattattacaatgaagggaagaaaggaagac1140
atgaaggggaaatgggactatttaccaagtgtatctgcatagactaaaggagacaagagg1200
aagtactgagcaccttgattcctgcagataattatttaagaaccataagaattctttcct1260
agcttctcataagcctgctccttcaaagggtgagtagttgacatgattttacatcccatt1320
tatatttctttattagataattttatttcaaatctagtcttattttttctgaaccttctg1380
ggatatataacattttatattatcatttatgtcatcaagaatgtagatttatattctttt1440
ctattcacatgtttatgtaaataattgaacacctctaaatgacagatactatcattttat1500
atattgttaataagtatcttcatggctgggcgtggtggctcacgcccgtaatcccagcac1560
tttgggaggccgaggtgggaggatcacctgaggtcaggagtttgagatcagcctggcgaa1620
cgtggtgaaatcccatctctactaaaaacaacaaaaattagctgggcatggtagcatgcg1680
cctatagtcccagctactagggaggccaaggcaggagaatcgatcgctcaaacctgggag1740
gcagaggtttcagtgagctgatatcgtgccactgcactctggcctgggcaacagaatgag1800
accctgcttcaataaataaataaattaattaattaattaataaagtatcttaatgacaaa1860
tatttaaatatatataaatatttacatttacatatgggaagagagatctgaaattttaag1920
caacttttatccaaaaacctatttttttcaaagttcctccaacatctataaaagaagtaa1980
agtcacttatagatctatcttacttcagggcctatgttttcctctaccatacaacactgc2040
acattcacagacacagaaatcttttacatttctaaaataaataaaacatccaaacttcag2100
tttaaaaaaaatggatctacagatccaccatagactaaacgaccaaacatagtcagaggt2160
gtttacttgtttgtttcggtcttaagggaatcttcaaactaccctagagcctcgtgtatc2220
caatgagagcagtctggacattgaatgaatggtgatgtcattaaatgagctatggagcaa2280
gatgtaagaacacgctttagagtaaataacatatttggcttctgaggtataaaaagggaa2340
ggaggctttctcaggacatttgggtacctggtccttcatactcaggaggtttttccatct2400
tcatgtcatggaataaactatgctttaaagaaatgctgcgtcagcagaaagtgtttcaaa2460
tataaggaaattgtcatagctttgaaattatgtcaaatatcattttaactaagagagcca2520
ttgtctttccatatatttatctagaagaaaatttactggacaaaataaatatagaacaac2580
ttcatgtgtagtcattaatggtcggataggcagttactataaaatatgaataatctaaaa2640
atcattttagccatttgtttttaataaatctcacttgtgattgatttattaaaaacaggg2700
cctccagaagaaagaaacttaatacctttcctccatcattatgaaggcactagtactgac2760
gtaactaaaattagatggcagcttgagggaggaagagatgatgtagagatggtgtgtaat2820
ctgtgtaaacagtctctcaactgtctagagttagctgtacgaatctgttgttggctccag2880
ttataagaaccaagatatgtatgtaaggacaaacatccttaatttgcttagcaagtcgta2940
tgtatttgatagaccaccaattttattttattttattttatttttgagatggagtcttgc3000
tctgtcacctgggctggagtgcagtggcgcgatctcggctcactgcaaactccatttagc3060
aggttcaagtgattcttctgcctcagcctcccgagtagctgggattacaagtgctcaaaa3120
ccacccccggttaatgtttttttcttttcttttcttttcttttcttttcttttcttttct3180
tttcttttcttttcttttctttttttagtagtagacacagggtttcactatgttggccag3240
gctggtctcaaactcctgacctcgtgatctgcccacctcggcctcccaaagtgctgggat3300
tacgggattacaagcgtgagccactgcaccagccctgatttttaaaagggattttagaat3360
ttcagttgaacatgtgtttttgaagtaactccatattgaacaggggaatcagagtaagta3420
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
109
aaccactacaggaaaatcaggaaggcagactccaatttatgttttctgtgtataacctac3480
tttaataaagaattaaaaatcataagagtagttttatctagtggcctagaacttgattat3540
gaaaagtaagacaaaggaaatctgacctcatgccagtgtctggaagccttacaggaactg3600
aaaggacccacgtggaacagctggcaactgaaactcatcttgtcaatttcaagtgtagtc3660
cctcttcccaattcaccggagaaaacacagccagctttgcatacagtgtctggtgtcacc3720
agagaaaacacagtcagctttgcatacaatatctggtgtcagaatgaccaaacgattggc3780
ttctatccttcaggattgtgaacagagagccaaggcatacaaccagtatgcccactccgt3840
cagctgcgagacagaggagataaagaatgctgaacattatgggtcactgctttgaagtat3900
tcagaggccaaaatagttcaaaataattgtgttaatcattaaaagtagaagaagtggaag3960
ccaaaattatgcctgcctatatttcagttttgaatgtgtggagatcagaaatttaaaaaa4020
aagtttatgagtttccccttttaaactttgagaaaagaccataagaaccggtgttttagt4080
aaatcatcttcaagagtaatttactcataaaaagaaaagaactcatgataccgtgtaaac4140
aaaaggctaataaatgctggtgtaaataagattaagggaggacaaagatgaaggaaagca4200
ggacatatcaaaaaacaaatanaataagaaattttcagagcttgaatatacaaacaggca4260
catcaaaagaggttcaatggaaacctaatgcaatgaatgggacaattaatgcttttaaac4320
atcacttggaaccacagaaaataccaacagaaaaatctggtcacgtacaagagataagag4380
tcagggttccatggatgttcttcttagatgagaaggacacttcacttttatggcattgtt4440
cccacaaatccataacccaagtttcatcatgagcaagcctcagccaaagaaaaattgaga4500
tgtattttacaacatacccgttcaggccctttaaaaatgtcaaagttggccaggcaccat4560
ggcttccacctgtaatcccagcactttgggaggctgagatgggtggatcatttgaggtca4620
ggagttcgagaccagcctggacaatatggggaaaccccaactgtactaaaaaaagataac4680
aaaattagccaggtgtggtggtgtgggcctgtaatcccagctacttgagaggctgaggca4740
ggagaatcgcttgaacccaggagccaggaggtggaggttgcagtgagccaagatcatgcc4800
actgtattccaacctgggcgacagagcaaaactccatctccccccaaaaaaagcaaagtc4860
gtgaaaaacaaagtaagactaaggaactgtcagattagaggggactgaggaaacatgaaa4920
attagatgaaatagggtatacagtttagaattatagaacagaaagcaggacatcagttga4980
acaactaaagaaatacaaataaagtctattttagttaatattgttgtaccaatactaatt5040
tcttagttgtaacaaataaaatatcattatgtaagatggcaacttcaggaaaagttgggg5100
gaaagatatacaggaatactttgtattatcttagaaactattatgtcaatattttaatat5160
aaaattattagaaattgtgtcagaaacactggatgttagaagacaatggaggaatgcctc5220
aaaaaatctacagagaacttcttttcaatctatcatcatagcatcaatcaagtatgagct5280
tcaaattatgatattttataatatgagaataattctgaaaatttaccttataccaatatt5340
ttcttagaagattactttaggatgtgctatagtcaaacagaggaataaactaagaaaaag5400
tatgatgtgagatacagaaaaatatatagaaacaatttagaaaaataataaaaagtagtc5460
ctatgataatagcaatataagaatgtttagattggaatagaagatgaatgccctcaagag5520
tataacctctgaaagaaaaattaaataaataaaaaaattctgacaggatacctgatcaga5580
tagagatgtgacaaaccagtatgttgaaaggtgatgacagaaagagagaacggaaagaga5640
gaggcaggaaggaaaggggaaaaaaagaaagaaatgaaaggcgattctcacaccagttag5700
aatggcaattattaaaaagtcaggaaacaacaggtgctagacaggatgtggagaaatagg5760
aacacttttacactattggtgggactgtaaactagttcaaccattgtggaagtcagtgtg5820
gcgattcctcagggatctagaactagaaataccatttgacccagtcatcccattactggc5880
tatatacccaaaggattataaatcatgcttctataaagacacatgcacacgtatgtttat5940
tgcggcactattcacaatagcaaagacttggaaccaacccaaatgtccaacaatgataga6000
ctgggttaagaaaatgtggcacatatacaccatggaatactatgcagccataaaaaatga6060
tgagttcatgtcctttgtagggacatggatgaagctggaaaccatcattctcagcaaact6120
atagcaaggacagaaaaccaaacaccacatgttctcactcataggtgggaattgaataat6180
gggaacacctggacacaggaaggggaacatcacacaccagggcctgttgtggggtggggg6240
gaggggggagggatagcattaggagatatacctaatgctaaatgacgagttaatgggtgc6300
agcacaccagcatggcacatgtatacatatgtaactaacctgtacgttgtgcccatgtac6360
cctagaacttaaagtataatatatatattatatatatataaagaaattccaagaaaatca6420
aaaggctgcatacaaatgaaatactatatgaccattatttccttcttggctttttcaaga6480
acaacatttacttagctaccacactgaaattactattcattaattttaagtaaactggca6540
ttgaaaatatggttaatctggtttttctttttttttttgagacagggtctcgctctgtta6600
cccaggctggagtgcagtgctgtgatcttagctcactgcaacctctgcctcccaggttcc6660
aacaatcctcccacctcagcttcccccagtagctgggattacagctgtgtgccaccatga6720
acagctaattttatatttttagtagagatggggttcgccctgttggccaggctggcctcg6780
aactcctgacttcaagtgatctgcctgcctcagcctccccaagtgttgggattacaggtg6840
tgagccaccgtgcccagcccagaaatgtgtttagtagtttgaaggggcaagtaccaggtg6900
ctaagagttcacaggggagggatactggacttagaccttcggaatcaagaaaagctttct6960
atagaaagtactgcctaagctgaagactgaacactgaccaggctgaatgaaagatgtagt7020
gctggagaggatttcagtcagaaaaaacatttgagaaggtccagaagaaaaataaaacaa7080
tttatttcaaggtactgaaataaattgagattaaggggagtgaagagtcaaggtctggag7140
aggtattgagttgtcaagaaatacagtttgagaggtaaaggccatattaggaagtaatat7200
tgctgagctggtaccactattgggctgctaagcactgctaagcattgccttcagatgagt360
tacctagcctttgtaaagctcagattccacagctataaactgagatgaataataatacac420
aaaacactaagctgttgagtagattaaatgaaattatttatgtagagcaaatagaaca
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
110
atttttaaac ttttgaagct tattctaagg ctaataacaa agtggtgtag gcaggaaagt 7260
tgcagttatt ataaaacttt cagaaagatt tatttaaatt aattggaatt gagaaagaaa 7320
ggcattattt tacgtaataa aaatatttat ttgttgtgta aaaaataaat agtttggcct 7380
agaggagaac agggccagta aggaagagga gaaatgcata gatataaagg gtgttaggat 7440
aaagcataag taagacttaa tgataattta aacttaagga acaaggaaaa tgaaggagta 7500
atgaatactt gagtcacttt gtagatagag gcaccaatca ctcaactcag acagagtaga 7560
ctagaggtgg ttttggggaa gctaaagact ccacttttag atctctggaa tatccaagat 7620
gggaattcaa ttaggctatg atttcaagtt caaacaagag aaacgggatg gagatatttt 7680
tagataccat ctgataatga ttagtgattg aagccatggg aatggatatt ttgtcaatgt 7740
tcttttgaga gctgtatcct tccgtagtta tctgatgggt tttttaaatg gcgtaaaata 7800
atcagtaatt tagaagtttc tataaagaaa gttcggctac aaatacttat cctttctctt 7860
tcattctcaa accatgcatt aaccacctat taatgtgttt agaaaaacag taagtaattc 7920
agggttcatg ctgacagaga agacccacat aagcaaacct cgctataata caaggagcta 7980
aattccccaa tataagaatg cagtgtgctc tgtgggaata tggagaaaca aagataagga 8040
aaacctaggc agaaatagtt caattgattg ttatttcata ctgagacaaa tttgccaagt 8100
ataaactata tcctattaca aatttagatg ctttgggcca tgggtcagct ccacggcgac 8160
acctacactg aagttgtatt taagctatct gtctggatca cttggttcac aaaaatgttt 8220
ggattacaaa aaggaaatat catacacctt ggaagaactg gctcattagt caagatgctg 8280
cttaccagtt gcctgggttg gctgctgtgg taaagsaata tcggttggaa agccggggct 8340
ggaagtcggg gagaggctgt cttctatatc ttacatttgc tatgtctttg gaggaaagat 8400
gctttcggca gtgttcctta aatttaaata tcttttcctt ttggactcaa gggtatgttt 8460
attcgacttc atcatatcta atctcctaga atattattaa cctgaagtta ttgtcagtat 8520
cgtatgatat ttattgaata acaatatgct ctgatactgc atatgaaatg aaataacaaa 8580
tgaacctccc ttactttaac ttaactacta attaattaga aaagaacctt cactcaaggg 8640
gtttggaaag gtccaataag ggaattaaca gatgagaatt taagagtacc tgaacccatc 8700
tcgatttgag atttacgtga tgctgggtga ttagtgataa gaacagaatg aagtcagctc 8760
aggaggcatc gtgatctgga aaggagggag atatttcagt gaataattga gaggattcag 8820
acaaagtcat atgagagaag cagagacaga cagagggcag gagtcagtgg atatgagaat 8880
gatactagga agatgaagaa tggactgatt tgtaaagaaa ttgagaccca agttatactg 8940
tgttaagaga taagttaaaa ccattaaaaa atattgggag atcctgaatt gctttcaagc 9000
ctagtaattt gatgtaagaa atagtgagaa atgctcttga tgttgtgtct gtttcaggga 9060
aagttttgtg gagacaatga aataaataaa atagcatatt tagatcaaga ggctggtttt 9120
ctttttcaca ggaaacatct aagaaactgt taaaagggac aaggtttgag tgttagaacg 9180
tgaaataggg ctatggtaat aaattgttac cattccgaag attatcaaat tatctcccag 9240
ccaaaaaaag agtttttaaa caaacatatg aagatataca atataataaa taaactagta 9300
tgtttatttc agattcaacc attttaacca caaagaacaa aacaacctca actgagagca 9360
ggcttgattt atgtaagcaa agatttggat ttgaggcagt gaatatagga ggcattggaa ~ 9420
aagtttggga aaaggctggt gggctttgtg agacaaagtg accatgccat gagaattgtg 9480
aaaataatgt agatgtggaa tcctgtaaca atggcaatta gtgatgaagt ggtgacatgg 9540
gaataaagag aaatgggtca acgtggatca tttttagaag gaaaagcact gaaactttgg 9600
aatgagatta tgaaaaaaag aggatgagaa attatgtttc caaggtttat tgcaaaagct 9660
gtgatgatgg catacctcag atagaaatga attattttaa aggaaaccag tttttagaga 9720
aagataatga atccaatttt gaacacattg aattcaaagt gacaatccgt catccatgca 9780
gactaccatg tagacagata accaaataga atagaaacac ccaccatata taataaaacc 9840
acaggtgcac tcattgagtg aaccagtaca gataaactat attgtagggg ctctcacatc 9900
tgggaatagg aagactcaat gaaggcaata aggggaagtt aaaaagaata agataaactg 9960
gggaattcaa gaagatcttc tttggcttcc ataagatcct agactgtttc taggaagcag 10020
tcacagttca gccatggccc agaatggtga tgaccgaggg cagggccatg gtttggtgct 10080
cagagaccat ttgccctcta ggagcaactg atggagagaa taaattgggg agagaataaa 10140
tctagggcag ttgaaggaga gagtaaattg taaaccaaga atgccatagc taaaagggaa 10200
gcagcaggca agtttgcact tttgaggaga aattctagga agggatttct ccacatttcc 10260
attttaggcc agaagtcttt gacatgctag agagaaagat ggattttttt tttaatgaat 10320
aaatgagata gttggcattt ttggcatttt tggcaaagaa agatttcatt ttcaagacca 10380
aaatttaaac agcaatattt agcacaaaaa atgcttgtca aattcctgct gaatttgaaa 10440
gcaacagcat attaaagctt tttcttcttt cctgcaatag ctgatgttca cgatacagta 10500
ttcccttgcc ctggtgggag tatgtcctcg cttatcctgg tgggaatatg ttccccttta 10560
tcctggtggg atatactccc tcttatccta gtgggacatg ttccaagact cccagtggat 10620
gcctggaacc atgaatggta ccaagcccta cacacactat gttttcatca tatacataca 10680
catgtatgat aaagtttaat ttataaatta ggcatagtta gagataaaca ataatagcta 10740
ataataaaat agaataatta taacaatata ctgtaataaa agttgtctga tgtggtctct 10800
ctttctttca aaatatctta ttgtactgta ctcacccttt tttgatgatg tgagaagata 10860
ccatgcctat gtgatgtgat gtgatgaagt aaggtgaatg agaaaggcat catgacgcag 10920
ggtggcctac tattgaccta ataagcaggt tgtgtctgca gcatggagac tctggaaaag 10980
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
111
ggatgattca tgtcaaggga agaattgaat gggacagcac agattttatc acattactca 11040
gagcagtgca caatttaaaa cttatgaatt gtttatttat agaattttcc atttaatatt 11100
ttgaaaaggc agtgtgccac aggtaattga aaccacagaa agtgaaactg cagatgaggg 11160
aggactactg tattcttaga gcaattgtat atcattggaa tattattgat agtttaatga 11220
aaaaacaaat tagatcaaca tgggntggta ccattaggaa agatggtaga ttttcaattc 11280
aaattcacaa ctttcaaaga aaaatattgt gagtctctgc tatgagatag atattgagaa 11340
atggtgtaga tatatattcg tctgttttca tggtgctaac aaagacacac ccgagactgg 11400
gcaatttaca aaagaaagag gtttaagaga cgcacagttc cacgtggctg gggaggcctc 11460
acaatcatga tggaaggcaa gaatgagcaa atcacgtctt acacggttgg cagcgggcaa 11520
agagagagaa cttgtgcagg gaaactcctg tttgttaaaa ccatcagatc tgatgagaca 11580
tagtcactac cataagaaaa gcacaggaaa gatccacccc atgattcagt tacctcttac 11640
caggttcctt ccacaacgtg tgggaattgt gggagttaca gttcaagatg agatttgggt 11700
ggggacacag ccaaaccata tcaagatatc agcagaaatg agcaaaaaat gagtgatttt 11760
aaaattactc ggtttattac tgacattctg atgtgcattc cttaagagat aattacattt 11820
tacacctaat gccaaagttc ttacagttca aactctagga gcaagagctg cccaagaacc 11880
attgccaaaa agttacaggg agagcctcag tgtttgtttg gactctccag ctcctacctt 11940
cccctctctc tttccttgct cttctctctc catcattctt cccagccttc ccaggttctg 12000
gggactcagc ttccatgatg ctgcctcaga ctttctatcc atacggtatt attgcactgt 12060
gtctcagagg agaagaggga ggccatctgg agaaggtaca gggcacctca gcagtgtctc 12120
ttgcctgtcc attgctcctg cttcctgatc cctgccaggg gcacacctgg agaaacttag 12180
aaaacccttc agaaaagagt aacagagaaa actcaccaaa tacaagccat tcaatgtgcc 12240
atcataggtt caacccaaat cttgtttcag gttacagata gagaattcca gtgcttctta 12300
tcagctttac gaattttatt catgcttcag aaagttgcta aacagtgtaa atgaatattt 12360
gggagaagaa taaaagaact actccgaaaa tctgaaaaga gttaaaataa attccagtgc 12420
actttgattc ttcctttata aatacaaagg atttatggtc ttttgcatca gccagggtgg 12480
ccactgggaa gtcagagttt atctatatcc atcttcacat ttattacaac cacacacagc 12540
atttatcata cttgtattca gacatgatgc tattattatt ttccactggc atggctttta 12600
aaccccaaag cattagagac agatagatag atagatagac agagatattt atacaataaa 12660
agaattatat atataaataa aatttcttta tataatgaag aaattcatat aaaggaatat~ 12720
attatatact atatatggtt gtataaaatt atatattata cattatatat tatatgtaat 12780
ttacatgttt ataatttata attatattat atataattat ataatttata aaattatata 12840
taaaaattgt gtatattata aaatatgtaa tatataattt ataatatatt ataatttata 12900
tataatacat aatatatatt ataatttata tataatacat aatatataat atattataat 12960
ttatatataa tatataatgt attatatata tgatgtattg tatatataca tacatatttc 13020
caccaatgtg attttaaaag actaccataa actcactgaa aagaaaacat aacagttggt 13080
ttccaagaca tgaggacatc agttggaata acgtttcttc catagaatta aatgcatctc 13140
tggtgtcttg gaaaggcaat ttcctctcaa atgggtaaag tgtttgtact aatactgtat 13200
aaaaatgaat acaataaaat aggcgcaaag aatctcacaa cttaaaacat cccatcttta 13260
ttctatagct gtaagctcag agagacaatg atcccatgat tttatgggag tagaaaaaca 13320
ctttattgag tgttttctat gtatcagaca ctgtgtacat tttgctatgt tgtcccgatt 13380
ttattaaatg cagtcctttt cctgttcagt gtcaccattc ggaggttttt ttcaagacac 13440
tctggtgctc catgagatct aatctccatt aatgtgacat atatgctgat attatgtaag 13500
tgtgtgtgca tacgtacact gacacacatc gtttgcattt gtaatttttt tttacccagt 13560
tgcctcataa aagattaaaa tggaagatta gactccattc agagtttgac aatgcctcaa 13620
taataaatca gttctcatca tttgaagaac tatgaggtgg aacaaaaact gatttgagat 13680
tcataccgtt gtatacctac tctttaaaaa aaagatgcaa tttacacatc tgcaaatctt 13740
aggaaatggc ttagagaatt tgcatgattt gggcacatga agccatttta gcacataaat 13800
tccttccttt catctctaac gggtgtagaa aggatacaaa catatttttt gcagatgatg 13860
tgaattattg actggcataa atagcaactc acactaaatg cttcagaaat gtgtttttta 13920
attgagtgaa gatggaataa aaaaatgcag gaaaagtcct gttctatgag agctgaagat 13980
atggaattag atacagtatt tgtgagtgtg tgtgtatgtg tgtgccatag ctaatattat 14040
aatttttggt tggtcttcct tgtccattta atgtttgcag catttgttga tggattttta 14100
ctaaatgatg acaaaataat gaagcagatt agtaagaaaa cctacaaatt gtttactaga 14160
tcttcactat ctatattaaa tagatgaact aaaaggtaaa tatggatttt tacctactaa 14220
agaaaactac tagaatttat tgcactttaa aaatatcatg tagtgtgttg taaaatgaac 14280
ccaatcagat gttctcttaa aggactatat tagggtattg taaatagttt tcctaaaagt 14340
ggattttttt tttttgcacc acaattcaaa taatgccaga attgccagct ataaaccaaa 14400
tgtgaagtcc atgagcttga aaagcccata gtgttcacgg ggatcagtcc ctttttttac 14460
actggaaaca gccccagaaa gttccagcca gtaatgaaag atggtgcaca atggctgtga 14520
cagaaccgtg atcaaattcg gtcattgtga gtcttctggc cagcgtcgat tttctaccac 14580
atgtgttttg cggcctccat aagatgttaa aggaacactg aatcattggc aatccataat 14640
actcagattc ttggcttaga gagattattt accccggggt gcctttctaa cataaacact 14700
agccttgggt atagtaacag ggagtwcata gaayagtcca actcatatga atgcaagaaa 14760
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
112
ttataatgtg attaattttt ttggtcattt caatttattg aaggtaattc agttggctct 14820
gtgaatgtat ataggaaatt tagaaatatt awtatgtttt tatttttttc ctctaggtta 14880
actgmagtga atcaaactat tggattataa ttccatgaag gtaagaaaga gctccagatg 14940
kttttcatcc tatcaccagg acctgcacag tatgagtamc tggtgcataa caaactttat 15000
taattatctt ttctctcttt ctttccccaa ccatgtgtat acatacacay gcacacacac 15060
ayatatatrt acatacacat atatacatgt gtatggatgc ataatcacat acacacgtgt 15120
atatatacac atatatacat gtgtatgtac atactcacgt acacatatgt gtatatattc 15180
acatatatac atgtgtatgg gcatatacat atatataata catgtgtatg ggcacattcc 15240
tctatataca cacatacaca cacgtacata caataaataa atggttgaat ggcaaaatga 15300
ctaaatggat ttagtacaac ctaatgatat gccacagatt tgtcaaagag ccctggaatt 15360
gagtaaaaat gaatgaacta aattccaaga tcttttacaa cctatgattt cattccagca 15420
gaaatttgta aatatgtgta ccatagattt atacaaaacg ttaatggtgg cattatttgg 15480
aatagctcca aatgggaaaa agcccaaatg tcaatcaaca gtagaatgga tggattttgg 15540
tatatccata gaatggaatt ctagaccaca gttaaaatga gtagattatt gctacaccca 15600
gcaacatgga tgaaactcaa aactccttga gtggataaag ccaggctgtt tacgattaca 15660
ttctctgtaa gaacttttat tcaaatttca aatacaagca aaactattct acagtgagac 15720
aagtcagtgg ttacctttgg cagttagtgt acccaggctg gggcaggagg gaagtttcta 15780
ggtgatgaag atgttttaat tcctgatcta atcctagctt tactgatggg tttactttga 15840
aaaattcatc aaggtgacta tgcactttct gtaggtttac atgaaaattt caatgacaca 15900
cttgattgta tgactttgga tattactttt cttttctgtg ccttaatttc ctcaattgaa 15960
aagtgaggaa gagaatgctt acctctaagg attgacatca agattagtgg ctgagcacgg 16020
tggttcacac ctgtaatccc agcattttgg gaggcagagg caggcagatc acaagatcag 16080
gagtttgaaa ccagcctggg caagatggtg aaaccccgtc tctactaaaa aaatacaaaa 16140
aaaaaaaaaa ttagccaggc atggtggcat gcgcctgtat tcccagctac ttgggaggct 16200
gagtcatgag aattgcttga acccgggagg cagaggttgc agtgagctga gatcacgcca 16260
ctacactcca gcctgagcaa cagagcaaga ctccatctaa aaaaaacaaa acaaaacaaa 16320
aacaaacaaa caaacgaaaa gattagatta gcaagtagag tatgtgtaaa accacctgga 16380
aaaatgcctg gagtgtgtgt tcagtattta attgtagaaa cagttacctt cataaacaac 16440
aggacattgt gggaacatct gttaattacc gaacagtctt tttaggaccc cctggggttt 16500
gtggatagta atttttatta ataacacctt tatatgggct gaaatcacaa tgatactgtg 16560
tcaaattaac cagcagttaa gagctatgct tcttcttttt gccaatttac ttgttttatt 16620
tgtttttaat tgacaaataa aattgtgtgt atttatcttg cacaacaagg tgttttaaaa 16680
tatgtataca ttgtggaatg gctaaattga gttaattaac atatgcatta cctcacacag 16740
ttattttagg aactacgttt ccagaagtct gtaaggtaga tggattgata tttttaacct 16800
gattcattca ttcttcattt aacccaggaa ttttttgagg gtcagtttca gagcatgcgc 16860
tacactaagt gtcgggatta ctaacatcaa ggaacagtta ctgacacaac aaatcgatgt 16920
gaagtcctaa aagagagaac atagacagac acataaaaac atagtataac acaatatatt 16980
aaaatataca caacaaaaca tataagataa acacagaaat gtttggagca atgaattaga 17040
tacttaactg gtttagaaat gttttgaaga aatgtatgct aatatgtctt ttgttcaaaa 17100
tttattaatt atataattaa cttttaatta tgataaaata cataatataa aatttattat 17160
cttaagtact tttaagtatt cagttcagtc atgttcacta tatttatatt gatgtggaac 17220
agatctctaa aacattttta tcttgcaaaa ctgagactct acaccctttg aacaaccttc 17280
cattaatatt gtttacatgt taacacattt cattatatta taatgtatta tcgataacat 17340
attatatata aatatattta taaatataca tgaaatttgt atatttgaag tattagtttc 17400
aaacaatgct acatatatct aaggcttcta gtcctatatt ggacttacag tggaaatctg 17460
ggaaattggc cagcatttca gtgtgaagga ggaaggatgc cgtgttctct cccatctgtt 17520
tcagaaaacc agtgtggaga agatgcataa taggcttgac gcatttttta taatgatgtt 17580
tatattttca ttttcttttt catagtcaca atgaaagtga aagcaaagga aagagctaat 17640
gtcccacagg ccactgggta atagcgaact gtgaagggtg tggagtggac tcactgggag 17700
acgggagccc atggacccct ccccagctcc tttgctccca cagcaatctt ctcccttctc 17760
tttctttgtc tcacagtcta gaagagtgac atttcaaaaa ttatagcagc agaggtgttt 17820
ttacctatag caaaagatgt acatgtaatc acattatgac atactacaaa acaggtaaaa 17880
acagtagttt ttagtacttt tataaattca aacttagcaa ttttccttat ttcaacatta 17940
atatcaatag gcattaatgc cagtttttta atgccagtga tttttaacct gctgaaattt 18000
gttttataac ttactgcggg gtaaatgaga tatttagtta tacttttgaa agtattgctt 18060
gtgtataaaa caccttgaaa taaaagtttg aagatgtcct atgagttgct gtgaaaagag 18120
tagttgtgaa agtttcaaaa tgacagatgc attttaatgg cagagtagga gttcatttat 18180
ccaaaaaaga gggaaataca gctcaaagag taaagcagat gcagagaaca gcaaacaacg 18240
gtcagagcat tgtgaatctt cggctttgat cttgagtacc tagctagata ttactgtcaa 18300
cggctaagat taaaatgtaa caatatcagg ggaaatgcat ttgagaacag taaaacattt 18360
attttgtaca tatatagctt gaaatgcata tgggaaatgt aggtggagat ttttagtagg 18420
caatagcata tgtgagtttg aaatgtaatg cggatatata atctaaaact ggttctcaat 18480
tctgactgca cattaggaaa tttactgctt aaaatgacta aatctcaggc ccaactgcag 18540
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
113
attgattaaa ttaaaattta tggggatgtg cgcctgaatt ttttttttca ttaaaaaaaa 18600
aaaaaaaaga ctccccaggc gattataaga aactgccagc tttggaaact gctggcctac 18660
aattagtgtc aacgtcatca ttgtgtgggc tgttgttgga tggatgagaa caaggatgga 18720
tgagaacatc tagagagtgc aggttgttcc tcttcttgtc ttctatttgc ccttcagatc 18780
tgccctttca tgtagtctgg gcaccagagc accctgagcc cagtggactg caccagtgga 18840
ctcttccatc ctcagggttt tggtaagcac catctagagg aggcatagag agaaaatcag 18900
ggacccagga aggtgaaaac aggttttgtt ttcccagctt cctttctgct gggtcaaggg 18960
gtaactgcag gttgagggtc atcctcagtc aaaggccaca gctgcagcag gtgcacctct 19020
tcacacagct gcttctagag tctgcttagc tgcttcaggt caagggatga tgaggtctcc 19080
caactgttgc tagctctata gttctcagcc atcttcagtt gattccccta aatcctgcct 19140
gccccttcgt agacagtacc ttcattaaat attcctcatt ggttaaaaag tagtgacctt 19200
gtgctgaata ttctatgcca agcctctgcc tgctgcagta acataagaag agttgtggct 19260
gaagatggaa ccaagagaga aaatgacctt taaaagatgt aacgaggtgc ccagggaaag 19320
ttttggcaat ggaatctgag catgtagagt ttaaatgtaa gaacggaaaa atatctgttg 19380
tatttgaaag gtcacgaaag gcttcttccc gagaggaatt ttagtggtgc gctaacaaaa 19440
atcagatggc aggggctggg gcatcaatgc aagtgaagaa atgaagggtg gttatttgac 19500
aagtttgatg ataggaggaa taaagaattt ggatttatta aaaataagac atggagctaa 19560
tcaattgaga ttgccaaact cttttaatga aaagtagctg tgctctatct ccagcagttg 19620
caacagagca ctaataatat caccgagact attgatgtga gggcaatata catactcagt 19680
gctgtaaagg cttagatttt tgatagctac tcaaggaaga acacaaagaa ttaagtcttg 19740
atttttaaaa tgaacaaaga tataaagaga gaaaatacag aatgtatacg aataatcaaa 19800
acatatgaaa cgacagccat ctctggtaat caaaagaagg ctactacaag caatgatata 19860
tgttttgcct tataacttca taaagattca gaaaatgggc catagccact attggcaaga 19920
aggcaaataa agtccatttt tggtcagaat gtcaatttat gtatcttttc tgaagtctgg 19980
tctttgcact cttacccttt taaagaaaac attaattgtt tcactgaagc tctgagttca 20040
tatggccatg ctctcctgcc caggtgttct ctcccttaag ccttctcttg agcacttatg 20100
tgccactcat catcatgact tcagtcctta aagtttcttt aataccactg gactataaaa 20160
taggactgac gaaaagaccc attcaacatt ccattgaagg attaaatgct atgttttaag 20220
atataatttt ataacataca tctatcatga aatccattga ctcttcacaa ttagatgctc 20280
ttacatagaa aacatagtta cttacaaagt catggttgaa atgaatctct gctgtaacgc 20340
cattacatat ccctaaaaca tatttaagaa ttatgaagag gagcattatt gaaaacaaaa 20400
tgtattgaca ctaaagagta actattttaa aaaggtaata tcatgatact catatgaata 20460
tcaaatgaat gcatgtcaaa tattttattt aactctttaa ctaatgaaga aatgggtatg 20520
atgctacacc caattcaagg tagaattcaa aattcaaaat aaacacatat atacataaat 20580
caggaatttt gaaatgaatg tacaaaatga tgcaaaactg gctttttcca tggagattgg 20640
ggtcgttgtc caggaatcag tagttatttc cagggacaaa attcatttgc atttctatgg 20700
gcaagtgtca tttaaactgc aatcagttat ctacaattta tggaatcgta accactttaa 20760
aaaagatgaa aacagttaac ctgaaagttt ctcctgcact aaatgagaaa gaagctcagt 20820
tatttttaaa tttgcttatt tttgtcttgt tcttttttaa tttcacaata tttgactgac 20880
agtaacttac ctgatagtga taaatcaatt tgtgccacat ctcatggcat atcagctttc 20940
tgtgtctttg tccatctcaa acaaccccac atgcctacct caacatgagt tttatctccc 21000
ttcaaactgg attaatggta tccatgttac atgactttat acgtgttctt cactttacag 21060
caaatagtta tgaacaatta atggaacaca cacacacacc cagataggaa tgggaccctc 21120
tgagttttgt tcacagagtc tatactcttt tctattgtgt catataatgg tgacaattca 21180
attaggtggc ctatgtccac aatccatggc ataaacgccg gtaaatttac agattctccg 21240
catcctattt ggcaagtgct tcagtgatat ctgtagcctg aagagaaaag ctaagttttt 21300
cctatttctc tctcttcttt ccttcccttt tcttttgaat ttcctaaaac aaaggaagaa 21360
aaaggagggg aagaatttgg caatgtgtca gttaatttca tcaatgtaga caaagttaaa 21420
ttaggaggct gaattaccaa gactggctgt ttccattgat gaaattaaat caggtaaatt 21480
gccagtgctt cacaaatgct gtctcaggtg tgactgaagt tgtgattgat tggaaagtac 21540
tcacagagaa aacaagtaca ggaaaaacag cactattcca aaatgcagaa caaaaccaca 21600
catatttagg ctttacagtt ttcgtgctcc ttcatattct tactttgatg tatttctgcc 21660
ttttaattta gscttttcct aaaaaaaata gtttgcttta cagtttacaa agtaagatat 21720
gctttaagag gtagaaaaat gaggcaagtg aaaatgaatt aaaaaaaaaa aaagaatcca 21780
ggagcaaagt cagtccacaa agtttgtctg tgacatcatt gtccttccaa acaaggagct 21840
tcgagttcaa ctccaaacat tagcagtgca gacgggaaaa tgcagtgacc aaaatcagag 21900
tccctgggtg aaaagcaagc catttaatag gaatgaaaga gtcctgctat aaatactaca 21960
gaaaataatt ttcaaatcta ctatcctaag gagaacactg tgcaagataa tgaatatcat 22020
ctttagaaac atcttcttgt aattatttct taaaatatcc ttccagacaa agcaatgaca 22080
tcattacaaa ctccaactta gcaaaacgct ttttggaaaa aggaaagtgg aaggacattg 22140
agtgatgtcc acatatgtag ctctctgatg atttgacttc atccaagaat cgtgtggaaa 22200
cagctagaat ggggtgaatt ttatatctcc caaacagttt ttcataaata tcattttatt 22260
tgactaagct ttcaagtgtg actcaatgat agtaaagggg agaacctaat tcctgacaat 22320
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
114
tgcatgagat gttggtcttc agtgttgcca gttaactgag aaactatgtt aataatcagc 22380
cgcgttagcc cttttctgtt agataatttt attattcgca attctctttg atgggtatta 22440
ggtttagaca attgaccagc aaactatttt tttttgaaaa tgaccacaaa catgttaaaa 22500
atggatgaac cctgagagga gacaggaaaa cagcacctaa aaatagtaga aggatattat 22560
ttctctgcca ttatggactt ataacataat aaacatttag ttggttcact tttttagtat 22620
caacactttt attaattgct tcttttttta caaatttgat tttattattt tgatacctac 22680
tgatctctaa tttcttgaga aagtctgtct tactttaata aaatgacata cagtgcattt 22740
taaacttaaa tactgtatat tcatatttaa atctgagatt attgggacat aatgatataa 22800
gaatttatat aaggccatcc tctgaatcca tattcaatta aactaaaaaa ggatgtccga 22860
tttaggaatc ccacagaccc atcagtaatc aggcaagtac ttaacagcca tcctatcatt 22920
ggtctctcta gtttttattt attcttgtag tattagcaga tgatttctat aatgttgatc 22980
aaatcagatt tacgatctaa gttgagttaa atctcagaga atcaaactcc attgtggaat 23040
ggaagttttt agtttcttat atatggcaat attttgtaag atattttcat aactaacaaa 23100
gtattctcat tataaattaa gtacatttct cccttaagct ttttaaaaaa aatgatttta 23160
gaaaattcct gaaataagta tcaaaatgca agattgtaaa atacgttttg ataaatcaga 23220
aacattctta ttaagagttt tctttattga taagttatac ttctatgttt ataaaatatg 23280
ttgtattgtt aaatgaagcc aatgaaattg atcaagggtt aggttttaga atatttctgt 23340
ccagagcttt gctcctccaa attctgtcgt gttagaattt tattttttga ctacaggagg 23400
atagaagcct aaaacatttt aaaactacat aatccgtttt taaaattaca catgtaaaat 23460
ggtgtgcaca aataaatact ctgtcacaca aacatgcaca cagagcataa acacatgtac 23520
acacattaca tattaatgct tcttctagga cagagattaa taagtagtag agaaaaaaga 23580
attacagata caatctcaaa gcttgtcata tttctacaag gtaaatatat atctcagtga 23640
tagtgctatc aaaaccatac catcaggtta aagaagtggg taaatattat cagaatttaa 23700
tgtgaaaaca ggattatatt cctactattg cctggtgaca tagtactcaa cacatttttt 23760
ttcgtgttat tcatgttaaa tgttaatctg ttaatttaaa ttaaatcaaa ttaaataaaa 23820
tctgttaaag aaaattgttc aaatagcttc tccctaaagt tttctttagt tcaaaagatt 23880
ctgatgctat attttaacct acagcttaca aacaaatttg ggtcttttaa aacttccatt 23940
ccctcaattt tagtaaaaaa gaaccctact tttataactt acattaaaca ttggaaataa 24000
tgtataactt acttattagt cttaactttg ggagagaaga ggtttaagta cgtattttaa 24060
aaaaaacaac agaaatgagt actcatgata aatagtatat gcacctaaaa tatactaaaa 24120
ttaatgagta caaatactca ttcagctctc aaagtaactc tcccaactga ataaacacgt 24180
ttaaaaatat tttaatgtat ttatttgtga gttacacaaa tccattagtt taatatttag 24240
ataatatgac aatgatatat gagacacaat ttattttaag aatatttata taataaataa 24300
ataaataaat aaataaaaat aacataacct aagtatacct tagaaaaact atggggaaat 24360
gttaaagata aggcttggga actttgccag cacagtgtgg gtatcatagt gtaggtattc 24420
ttatttcaat taaactagtt gctttcagtt taaaaagtag atgattttac atacaagttt 24480
gcacttctag cttctctttt caaaatgagt tcaggccttc ccatcctgac accttgaaaa 24540
agctgtggcg aggccgggcg cggtggctca cgtctgtaat cccagcactt tgggaggctg 24600
aggcgggcgg ctcacgaggt caggagatcg agatcatcct ggctaacatg gtgaaacccc 24660
gtctctacta aaaatacgaa aaattagccg ggcgcggtgg cgggcacctg tggtcccagc 24720
tactccggag gctgaggcag gagaatggcg tgaacccggg aggcggagct tgcagtgagc 24780
ccagatggcg ccactgccct ccagcctggg gaacagagag agactccgtc tcaaaaaaaa 24840
ccaaaaaaac aaaaaaaaaa acaaaagctg cagcgaggcc gtttctgaag atggcgggta 24900
ttgggcactc tttacttcct tgactctact cctgcactct gagactgacc gtataacatt 24960
tccgattttc tttgatttgt gctattgttt ttcttatagt taagggaaat gtgaaatatt 25020
attgtacctt tgtctgtcaa aatttagaaa aatgaaaaat agaccaaagg tgggagtata 25080
attcattgca aaaacttgat atcctaagct agtgtgtcaa aagtgtacaa tttcgagcat 25140
tattatgaaa taaatttagt aagatctatc accaatatat aagaaatagg atacaaagtt 25200
ttatgaacta aaaagaaaat tctcattgaa ttgtttttta atcaaattaa atgaagctac 25260
atcgaaatat ttaaaaacat gttggcaatg atgagtctat aaagcaattt agtgggtata 25320
accctcccaa tttgctgata tgggccctgc ctggttttgg gggccttgaa tctgcaatcc 25380
ctggtggagg acaacacccc tgtttctccg gacctgagag tttttctttt aatctaattt 25440
ccttcacatt ttaatcatta gcttatcttc aaactttttw aagaatgatc ttaacaaatt 25500
aaaagtaytt tacaatgtat tgcatttact atgtttgaat aaaacattat tttgccacta 25560
tcccaaagga ttgttatatt tttctatttt agtaagttta ttgaagacaa acaggccttg 25620
ggccgctgcc tctgtctctc ctgccttccc cactgaatct ccagcccaca ttcacaaacr 25680
aagacaaacc tgtgtaaact gaagcaccac aaaactactt ttatgaaagc agamtggaag 25740
gtaagtgtca taatctgttc ccccttgyac tgtagcataa actttatcga actcactgca 25800
gcaaatacct ttgtctttca ccaagaaatg gaaattgttt ggtgtaattg tgccttacct 25860
tcccgaggta tatttctgga tttgatttac tgaattcaaa gttgaatgat tcaccaaact 25920
tcttggtttt caatgcttaa agtcccaaat aacttttctt aaaatcagag ctgccaaagt 25980
taggaatgat tttaatatca attcccgaga ggtgtagaag tagctactgt gctatttctc 26040
acactttatc aaccaaagtc accttcacaa gcatcctcag gatgaagact tcaataactc 26100
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
115
ttaggctgtc catttctcta atgcacattt gtggttgtca gaaaattttt tttatattga 26160
tttgaatcaa ttgatccatg ttttgcccac cagaacaaca gaaaccaaat gtattctttt 26220
tgtagtactt ttcattttta aaaacaatta ctagaatccc ctgagtcttc ttttgttctg 26280
tggtccttcc cccaggacag tgtgtccagg tggactgccc ttccaaccct ctcctctctt 26340
tcagacaact ttgtccatgt ccctttgcag aggccctggg cagagattcc cgccgggagg 26400
tctgctcaga ccagtgcacg ctgaagctaa tgagtcattt tatatggact tggtgatgat 26460
ctcagtgtca taaaaaggag attccattat ttctctttca aatacagccc tagctgctga 26520
ggcagatctc tctgattctg tattttaaat tgatttttga atttaaattg agagatttca 26580
ggtcttatac ttttagagcc aaaagagaac gttcacatca actggagatt agggttaatg 26640
ttccagatca acggccaaat agttacgtgg gcttgaacaa ctgtcccagt tggcctcctg 26700
ggacagctgt ttgctgtaat atgggaatag gaatgtcatc tccccctgcc ttacaggact 26760
cttgtgagga tctactaaag aatacccata aaagtctttt aaaaaggtta gagaacagaa 26820
gatgtcattg gtttatacgt gtatcctgat tccactcctt ccatatcatt gtctcttcgt 26880
gaaaaccaga cttctctaaa agctcttgta ttattatttt ttttttttcc aaacaccaac 26940
caatactctg acaccatctg tgtggacagc agttcaattg gattctaact aaccagagtt 27000
agagaaaacc ccacgggatg agggcccaat gccacaagat tgcccccata tcacatgcca 27060
gccacaaaaa gagtgccagc cttcctggtc tcctgccagg cccactacaa acacagggtt 27120
cccaccattc ccacccctcc aaatgtgaca actttttaga acaactcata gaactcagga 27180
gaacactaca cttactgatt ttttnnggtt tnnattatga aggacagttc aggaccagtn 27240
caaatggaag tggtgcacag gacgggctgg gtatggggta ggggaatgac tgggagcgtc 27300
ctcaccctct ctgggggcac caccctccca gcacatccat gtgtttngcc agcttggaag 27360
ctccttgaat ctcttttngc tcacgagttt ttataaccca atctctaata ccctcctttc 27420
cctggaggtt agggggtata gctgaagatt tccaacgcct aatcaccatt tggtctttgt 27480
tgtgaccagc cctatcctga agctatacag agggccgcac cctaggttac ctcagtggca 27540
taaacacagg tgtagtagaa aggggcttat tatgaataac agaaggcact cccatttctg 27600
ctagtcccga gggttttggt agttctgtgc caagaacagg ggaaaaagat gaagtacaat 27660
ttttattaca ccactgctgt ccatactggt taccagcatt ttctttggtc tctcctcaaa 27720
tgacaccact ctccgctgcc ctgtcacttc cctgaacagt tctcttggtg attttctctc 27780
ctcgtcctac tttccctttc atgagcacaa gaagtagtca agcggtgaac cctttatcgt 27840
tcttgaagca cctctcactt tggagacttt aataccacaa cctgcttgtt ttccttccat 27900
gcttctgact cttcctgctt tgtctccttg gagatatatt agtgagagaa gtaaaatgtt 27960
gcaactggtt taaatgataa tttgatatac agatatatgc attctccaag gcacagaatg 28020
tatttatatt gctaagaaat gtgctaaaaa gtggagacaa ggcctgaaga atccctgagc 28080
agacaacact agtcaggcct cataagtgac ctcaaccttg tttgatttgc aaacataagt 28140
gaatgtcagc ttgagctatt tcttgtaaat gcctgtattc aaaacagaac ttaagcttaa 28200
ccagtcagaa gcagtctact cacttataat cctataactg gggggacttt ccgaaggnat 28260
agatcaaata aggcaactgt ataactgaaa ccaaccaaat gctttctctg atttacttct 28320
gtgttgttct ataaaagcct cctctttctg tttcctcagt aaagctcctg aaccagttct 28380
actttggagg tgcccaattc atgaattgct tgctcaaata aactattctt ttaaaattta 28440
ttgggcctcc atttactttc agataacagt aattatttgc atgcctatgg aaggaaacat 28500
tggtattact gtcttttttt tttttttttt tacaatttaa gttctaactc tacagaattg 28560
taaaataaca taagaattaa cccaaaatgt gcattcctat caagtcagat aatcacccag 28620
aaatcctgct aaaataattt ccagaatttc actgaaagga cacctagtca tttcttttgc 28680
ccatttcctg acagtatctc cactagtaat aaaaataata ttgaaagaaa attcttaatc 28740
tcaaacaggc caaggatgcc cataaggttt gacctgatat ttacatagtt gcagaagaat 28800
ttaaactaac catatgggca tctttgagtt tattctgtag ttcttaatca atgaattatt 28860
aagcaactac taagaccaga gaataaactt atgactagga gttttcaaaa gaaatctttg 28920
attggtcttc taaaaatccc tatgattttc ttttctgtat tagttcattt tcacactgct 28980
ataaagaact acctgagact gagtaattta tgaagaatag aggtttaatt gactcacagt 29040
tctgcaggct taacaggaag catgacttag gggtctcagg aaacttacaa tcatgccaga 29100
aggctaaggg gaagcaagca catcttacca tggcagagca ggagacagag cgagtgaaca 29160
aagggggaag tgccacacat tttcaaacca ccagatctct tgagaactca ctcactatca 29220
caagaataac aagggagaag tctgcctcca tgattcaatc acctcccacc aggccccttt 29280
cccgacacat ggggattaca gttcgagatg agatttgggt ggggacacag agccaaacca 29340
taacatattc taagacgagg aaactgacca caagaaactt tctccagcag atttcacctg 29400
cawttcctac attcaactga atcctttaaa ttgactgagg cacatcctgt accaaggaga 29460
gacctttgtt actgcctttg atcctgagac cttctgagcc aggtacttgg gtgcttttcc 29520
tggggaggct ttgaggygtt tactycacac ataatgtcaa acgtgtttta taatagtggg 29580
atagtcagac ttgattaaat gagaattatt ttcaaatatg atactaagta aggtcttgag 29640
tgtagaatca aattstccaa ttatatccta ataaaaagga agacagattc ttagtggacc 29700
ttttcaacta tctatacagc agtttcataa aacattagga aatttagtaa accttattac 29760
ttctggggag tcagtgagaa tcagatacat ttcttaaatg tttcatttca tcaagagcag 29820
agtctatgaa attaagggta agatttgctt caaatcttaa gaagaaagca ctttgatata 29880
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
116
tatcttttaa aactaaaaac aacattgatg gtattctaca atacttgcat tttcctctca 29940
cttatgtagt tcattcctgt tctcaggaac cctgctttta agaggaaggt cttggccagg 30000
ctcagtggct cacacctgta atcccagcac tttgggaggc cgaggcgggc agatcacctg 30060
aggtcaggag ttcaagacca gcctgaccaa tatggtgaaa ccccatctct actaaaaata 30120
caaaaattag ccaggcatgg tggcaggtgc ctgtagtccc agctactcrg gaggctgaga 30180
caggagaatt gcttgaacct gggaggcgga ggttgcagtg agccaagatc acaccactgc 30240
actccagcct gggcaacaga gtgagactcc atctcaaatt aagtaagtaa ataaataaat 30300
aaataaataa ataaataaat acagtgtcct ggaaagcctg actcggtaga tggttaccct 30360
ctgagagttg gttaagtaat atcaccttag caggtgatat tacataagag accattctgg 30420
aagtataaaa agttaaagtt gctggtacaa acatttccac aaggctctaa gagccctctt 30480
ttactgaaga caaactgtgg tgtgaatctt acatcagtat ccaacatcag agtaacgaga 30540
aactacctgt agatgacaaa gactgaatgg ctgtggccaa tttattataa taaccagtga 30600
tgtcagaatg gagaagaggg gaattctcta tggggtgtag taggcaacaa ttccataaga 30660
gtttggcaat gtttctcctg tgctgggaat tatcatgtac agccagagta ctggcaaatc 30720
ttctggacct tcccatgaat tatataattt ctaaaatatt tatattaata atttatatta 30780
ataaatgaaa ttgtgtcctt gaagttcata catcaaattc ctaaccacga ataggactct 30840
atttggagat aagggctttg tggaggtaat gaagtttgaa tgagatcgta agggcagggt 30900
actgtgatca taagaacccc aatatgactg gtgtccttat aagaagaggg agagacacaa 30960
ggagcatgct tacaagaaaa ggcaatgtga ggacatagtg agaaggtggc catctgcaaa 31020
tcaaggagag agaccttaca agaaacctac cttgccagca ccgtggtctt ggatttccag 31080
cccctagaac tgtgagaaaa taggtttatg ttgttcaagc cacccagaca gtgttatttt 31140
attatggcag ccaaagagac taatacaata atatttttct gtttaaattt tatctagcaa 31200
tagctgagga tctttcccaa tttaataatg cttgctatgc agctctcacc atagtgtcga 31260
ggtaatttaa gaaatatagt gcacatcaca aaacataatt atttgtagca tcactctttt 31320
cttaaggtga aagaataaat ttttatgaaa tctcaaaaga gatgtagaca tttgattcat 31380
ttttcttaat ttaggataca atcttagaaa gccaaaatct aaataattgt tggtggagat 31440
ttgggcactt atttaggata agatcatgga tacctaaaaa acagtggttg gttaattcat 31500
caaaatgaca tcaaaatatt ttaaagtaaa cttagaagtt tccacaatta taaatattct 31560
tagctctttc caaagctaga aaatgtttta tttttagtaa tcaaagatat atgaaagtaa 31620
acacagaaaa attattcaag tgggatacag aatctctatc acctattatc agaattttga 31680
ttacacaaaa gattaaaaaa tgacttttca cattgtaggc aagtcacgca tcattaaacc 31740
aagggaacaa gcacatcaaa aacagagtga aatttgccaa aatataaaat attttagttt 31800
tgttttagat taatatgtta ttaacaaaga caaaattcaa tttctaagtt ttgtttttca 31860
ctatactctt tcatattctg gaaagatctg tcacttttct aaaatacaaa actaattctt 31920
ttcctcgaaa gacaaaaata tacacacttg tgtttccctg actctattat ccttagtaga 31980
gtctcaatca cccatttgat taagcttatt tcatagaaaa aactgggtta atgggggaat 32040
aattaagaac ggatgtcata cagtatttac tgtattacca aaggtcacag gaaacacacc 32100
tggtggccgt gtcatccatc ctttacatct gcttgccatg gcaaaaataa atatactcat 32160
tgatatagat gtatcccaag agatagtctt ctggacagca tataaaaata acaagcacaa 32220
gtatgtaaac ttaaatttat atttagtagt caaggactca actgttatac attcattaga 32280
agttactttg ttttctaaga attctccaat tttaagggta tttaacatta gtcaaggtct 32340
taagtaacct aaggaagtta gaaactaagt taaagctgtc acactgcaac acatagttac 32400
tattgacaga aaaggtttat cataataata atttaattta atgcaatttt tcatatttta 32460
cacattgtgc agaaataatg ttagttttta tgatcgatag accactataa attcagaaat 32520
tgcagtttga ctcttatcat catgagaaaa gcaaccaaaa tagagtgaat tgtaggtcaa 32580
attatattta gtgtggcttt atcagaaaaa acatatagac tttttaataa atgaaattat 32640
ttatataatt tgcctaataa tggaattaga taaacttgga atttaaaaat gcttctgaac 32700
taaaggtttt ataagaacat ttttaatgtt ttccaacttt attggtttat aattaacata 32760
aaaaatgtat atgttgggtt gatgcaaaac agcaattact tttacacaaa ccaaatattt 32820
aatgtacaac ttgatgttgt gacatacata tacactgtga cgtgacaatc acaaacaact 32880
tagtgtatgt atctattaca taccatggtt atctttgtgt gtttgtggtg aaaactctta 32940
atatctatcc acttagcaaa ttttaagtat acaatacact attaaagatg atatttttaa 33000
tctagtgtat ttaaagtatt agtttatttt tctttttttt gaatttggaa aaattggatt 33060
tatatgtaca tttatcttta aaagccaatt agaatagtac ctctttaatt aaagagatag 33120
gaacatttat atccactaac tgaggtcaag acctttcaca attacagagt cacaaacgtg 33180
ttagagaact cacagcctga tatcttccac ttcagccacg agtcaagaat acacacaaag 33240
atgcaaaaat ccaatggctg agatctcaaa gagaagttca gtttcccaat gtgcataaaa 33300
ttctcaattg atttgagctc acaagtaaaa caaaatagac aataagaata ataagccgat 33360
tacgtcatct tttattcaac agacagtaga cctacagaga tcatcgaatt ggcagatcat 33420
aaagccaaat tcctaattgc ttcctccagt ggaaaataag ccatcagcta tgtcttactc 33480
agcaacaaaa caaaatatat agttagtagg aaacaaagtt aaagaaacag agtgaacaag 33540
gttaaatatc tattgccatt tgataccctc tctgggaggc aggaaaattg ttcatgggct 33600
taagcaattc aggaggtcca tttcttcagc cccacagttt acctgactct aagttgatga 33660
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
117
actagacatt ttggcagata atctacctct aaacccatta acacataaca ttcccacagg 33720
taaaatcaca attctcatgg aaatatcaaa taaacatatg tcaaatgtta tttaactcat 33780
cagtttaacg aaagaaccag taagatgttg aaatcagttc tcagaaattt gttggttttt 33840
ttttcaacca agaactcccc actgacacca accctatcaa aaattgccat ttgacatttc 33900
atctggatgt tttaaaggcc tctcaattca ctgtgtccaa aaaggaattc atgactttct 33960
tttccaaatc tctttccttc tcttggggtg ttcactactt ctggcaatga tcccactttg 34020
tgttgaatta tttacaccag aaatctaaga ctaataaatg atactttatc tcactacact 34080
ttcacctgcc attacatgtt tattaccaaa ctctgttgat tttactttct aaatatctct 34140
tacctgtatc tgcttctaac ttaaccacgt tcatccatac catgacacca ccatcaccat 34200
ttcatctgga ccatatcact tagactaaac cattagccat atgtttttct cattggtttc 34260
actacctcaa gcatcttctt atccctccag ttttgtccat atatcagcca gagtgataga 34320
tatgataatg tattctacta ttagaaatcc gtaatgattt cctattgctc ttgggataaa 34380
aaacaaaaca ctatgaagcc ccattgatct taggataggg acttaaactt tcttattctc 34440
caccattttt gtgatagaga ctcaaacact gtgatcctcc ctcctcttat aataaagacc 34500
caaaccttat aacacttcat ctctcttagg ataaagacca aaatctatga taccctgctg 34560
ctctcaggat agagacccaa gccctctatc tggagtacaa ggctctctta caatgctgct 34620
agttacccta acttcctctc ttcaatattg tcatgaacca ggattcccct cactttctgg 34680
ctcagccttc cttaatttct tcataggttt ctcaacttct catcactgca tcttagaagt 34740
gtataattta tttatttatt tatttttact ttcaatattt ttctcttaaa tctcctactt 34800
tgctgcctgg ttcaaaccta tgattatcca agtttatctc atttttattt tgtcagggcc 34860
ttttccttga ctgttcaggc aagaccaagt tatacccctc tcctgatagc acttaaaaaa 34920
cattgtaatc ttggccaggt gtggtggctc acgcctgtaa tcccagcact ttgggagacc 34980
gaggcaggtg tatcacgagg tcaggagttc cagaccagcc tggccaatgt ggtgaaaccc 35040
cgcctttact aaaactatga aaattagcca ggcacggtgg ctcatgcctg taatcctagc 35100
tactcgggtg gctgagacag aagaattgct tgaatctggg aggcagaggt tgcagtgagt 35160
tgagctgaga tcacatcatt gcactccagc ctgggcgaca gagcgtgact ccgtctcaaa 35220
aaaaaaaaaa aaaaaattgt aatcttacat tgaattttgt ggttcagttt ttttctctac 35280
cactgcacag ttaatttcaa gagggcaggg ccatgtctaa ttctacttat tatattccta 35340
ctgaatatta tgtagttgac atatattaaa taattttaat ttaaataaaa tgtatttatt 35400
gagtgaatgt aggacttgct gtcatataac atatttctaa gtctgattct atcttctact 35460
atactagata attagttcca aattttatgt atatacgtta taatgtgatt agactcccat 35520
aaaaaagtat taaataataa agagagttaa tgtgtcatat cacaagaagg ccagaagtag 35580
gaaagttgta gtagtttagc ctctgaatca gatggggtta taaattaact tcttttactc 35640
accagctgtg tgagcacagt tatatattta cagatcactg aaacattttt ttgaaattca 35700
gtctgctcaa gaaaaaaaac aggaatgaga atattacctt tcacacaggg attctttcaa 35760
aattactgaa ttaatgcatt caaagaattc tttcagtact gttcaagcac ttcaatatta 35820
ccaatgacag tttcctgcag tatcttggat attattcacg tggacctata gagtgttagc 35880
catttaaaag tcatcagctg cttttgctgt ctccatgttt attgcagcat ttaggactag 35940
gttcaactac tcataacaga aaatgttact gtagtggctt aaacacaaat aatttatctt 36000
gtgcaaaaca ttcaggggtg agcatttggg gagaataaca ccaagaagcc agaccctttg 36060
taacttcctg cagtggtttt agcaccttca ggcgggaaag tcaaagaaga gaggagtgac 36120
attgggagac tttgatgtac gtatcactgc ccagaagcaa tcatttctaa cagtgaaaaa 36180
ggaggggaaa tgaaggtttt tgcctccaca atctctatag tagaagcaga caaggcaata 36240
ggggaaggga aaaaagtttg gtccatcata tatcctaggt gtaggtattt gagggtgatg 36300
accataccag ttaattaggg ggagatgagt agatcctcat ctcttccaag tataggaagc 36360
taactttgcc gtaattgtta ctaatacacc cttcaaaatc accattttga aaggttttgt 36420
gaaatgagca ttattttctt ttaatacaag gtcagacctt cagaatgatg aataaactca 36480
tttgagggca agtaccaatt cagagctgct gtaaagtagg cattttcaag aagaaggaat 36540
acttctcatg tttgaactgt gtaagcaagt ctttatttat tttttgaatc ctgaaacagc 36600
aattagaaaa gagagaggaa gatatttcct tttctgaagg ctgccaagaa taaatcctat 36660
tctcatttgt taaaataaaa agaggtaata agctaaagta agaatacact aaccttattc 36720
ttgaacccag ccgcctctag aaaaaaacac tataaaagtg aagctaagtt cagtaatttt 36780
tgcagtcatt gcctttttgt tagctctagt tatctttcaa gttttattga taataaaaca 36840
ttaattgcaa ggacaacttt tgaaatctat tattgaatac ctaggacact catgatgtct 36900
ctccacattc ttgccaagga attgctttat gaattaaacc acttggggaa ttaaaccact 36960
atcaattaaa catacagttg tataaggata gacatatact actttacatg caaaaattta 37020
ggccatagca atttagtaac taccacgtta cagggactgg aacttttcac tcctccactt 37080
cttctatctc accactctgt tatatgaagc tatgattctc cattcagaat ataactacat 37140
tagtttttga aataggaaaa tatgaaggac agactctaga aatatcagaa tcacttggac 37200
aacaaagtcc aaaatatgta ttatgaaagt gaattatcat gtttgactca atatgttgct 37260
gcaaataaat aaaaattatt tgctcaatat agatactcct tatatgcctc aatattttat 37320
atacactgac tgaatattta tgactatgta tgagcagaat aatgagaaaa aaacttacta 37380
aaaaatctaa ttattttgtt ccttttctta ataaatgtcc cgtttcacag ttataacact 37440
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
118
ttctggattt ttatttttat tctgacttta taaaataaac attattttta gaatagtttt 37500
aaattaacaa aaaaacacac agagattaca gaatgctcca tatatgttat acatatatat 37560
atatattata tatacacaca cacacatata tttaaatacg tatattatat atatatttta 37620
tatatcccgt cccctcccct agaaatcact gaattgttta ctggctctaa agttttgctc 37680
tcattattaa atatgtaaca aatatatatt atatatttat atacaatgta tataaaataa 37740
atatatatac acatgtaaaa aaatatatat atattttgcc tgctccagaa ttccattcca 37800
tccaggatac cacagaactt tcactaatct tgtctctttg ggtgcttctt ggctataaca 37860
gtttcttagg attttcttat ttttgatgac cttcacagtt ttgaggagtg ctggtcagat 37920
attttgtaaa atgttccttt cttgtaattt ttctgatttt ttaccatgat tagactggac 37980
ttagggcttg tggggatgga ctgtcacaga ggtaaaatac attctcatca cagcatatca 38040
agggtttata ctattgacat gacttaaaac tattgatgtt aacactgatc acctggttga 38100
ggtagtattt gtcaggattc tccactgtaa agttaatttt ttccctgttt ctatattgta 38160
ttttagctat atcaataaga actcatggac atttctcttg tactttgggt tataatccaa 38220
tcttttttat ttttgctcaa attgttccag ctttggtcat cggacacttt aagtagctgc 38280
tgtgtgcttt tgatgttatt gcagcttggt ctgtttagca ctttcttact ttctaaaatg 38340
tcaagatgct ccaggcttat cttgtatatt accttatgta gctccaggat taaccatttc 38400
tccaaggttt tgacaaactc atagtgtcat gtattcacca ttacagtatc atacagaata 38460
attttacagc ccgagaacag ccctgtgatt cacccagtca acctttccct cccttagaaa 38520
ttactgattg cttactggct ctaaagtttt gctctttaca gaatatcaca taaatgaact 38580
catgggtatg tagcttttac agactgactt ccttcattta gtaatatgga tttaagattc 38640
atccatgtct ttgtgtatgt tgatagccca tttttaaatc actgaataat atttcatcac 38700
atggatatac catggtttat ttgttcattc acctattgaa aggcatcttg attgtttcca 38760
atttgggaca attataaata aagttgccac atgtataaat atgcatgctg ctttttgtgt 38820
ggatataaat gttcaaataa gttagttaaa cacctggtag tctgattgct ggattatatg 38880
ataatgctac atttttcctt gttaagaaac tgacaaattg tcttctaaag cagttgtgcc 38940
attttgagtt ctgatcagca gtggatgaaa gttcccatta ctccatttca ttgtcaacaa 39000
ttattttcat tatgttgttt tctttttggt gagttttaaa atggctttgt atattttata 39060
tataagtaat ttattagata tgtgttttgc aaatatctcc ttttagtctg tggattgtct 39120
ttttattctt tgaacaattt attttataaa acataagttt ttaattttga taaagtccaa 39180
cacatctatt tgtttaattg attgtgctat tggtgttatg tttaaaaact catcaccaaa 39240
tcctgggtca gacagatttt ctattatgtt tttgtctaga aatttcatca tttgtatttt 39300
acatacattt gtgatccatt ttgatttaat tttgtgtaag gtataaggtc tttttctaag 39360
tttatttatt tatttatttt tgtatgtgga tgttcaatta atccagaatc atttgttgaa 39420
aaaactattc tctttttctt tcaacctttt tgaccctttt gtcaaagatt aaatgatggt 39480
atttctgtac aataatcata tgatgtggct gtgtcccaac ccaaatctca tcttgaattg 39540
tagttcccat gattcccacg tgttgtggga gggaccctgt gaaagataat tgaatcatgg 39600
gtgaggtttt ccctatactg tcctgtggta gtgaataagt ctcatgagat ctgatggttt 39660
tataaggggc acctctttca ctcggttccc attttctctt ttgctgccgc catgtgggac 39720
atgccttttt ccttccacca ggattgtggg cctccccagc cacgtggaac tgtgagtcca 39780
ttgaacatct ttttctttgt agattgccca gtttctatca ggagcacaaa ataaactaat 39840
accgatgata tctgtctttt ctgttctgtt ccattgatct aagtgtttat tgattggcta 39900
atatcatgct atcttgatta ctgtagcttt gcagtaaatc atgaaggcta ataggacaag 39960
tcttttgact ttcttcttat tcttttttac tactgtattt gtttttccag gtcttgtgcc 40020
atttgtatga aatttagaat cagtttgttt ccatctacaa aatagcttgc cacgattttc 40080
tttttgtggt tacattgaat ctacagatta ggttgaagga aattgacatc tcaacaatgt 40140
tatgtcttct aatgcataaa catgaaatat tgctccattt attgagatct ttgatttttt 40200
catcaatgtt ttatagtttt caacatacaa atcctgtgca tattttgtta gatttatatt 40260
tgagtatatc atttattgga tgctattgta aattataagg ttttttttac attttaattc 40320
caaatctttg tctttcatgt atgagaaagc catggacttt ttatattgcc ctgatatcct 40380
gtaaccttgc tgtattcact tattattcca cctaagcgga tctcagctgc atctgctgga 40440
tgaggtggtg ctttatccta taacttctat tctctgatgc atccaataaa attcattgat 40500
tttcactttg tcctgctttt ccttgtaaga acaggaataa tgaagtccaa gctttcacac 40560
ataggagata aaactgaaag tccacacatt ctgattttaa aaaatcttct attcttttgt 40620
tttgctattc atatgtgttt tttaaatgtt tatgcttgag gtttgaattg tttatgtaat 40680
gtagaatcca cagataaaca caattagcaa atgtaagcta taattcttac agttttaaag 40740
gtacctttgt atgtacccca caaaaaatag atgtcaacaa tttggaggct actttttatt 40800
taagtaattt tacacctgct ttctcttttt tttaatgaaa cccagttgca gttctttgaa 40860
caccaggaaa aacttcctag caacctctga tgtattcctg catctagagt agaaacacag 40920
cacacagcac agtagagaat tgaaaaattt gagaaaaaga gtcagttgtt ggccacattg 40980
actaagactc aggcacgcac atacacatac caaagtgatt agcaccttag ttgagctcaa 41040
ataaggagga aaaaaaccag cattacaaga gtgagacagt ggcaggttac tactagccct 41100
gcctgtggta tttctcttcc atttgaccag aaatggcaaa ttctgttgaa aagaatggcc 41160
cattttcagg caaagcttta ggaagcacat gatttccaca tagaatctgg cctttgtcag 41220
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
119
acatggtatg ggactgtaaa aatgacttat tccaagatga gaacacatgg ggtagagctt 41280
taaaacctgc aagccatgcg ttgttctctt attgaagttt tgttaaagct gttccagaca 41390
tttgctgcct ttgcttccat ttttggactt gagagagaag aggcatcaag acgtctgcag 41400
gggggacatg aataagtgtg tgtgcacatg cgcacctgtg tggatatgtc aaaataataa 41460
agtttaataa ttgatttcta taattattaa atatagcttt actaattgat agctataatt 41520
attaaacata gctataatta ttaaatatta attattttat atgtttagaa aaaatcctat 41580
acctttgata atattcatgt gtgcaaaata tattcttctg tcctggtaac tgctctgttc 41640
ataatcatct ttttttggac aaacaaagaa aacatataga caaacaggat taatataaaa 41700
tttaacaatt atatagcaat acagtggcta actatagcta ctctaattaa ttacctgttc 41760
tagagtgatt ggactatcgc aggtataaac cctagcaggg ataaaatctt tttatttata 41820
tgctatataa ataaagtatg ttctaaaaca cttgcatgat ttattccacg aatactgcat 41880
ggatttcgtt gcacgtgaga atttctctgc ctgttcttcc tattaaccac taaatgttat 41940
gtcatgctgg ggatgtgagc cctgaagcag tgacaggaaa tatctgcaaa atggcaaatg 42000
cctcccatta ctgagagtgc tgattacaaa gctacaatta catgtggatt attcatgttt 42060
gcagcaatat aatgaactgg tttatagttt ttcaagaaga aagcatctgt agtatagtaa 42120
aaattactct gaatcttgga tcaaagaatc cgggttccaa tccagccttt gttaccagta 42180
gctgtgttag ttaactattg ctgtgtaaca aattatccca agacttagtg gcttaaaaca 42240
gtaagtattt gttatctctt acagatttga tgggtcaagc atttgggaat ggctaaactg 42300
gacggttctg gcttgggatc tttcatgagg ttacagtgat gatgccagtc agggcagcag 42360
ccacctgtag gtatgacagt ggctgcagca tcggcatccg aggtatctta tttatgtggt 42420
attggcagaa gatatccact cctcactggc agcttgactg gcctcacttt ttagcagctg 42480
actttcccca gaatgggaga tacaagaaag agagggtgag aaggaaacca taatgccttt 42540
ttgacctggt cttagacgtc acaagtcacc atttatacac attcagttta ttggaagtga 42600
gtcactaagg gtggtcatac ttcagagcaa gaaaactagc ctcccttgta tgaagtgagg 42660
aatgatataa aaaaaagggt gtattttcat accaccatgg tggccatatg agcttcagta 42720
gttaaacctc gctgaacatc agtcttctcc acaaatgaaa ataacaatat ctacctcaaa 42780
gaattattgg ggctgttcag taagatgatg catctgacat attttgtaaa atgtaagcta 42840
ttgcatcagt gtaaagttga ttgaatgtaa tgtcagtgat gttttgtcat agacatcacc 42900
aatgcatgtt gaggaaatct tgtttagtga cttccaagtt aggcagacac tggtactgtg 42960
caccctcctc tcaaaaaaga agcatgcaaa tctttgactg ttaaagtata tagcattcaa 43020
agattttgtt gtaatcattg agaataataa tttaattatt tatatataat taattattgt 43080
ttaattatta attaaattat tatttaatta tatataaata tataattatt taattattat 43140
ataatgaatc aggtgcagtg gttcacgcct gtaatcctaa tcccagcact ttgggaggcc 43200
gaggctggtg gatctcctga cgtcaggagt tcgagaccag cctggccaac atggtaaaac 93260
cccgtttcta ctaaaaatat aaaaattagc caagcatggt ggtgcatgcc tgtaatccca 43320
gcaactcagg aggctgagac aggagaatcg cttgaaaccc aggaagcgga ggttgcagtg 43380
agctgacatt gcaccactac actccagtct gggcaacaaa gcaagactcc atctcataaa 43440
taataataat aatttgttaa tgaaaaatgt taatttccaa agaatgatag agtttaaata 43500
tcagaattat ttatcttatt atttttggtg gattgcctaa atatacagac tttgtttttc 43560
gtgtttttgt ttgttttccc atatgacaag aggctggaga ctggcaggca ggcagcatga 43620
gcttctgcag cagcgcagtt ctgtgagcca tggcccctct gtttctgggt aatcaccctc 43680
gtccttggta ccttctgcct gctccccttg cagcactgat ccttcattcc aggcagatgg 43740
aataagatca aagcacaaaa aaaaaagttt gctgaatatg ccctgtttta ttttaatttc 43800
ttattttcaa ataaatttag acttttggaa aaactgtaaa gatagtagaa agtttttgta 43860
tacttttcat ccagattcac ttaaggataa cgtcttttat aatcatggta tatttattga 43920
aatcagaaaa ccaacattca ctatgagcca attggtatta gttacgctat aactaattat 43980
tattaactaa tagtatcatt atttacttat ccacaataca atgatgtaat aacaaaatgt 44040
agtatataat attaaataca gcaatgtagg atagtaatga tagtactact gctagtttta 44100
gttaataata ttaactaatt tacaggcctt attaaaatat tttcagtttt accactaatg 44160
tctttcttct ggttccacga ttcacaatgc atttatgtgt catgtcacca ctgttgtctg 44220
caatctgtgc cagtccctca ctcttttctt gtcttttgcg aacttgaaac tcatggagaa 44280
cgcttggtct gttattgtgt atagaatgcc cctcagtttg ggttagtctg atgttttcac 44340
atgactaaat tgaggttatg cagtttttca aaactgcggc agatgtgatg atactgtgct 44400
tttccactat atgatagcat gtgatgtatg agatgtaaac acggatcatt gttttctttt 44460
cctttttttt tttaagacgg agtctcgctc tgtccccagg ccagagttca gtggcatgat 44520
ctcggctcac tttaacctct acctcccagg ttcaagcgat tctcctgcct cagccttcca 44580
agtagctggg attacaagca tgcgccacca cccccagcta atttttgcat ttttagtagg 44640
acgagatttc accacgttgg ccagaatggt ctggatctct caacctcgtg atccacccac 44700
ctcggccttc caaagtgctg ggattatagg catgagccac catgctcagt ggatcatttt 44760
ttttttatgt tttgtttgtt tgtttgtttt gatttctatg ttgtctgtca gatgtctttt 44820
aagtgatttt tttttaaatt tataacttgt aagtgtcttc tgggaagata tttttaggct 44880
atggaaatac tctgtttttc atcatacact tgcccactaa ttttagcatc aataatggct 44940
tttgcctgca gtgactactt atgtagtgtt taatgtgatg atttctgtag ggatatataa 45000
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
120
atgagccaat gagaaaccac agacatcaca tttctagctt aattctgaaa ggtaaacgtc 45060
tcattggcaa attttaaaaa gttaagacaa tttggtttca tcaggagacc caaagaaaaa 45120
atgagtagtt tgaatttctg gtcataagga tagtattctt gatcttctta atatggaagc 45180
aactaaatat atttacaaca ggaagaacta gatatacttg caaaattcaa agagaaaacc 45240
aaagcaatac agccaagttc tatttgcagg tcgagatctt ccaaagaaat ggcagtattg 45300
tgatagttat gtacttttaa aactggaaag agatgggaaa ggtacaagtg gatgttcatc 45360
atggcgtaga catcaataca tgatcagtca agttttactt cttgttttaa tgagaagaaa 45420
aagctgtgat tctttattta ttcaaaatca ccatcacttt tttctttaaa atagtcagac 45480
tactagggcc tctgatactt attggaagat aaagttaagg agagaaaagg ggtgtataaa 45540
gtaaaaatat atggcagctg tccaacaaag tcaataatcc actttaggga ccccaaaata 45600
gattttctgg agtgtctgtc tgtgcacaag tttgtcagca tttgagagaa atgactgagc 45660
agccacaaca aagagtgttt aaacaaacca atctggatgt caaaaggtta tgtgccgcag 45720
agggctgctg gtgttaattc tatatggatt aacaccacag ccgtttctta aaatagaaaa 45780
acttgaaaga agtgagtgag ctcagagacc tttttttttt gtaggaagtc tagatgagac 45840
atttattttt ttctttgaac tggtgaagtt ctctctactc agtgcgactg gtgaggttgc 45900
atgaaaagtc tgtgaatcaa tcacaggacc cagttctgcc ctgagacctc aaggagagag 45960
gaggctatgc tggaccccgt actgtagagg atccccactc ctaccctctt gtggacaatg 46020
cacccctcgg catggggcaa gaagtccaag aacgccataa gccaagggaa cgtacacaca 46080
attagcctgt gtctccttct gcacaatgct ttctgcggct cttccttgca gagtgtggag 46140
ctcatttgca agagcagatc tcttgcttgg attcatgttc ttgtggtcac accacaccat 46200
ccccagtatg ggcctctctc cagcaagggg atgaggatgt tgtttgatcg tggggctaat 46260
gtacatgacc actgggaccc tccaaggtgt ggcaggctag gcaggaatag cagagaattc 46320
actacagggg tgtgtgtgtg tgtgtgtgtg tgtttgtgtg tgtgtgtagg taaggaatat 46380
agagcaggag gctttcacaa tattccagat ggaagacagt gaaatccgcc aagcctaaat 46440
tcaaatcata ccaaaaggta taaggagtta agagaagaga ataggatata ccttacttgt 46500
ttaacaaatt gtttcctttt ttatataaag taattttagg tggtaaaata tacagaaaat 46560
ataaatatat acaaaaccta cataaaattt accattttca tcatttttca gtgtgaaatt 46620
cagtggcttt aagttcattc atgatgttgt acaaccatcg gtactatata cagaacattt 46680
tcataatttt aaacgaaaca tttgttccta ttaaacgcta acttcccaat cccctgtacc 46740
ctcaggcctt ggtaaccatt attcttcctt ctgctttcct gcatttgcct attctagatc 46800
ctgaatatag tggacacatg cagtgttttc cctttatgtc tagcttcttt cctgtagcac 46860
agtgttatca agtttcatcc atgttgttgc gtgtatcagt acttcattca cataatttta 46920
tagataaata atatttcatt gcatgtgtgt accgcatatt gcttatccat tcattagttg 46980
ctgggcactt gacttgcttc catgttttaa ctacagtgaa tatgctgcta tgaacattgt 47040
tgtacaagtg tctgcttgag tccctgtttt caattttttg gggtatataa ttaagagtgg 47100
aattgctgga tcagacagaa actgtatgtt taacattttg aagaactgac aagttatcgt 47160
ttccttggct ttcccttata ctatttgcac atgtagcatg cagatctcca ctgtagccct 47220
gggtcctgca aatattatta gggacaggac gtgacagcaa ccttatggat ctatacatgt 47280
agacagtaaa tcaatccttg taaatgttag tctttcactt tttttcactt ttgctttcca 47340
tattatataa atgagaaatc tgggtttcca tcagtgttca aacttggaaa cttttgtgtc 47400
atattaaaaa aaaaatccaa atcaagctgt tttgtggtat ttcagatctg actgaaacca 47460
ggaagtaata gaaatataaa aagaaaactt gatcttctga ggttttcttt accaaagtaa 47520
ctgggataaa aattaagcct ttaaaatttt tgaggttcat atatcaatgc cactgatttc 47580
taaaaaatat tgtatgacta gcttcttttg gaaggtaaaa aaactcagtt ctcctacaag 47640
actttgtaga aattctttgt cttaaatcat atagcttaaa aaatgagcct tttaaaactg 47700
tgaaggatat cagaaagaaa tgtgaagaaa gaagaaaagc acaaattaaa agaacgaaca 47760
agagctacgt tagcagtgag acccaattta aagagtttgg gtccagccag agcttttcaa 47820
atcttttgaa gcttatacag tgttctgatc cctaacaacc catattcttg aaaaattaac 47880
cagaaaacta gcatgagcta aatgtcttta tgtttgaatt agagaacagg gaaaggtctt 47940
gctgccttta gggaaagctt ttaatcagaa tgtctcttca tcctggcttt tgacctttcc 48000
taacattcaa ttgttttttc acactgctct tgaaagagcc tgcggctcta agaaagaagg 48060
atggatatct tccccttgct tagcacggtt tatgtcaaga ttttgccctt gtaaaagcac 48120
ctaaatgtgc tggtgacaga cagagaggga tgatcattca aaagtagtct ctgcttttgt 48180
taaactttta tttcaaaaca atggagagca catcccatca ctgctacgaa aagttctaac 48240
ttccaattca taggtcattt ttttgaaatt gtattttctg attaaaaaca catatttctc 48300
caactagtat ccatccttat ttctagaggt atcaccgtgc atttcgcacc ccctaaataa 48360
ccttcttgcc ccgtaaaaaa tattttgtaa gtattcgtat gtacccacag tccataatta 48420
ggacatctca cttctctttg ttaaaaattc cttatgttta cagcttttca aagggctttg 48480
cattcactaa ctaagtagtc ggaaactttt gagacagctt tgcagaacaa gacacaacaa 48540
ctacatgttg agtaacttgc tcacggttac atgatagtta tgtaagatgc ttggtgatag 48600
gactgggcgc taacatgttt ttcccaagaa aaataaacct ccattgcatc tagtccacac 48660
taggacgatg ttttgggcat atgtttttcc aagcatctgg tagggacaga tcaggtctaa 48720
gggatttctg aaaggtttaa attaaatagg atttcccttt aaaattttga tagagaaatt 48780
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
121
tagaaaaaaa aggaatcaaa tgctaattca gaaggtattg agaacaggaa aaatattagc 48840
ttatcaggga acttcttaag gtcagagttt cactatcaca ttctagcttc ttcagtgcct 48900
cctcattttg gaaagtgttc aggactttta ggtgcagttc tggacacctc acatgtctga 48960
acatatccag tggtctttct taaagattat aaggacttag cagcaaatta gtctgttttt 49020
cacatggtcg gagatggctg aggcttaaga atgctgcaca gcatcctgag gtgattatta 49080
gtactcagaa ggcctcccca cctctcttgc acctgtgatc ctcatcttgc ccttttccaa 49140
atatcgagca gccaccataa tatgtgtgtg tgtgattaat caattattac taaaggatca 49200
gtaatcctta acctctgaga ttctcactgg atattaagga tcttaaaaat aggagaataa 49260
tcaatttaaa cctttaagct gttttgcttc tgatactatt ccatgtctta gcattcaatg 49320
tatttttatt ggtggatcca tatgacaaag tgaaaaggag gagggttttg gaaaaagaga 49380
tacagaagtt cacattttag ctacccgata actgtaaaaa caagggcaat tctgtattgg 49440
gcttacattt atcttttcag tggatctatt taatwgaaat agaaataaaa cacatatcaa 49500
taattgcacc aagatactga aggtagtttt tattgaaaac ttgatcacta aggaattgac 49560
agaattgaga agtgagaaaa tttcaaagat acacatgcct gaaagcagaa atcatatctt 49620
atatgtcaaa catgaaaatc aaagtcagct gcttgaaatg tgggcctaat aaatcttgaa 49680
tctctgcaac tgtagggaat agttattgtt ttctaatcta gcacacattt tagtaaactt 49740
ttctgtcctt aatgttaaac ttcatatttc ctacacatct tttttaatgt taattatttt 49800
aatatgcatg catatattta ccacttatta catgggaaga aacaattctt aagtctgaga 49860
aggttggtaa tcatttacat ttctgacaca aaactgaagg catggttgag aattagaata 49920
attaaaatag cactggggga caacctgaaa actgtgactc cattctgata gaaggagtca 49980
ttgtccttga acaatttgca aatatgttcc cttcttttcc caaatatgtt cccttctttt 50040
cccataacag gct.tccatgc tttatgcaac taatgcgtta tgaattgcag ctctgtttct 50100
tacagagaag tgaatttaca aaagacatac ctttcacatc atgttcacct ttttcacctc 50160
aatgacaccc tgctcccttc tcttaccttc cctgacacca cacagttcac catcagctct 50220
tcctccttct caacacccta acttctaacc tgcaactgaa gctcacagtt gtgcttagta 50280
tctgcgtgac agttcccttc acttgacaag ttttaaaagt caactttctt tgtcttacag 50340
tttattgtct tcagtctttt atttccctta ccttttaata aaaggattca gtattccatt 50400
tctattaatc ttttattaaa gtttattaga aatagaatgc tgaatagaaa ataggaagtt 50460
tagctgtagt taagattgtg attattcatt atactgatat ttttcttata ttgtttttga 50520
actgatttat gggtagttag ctccaaaact gaaggaatac tatgatattt tcaacactat 50580
taccagcact atgtcaggta ttaagtttaa tccatgagca gagtgcaatt tcaagatcat 50640
gaattttcac aaacttcaat gttactactg tgtttatgct gaataaatgg tttctttggc 50700
acctctttca cacacacaca cgcacacatc tatacatggt aacataggct aaagcaatta 50760
gagaagttca ggtatttcaa tgactgaatc acaaaaatat gttattgatc tcatttgtta 50820
atcaatgaat ggttaataag aagattaaga agacaaatta caaggtcaca gcccattcag 50880
ctgaagcatg ttgttatggc cagaggctca tgagaggaaa aggtgtggct aagaacagaa 50940
gatccgttaa gctccaagcc tgttcaatta tttaagtcac tgagacaaag tagatgtgga 51000
gtgtgagacg ccagtgtaga gccttcaact gattttcctt ggggaggttg acctgactta 51060
atagtgtggg aaatcaggtg aattttggct gtgactagat ttgaccaaga tggagttttc 51120
catgaaaatg caaaccaatc tttagaattt gaattccata aagcaaaaaa ttcttacata 51180
aatgcttata attttaccac tctaccactg tgggatgcat gccacgagat tttgtgagta 51240
gttctaaaaa gtatgtcttc ttggacaaca tccaaagtag accacatgca cactgaaaca 51300
agccttacac aatagctttt ctatatatgt atctatatct acatctatat ttatatctgt 51360
atctagctaa aagaaaagct ccacatactg atagaattat ataaaagcaa atactaacgt 51420
ttgggaattt cgattataat acacttaatt gaaaacaaaa caaaaatatt ttttaaagta 51480
ttaagcaagc atagagagac attttggtgc ttacaaggat ttctgggaat acaagcaatt 51540
attttttgtc agggaccata tatttaggta cagatcatta acaatgcttt ctttaatatt 51600
tatttagtga attgtacatg ttaactctaa gggcaattaa aacccataat tataatatga 51660
gaaacttttt ctccacttag tattttttat tataaatatg gctagcattg aatcattggc 51720
tataaccatg taattttaat gcttgggaaa catctgttag aaaaactttc cctatagaag 51780
acatttatca atgtcctgcc ttatctctgg ttatctttgg tttattacat tttatgataa 51840
ccataaaact gaaaccatcc tcatttacat ttttcctctt ctaaatttgg ggaaattata 51900
ttttaagtgt ttatcattat ctcattatat aatctacaga aataataaac agcagcatac 51960
ctgattttaa aatgagactt ttgaatttct acaataaata gaatataacg aactctgctt 52020
ctttgggtat atcacgtcaa atatacatta atgagcagat agctttaaca tgtttatcat 52080
gttataatct gattgttgtc tttactaatc aagataccta atttaactga agtatcaagt 52140
gatctcaaaa cctcagtagc atctgataaa ggttgctgtc tcacctgtgc cacatggcca 52200
ttgccatttg actgctgctt cacccacatc acctgcactc ccaaactcag cctggctgga 52260
tatcttttta caagatacct gataatgaag gagagaagga acatggtgaa cactatgcag 52320
tctcagaaga tctgcttgga agagacatgt tacttctgct gtcatttcct tggccagagc 52380
aagtgaaatg ctgaacctga tcagtggctt attgtttgaa cagtaataca acctactgtt 52440
ctatcataga atgatattgg agtcatatat ttcaattagc cattatcaat gtctctcata 52500
attttcttta cacattttct cagaatctag agtaaaattt aaaaaaggaa agacagataa 52560
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
122
atgctctcat ctccaaattc agtgtcctaa attccactta ctttaatcag tataaaaatc 52620
aggtagctca gattttaatg gactagtcac ttttgtctct ttttttttgc tatcagcgtt 52680
tatattgatt atttggaaga aaaaagagcc ccctcaacct tccagagcgg acacacacac 52740
gtacacacac acatcggcaa cattagagag gttgacctga aagtgtttta aaaactatga 52800
cacagttaaa ctatgatttc aaagtttttc caagcaagtt atatgtcaga atatgagtag 52860
gggaaaacta ttgaactgcc acaattctgc tggtggtttc attggcaatt ccaattatgt 52920
tctgatcata gtgtcatcag agcaattagt tcatcccaaa cttgttttgt attgccactc 52980
cacagggaaa atagtaaatc tgtcctactg actgcagttc tctaaaatgt ccttaaagtt 53040
tagttatttc aaacttagtg gaagaaatat gttgttggta gtggtcatcc ttgctagtac 53100
tctttaatca ttacctgcca ggaaacactt tttatttacc agtgcatgag agtttaggtg 53160
agaattattc tactaccgaa agctcaagat gtatttgtgc tatagttata aatatagatt 53220
ttttttttgt aattctaact tttcaggtac ttttctcttt agctgtttta ttttagtata 53280
tgtatttttt ccatttttta tggaattgta aggcatattt ggtggttcta gtttacaact 53340
ataacatcat ttccagagtc atcaattcct ttgtcaggac atgacattat gtttttccat 53400
tttttagact tcctaaaatg tcttgataac caaaacacag agggttatca ttatacagtt 53460
atgtatgata cggtttcctc tatataatgt gtcacataga gtattttatt tccagccaaa 53520
gatcattatt ttttaaagaa actcaggaac aagaaataag gatgcactca cacaaataga 53580
cagtagtgaa ttcagaatgc atagcagagt gtgcaaagta aagcaaatgc atccatgccc 53640
aattacctaa tttgtaattg cagctattca ttgcacttga ttctttcctt caactccttc 53700
ctctccttcc ctccccggag ctcctccttc ccagcgtttg tatggcagct tcgtaataaa 53760
cccagaacac ttagcaattt ctgctccgat ttgctctagc ttcaaaggtc tatggtcatg 53820
attacatgca ataacgatac attcaatgtg aaactacaat ctgtgtaact ttgtatttct 53880
ctttgaaggt ttagatacga ttgactgtgt caaccataag cagaataata attcctgtgc 53940
tcagagacaa gtcagagaga gagagagaga gattgacaaa caaacaaaca aacaaacaaa 54000
caaacaaaaa acagatttta agaactgagc cctaattcat ttttttttct tttttattgt 54060
ggcaaaatac acatgacatt tactatctta accattttta aatgaacagt ttagtgatat 54120
taaatacata tattacattg tgtagacatc accatcctcc atcttcaggg ttctttccac 54180
ctttcaaaac tgaaattcta cccattaaac aattcctcat tccccccctt cccccagctc 54240
ggctgctggc aaacagttct acttattgtc tgtatgattt tgatcactgt aagtacctca 54300
tagaagtgta atcatacaga atttaccttt ttgtgatggg cttatttcac ttagcatcct 54360
aaaggtttgt ccatgttgta gtctatgtca gacttggctt cccttttaag gctgaatgat 54420
attccattgt atatataaat cacattatat atgttatatt ctaagcattt tatattttta 54480
ggccttacat ttgggtcttt gattcatatt cagttaattt ttatatggag gttcatataa 54540
ggttcaactt cattccgttg catgtggaga ttcagttttc tcagcatctg ttgttaaaaa 54600
tagtgtcttt ttcccattaa atgatcttgc cacccttgtc aaaaataatt tggccatgta 54660
agtattttat tctattggcc aacatgtttg ttttacgcca gctgatataa ccatatgtaa 54720
ttattcactt attagttctg aattcattta ttagtttcat atgggatttt ttggtggaat 54780
cataagagtt gtctacatat atgattatat catctatgga cagagataag tttacttctt 54840
cctttattcc aacatatgtt ctctcttttt cttgcctaat tgctctagct aggatttcca 54900
gtactacgtt aaatagaagt gaggaaagca gacacccttg ctttgttcct gatctgacag 54960
gaaaaacttt ttaaaaaatt gtgatgaggt agtttccttc tatcctagta tactgagtat 55020
tgttttaatt atgaaaggtt attgaatttt ctcaagtgct tttactgcat caataaaaga 55080
tgattacatg tcttttttct tcattagtgt ggtgtattcc attgttaatg tggtatattc 55190
cactgtttaa tttttgtgtg ttgaaccatc tttgtattcc aggcataaat cctactttga 55200
ttttcgtatg ttgaaccatc tttgtattcc aggcataaat cctacttaga aatggtgtat 55260
aattccttta atatgttgca aaattcagtt tgctagtact tttttgaaga ttgttcccat 55320
taatgttcat acggaatatt gatctttagt tttctatttt ttgtgatgtc tttgtctgac 55380
ttgggtatca aggtagttct ggcctcatag aatgtgttag gaagtgttcc ctcttctttg 55440
atattttgga aattattgaa aattggggtg agcccttctt taaatgtttg gtagaattca 55500
gcaaaaaagc catcaggcca aggacttttg tttgtcagga tatttttgat tagtaatcta 55560
tctcctgact cttaaaatgt ctattacaat tttctatttg tttgtggttt agatttagta 55620
ggctttgcgt ttctagaaat ttgtccactt catccaggtt attcaatttg ttggcatatc 55680
attactttcg taatactctc tgctgatctt tgtatttatg tagacttgga agtaatgttc 55740
ctatgttcct tttttttttt tttattttgg taacttgagt ctttcttctt tctttctagc 55800
taaaggtttt ctaaatttgt tactattttg aagaaccaac ttttggtttc atttattttc 55860
cctattattt tacattctct attttatctc agctgtaata tttattattt catttttttt 55920
gctagtttcg ggttcagtat attcttattt ttttagttcc ttaagttgta aagttaggtt 55980
gatgatttaa gatctttctt gttttttgta atgtatgcat ctaaattttc taacagtgct 56040
ttcattatgt cccatatgtt ttgacatatt gtttgttcat tttcgtttat ctccaagtat 56100
tttctaattt ctcatgtaat ttattatttg atccattggt aagagtatgt tgtttaattt 56160
ccacaaattt gtaaaagttc tcgtttttct tctgttactg atttcttact ttatcccatt 56220
ttgatcagaa aaatgttttg tatgatattt tttaccgtaa gttttttgag acttaatttg 56280
tgacctaata tatgttctat ccaggaaaat gttccatgtg tacttaaaat aatgtgtatg 56340
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
123
ccatagaaac tgggtagagt gttccgtatc tgtccattag acctagtcgg tgtattgtgc 56400
cattcaagtt ctctgttgcc ttacttatat tctgtctcat tgttctattc attattgaga 56460
gtggggtatg ataactacaa caattattat agaactgtat gtttctgttt tcaattctgt 56520
cactttttgc ttcatatatt ttatggtctg ttattagatg cataaatatt tataattttt 56580
atatcttctt gctacattaa accttttaat aatatataat gtccttcttg tatgttttaa 56640
aatctacttt gtctgatatt agtatagcca ctcttgctct tcttcactta ctatttggac 56700
aaaatatatt ttttcatcct ttaactttca gtgtatctgt gtctttgggt ctaaagtgag 56760
tctattgtag actgggccta catcattttt taaaatccat tttactaacc tctgtcttct 56820
gattggagag cttaatccat ttacacttaa aatcattgct gataagcaag caattttgct 56880
atttgttttt tatatgcctt atagctttct catacctcat tttctacatt tctgtgtttt 56940
gtgtttagtt catctagttg atttttcagt taaatattaa aagtcttttt ttctgctatt 57000
ttctttcttc tatattcttt gttgttacca tggtgattat attcaacatg ctaaagttat 57060
aacattctaa tttgaatttg tgccaactta attttaataa tacactcaaa tattttttac 57120
agctctgtcc ccacctcttt cagctgttca tgctataaaa ttatatctta tacatttcat 57180
gttcgaaaac ataaactaat aattctttga tgcattcatc tctcaaatta tgtagaaaac 57240
aaaatgtgga attgcaaacc aaaattacaa taccaacttt tagcataata attatcttaa 57300
tgttttagtg tcttaaatga agtagaaaac aaaatgaagt tatacagcgt gttacaataa 57360
tactagcttt taaaattgcc tatttttaat tcagatttaa tttttgtata gcttttagtt 57420
attgtctagg gtcctttaat ttcatcccaa ataactcccc tgagcatttc ttgcagggaa 57480
ggtctagagg taataaactc ccccagcttt tgtttacctg gaatgcctta atttctccct 57540
cattttagat aacagttttg ctgaatctag tattgttggt tgacagtatt ttacacttag 57600
tattttgtat gccttctgat tttcacttga aaactgagca tttgaatcta ataatatgtt 57660
aactctgata accggattct ctttctttct gagggtttgc tgttttgttc ttgacttttt 57720
tttattgttg cagctgtctc tgtgccaagt attagcatga ggtgtaaact tattctctcc 57780
tcaggttttt ttctgaactt gtatcttccc actgtgtcta catggtgact tcctaatttc 57840
acccatatat acagttgctt gtgaatgtct ttatcttcaa tgtcagccgt ccaaaagagt 57900
aaaaagagaa aaacaaaggg agaaaaaatg aggcaccacc ctctttacat tccctgggaa 57960
ccacctcagc caggggagag gggctgacaa taattgagga ggagcataac aatggccact 58020
gtttctttgt ctgcacctct gggatcagaa gcagtgatca gtgatcagag cacgggtctc 58080
tgttatctgg caggcagggt tgtttgttgc ccaccctagt ttctgcaagc tgtgtggtag 58140
ctgctccagg caccgctgcc tg~ccacagag ttgagaggtg gggaatgaat aggtgctatt 58200
gtgctaatag ctaaaattga ccacaattaa ccacaactga cagtctaagc catctcctgg 58260
gagtttgaag tgcaagtctt tccctggaac ttaatttcaa tagtttccag aattccaaaa 58320
tagtaacatc agacagattc tgtcagggca ttattttttt ctatgtaggg atacatattt 58380
ctagtgctac ctactccacc atctttctag aatattctcc tccccaataa tttatatcat 58440
catttctggg gttgtaagtc aacaatctgt attttaacaa tttctctagg tgtctctttg 58500
cctgctttaa gttttcaatc cagttagccc tctctatcct caatataaaa caaaagcacc 58560
atgaaaacat ttggctctaa gtgtggttgc catttaattt atgttccaaa ccagaaaaaa 58620
aaaaattgag agtaaaagaa cgtgctatta ataattcatc tgtaataata tatatgaacc 58680
tggactgtct gaaacagttt tttgagagac acttagaaaa aattatgctt tggaaatttt 58740
ttatggggtg tcattaattt gtttttgtcc aatttttgca acaaaatttt gacttctata 58800
gtgaggtgac attcataaat ctgagtattc atatctaaaa acccaaaagc atttttttct 58860
aaggatgtca tgtagatcat ataaaataac tatagaaata ttgaatccat aatatgtcat 58920
atgagttgca gccattttaa tattttgtcc atttttatat attctatgca tataatatat 58980
ggtagttttc tgatagtaat ttccaattcc tctcccaaaa tggactggac agatttctta 59040
gtgagggaag actgttttta tatcattcaa attttatcag tccttttctg tgggtcccct 59100
gctgttctta ttccatagca tcttatgtag gattgatctc ttccttgtgt tagagtcaat 59160
attattattt tcagaagtct tggtttttcc attggcaaat gttcaaataa aactttataa 59220
ccaaatcttt ataatgctgt tgccaacttt gtgtctttaa ataaagtcca attgccatag 59280
ggcaattgtg cagtgggatg gatatgtgaa tctgtgtgaa aaatgatatt ttaaatgctt 59340
tgtggggaag agtaaccagt ctggattgaa ttgaatgcta aattggcttt acatttggaa 59400
aaaatttaga tgttatagta gttcttatat aagaacatta aacatctcac tctaaatgaa 59460
gtacctcagg tgatactgtg atagctataa ttgtttatga cggaaatatt cactcttaga 59520
agacttgggt attgacaaga acttggaaaa ggatcaagca gcaacatata tgaaactgtg 59580
cttcagcagg ggaaatacag ttatgttcct gggtcactgg actcttgtta tggactgaac 59640
aatccaagct atataaagag acataataac tatgatcaga actttgtgaa atatgaccgt 59700
tctatttgaa ttcaggttct aagcagtatt ccccaaagag atctgatatt gaatcaatgt 59760
tgtagctacc agccttgaag ttacctgaac tttggtattc tattattccc ttagcttgta 59820
gaaactgact atggtgaatt cttaccccaa atgtattttt ccctagtaga tgaactataa 59880
tctttcttat tcatagtcta tgattggtgc atcttctcta gctccctttt ttagatgtgc 59940
tgaggaagtc cgctgtggtc ctaaagctgc acctgtgtgg ctgttgtcta atgtcccgtt 60000
ttggtgctca atgtcatgag tactaagatg attctgagta agagtcctaa ttaatgccac 60060
caaaatttgg cgaacccttg tcttttgggg aagaggggca gaattcttca cgatatgcct 60120
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
124
caaacctggc ttcttcactt ctgtgtacga gataatttca aactgctttt ctcactttta 60180
aattttattc atagatgtaa aattttggca ttttggctaa tttaatttca aatttgtatt 60240
tgcttgttcc tgctttgatg cgctacttat gttgtgtttg aaacatagta gaaaagaggc 60300
tgcgtcggac aagtatgaga agacatgctt acagtcacat aaaaggagaa taaaaatatg 60360
tgtgtgactg tagaccgtac ctccatgaac attacaaatt tctgactgcc atctagaaca 60420
cgtgctttat caacatgata tcaatgatgt ggatatttta cttactttct attttgttat 60480
acatgtttgg tttagatgtg acctttgacc atttctgtat aattttaata aaatagattt 60540
aactacacaa aaatcaccct aaaagtaatt ttccatgatg cattttaaag gtcatgtttt 60600
ccctgatgac agcatgtttt tgtagttaga ccttgggaaa gacaacaagg agatctgaga 60660
gctaatgcaa aattatcttt actagctgga tctccttgga ctggtcattt atcctctgaa 60720
tcctaatttg ccccttagca ctcacaaatg tcatctcccc aaagccatag ctgagcagaa 60780
agtggagctt agcatttttt attctgatag aagagactgt gtccatgcaa ttatgacagt 60840
aaaaataaat gagcatagct tcaaacattt ctttaataga aacttagcct ttgggtttaa 60900
ggttatataa agtgaaagga atttgggtaa ttaatatgaa gtcaaacatt aaaagattcc 60960
tcaagtaatc caaaggtatc aaatgttcaa tgacataaaa tacctctcta gtccttatga 61020
tgagaagaga aggtcctgat gagtggctaa gtagtgatga aagtctaagg ctaaatttct 61080
atgaagaaat attgtaataa aatttttgaa agatactcag agatatttct tgagatcatt 61140
atcatgtatt ctgtacacaa atgtattctt tccattttat tttcagtgat tttccatgta 61200
cagctataac tttagaaagg ctgattgtta ttctttggct tttctccctc aattaaatca 61260
tgtttttttg gtggaaagag agatttaaaa taaaatggaa gcaagtggta ttaattcaga 61320
gttactaaaa ctgaaaatta gggaaatgta gaaaatataa actaatatca agctaattct 61380
tttctgtatc agtgttagac cttttatggg tgaatgaggt taaatgtgtg ttagtataaa 61440
ggatgtaaag gagtaagcaa agacactaag accagagcat gactttatat ctatatcagc 61500
ttgagtctat ttatagtaga atcactagaa agtggtgacc acacagagtt gcattttttt 61560
cttttgatat gcatacattt tccctgaaag aaaaaaggaa ggaaggaagg aaggaaggaa 61620
ggaaggaagg aaggaaggaa ggaaggaagg aaagatggaa ggaaggaagg aaggaatgaa 61680
ggaaggaagg aaggaaggaa agaaggaagg aaagattgag gtaaggaaga aaggaaggaa 61740
gggagggaga aagggaagaa ggaagaaaga aggaaggaag gaaggaaaga aggaaggaaa 61800
gatggaagga aggaaggaag gaatgaagga aggaaggaag gaaggaaaga aggaaggaat 61860
gaaggaagga aggaaggaag gaaagatgga aggaaggaag gagggagcaa ggaaggaggg 61920
agggaggaag ggagggaggg aagaaggagg gagggaggaa ggagggaggg aggaaggaag 61980
aatatttttt aaaaagaaac tctttgatga ttcaacatca tggagaagtt attattatat 62040
tgagcttgac ctggatctgt aactcttgac atttagctct tgaaaataca tctgttttct 62100
tggctgatag tcttaaaaga cagaatccaa cataataagc ctgcacatgt atccccatat 62160
ctaaaatgaa tgttgaaatt ataaaataaa atacaatata tgttcacaaa tattaaaaaa 62220
atgtgcagag atatgggaat acatatgtgt cttatgtgtg cttatttcta tgaagtcgtt 62280
agatgtcaaa gctctttctg catgcatcct tgcttagacg ttttgtctga aattctgttc 62340
acattgacat acgtgcatta aactaatatg agaatgtatg cattaaacta gcttgaatga 62400
tgtccacatt ctcagttttt tcatcataac tttttctttc cagagtgcat gatgccgcag 62460
aaaagaaaag ctaactgtga aactcaaaga aagtctttgt tagggcctga gtattttttt 62520
tttaatctct atgactttca cattcttagc ttcagtaatc cttgaagaga acagagtcaa 62580
accttgtatt ttaattagga tctttcagtg tttgtggcct tgaggagcga gagcaagaaa 62640
gacattctat gggtgtgcgt gaaagagagg accaaggttg ttttctttgt gactagagat 62700
tatattgtgt aagagcagat gacaaccttg agattcgatt tgtgatatga aaccaaatgc 62760
actaaaagga aagcgtacca gtttggatta gatacattaa atcagtatgt catgtaaatc 62820
agtgactatt aaaagagaat atataggaga aaaaggtatt agaagttgca ttttttaacc 62880
aattgcaacg tttgcaaatg ggcttgtcac ataccatcat gtaagtacta gtgaagtcta 62940
aggtataagc aagtattttt catttttaag gatcattgca aagatagaga atttgacaat 63000
aaatgaactg actggccttc tacaagtatt tacttacaac cacaattgta atttttccat 63060
ggccaagcta tgaattatta aaagaatatt gacattttgc tatattttta aattatcttt 63120
aaatcatttc aaatagtgaa atagtattat actaattaaa ctttattaag tacattttca 63180
agctcagcta agttttttaa tcaatgttta tttcagttag gggatagttt tgtttttttt 63240
cttctttgaa ataatatctt tgaaaccaat gtccacattt ctttacagat aaaagagttc 63300
tgtttatgaa ataagaataa acagcctgta attttaatat caccaaaact attttaatct 63360
ctttttggat atgtacttca acttaaacta catatatagc tatagatata tagatatgtc 63420
tatatctaga tgtagacaca tcccccaaaa cctatagaaa tgtatttctc aaatgtgtaa 63480
agtatagtga aactgccaga ccacaagcga tgttttgtat ttatagatct acttgcaatt 63540
tggggtgtgc caaatcccca caccttgttg tcaatattag tttaacaaaa ctaaaaggaa 63600
atttaaaata ttaagatcat cctctttagg atctacttgg agcgctgaaa aaggtgtgaa 63660
aatactgatc tcggacttct tgtgagtttg atgtgtttta catttgtaat gctattctct 63720
tcactgcatt catgcgtgtg cttgaagctt gctgccttgt aggagacaat gcaacaactc 63780
ttaccaatgc cacttttata agattttgcc tgcagtgtgt caatgtgact cttcagtacg 63840
ctacttaagg gagtgcaggc aagatgacct accctgagtc atccaaagaa tatttctcta 63900
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
125
gttcctgttg gtcctgtgaa ttcctaatgt ctttataata aatggccacc taaaaattaa 63960
tgtaactggg ttgattgtgt tgcatgacat taagtaaacc taactgccgc aacagggtgc 64020
agtctgcatc atagcaaata cgttacggga gagaggggca cgtcctccct cagcgcccac 64080
aacagggatc attaaccaag gctgacacaa ttctccagtg agaacagatg taaccttgga 64140
atctttctcc acacagtgct ccaggaagcg attcgacatg agtctgtact ggcataggaa 64200
aataaaactg gcatggctgc cacatagatc ctattttctt ttgcctctta ccaagagtta 64260
ttttaaaaat gaaactattg tcggccaggc gtggtgactc acgcctgtaa tcccagcact 64320
ttgagaggcc aaggcaggca gatcacgagg tcaggagatc gagaccatcc tggctaacac 64380
agtgaaaccc cgtctctagt aaaaatacaa aaaaattagc tgggcgtggt ggcgggcacc 64440
tgtagtccca gctacttggg aggctgaggc aggagaatgg cgtgaacctg ggaggtggag 64500
gttgcaatga gcagatatca tgccactcta ttccagcttg ggcgaaaaag tgagactgtg 64560
tctcaaaaaa aaaaaaaaaa agaaactatt gtcaaccaat gagtgtaaag gtgttatttt 64620
tgcttttttt taagtttatg ttttgaaatc ctctctcaat tgcagraaaa aaaataagat 64680
acagaatata aagagacagc ataaatgata gaaaacaaaa taagcatgtt catgagccag 64740
aaatcaagaa gaaaagrcaa tgataaaaag ggctgaagcc ggaggcatcc caggccmtgg 64800
gtctggaagc aggtactcac agtggcattc ttgggcactc tggggcaccg aggtctgtaa 64860
gtaccactca taaygtgrct ggccagcaaa atttactgct taacataaac aatgtctkgg 64920
cccccacctt gcaaaataat gctgaaataa aaggtgttac tgatcattgt ctgggactaa 64980
ggtttagtga ggtttactta cagaaaataa aaaagcaaac agtcatacac ccaagattgg 65040
gccaagctgc ctgttggatt tgacatatcc tgcaatcaca gggaaaaggt tggtactata 65100
ctgagatgtg gctcaggatg ggagaccaca gggcaggcag gaaggaggca aaagcaatct 65160
agaagacctg tgtgactagt gagaaaagca agagtaagag aaaggaagaa agagagaaga 65220
tggatgtcct cttgttaaaa taaatgtact aaaacaaata gaacaatatg aaaagaccct 65280
acataggtta agtatcttcc aaaaaagaca cagcattcat gtgagcttca tattgctact 65340
atagcaaatt gccacaaact tagtagctta acacaacatg cattcattac tttacagcag 65400
cttagacatc caacatgggg cccactgggc tcaaatccag gtgttggcag agctgctttt 65460
ctttctgaga ctctagagaa aaatygtttg ctttggtttt tcarctctgg agsctgctgy 65520
rttccttggc tcttggmtgc ctctccatct tcaaagtgca tcactgcagc ctgcgcttca 65580
tccatcacgt tggctytgtc gctcacattt ctacttctct cttgcaagga cccttgggat 65640
tctattggac tcacctggat aatccaagat aatcttcatc ttaaaatcct taatttagtc 65700
acacacagaa aatcacctct gttatgtaaa gtaacatatt tccatatcct ggaggaaggg 65760
ggcattgatg tgtctaccac agcatccaca aagggaacaa aaaatattgt ccaataaatg 65820
catatagaaa taaatttgtg gattcaggaa aaagtgragt catggaacaa aaatatttaa 65880
tagatagaag agtttccaga ctagacatcc aggaaagaat tcacccagga tgcagcttag 65940
agaaaaygcc aaggaatatg cgaaggaatt gcatgcatgt acatgcgcgc gcgcgcacac 66000'
acacacacac acacacacac acacacacca catagaaaag aacaattcac agataggagg 66060
ggtagattta gagactccga catataacca tgaggtttac aataaaaaga ataaaggaga 66120
aacaatactg aaaaaagtaa ggaattttcc acaattgaag aaaaacatga gccttcagat 66180
aggatgtgcg tgtctcgtac tgagaaaaat aaatgaaaat aaatccgcac agaggcacaa 66240
agtaatgaaa ttgtagcacg tcaaaatcca tattctcttt gggtttgaca ggaggaataa 66300
attcaagaga tgtattttac aatagggtaa ctacagttaa taatatttat tatactcttg 66360
aaagttgctg agtagatttt aaatgctctt actataaaaa tgataagtat attaaataat 66420
gcatatatta attagcttga tgtagccatt ctacagtata taagtatttc aaaacaacgt 66980
tttgtacatg ataaatacat agtcaaaata atttaagaat ttttaaatga taaaaaatac 66540
attttaaaaa ttggaaggcc atattcttaa aaactaaaca tgagaaaagt attaccaaca 66600
aaaaataaca attaggcctc tctagaaacc taactcttaa aaacagacat tacagaatac 66660
tttcaaaatg ctttggcaaa aacaaaaaac caaataacag ggaaagagct ctatgaatta 66720
aaaattttgc actcagataa agcattaatc aagatgaaat acaaaatgaa gtacatggtt 66780
tcttacagct cagttttcct atctggatta actttagttt tgcaatagta tttcttgcag 66840
taacgttcta ttatttgtgt gtccaaacat gcatatttat ccagcaacta attcaaggta 66900
tgagaggaat gaagatactg atgacagaaa ttagagcagg gaatcagaag agagaagtgc 66960
atgttccctt gcatggcact cttcagttga caaaaggaca tgtgatccca agatttctct 67020
tgactgagac tacatttaca caaattaagg agttgtgtaa cattaaataa ccaaagtcat 67080
agccttagga acttccattg caaaaaagga gtttaacatg gagctgttgt taaagggagg 67140
gtcagatggt cgaaaaatta attggcaaac aagttgattg cataagctgg aagtactgtt 67200
gaaaactttg tggttcttta ttaaacgaaa acacttcgga tattgggaag acagcaacag 67260
tgaaatttcc ttggaatcag gaataagggc ctttatatat tctactcact gtctacatgg 67320
tcatgatctc aagttattgt ttctcataca tatcagagat gtgctaaaat ttgaaatagg 67380
ttttcaatca ggagccaatt ctaatcacac atcagtggca acttggagcc ttgagtttgg 67440
aaagattttc tttagtgtgt taggttgttc ttgtgttgct ataaagcaat atctgagact 67500
gggtaatttg taaaaagaga ggtttaattg gctcacagtt cttcaggccg tacaggtagc 67560
atagcaccga catctgctcc tggggagtct tgaaaaagaa ggcaaagggt cagcaggtgt 67620
ctcacatggc aggagcagga gcaagagtag ggagaagtgc cacactttta aacaatcaga 67680
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
126
tcccttaaga actcactcac tattgcaagg acagcaccaa ggggatgatg ttacaacact 67740
catgagaaat ctatcaccat ggtctaatca cctcccacca agtctcacct ccaacattgg 67800
ggattacatg tcagtgtgag actcaaagaa gacacatatc tgaactatat catgtacaat 67860
tccaagacaa agtctactaa agtctgagat caattaattg tagatatctg tcattaggta 67920
actgaaatag aaggaatggc cacagaggtc ttgtaggttt gtggcttgtg caggtgtctg 67980
ctgataaatg tttaacaata ggttttcata ggtggtcagg gaaggcctta tttgtagcat 68040
ttgccaatct ccctgatata aatattccaa ccatggatga tttactcaca agatggaact 68100
gaattctgac cacagctgtc tcttgctagc tggtgtgagt cagctccaga acctcaggag 68160
tctggtggct taatgctgaa acttagtatt taaagttgtt atcttttgtt cacctgtacg 68220
gaagtaaagt atgggtgtga gaaaagtttc agttagttta gttagtattt ataagaaaga 68280
gtttaaaaga aaagaatgga aatggctcgt gggtcgcata attgagacta tgaagagtgg 68340
ttgaataaat tggtgtgttt tatcctggag aggagggagc tggagagtga tttaataatc 68400
ttcatattta tggaggtttt ttttttttga cagaagatgg ttcccagtta ctttccatcc 68460
ctaagtttca aatcaagata aatctagcct taagtattcc cctttcctat ccaataatta 68520
tcgctttaaa aatattttag aaaaaaatgt actgtataaa gaatgctttc ttagattggt 68580
tatcagttga tccagtttct acactttaaa tcctgctggc cttttacact atatgtaaga 68640
ttaggcaata aagataggga aggttcaagg gaaaacttct gaggccaagt aatccaatag 68700
gaatccaata gcaatatggg aaggcaggaa ctattttacc caataactct agctagaaat 68760
ttcaacaatc accaaccatt cctgctcccc cacatgtcat tcatcacact gcttcatgaa 68820
ttctaactcc agaagtcctc ttgaattttt cccagcctgt cctgtcaaat cgctggtcta 68880
gtgcaagcta ctctttataa tattgcaatc tgttcttatt ccactttaaa taaacagagt 68940
agagaattgt tgaccagatg aataaaaagt tggccaccaa tttgacatta tccccctaac 69000
taacattatc ttaaagtatg cttctcagga gggcatttta agtcatttga agttctaaat 69060
gcaagactga atatcttctg cacctgtttt cattggttca atatgaaaga ttatactatt 69120
tccaccatgt taccaaatat gattggcatt gtgttaaatg ttcttaggtt taatcactct 69180
gaatcctttg cctaaaatgt agattttttt ttttgctata aaaaagacat tagagtctat 69240
gccaaaattt gcaattcttc tataaaatta ttttttgtct aaatcttaaa aataacttaa 69300
aatcactaaa tgttcaggga aatctctagt gagaaaaata aaatttatag ctcacagact 69360
agattgaaca gacaaccatc tgttcaactt aaaacatttg tctcaaataa cataataact 69420
cacaaatgat gatggattag gtaacttcat ttcatattta ttaaattatt aacccaactc 69480
tttttaaagc catcaatttg catgaagctt atgagtgaga gatatacaaa aaaaacttaa 69540
tatttgatga tctcctaata tgtgctaggt gctttatatg tatgacattt taacaaatat 69600
ttaagtcaga tactatctct tttttcagat aaagaaattg agacttaagg taaataattt 69660
acttacagtc acaaaaatga agtacgctta tacaatctga atctactgat ggcttcaaaa 69720
tccttttcta cgatgaaatg tagcttcatg taggggagta taacatggaa ataaggcagg 69780
tagtttttcc tttccaaatt tttagtatag atgaagaaaa agacattctc aattatcaat 69840
actgtttaaa aacaatgtct ttgatttaat atatggtaaa tattaaatat gtggtcgtga 69900
aaataagtat atttttagag ttcaaagggg aggaaaatat cctttgtaag ctggggcatt 69960
ttcaatattc aattttattt attttttata atgaaatagt cagcactcca accatccatc 70020
tatccaccaa ttcatccatt tatctacctg tccatctatt catccatcca aacatctatg 70080
tatccatcca ttcacacatc cattatttca tcctgcattc atacatccat aactactctc 70190
taagaaagaa gaaaaattta ttcaggcttc tatgtagatg gaagtgtttt gatactaaaa 70200
tgtggatgtt tgtaatttta ttattgccat ttcctttcca aatgtatgcc aatcatacat 70260
ttttctaaga cttatacatt acctctgaaa tgcttcctct tggaaatgat gcacgtcact 70320
tctactgaca ttttattggt caaagcacat cacatagtca tgcctgagcc tatcctcagg 70380
aagacaaggc catttgacca ggaaacacag gagatccaga aatattggtg aacactggta 70440
acgtccatca ggctgaaaaa atgtggtata aatattaata tttaagacac aaagaggtat 70500
ttaccatgat aaaacatatt taagacaaag gtttttacta agagcaaaaa cataaacttt 70560
gtgttagtca gttctgtcta ctctaacaga ataccataga ctgggtggct ttaacagcag 70620
acatttattt ctcagccagt tctgatggct ggaagtctga gatcagggtg acagcttctc 70680
ttgaggacca tccttctggc tgcacactgc tgacttctcc ttgtatgctt aagtggcaga 70740
tagcagcgac ttcctggagt gacaagggct tcaatcccat tcgcgagggc tccgcctcat 70800
gagctaatca cccaaagtct ccacctccta ataccaacac cttgaggatt agaatttcaa 70860
aatatgaact ttggggcaca caaatattta gtccataaca gccttggagg taaaattcta 70920
agtagcagaa atctttcatc tcttctaaaa ctaacactag tggaaaacat aatctttcat 70980
tcaacgctta gagtctgtct tggagagcag gaacagatgt attatattac atgtgcacac 71040
atacacatat acacacaaac atttgtttgt atgtgtgtgc ttatgtggat atctatatgt 71100
catatataca ctgcatctag cacaataggt aattgctatg tcagggcaca tttattatag 71160
ttttctctct aactcataag ggagagtttt ttaatcagct ggtaatatca tatatttcag 71220
ttttttcttg caaataagag tggaatagaa agattttcgc tgttgagaat tgtgccctta 71280
agtgttaaca atattcacaa gtgtttaaag aaataattag gttcatttca ttctatcatg 71340
cttgtactat atttataaca tgacctttgt tctatttata tatacaagta atatattcta 71400
ataggaattt ttttgtgaag aagaaacact tgataatatc ccaattccct aacagaatta 71460
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
127
tacaatagtt cctcaatgac cttaccttgg gaaaaaatta aatgaaagac acctgcatta 71520
gagatcaatt tcctgatgct cagtttatat tcatcatgct aagctatcca aggacacctt 71580
tcttgtccta tcatttgatg gaaacgattt ccatgtgttt tatgattcaa ctccattctg 71640
ccttagacaa tacagtcact tcaaacagtt caactctaca gttggctggc tgactttgcc 71700
ttgtaaaaat tgcttttttt ttttttggtt cagagtattc tatattttac ctaagaagtg 71760
gaaaacaaat tttgggcaag aatagtggca tacacattac agagtgattt cacatttcaa 71820
tattatttac aaatatgaca tcaaacatta gtggttttat ttcattttta tatcagaggc 71880
attctaaata tgatgtgaca aagttaactc cgaatttcct ggtttttgtc agtttaaccc 71940
agatctttgc tatgcagttc tgaacactgc catgctttca acttttcaac aagaaacagg 72000
tggttaatac acacatgtaa ctctacaact tgatcttagc atttcatgta atactttggt 72060
aatgcctaaa tattatgttt gtagttgtcc ggagcatctt attttcactt tttcaattct 72120
atcaaagagt acattaatag aaaattaacc aaaactgaat aagaataaaa cctcacttcc 72180
ctaatttatc ctcttataga aaaatatttt cagtgtttat atttatgtga taccagccgc 72240
atctgggttc agtaagcacg tgtttcgagc atactttgag atgcattgtt ccttggcgca 72300
cctcagtttg tactggaatc attaatgcat aatctgaagt tgtgattatt gagatttttc 72360
actcaataat gggattcaaa tgctgccctg tttgatctgc attaactgtt tggaattcca 72420
gaatattgac tggcacttca gaagtcacca gagtattctg tagccttcag agggtaaatt 72480
tcagtcacgt ggggatgatt tttttggcaa agagcatttt gcactctgag tcatcacaca 72540
cattctcaca agtttttaag cccaggacag tctccattcc accacttgta ggtaaactgg 72600
tgatgatttt aaaggtaatg tcagcctgag aaacagtgaa atatgctgaa gatatggaca 72660
caggcacgga gtctgcgtca tcttagtccc taactctcac cttagtgaat tgttccaaca 72720
atgacataat gaattatatt taacttttcc tgctgctcat gttttgatat ttgtcatcaa 72780
tcggagctgg tgagagtttt aataaagtgc ttagcatcac ctgagggtaa atttctatat 72840
cctttggatt ccttgatcct cctctgcact ttatgtaatg agtgaccttt ctatctagtt 72900
caaatagaga atgtagagaa gtaaagtgct tcatgcaaga gggcatcact gatgtcaaaa 72960
tgcagggcca acatgaaaga agggcagaaa ggttccggac acaaagggca gggcactgcc 73020
tggactggct agtgtcgggg tttcagccag aaccttcctt tagaatttgg aaactatgga 73080
gaaaacacag tgatgcagat caatatatac cagttttgtt acagatgttg aagaaggtgg 73190
ctcactactg tgatcataca tttgggcttc ccaacttttt ctcttgaatt aaacatatta 73200
ctaaattggc aggctttttt cctaacaact gtgaaatgct agtctttaga aattttcagc 73260
atccagcagc aaataacatg catgtccaac ggcgaggatg gctccaaaaa agagagaacc 73320
ccaaatgaaa atgagtcaag cattcttttt tctttaagca gagcaagatc attcttatca 73380
gaggaaattg tgagcagggt acaagaagct gcacatgcct aggaggtgag agttctgtct 73440.
actccaggga aaaatgagaa gtgttgaaca agcagcactc ccagaaaata acacattgta 73500
gtagacgccc gttacggttt ctccatgtat taaattggtt tataacattg tctttttgtt 73560
tgtctctttt gagtttataa gttcccatca atattttatt tcctttactt attttgggtt 73620
taatttgtgc ttttttctat ctttaagata aaagcataga tgataactga ttttagactt 73680
tgcttatttt ctaatatagg catttaaaga tgaaagtttc ctcttacaac tgatttagct 73740
gtattcttca aattttacct ttcaaaattt tatagggttt atttttatta ttgttcaatt 73800
tgaaatattt cctaatttcc cttgtcagtt ccacttttac atacagatta tttaaaatta 73860
tgttgcttcc caaatatttg ggaattttta cagatatatt atactattgt ttgtgatttc 73920
taatagaata ccattatagt cagagaaaaa tgtcatgtat tatttcaatc cttttaaatt 73980
tatcacaact tgctttgtgg ttgagatggt gatctacctg agggaatgtt ttatatgcat 74040
agaacagata aagtgtattc ttcaattgtt gaatataatg ttctatatgt gtcatttaga 74100
ctaatattga tattgttgaa gtcttctagg tccttattaa ttttttatct attagttata 74160
ttaattgctg aaaaagcatg tttaatgtct gtgattggag tcttttctgt aattctcctt 74220
cagtttttta aattgttaca tttatgtagt ttaaagcttt gtgattatat ttatccacat 74280
atttaattgg aaatttttgt tgttttaaaa atgtttaccc tttctggggc tttttcttcc 74340
ttccaacctg gtatttttcc tcttcagcct gaagaagtta cctcagcatt ttttatagaa 74400
caggtctgct ccagacgatt cagatttttc tggtgaacat ataaaaatat acagaaatgc 74460
ttttaaggca ttgtctcagg atatttgcta tcatgtttac agtcttttat cttctactat 74520
ctttcaactt tttttttttt tttttttttt gagacggagt ctcactctgt cgcccaggct 74580
ggagtgcagt ggcgcgatct cggctcactg caagctccgc ctcccgggtt catgccattc 74640
tcctgcctca gcctcccgag tagctgggac tacaggcgcc cgccaccgct cccggctaat 74700
tttttttttt tttttttttg tatgtttagt ggagacgggg tttcacagtg ttagccagga 74760
tagtctcaat ctcctgacct tgtgatctgc ccgccttggc ctcccaaagt gctgggatta 74820
caggcgtgag ccactgcacc cggccatctt tcaacaattt aaaaacattt tatggtcttc 74880
tagtttcatt catcttatga gcacaatgcg tgttttttat ctcctccagc ctctttcaag 74940
attttctatt catgtttggt tttcatcacc gatttgatga tcgtttgcct agttcttgtt 75000
atatttgaat gtatttactg tttcttatat atgtgagttg atatatttca tctaatttag 75060
aaaattgtca cccatgttct cttcaaaaat gtcttctacc tcattatctg tcctcttttt 75120
acaagaccct taacgtaaat atatttgatg gcataatatt ttctacacat ctcagatggc 75180
tctccttttc gtttttattt tattttattt tattttattt ttgagaggag tctcactctg 75240
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
128
tcacccaggc tggagtgcag tggtgcaatc tcggctcact gaaacctcta cctcctgggt 75300
tcaagtgatt ctgctgcctc agcctcccga gtagctggga ctacaggtgc ctgccaccat 75360
gcccagctaa ttttgtattt taatagagat ggggtttcac catgttggtc aggctggtct 75420
cgaactcctg acctcagatg atacacccac cttggcctgc caaagtactg ggattacagg 75480
catggctctc ctttccttct tctcttctgt atttttctcc ttcttcctct ccatctctcc 75540
ctccctcctt ttttttttct tatatttcaa tgtgggtgat ttctattgat ctatcttctt 75600
gtttactgat tcttttcttt ggtatgccag tttactaata gacctgtcca attaattccc 75660
catctcwata ttttattttt tttccctatt cttgacattt ggctttttag ttgtgtttat 75720
ttctctgcta aaattcttca ttttttttct gaaaaattgt ctaaaaatag tgttagatta 75780
tctgacatat ctattatatt taatataaaa ctcctctctg ataatttcaa catctatatt 75840
tggaactgcc tctatttctc tttcttccct tgcccatatg gcatagttat gtttatacat 75900
cctataatgt atatatatat agcttcttca tgtcttgtaa ttttttacga tcccttccat 75960
ttaacagggc atgagatcta agcaagggag agcctcggat ttctctttgg gctttataac 76020
ccagctgctg actccctgag tccgggcttc cagtgaattc tctttgctgt ctggttgctc 76080
acccagcctt ttcacaactc agatttctac gctttgctgc tcagctctga gcctttgagg 76140
cttgagtgga ctcagtgaag tccccgggag ccttggaggt gtttcccact gctgtcctac 76200
tctacccagc tttccgcaac agctttttgg cttagagggt tttctcatgg ctctcctgag 76260
ctgctcccag cctcaagtca gctatataag cctccatttt tcagatcccc tactgtgccc 76320
ccaaacttgg gtgcattatg tccatgtact aaagtaaagg ccccctggga cagagaggtg 76380
ggtgggtgca gagctgcctc tgatggagct tcctcaggga cctgagtcat cacacttcat 76440
aagcttttta aaatgtgttg aaaattggac ttgtttctca catccctttg ctggcaaatc 76500
cctcctcctc ttcccatcac tccacctagc atcagggaag cacttcattc ctctctcata 76560
ggaagagatc atgactttct agattttctt tcagttaggc tttttttgca tctccagctc 76620
ttcattggct cttataaact gtgttttgtt attgttgttt tcaagttatc catcttgttc 76680
tcatttgtag ttctcttatg gctttctaat tcctaaccag aagtggaaac tgctagctat 76740
tgtttataac atggtccatt tgcagtttat aggggtggta tatgaatcaa gtgtggaaag 76800
gaccagaaaa aaattgtaat ggcagatgtt atgttgtctt aagccttgct ttgcttttgc 76860
cactgaggct gtgttgtttt taatcttact gtgcatggca ccttctcatc acactagtgt 76920
tttgccttcc aggggtatca tccatataaa taaactgctg gaaggccagg cgtggtggct 76980
aacacctgta atctcagcat tttgggagat gaggcaggtg gatcacttga ggtcaggact 77040
tcgagatcag cctggcca'ac atggtgaaac tcgtctctac taaaaataca aaaatgagcc 77100
aggtctggtg gcacacgcct gtagtcccag ctactcagaa ggctgaggct ggagaatcac 77160
ttgaacctgg gaggtggagg ttgcggtcag ccaacgttgc tccactgcac ttcagcctgg 77220
gcagcagagc aaaactccat ctcaaaaaat aaaagtgaat aaaaaataaa aataaactgc 77280
tggaagaagt ttatgaggta tcctaagaca tgtacaaata ctagtgtaag acccaactgg 77340
gaatctttat gtcttatttc gtccacagct ccccacccac accatggatt taagaaagtc 77400
ttttaaaaca tttgtagatc aagctatctg gttctaaaac atttgtagat caagctatct 77460
ggttttcaag gaatttatat taagattgat tttcaaatcc tgtgtgctct agtctaggag 77520
gataattatt tgttaatgta gatatttcat agagacttca ggcaaacaca tgaatgagga 77580
gcaaggaaag acccaaagaa agcatgtaag tagatatcct aaatcaaatt gttatttgac 77640
caaagaattt ggtgatatga taaaatccaa tttctaaata atgagttttt ctgttaaagc 77700
tctcaatatg aattaggaaa gccttcagct acacgtaaaa gaaaatctaa ctcatagagt 77760
tttaaacaaa tgatgagtct tttctttttc cttaaatctc ctggaatcct gttgacattg 77820
gattagcaac aatggtgtca aggactgaaa gctagtgatt gcttttgctt tagacttcat 77880
gcctacattc aaaacaagaa gagggtagga tacagcgtca ttcattctgc atcatcagga 77940
aagcaaaaag ccttcctaga agcctcttgg cagtcatata cttaacacct ttttggcaga 78000
aactgggtca tgtgtccgtg tctaggtgtg agagagggat ggaaggtggg aacatggagt 78060
tgttaggcca attgtatttc atctcttggg aatgggggga ttgatattgg gtagacaaaa 78120
atcagttgtt atcactctac ctaagtgttc ctctgaaata tattacttga ttctggaact 78180
ttatttgaaa agttatttga tattcaatag ttataatggt aatccaatac aaaatatata 78240
tgttgccttt aaaatgataa atagcaattt aatatctaga gtaatctcat ctacatttga 78300
cagtaatatt aactattcta ttctcataaa tcttgtatca tttttttgtt aaattgtcat 78360
taatttaagt aaggaaaagt agagtttatt tcccagtcac aaatagaagt aaccggttgt 78420
tgtaaaatta tcaatgtttc tttcttgaac cactgcacct tgaattttga ttaaagagtc 78480
gaagtattgt taacatccgt ggaacttaga aaaaatacca gtgctaacca catcacatct 78540
aaaatataag cacatttcaa atttatgtga attttaaata atctgttttc tttggcttgt 78600
agaaaaatta ccaaatagca tattgtatta agaatgaaat gttctgtaat caagatcaaa 78660
ttacaatctt ataataataa cagataattg tatacatgca atattaaagt atatgagcat 78720
attctttaga caaaatatcc aaagacatca atgttttcat tattaaagag ttactttcca 78780
gttcactgaa taaatgaaaa tattaagaat ttggttatat taagaataaa ctctaagatg 78840
tttcttttac ttcagtatga aaagcatgca aaaatgataa ctacattttg ttatgatggt 78900
ttgaaaaatc tggcataatt taaaagcaac tttccatctg gctggtgcag taagcaagtg 78960
gaattagaag agttggtctc tgtttcttga tgtgaatgat tgtgattagt ctgatttctt 79020
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
129
tggtttgctt ttattactgt tttcacttct tttcttggta tatgtgtgtg gatatgcata 79080
caggatgaca tttctatcac attatggctt aacaaataaa acagaaaata tgtttacttt 79140
ggatgtgtgt gtatttttgg agacggtatt tgttgcctac tcaacagtgt tctttttact 79200
tcttggcagc ctccttggta taaccacgca tttacggaag atgacgttac cagcagccct 79260
ggggtaagtc tcagtcatcc gaagccagtc ttggtaatcc cagcagacta gcaagggaac 79320
acaacctagt tctgtcaagt ggaaagtgaa gagagctgtg ctgggaggct tctcagaaaa 79380
ggtttctttt ggcaaaagaa agagaggggg gaacagttct ttttcttctg ccggacaagg 79940
tcatgtgtgt acgtaagaac tggaagttct catgcccact gagcatgggg agagtcctgt 79500
ctagggtgac ctggtgagaa cagacaaccc ttgagccacc ttaccctagg aactcctggt 79560
gataagacag aatacatttt ttctcactgt taaactcttt tttattattt gtagctgggt 79620
gcctccaaac caatataatt agccgtatgt aaatattctg aaatctctgt caattcaaat 79680
aacatttagg gtttttttcc cagtgatcaa aaatacagca tctcaagcaa tattgtgtgt 79740
gtgtgtgtgt gtgtgtgtgt gtgtgtgtga tattattaca taataattgg aagacttttg 79800
atgtagatcc tagtggtgat cttaaatgtt gagtatttga ctttttttag catttaataa 79860
ttgtcacaat aaatttatat ggagagatat tttaattata gaaactcatt agtttgtcca 79920
taatgtaaaa gagttaaata atatagttct gttgataatg atattttgta atagatattt 79980
ttaagctgtt aggcatgaag gaaaataatg ttgtaagtaa tcagttttat atagggttta 80040
tagatatttt tattatttgg tattgtcatg ttgtttcatg cctcataata gctgattaca 80100
aatagatttt aatcaatcac tctctttatt ccaaaggttt aagcagataa agaatacaga 80160
gaatgcttgt aaagcatttt ctaccaatat attaggacca tttctggata aggtccttga 80220
cttcttcttt taatcgtttc taaaataaca tttccaaaaa cctcaagcaa aaccacttta 80280
aaaaatctga attcatataa ttttacctaa tgtggaagat tgggagagca gtgactttaa 80340'
tataatattt taatgtcaat gtgtgtacat ctgtaattaa taaaattagt acaattcaca 80400
acacatggtc gttcttaagc g.acagagaca tagaaatgta acagcacatt aaaatcctct 80460
tctagtggcc ccgagctgca ccccataaac tctttgatag ctcttaacaa atgcaaatta 80520
atgagcatta acccaggcat tcgaaggtcc agataaatca ccatgctctt caggaattca 80580
tatgaacaat tcacagtgct ataatttttc ctaagttaag actagactaa tgttgagaga 80640
gacagaaaga gaaacaaaat ataggtgcac tctcctctgc tcattatagg gttctcttcg 80700
accttgagga gactgctact tggggacatg tactgattca ttttctgact ccttttgtcc 80760
ttgattttga catagccttg gtgttgggaa attcttccct caaagcctca atcgctcatg 80820
ctcaaattta aacacatttc cttttctgta atcagtgagg gaagagcagc tggtcaccat 80880
cttctacaca ctaaaccttt gagccttttc ttcagaataa atgatcctac ttcttagaat 80940
cataaaatta gaaggggttt tgatgtcaga ccatcctttt tctgccttta gacaagacta 81000
cccttccctc ttaccatccc atacagatga gcaaaaccat cctattttta aaagagatca 81060
agagaaacta atcaaaagcc tccaacagtc acacattcct ctgatgagca acccttactt 81120
tcaggaaatc atcatcatta tcatcaaata gcattttcct aacacccaca tgtgcaaaat 81180
atgtttgtgt attcagatcc taaagagggc cctagaggcc cagaaaaggt tggaaaaaga 81240
aaaaaaaaaa acgtgcaaag gtacacaagc atcactaggc tctttgcaag agagtctagt 81300
tcattgcaat aataaattat ttttaaaaga cattccagaa actccagggg attttcattt 81360
tctatttagg aaagcgatct tataattaaa gaatatatcc attcattttc ttttgtttaa 81420
ctattaggac ttagtaatga ctatcaaact caagtctaat gaccaaagat tgagaacata 81480
aatatgcagt gtattaaatc tgaaacaaat ccatactaag gttttaaaat ttgcaacacg 81540
tataatactg aaccagttgt ctctgttaca aagtgtgtat gtattgaggg gaattgtctg 81600
gaaaaatgtt taaagctctc ttctctccca ttctggctcc tcctttatgc tcctggagaa 81660
cagagctcaa aggctgctct caaatgttca aaactcccca cccatggctg gaatggctct 81720
atgtccttca gtttcacctt ccagtcaagg aattcccaat ttctgagtat tactgatttt 81780
tgctaggttt taactaaata aagcaattta attgaaggta agccttccct taatttataa 81840
atatttgata aagggaaaat ttgccagtcg aacatgctgc ttgatgcggt gggggggatt 81900
ttgacctggg tggcactcca gtctggactt caccttacct ttaattgctc tgccagggga 81960
tgcaacacag agtaaggtcc cacgtcatcc attcactcct tcctcttttt gggtttctca 82020
gctcctctcc attgctcacc ttcacgagaa gttccctgta accgtgaagg ttatcacaag 82080
gctcagaggg taggagctga cccagcacct gcagatcctg aagggcccct aatctaaata 82140
caccattcac cccaacaggt gggaaacaat ttgatacaca ggctcaaaag tttgttttga 82200
ttactgttgc tgtgaagttt tgatttggcc tcctaaagta gaggagccaa tttgatattt 82260
cattgcataa ttcctgtact atagtagtag gtactatcta gcaagacttt actgcaaaca 82320
taaaatatat taatagaaca tacaatggta ttggcataca gctcttttta ttttttatct 82380
tttctaatag atatgtttat tctatttcct aaacgtattc aagacttaaa attttcacta 82440
ccaatgaata acatgcttaa atattttagg gaaatggtaa aatggtaaac agctctatta 82500
gtattattga atatctcata tttgaaagga aagaaagtga cacttgctgc tttctcatac 82560
gctatcacat ttaaacctaa ttacatttca agacaagaat atttatcatc tttttttctg 82620
ttaaagaagt tgagcctcct ttacgataaa ctgaactcaa atgtaagcat ctctaattct 82680
ggagtgcata tgtgcacaat tacataaata atttggttta agaatcaaca aaactaaata 82740
aatgttaggt ttctagaatt tatccaaaca tcatgatgat tgactattta ttgccgattt 82800
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
130
tcctattgta atatgcagaa gtttcaattt taagatataa tcgttatgtt ctccttattt 82860
gatctcgtat ttccacagag ctactctgtc attaagtgta cctaaattct tctccatagc 82920
cttttaagat tttccgatgt ttatctgttc tctgtatcag tctcgatcac tgtcttcact 82980
ctaaaagctg cacttaatag cttacttacc gaattagtaa tttgggaatt accgtatagt 83040
tacatggaaa tattacttcc ctctgtgcca cagactgggc tttgattact tcgatttcaa 83100
tgtcccagca gcatccagat tttatgaata ccatttccga tgctttgctt aaagttaggg 83160
gccaggcctg agctcaagtc tcaaggctga tgttgttaat atcaggacag gcgggttcaa 83220
aagcacaggc gccagctgcc ccacctccat ggcacagccg tcatggagcc agccacaggt 83280
ctgtttcaga ttgcaaagga gggtctctga cttctgtttg cttttgtgct ctaggaagac 83340
attgtaggcc tccataaaca aaaataaaat gaaatcgaat tacaacttct ttttaaccta 83400
tttaggatgt aaaggttaaa tatatatgta tctatgaaga aatgcatgtt aaaaagtggt 83460
ttgaaataag acatgcggaa gcaaaattca tttttctttg tatgggtaag tagtatgttt 83520
ttctttgtat gggtaagtag tatggctaag tagtatgttt tctttgtatg ggtaagtagt 83580
atgacaatac gccataatca ttgtccttat ctattaacta aacctcaatg agaaagataa 83690
attattacat tgcagagata tgagacttaa gacttactca aaaaatttta aaggctattc 83700
cttaatgtaa tacacttcta tcaggaatag tacagaattt tatctgagat atttgtatta 83760
atcaatattt ttgattcata tgaatcatta tttggatcag attttgatcc aaataaatgt 83820
gaagtatatt gaataattca gaattaatta gtttccattt aatcagttca atccttctga 83880
gttcatgatt aggcaatttg gaaaagacta tataaaataa tattctattt gaactatgga 83940
agtattcaaa agaaactggt aagttcatga gtataattgt ccaagtgagc tctgtaatct 84000
atgaatatat aggaagttct tgtctttgag aatacatggt ttaagtgaat tctattatct 84060
atattgtcat tttgattgta tttcaatttc gttatgtgta aacggaagca atggatgtac 84120
tctttgaaaa cagtttcaca aattaagaac tttaaacaag cttttatctt ctatttaggt 84180
caatttgtct aagtatttga ggtaattttc atcctcatct ttttatttgt tatcttgtcc 84240
aatcctatta atgagcataa atggctcccc aagtgtaaat atttgaaggg aaagattggg 84300
tcattgtaaa ttcaggtagc atccatagtt gatgacagaa tgacgggaag aaactttcct 84360
cactaaatgt caatcaaatt catcagcatg atacttttac atgtctgcac agctggaaaa 84420
aacagtcaat tctgtttcat tgttatgtaa atttatgctg atactcaatg taatcaacaa 84480
ccgatgctag aaccatcctt gaaacagatt agatgattgg attcttttta atataattct 84540
gaaactggaa ccctaggttt ttcttaggca cttcttaaat atttatggtt atccagcata 84600
agtaacacag aaattctgtg gtcagctagt ataatctttt tcaagcagtg tatgctattc 84660
ttatacccac accaacaaaa ttgtatctaa aacattggta tctaacctag gaaaaatctc 84720
aggtaaggtt ttacgattca gtgccttagt ccccttaagt catttcggcc acagccttaa 84780
aaccctcctt taaagggatt taccatcacc tcttgtaaaa actggatttg agcaagatgc 84840
attttattaa tcaaatccat aaggcagtca atacattact tcttttggaa tgaaaaagga 84900
aaagagttat ttcacaagca gatgaagact acatatgtaa ctctacttcc ctcggtaggc 84960
tccaatacag gtttaatcct gaattttccc attttgaaag gcttgccaag tcagttctca 85020
gacctttcgt gaaacatgtt gctcagaagt gacatcaaac gtgatcctaa tttttgacag 85080
attcttctat acaatgacac atacctggcc ttcaaaatag agtaaactaa aactcactga 85140
agaagaacaa aaaggtcact cttaccattc ttgaggattt cgaaaatcaa tgatcctaca 85200
gaaggagaag aggccattta tcattatagc ctttttgatg tcaaagaaga aaaagaaaaa 85260
gaaacagaaa aacatgcctt taacatagca gctgatatta gtagctttag aatttacaaa 85320
gcactttact gttccgttat ttcaattaac actcataatg ttgttgttca gccagtctta 85380
acatttgtgt tataattatt tcctttgaaa gctgaggaca ggagggtcaa ataacttgta 85440
tcatttccca aagtcttgca gctgataagt gatggttcta ggagtctatc tccgaaagat 85500
tgagcatgaa atctgttttt tttttccatt ccattgaagt gtgtatttac taactgggta 85560
tataattatg aattgaagac taacctttat ttaaattagt gcaatcagac tatatccaga 85620
atatttctag aaatgatttt taagtgattg atgagtaaaa tgaagggtaa aatatttttt 85680
gtttgttcac ttaaatgcaa accctctgag ttaaaatttt ctcaataatt atgtagttca 85740
aacaatattt tccaagatta tttgaactta gatacaatta ctgaatttag gcatatatac 85800
attagggttt cttaatcttg gcatcattgg cttttaagtg gaataattat ttgttttagg 85860
aagctgtcct gtgcattgtg ggatttgggg catcctgccc tctacttacc agatgctaac 85920
agtactccag gttgtgacat cctcaaatat ctttagaaat tgccaaatca tacttaggtg 85980
agaatcaatg gtctgtatta atttaactgc aaagacaagt gctgtttcta aatattacac 86040
tggacaattc taaaggttta ccataaatta gcagaggcat taatctttta atgatagtat 86100
tgtagtggat atactggtac aggacatagc tatctaagct aattctatat atacagtaga 86160
ccaaaactga cacattccag gcatcccttc taatcttcct ttgactcctc ttatctagag 86220
tgaaaatttt cttagcttat tttgcatctt cccagcatat cttcactggg agaaaattcg 86280
tctctcacat ttttgcacat cttgcaagtc aggcactgac cacctttttg ttctggattc 86340
tcttttgagg atgtttatat agcaaacatc cttggaaatg aagaatcatt tctgcctgtg 86400
aaacagtgtg caaacatact tactccccat tatagaacat tcaggttccc taagttcagg 86460
ttcctcttcc cctataaatt cctttgcccc ttgtaaatta ttgttttaca tgatcctctt 86520
tgtgttgcca tgtgggaaca aaatgttgat actctggata ctgctgttac taaacttttc 86580
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
131
ttgatctctg tcccaggagt cttctcattg cttcctacta gaattcatgt atccatatta 86640
ggatacattt tttgttttgc cagaaaggca aaatccccag tccttctcat tactatgttt 86700
ttgttgtttg tttgtttgtt tgtttttatg cagcctcggc gctctgtcac tcaggttgga 86760
gtgcaatctc agctcactgc aacttctgcc tcctggattc aagccattcc tctgcctcag 86820
cctcccaagt agctgggatt acaggcgtgc accaccacgc caggctaatt tttgtatttt 86880
tagtagagat ggggtttcac catgttagac aggctggtct cgaactgctg accttgaaaa 86990
tctgtccttt gaaatgaatg acaaattaca tgctatttat gccccaaaat gctaacttcc 87000
acatatatca ttttagtata tccttataga ttatctcaca tgaaatttct ttttgcaccc 87060
attgaaagat tattcctgag gatgtcatcc actctatcac ttattgtttc ctctttatat 87120
aagcatattg tctttttaaa ggaaagctga tttttaccta aacaacagtt tcatttcttt 87180
atagacatca caaaagttgc gagttactgc atttgcatcc tgcctatctc ttttaggaaa 87240
tgaaggcttc cttttttaag ccaacctcta gcagctgcat aatatcattg atagtaatgt 87300
tgggtgttaa ccttaccact gatttattac ttttctactt ttaaataatt gggtatctga 87360
ggaaatggaa ataagatata tattaaatat aggtgtgtgt atatatatat atatatatat 87420
tcaagtatgt atagtttcat gccaacctcc atattctata tataaatata tattacatat 87480
tatattatat atatgtatgc gccaacatct taaaaagttt acatagaaag acatcttgga 87540
ataaattgct attattagtg gagtgggggg aagaatcaca tgagcaatct aggtagcaat 87600
atatctaccc tacatgaaga agatcacatg atctttggtg tttctcattg agtatccggg 87660
ttagtagata acttattgac acagggatcc cagagatcct cagggaggaa agtgattgtg 87720
accccaacac aaagcttggg aaagtgatgg aatggactag agtggcactt gacaaactat 87780
tctgagagta gcactccagg agcatttgga gaattcacaa ggatggtaac attaataaca 87840
agggtggctt gatactagtt ttcaacacaa gctctggccg tcctaagaaa aggctttttc 87900
tggccaaaag tgttgcttac tctggaaatc cctaagcact ggccattctt gcatgaagtc 87960
tttcttcggg aaaacatgcg taaatgattg aatataaatt caaagaattt taattgttga 88020
gcccaagtat agagtgactt cactcttctc tggggactga agtggaaaga ccaagtgtcc 88080
ttcaggatgc gtggactcca tattccacaa cattgtgtgg cagcatcaga agccactgcc 88140
ccagtcggtg aaaaccaccc tctccacctt ctccactcta tctttctata aacaggatga 88200
ctgattccca tacactgaat tgaccctgga attcatggac attgtggttt ttgtttgttt 88260
ttgttcggtt ggttgtttag ttgattgaga gaagtgaggg gaaatgataa tatcagatgg 88320
ggagaataaa ttgattaaaa tttcttaaaa ggggccgggt atggtggctc acacctgtaa 88380
tcccagcact ttgggaggcc gaggtgggtg gatcacctga gatcagaagt tcaagaccag 88440.
cctggctaac atagtgaaac ccagtctcta ctaaaaatac aaaaaactag cagggcatgg 88500
tggcgggtgc ctgtaatccc agctgctcgg gaggctgagg caagagaatt gcttgaacct 88560
gggaagcaga ggttgcagtg agctgaggtc acgccattgc actccagcct gggcaacaag 88620
agtgaaactc catcacacac acacacacac acacacacac acaaaattaa ttaaaaggta 88680
ataaaagaag cacgatcatg cagagcgtta tgctggctac ttttacattt ttacttttac 88740
attactcatc tatgtttcat tattttatgt gagtttttag atctacttag gcatttgtag 88800
gtcaggtttg tttaatagtt aaattcatct acaatcaatc ttactttatg catatatgta 88860
tttatagata cttagaatga cattaaagat tttggtagct aaatctggcc agtacaaaaa 88920
atatatatta tctctagcct aaaatggaat gttgtcattt atgagttcat tgttacctga 88980
ctgtggtatc tgactaaaaa aaattatcat agtatagatt gctatttttt agaatgaatt 89040
attttaagga agcacttcca tggaccataa tctcagagtt ggacaagagt tctaaaacac 89100
aatgtagaaa aattgtcaat attgtcagtt attaatgatt tccagtgata taacacaact 89160
aaataaagta aaataaaaaa atgatcccat ttaactggta cttctaggaa attcaggtag 89220
gtgtctgagg tcactgaaga aactgggtcg gttaccatat ggtgtaatct aatctctttc 89280
aattctgtaa gtctgaaata tatggtattt tcaatgcttt ttttttttga gtattacatt 89340
aagtcaggaa acagtctctt ggcttgacgt ttgagaggca gtgcaaaaag ccttctactt 89400
tcagtgctat ggcattgctg atcacaatat atctatgaca ttctgataca agatctgaga 89460
aataaacaga aaaagggtca gtcatttcag agaggtgatt ccattataaa ggtgggtatg 89520
tgtagcattt tcttgagaaa cttttaagtt tttctttgat ttttctctaa gttttaagag 89580
ccctaagctg ataaatactt aatgaatttt cagtaatagt agacaacttc cattagtatt 89640
aaataacctt tgtgaatcaa cttgtataaa tcacaacaca aatagtgaaa acaaaacaaa 89700
gcaacaaaaa acgctaaact aaactacaaa gaagtcttga gtgtttggat ctgacccaaa 89760
gtgaccatta aagttgtaaa ttttctcatt aaattgataa caatgtaagc cattctctac 89820
atcaattgaa atgccaacgt acttctgagt aataacatcc cttccatgtg gtctctgata 89880
ttttgattct agctttttac gagcatgagt atattcttta ttttgaaggc tgtgttgata 89940
gatggctctg aattggaggg ctaccaaaat ctaaagggat tctttgctgc ttgtcatggt 90000
tacagtcctt tttctcttca gtagcttttg cttatctaaa atgatgaact ttctcagtag 90060
atgtgcaatt caatcgagtc atcttttccc agatacagga atggttatta atattctgcc 90120
ctctcagttc tctatgatac cctttatgac cattcagaca caggcattca tacctcactg 90180
aggacagcag ggacaggata tgctgctgtg ataacaactg aaccaatgac ttggcttcat 90240
gctctctaag agctgccaac tccagtgcgc ccaataactt ccaccccttc actacttggt 90300
ccagtggtca gatggtgggt ggatggggca ctgcaaggca ctgctttctg ctgttctgct 90360
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
132
ctaactcctg accagatttc acaaacagcg tgtgctagct ttaccatcca caaatgcaga 90420
gaacttttgg gggaatactt tgcacagccc tcaaccagtt ctttcctaaa atgtatgtga 90480
agtcaccaaa cacattgaag gttctcagta gattttcttc cttctgtctt tcagtttggt 90540
tacctcgcct ctttgttttc attgctttca gattctttat ttatagaagg gaaaggggaa 90600
aagctgtata ccacagccaa aatttcaatt ttgaaaaaat tccaatctac agaaaagttt 90660
caaatttata gaaacaaaag tataataaat actagtaaat acctttcaat taaattcacc 90720
agttacaaat tttgccacat ttgctttttt ctccctcatt atctctatat ctatccatct 90780
atctacctgg ctacatctct gtgtctgtct ttgtgtctgt atattacaca tacacacaca 90840
gatgtgttac cttttctatc cttttctatg tttactctag aaatcatgac aatatagatc 90900
atgtataaga aaatcagtaa taagttaata ttatccaata catagattta cttatactgt 90960
aatttgtggt ttcaccgtag tttgctttgc tttgttttgt ttctgatctc tatattctct 91020
ttcatggaaa gagaatgttt atctgtgtgg tgacttggtt tattttggtt tccgtaactg 91080
aatttctgaa gaatccagag gagttatcat tagaatgttc tgcattctga atttgtctca 91140
ttgtttcctt ctgtttagca gcaagtaaaa catttcttct gttaagcagc aagtaaaaca 91200
tagcaagaat actatgtagg tgatattgtg cacttaaagc atttgaacag gaggcacata 91260
attttatgtt gctccattac tgatgatgct ggtttaatga cttggttatg atggtgactg 91320
ccaggtgact ccattatgaa ggtgggtatg tgtgtgtata tatatatgat gtaagagtgt 91380
gtatacatat atatatgtgt gtgtgtatat atgtgtgtat atatatgtgt gtgacacacg 91440
tatatttata cagtaaatat atacatatgt atatgtatca cacaacatta tatttatacg 91500
gtaaatatat atatgtatat gatacatgat aagtgaagaa ttgtggcctt gtggcaatgt 91560
gagcatcctt cttcctaaaa attttcatcc agtagttttt atcatctaat aattggtcct 91620
tggtaaaaac agttattatt atgtattgaa aaaaagatga tatttctaat tttgtcatat 91680
tcttcttatt ttttaactgg cattctttga aaattacctt tctctttata tatatatata 91740
tttttttttt catgattcta agttatgtat ttaaggtatt ttaaatattt taagcatctt 91800
gaaaaattta aagtaggaca tgttttataa ttactgtgat ttcttatata aacatcacat 91860
tttgataaaa ataaagagta tattacataa actcattaaa gtcttaaatt tatacactta 91920
tctgtttcct ttcaaagcaa tttttgttaa aggtaggaag gagtaaaatc cactgtgcct 91980
tgggttttca ttttctattc caactaagaa gtgctgtcca cagaaatgta tcattcagcc 92040
actcagtcaa actttcctga gaacctgcct ccatcaaggg acttcgttag ctgtaaagtg 92100
ctgactaaac ttgtgtttat acctccactc atgaaatagg aaatatacac acacatacac 92160
acatatgcat tcgtgtttat acctccactc atgaaatagg aaatatccac acacatacac 92220
acataggcat tcgtgtttat acctccactc atgaaatagg aaatacaaac acacacacat 92280
acacacatac gcattcgtat ttatacctcc actcatgaaa taggaaatat ccacacacat 92340
acacacatat gcattcgtgt ttatacctcc actcatgaaa taggaaatac acacacacac 92400
acacacatac acacatatgc atttgtgttt atacctccac tgatgaaata ggaaatatag 92460
acacacacat acacacatac gcattcgtgt ttatacatcc acttatgaag taggaaatac 92520
atacacacac acacatacac acatacgcat tcgtgtttat atctccactc atgaaatagg 92580
aaatatacac acacacatac acacatacat ttgtgttttt acctccactc atgaaatagg 92640
aaatacacac acacacccat ttgtgtttat acctccacta atgatatagg aaatacacac 92700
acacacatac atatgcaacc atgtttatac ctccactcat gaaataggaa atacacacac 92760
acacacatac atttgtgttt ttacctccac tcatgaaata gaatatgtgc atataatata 92820
tattatgtaa ataaaattat atatatttat ataatataca attttctaat atgggctgca 92880
ggccaatata catagatttc tcctggctgc aggtgaccat gtcacttgca ttgattataa 92940
tatattttaa ttcatggaat ttaaataaag ttttaacatc agagactttc acagagattc 93000
agataacttg agatagtaca taatatgttt aaaaagctaa tttttttctg tgaatattgc 93060
ttgtttccat agacgtttca ttctacaaag gttcaaaata taattttaac taacaaacta 93120
tgaaggtaat tgtacccatt ctgcagtctg ttagcagctt ttgattagat tctcatagca 93180
gaattttccc atatacagtt gctaatatag aagaaaaata tcatctcctt attggattat 93240
attgttaact tgcttttgct taatattttg gcatcttttg gtaaatttct ggaatgaata 93300
acaataattt acgcagaata atctaataaa ggatatttat agcctatgtg aaaataaaga 93360
tacgcatttt agggactttt gcagagatac aaacacttgt tctgtaaaat atttgttaaa 93420
cgtagcacat agggaaagca cagatcctgg agtgaaaaac ctacagcttg aattccactc 93480
cagcatttat tagaccagtg acttggtcaa gttgcttagt ttctctgaac atcaatttac 93540
ttgtccataa agagagagtg gtggtacata atagatattt tgacaggctg ttaaaagcta 93600
gagatgaagc gtgtcgggag tctgatgcat agtacttcta ttaggcaagg tttttcagag 93660
gaaaaagaac caataggatg tgtatgtata catatgtaca cacacacaca cacacacaca 93720
cacacatatg aatgagagac atttaattta aggaactggg tcatgtgatc atggggctgg 93780
caaatctgaa atattcagga caggcaggca ggtctgaaga caagggaggt tttaacactg 93840
cgcttccagt ccaaaggcag tctggaggca gaattccttc ttcctcaggg aacctcagtc 93900
tttttctctt aaggctttca actgattaga taagtcacgc acattataaa ggacaacctg 93960
ctttaatgag tctactgatt tcgatgtgga tctcatctga aaaatacctt cgcagaaaca 94020
cttagtctga ggtttaacca catttctggg tgctacagat aaaattagct atcacagaac 94080
gtctacacag aaaggtactg acatttgtta aaaccataga attctattta catgaccaac 94140
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
133
cagaatgtgt ctagagggct ccagtgcccc tgcagatttt ctatttgtgc tggcagtttc 94200
ttggatagcg tctcctattg gctgctctta ctttctgtct ttccattgtt tctttgaggt 94260
ttcataggaa cagtcctgtt ttagttaaaa gtgccgctgg ctcccagggt cccaaagcca 94320
atgagtagat aatgaatggc aagcaatacc tgatcccata cagaagaggg aaaacccttc 94380
tctcccacac ctgtgcctta aggtagcact gtttatttaa cagacttgca aaaatctacc 94440
atgaaaacag tgacttcaac ttctaattta gcttttctcc caattcatgc tcaaaccaat 94500
tcctcaaatt gagaagcaag gacgagaaat gctycatcag ttaccttcat tacagtcgta 94560
tctctcgagg tgcactaaat tcctttgtct tcaactgatt ctctcctctc ccaacaggag 94620
atcaatgtac agaggaatag ttcctttaaa tccaggagtg catgcaacta agcaacttta 94680
gagatgaatg gttgcatatt ccccggagcc aattctagtt gagctcaaat gatatattct 94740
taaaaatagt aattctattt attttacaag tgctatgtaa acagagaggt aagtaccagc 94800
attataattc actaaaaaga cctgattttg ctgcacaaac ataactaaat ggctacaccc 94860
tttaattgca gaatccagat ttcctccaaa ctttatctca ttccagtcag gaaaacagct 94920
atcgtctttt tttttttcat caaatgcttt tattatcatg tttgaagctt ttgattaagt 99980
tggcatcgta agaaaccctt tcctattttc tttcatgttt ttcttgacaa gcctgagtcc 95040
gtcattctgg ctggtattac aggttcatgt ttttgggtac attcatttat catggagtga 95100
gtcactttgc tgtttttgtt tccactgtat tctgaaaagc acccacagaa acatgacaag 95160
aatgcaggct tgcatggaag aaattctcat gccgggtctg ctctgtctcc ccagtcagtc 95220
tatcctgcat aacgtcgtct ttaaacaata gaaagcaatg gctaaggata aaagaatggg 95280
ttcagataaa actgaatttt ctaccaccct gaatattcac tccatattta atctgaagcc 95340
aaatatttta acataaatgt atctttattg tctttgtcct ggtcttccaa tagggragtt 95400
tttgtacgtg gtacctcttt gtttttttgt ttgttggctt ctactatttt cttaatttta 95460
aattctaagc ctccaggtgt cttgcttata aaaacgattc tggattttct acttttaaaa 95520
tatggtttct taaccatttg cagttttgct aagaggaaag gagaatctat aaagtatgtt 95580
tacatgaaag gaaaatctct gtataacatt ctatcaaaac tgtaataaag tgaaaattaa 95690
ttattaatat tgatatgatt tggctgttcc ctccaaatct catgttgaga tgtgatcccc 95700
agtgttggag gtggagtctg ctgagaggtg ttcgggtcat tgggatggat ccctcatggc 95760
ttggtgctgt ccttccccac tctctcttgc tcctgctctg gctgtatgac gtgcctgctc 95820
ccctttcgcc ttctgccatg agcaaaagct ccctgaagct tcccgagaag ctgagcagat 95880
gctggtgcca tgcttgtaca gtctgcagaa ctgtgagcca attaaacctc tttcctttat 95940
aaactactca gtcttaggta ctgcttggta gcaatgcaac aacagcctaa tacaagtata 96000
cataatggaa agtgagccat gccatttgtt cctttgaata tatttggaca attaaaccaa 96060
caataaaaaa aagaaattat atgcagtttc tgactcgggt tccttgaact taagtggtag 96120
cagaagattc ccctatctgg aagagagaaa gtcttcctag gaaaatgcag gagctgtttc 96180
aagtgtgtaa tggagcagca ttcttctgaa acacattttt gcttggaagc ctaacatata 96240
aataaaaata tgaagaggga gcttttctat ttaaggtgtg agaagagggt gtcgggtgcc 96300
cggttctacc tcgttaagct cctttcaaat gctgagatgc catcgacccc tgattctgtc 96360
tcccaggaac tcagactcaa aactcttgca ccagaaacaa ctagatggag aaaactacct 96420
gacaaaagtc ctggacgatg gccttgaaat caattccttc atgtctttag agggtctctg 96480
tagtttttcc ataggtgctt accagccaca ttcttggagg cgagctggct aaagtaaaat 96540
tctgaactga actgagcttg atagagttct gtgctcatat tcccagcaca gtctccatgt 96600
tgggagggaa aattgctttt tctcccattg cagtaaaaaa aaaaaaaaaa agtcaatgat 96660
caagtctaga ttccttacaa cttctgttag tttcctgcac tccatggata atcaaattcc 96720
tcgcaacaaa acagatgagc tgtccctcaa aattgttgac ttgtgcctta ttaggttggt 96780
agaagtgaga atgtggtatt ttaaattctc aagactgact tcgtgtatcc atagagaata 96840
atgtatttta tcctattttc ttaactctgt atgtatttga ataagggcga tttaaaagtt 96900
ctctcacatc agtagaaata actgagctag agtttgcttg ttgacaatgt ataggyacaa 96960
tatatcatta gaagagtgat aatgactttt attttggtga aataataaaa aaggaatcat 97020
aaaaatagag ctgtctaata atgaaccatg tgtttaaaaa agaaaagtta actttctcat 97080
cactggaaat aaggaatgag ccagtggcca tggatcacag atataattgt aaagattcct 97140
atattgagtg ggaacrcaga caaaataacc cccaaagtct ttgctaaatc tatggtcata 97200
taaaagaaat acagctggat tgcctatcaa aaagatccag ggcagtggat actaactttc 97260
tttacttgca gccaaagttt tgaaatctta gtagagcgtt ttgctttaaa tttaatttat 97320
taaccctgat tactgcagtc agcaaattaa actcaagcct gtattatgaa atattatgaa 97380
ataaacactt tagaactgtc atctgtatta agcagctgta aaaaagcagt gtcaagcctt 97440
gatgatttca tataaaattg aaataatttt gaatattcct catggtgatt tgtatgtttt 97500
gttatgcaga cacagaataa aaacaagtga accaaaaaaa aatgttattt aaaaatactt 97560
aagaaaaaaa acaatttgga aaaaaatctc gatatcggca ctaatttaac tttgtaaatt 97620
ttccaatgta gttcatgttc agtatattag cataatattg attgtattag aggggctcag 97680
tatttcttac ggacttaagt atgtttaagt aagagcatat ccattttgat taatgaggtc 97740
tatatacctt ctctcttgat tactctccag ttttggggaa atcactttgg tagctgcatt 97800
agctctttta ggtcacctga aaacttctta ataaactaag tggtacacta gtaaacaaaa 97860
agaactcacg cggcttccct tgaaacgaat acatcactgg gaattctgag aaaccaatta 97920
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
134
aaacagaatt attgttttga atgaatcatc agagaattct agtctaaact cttctaaaaa 97980
cctacatttc tttctaattt tattacatta aatttaaaga tttttttcaa actttttgaa 98040
tgagaatagt catcagatta ttttaaaaga ttaggctaaa atatgcaaaa ttcccttcag 98100
taatacattt ttttaactgg aattataatt agtcataagg ggaaagtcat tttagtggga 98160
aataaaattc aaaaaagcta aacattaact gctgaagttg ctttttgccc tttgcaaatt 98220
ctttcttcat tatatcattc tctctatatt tttgaatgca tatatttcca aagaaattac 98280
tttttgctta atataaaatt ttaggcaatt agatgcaaaa gtgtagtaaa gcaacactaa 98340
agttgccaat ttaaacatag ggaagcaaaa cagcccagga gttaaagttc tgacagctat 98400
cttaactagc acacatggcc agtgccactc agtacacaga cacacaccca ttttcacagt 98460
cactgaggag ctctaagagt tgattttgaa acgtagtgga aattaccttt tttgggaaaa 98520
taacataaat ctgagataaa ttcttgactg tccgtactca aaatattttt ttccaaaatg 98580
aaaaaaatgc aaatgtcctc agcataataa tctaggataa gtagttaatg atgctacatt 98640
aaggcattac ttggggcttg caaattcatg actgacattt gatgatatcc caggttagaa 98700
gagttatttc ctttctttct ttcctttctt ccctccttcc ttccttcctt tctttctctt 98760
tctttctttt tctttctttc tttccttctt tttttatttc taaaggaatg tgtaaattaa 98820
taacaaaaac ctttaacata taaacagatt gataaattac tgagcaaacc aaactgtcca 98880
cccatgtttt tccttgtggt agtctgctcc aaccatacca gcaaggccta gaaagagcaa 98940
aaaaaaaaaa aaatgtatat atttggcggt gtgatatttt cttaaacaaa gatttttatt 99000
gtaatgccta actatttctc tcatttgaat ctgagttgca atttagacac aaatcctgag 99060
gtcagatcct ggcttatagc tggatactat agagcatgtg ctgtgttcct gactcctcat 99120
ctatgatgta gaaatgataa atcccacagc agaatgttca agtgaaaaag aaataggaaa 99180
atataacgta tcatgcataa ggcctcttat aaaaaacaca gattccaaaa tgacatggtg 99240
attatcatca ttttattata gccaataaat tgccagggat tttaaaaact atcattctct 99300
aagaattcta tttaagaaca tacatataga taaaatatgc attcaagatt ttgtaacagg 99360
atctggaaat aaagtcaaca caaaactttt ctatcctgct gctggtattc aattttctat 99420
tcttgaacag atattaattg tccacattcc ctactttctc tctcaagttt acttaaaaaa 99480
atatctactg ggattatcta catggtgcca gacacccgtg aaggataggg tagtggagaa 99540
aataaacatg ctcccgtttc tatggtgttt atcatataat ggaggacatt cttggcttgt 99600
gcatttattt ggttcagcta tgtaagggat ggtaaaggga atatgttcat tacagaaaca 99660
tattcttact ttctctccta attacagtaa atgttcagag gtatgggaat ggtcaaacag 99720
aaaatggaaa attataataa aaaataagaa agttatccaa gtccacagta aaactataca 99780
attttataac acagaccaag aaaatattcg catagaattt ggtatgcttt ccttgcccca 99840
tcaaatccac cattttagtg ctctatattc tctttctgtt tttaacatat gtaacggcgg 99900
ggctttctga gctggcttcc ttggagtgca gacattagta atacagacaa cttctattcc 99960
tcttccccct acacattgct tgtaaatcag ttattattta tttatatgtt tttaattttt 100020
tgaattatga cagagaagga gtagatgaat ttaggtagaa agataggaag gaattgctga 100080
gccaaaactg aacaaagaaa ctggtcttgc catggggtta gtctccaact cagaataaat 100140
tgaattttta tatagagtga cttgtcagat caggaggata gaaattaaag ctagaagccc 100200
tcaaaagttg gagaatataa tagaagatta tacccaaatt aagcagaaat tcaggatctc 100260
ctttcaggta tgtttgaatc aaaagcaaac cagggatttg caacacaaga tacacattgc 100320
cttgggacgt tcagctaccc tcaaaccatg aattttgctt aagggtctca ggttggtaat 100380
atcactaacc tgagtgtgac agagacaagt caatcaatct ctggaataag gcaatttcat 100440
cataggcttc agcttattca aatcagtttt caaacatgat gggcagcata tactacaggt 100500
tcaccaagca taggcagtga tttatctgtg aatgggaata aacagaaata acccattaag 100560
tttacagata ttgaaatttg tagacacagt ctacaaaaat actatgtttt tagggaaaat 100620
ggtaagtata taaactcaaa caagggacta tgtattaggt tatctaaaat atttaaaaca 100680
gatcaaagga aacttctata aataaaatct aaaaacctga aaccataaag cctatgggtg 100740
aaattaacag tacattagaa ggagatgaag atagaatgag cgagttagaa gaaactcaaa 100800
gaaattatac agaataaaac agaggaatta agagacaagg aggacagaat gaatggttag 100860
gctttatatt gaatcagagt ccttgaaaaa aaagaaaaaa ggatgggttg aaataatgtt 100920
tgaagaaata gtgcctgaga atattccaga gctgaggaaa gacacctgca ctcagattca 100980
atgattggaa caatttttca gtagtataaa tacaaagaaa tgttggtgat tgtaaaactg 101040
caaaacacca aaatcaactg aaaattttta atgtaacctt gaaaagaaag agaacataag 101100
aaattagcat gataggagaa atatttaaat cagtaattga tttctcatca acagcaacgt 101160
aagatgaaag agaatgaaat aacttcacaa gctgaaacat aataactgaa tctaatgctt 101220
gaatttcttt cacaattata ttgtctaata atccaacaat cacattagaa attaaatagg 101280
agcaagaata cttactgcag ccttatttgt attgctaaaa gcatagaaat agcatccagg 101340
tcaataagta ggcatttcga taataattat gagatagcag ttcattgaaa tgttgggcat 101400
ccattagaaa ggaaaaggca attcttaaaa atccacgtgg agttgtattc cagatgtaat 101460
ttttgcaagt gcatagccat ttgcatacag aaaatgtatg tgtatgtgcc gacacatgta 101520
tagattttgt ggtaatctct ggagagatac tcaagaaaat aattgtcgtt gtggagagaa 101580
atgaggtgct gaagaaaagc agccaaggtt ggggggattc atactttttc taccccttgt 101640
accttttaaa tcttgtttcg catgtactat tattcatgaa ttacatatat tttttaaggt 101700
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
135
tggtttgatt ttagttttta attaaaaaca actaaaatac aaatatctcc acagttatca 101760
acagcacaga ttaaggaata gtgttgtgaa gtgtcttcat tttaggggtg attgtgttaa 101820
agttctgggg acttaaatga cctttttcat accatccaaa taccgattga gaatgtaaat 101880
ccaaatctct ctacaaaatc catcctttta tttttactgt ttaatacctc cacatatttt 101940
ttaaacagtt ctatacattt ggtactatat aagttgtatt gccatcaaat gaatattcat 102000
gttcactcca acattcatac gtgtttttca acctatgggg tcctgggtag atgattaggt 102060
catgagggca gagtcctcat gaatgaggtg agtgccctca tataggagac cccagaacac 102120
tcccttgctg cgtccttcca ccatgtgaag gcccagcaag aggaaggcca tctatgaacc 102180
aggaagtgat ccctctcctc tccagacacc aagtgaccct gcaccttgat cttgggcctc 102240
gtaacttcca gaatcttgaa tgtatatctg tttataagcc aaccagtctc tggtattcca 102300
ttatagcggc ccatacatac caaaagctgt ggcactaaca aaatccagca aagaagagtt 102360
ggatctaatt gtttcattaa aatttgatta tgaatctttg ctacggccta aacagcagag 102420
accagagttc tctccttcca ctgtgcgagc ttacaaattg gccgctaaga gacaacaaat 102480
ctaccagcac cttgatcttg gaattcccag cctccagagc tgtaagcaat aaatttctgt 102540
tgtttatcag ccacccaatt tatgcttttt cattagaatg gcccaaaaca agtaagaaaa 102600
tcccccaaaa caaatcaagt gactggtaca tgcctatagg ctcagtaata tttttttgaa 102660
tgaataagtg aataaaggta gagtgaatgt gtattgcctt tgaatgtaaa cctttaatac 102720
caattgcagt atgatactga attcacttaa gaattatttt tacatagttg tgtagaagca 102780
atttataata tggaaatatt tctcaaattt acagaaattt gataaatatt atatttattt 102840
tatgtaaatt cccaaactaa aaagacatgt cttttctctc actgtccatg taagttagtg 102900
gaagacatcg atctcaaatt acaatattta actgtattaa attgtatata tagatgcaga 102960
ctctaggata aaagattaaa tgtttgatat ttttaagcca gatcctatta ttaaaatcat 103020
caatgatttt tactgtgaag gtgtagccac atgacattac cttcagaaaa cttcaaagca 103080
gcaaaagcat gtcgcagagc caaatgcagt tcccagtgcc aagaaaatag ctaatataca 103140
tgggcatggt tccaaaaaaa cccatatggc aatgtgagtt gaacatcttt tacagcagca 103200
attccattct aacccaagtt ctttccctta aatagcacct cttttatttc ctgtagtcaa 103260
actggctgta cagtcctcac tcttgccaaa gtccttgtct gggatgtgca tctccaggaa 103320
ccgaagtgct aaacctttct ttttactagc ctgctctgcc aaaatccatc ttgacacacc 103380
ttaaattata ttagatcaaa ggctgaaaat tatatgccat caaaagcaga aagataaaat 103440
gtttatctac cgcattaggg atgtgcaatg tttttaaagc acttgatgtt tgagtgagac 103500
attattcgac gtctctgcag tgcagcatgg cttacttcct tggagtagtt gatagatata 103560
ttgtaacagg ctggtggcaa atatgaagtg gcatattcag tatgtgttta ggatgtttat 103620
gtgttctctg attcttgtgg tgctctgtct aattggaaat aaggtttacg tggtgagagc 103680
agtgaagcaa cgacagggca atactataaa agcgactcct gccaccagca ctccatttct 103740
tttaatggat ttctacatat ttggaaactt ttctaatttc tccttaaaaa ataaacccat 103800
aaatgtcaag aagaatgttt ttcttcctaa tggagtttgc ttgccaagct ggctttgttg 103860
caatgtctgt aggtgggcta cggtaaagac cagtggaatt gaagtaattt ttaaaggaat 103920
attgtctcaa atgaaatata aacaaggaac tgtgtaccca ggcttcaaag tgataaacag 103980
atgatgctat aatcaagtaa tttttaataa atatttgatg gaatttactg aagtccatat 104040
ttcagtaatc catcatccac tcccagatat acattgagat tacaaaatta acaatttgtg 104100
ctgttgccag aattaaaatt tcctagtaaa gttgaactat tatataacct tagtattttt 104160
gcatccttaa ttttttccag attattttgc aggctataaa catgttaacc tttaggacta 109220
ttttatgtcc aggtactact taaaaatgta ttttagatac aacaatcata caatattttc 104280
taccgttatg gtttcacagt agataactaa aattatatat atatatatat tttttgagac 104340
aaattctcat gctgtcaccc aggctggagt gcagtggtat gatctcggct cactgcaacc 104400
tccacctccc tggttcaagc gattctcctt gattctcctg cctcagcctc cagactagtt 104460
aggattacag gcacctgcca ccatgcctgg ctaactttcg tatttttaat aaagacaggg 104520
tttcgccatg ttggccaggc tttaacataa ttgattatgt ttcaaaaaat aagaagcaat 104580
ttctgcatac aaatttcaga aaaattcact tggaaataag ttttattagc ttacactgtg 104640
ggtagagaaa agtaaaacat tgaaaaggta actgtttgct ttaacattta cctgtaaaaa 104700
cattcatgaa tttacctaca atttcttgga agtagaaata tattctcaat gttgttttag 104760
aagcacatat ttaatggaga aatttgtttt ttatagtgtt atttttaaac ataattttta 104820
atttagaaaa ttatgacaaa aactcgttca ttcccttttt tggaaaaacg atacttaacc 104880
actagtaaat gttaagtcct gcattatgca caggggttaa taaaatttag gatgacatgg 104940
ctcaggcttg tttaagacaa atagcactga taggctgttc cataaaactt gttatattgc 105000
ttggaagaaa tgaggcccat atataattga atatatcaaa gttagtaaaa agacaaccac 105060
cacgtgttta tccagcccct gcaatatagt gcattctgtg ctacactgtg aagatcgcta 105120
accattatga agattcttac agtcatggga tgacaagact tctgtaatgc aatgattaca 105180
gcactgtgtg atgaatgctc tggcctgtgt ggataaaatg ctttagaaac atgagagata 105240
cctgcaaaag gtagctagta aaagcttcag agaagatagg acttctgaat ttgggtctta 105300
acattctaaa aaaagaaata gtttgaccaa agacatggaa atttatttga atttgacata 105360
ttttgtttgc ttgtttgttt gtttgacaga gatagggttt ctccatgttg ctcaggttag 105420
tcttgaactc ctgagcaatc tgcctgtctt ggcctcccaa agtgctggga ttataggtgt 105480
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
136
gagccaccat gcatggtctt gaatttgaca tattttgata tttgggtaag gggagaagat 105540
tagtgcaatg gtttgcacat tggaccgctc caaacctcat gctaaaattt gatccccagt 105600
gttggaggtg gggcctagtg ggaggtgttt gggtcatgag ggtggattct tcatgaatga 105660
cttggtccca ccctggcctt aatgagtgaa ttctcacaat gtcagttctt ggaagtgatg 105720
gttgttaaaa agagcctggc acctcacccc tctctcttgc attctctctg cacacatcag 105780
cttcccttcg ccttccacca tcattgtagg tttcctgaga tcctcaccag aggcagatgc 105840
tggtatgctt cttgtacagc ctgcagaact gtgagccaaa taaacctctt tcctttgtaa 105900
attacccagg ctcatgtatt tctttattga aacataaatg gactaaaaca tttgatgtgg 105960
ttgaagtgta agttttatgg aagagattgc caaggatgtg tccaaatggg gtggtgggta 106020
aaagactttg aacgttttcc aaatgtatgc caatacatct agactttact tttgagctag 106080
aggaagaaca ggtgcagcca aaattaattg gaaaagtgat agattgcatt ttgtttgaga 106140
aggataattc tgctattaaa agagtagatt gcaatagaga gagtcaagaa gacaccagtt 106200
tcagtggtca ttgtgaaaga ggacttggtt tcatggagct gggggaaaga ggtcagagac 106260
catgggcagg attttgtggt caacttgaca tcgggatgat gtacaaagaa aaggcaaaga 106320
ggaacaatct gggcagtgat gtcagtcgaa atttgggcag atcgttttga tagaatggat 106380
caartggaat ccaaataaag taaaattctc aattatgaga attcaattaa ataattttgc 106440
tttaaaggaa actaagattt ttaaatgcca aagataaaag ctgaaagtca ttataacttt 106500
agtcttccct aaaagtgact taagcaagaa aaaaaaacag tatatttttg aaactagtta 106560
acagggtatt tggcttaatt taaatgatct ctccagcaga tattcctttt gtggtccata 106620
aattttcagt tgtttattta tttttggacc atacagtaaa gggttggaca gagataaaaa 106680
tcagggaaaa ggaaagtcca gacacagaaa ccgctgagtg ggcagaagca ctgtccgaga 106790
tcaggggggc acaatgatgg aagtgcagyt aaggttgttt ccacgctgtc ctagatgtac 106800
agagccaaga gggtgagtct ctcaaagcca cagttgagaa ggaggtcact tgagtagcag 106860
gagagaaatg ctggcaagag aactgggcca caaacacagt ccaaagggag atcacggaag 106920
cccatgagga aagtcaggaa ggagttactg caactcaata gctgctatca taaaaacaac 106980
cctgctgcta cgtgggagct ggtgtcttcc tgtaaaatat actccaccta attatcctac 107040
agcaagatac tgcatcagtg cattcccatt gccttgtaag tccgccttgc cttgtcttgc 107100
cttgccaagg gtgtgatcca aaactgagtg ggctgatatg aattgggtgg tgctttcrat 107160
tccctacata gtttgcctcc tgaaaacctc ctttggtatt tgggccacgg taatgcaaag 107220
gagccattca tccaggtaaa ttggagctgg aggtaggggc tgagcctctt ctggggcctc 107280
rgggggcttc atcatgggtc ctggcctgag tgcaaagata gcatctagta tcacagataa 107340
cttctttttg atgcctagcc atatttctga ttttcttgtt tattaagagt gagaactaca 107400
tttcctacta ggctaggtct tacttcgcag ttcttaaaat gtgttaaacc tatttgtggt 107460
tctcctttga attcttccca agttctctcc acgcctggga agttgtggag ctggtcctct 107520
agagatgcta tgtctatgat gccaacccaa ttacaaaaca caagcaaaaa caaacagcta 107580
cgctagactt tccaaactct aaaacatcra atctcctctt tgaccctatc atgaaagtga 107640
gttacttaaa ttaaagagta attgatttgc tgttaaatac attatttgcc aaataatttg 107700
actgtataat cccagtgtag ttataattct gtgtggctaa ccctgtgttg ctctggaatt 107760
ctgtcctctg attttatgaa ttctaagatg ctgatttaat ttaatttttt aaaatatctt 107820
ccagtttact tgagtccaag taggctgatc cacagaatca tattcaaaga attccaatga 107880
gctgttgagg aggattttaa gccctccact agcttcctgg catcagttgg ctttgagaac 107940
caacctaagt atttcagagc tgctagtgaa atgaatcttt cttacagata ttacagaggg 108000
ttacagaaag ttcagtttct gactcaccct gattttgaga aactgtttct tagggtcatt 108060
ccctaaggtt ggaatcgctc tctctctctc tgttggttag tgccctgtaa acactgacaa 108120
ttttctttct cttcagttct tcattcttgg tctagtgctt cagtttccaa gtctacatga 108180
ctatgctaca gtgtaaggtt atttagacgt acaatttcat gatttctttc ttctgggatt 108240
atttgcttga cttgtgatta gcttgcctga tcacagacaa tagtaacttt ttaaccattc 108300
ttacatgatt tcccttttcc ttaaatttgt tgtttctgta ttagaagcag gaaaaaaggg 108360
ccaacgttta gaatttgaaa agcagtgttt gaatgcactt gttacctggt aaaccagtca 108920
tttactgcta tcttacaaat gaccacagca catggtagac ttaaagaaca attatttgca 108980
catttctcaa ttttgtggrt cagaaactgg cagcactcag ctgagagact cttctgtttt 108540
acggggattc acagcgttca ctcagagaca gatagctggt gggcaggccg gtgtcaggga 108600
ccaaggatgg catcactcgt gtgtctggcc cttgacaggg atgctggagg tctgggctca 108660
cctgggaatg gagatggcaa cacctacatg tgacctytcc agcatggcag tctcagagtg 108720
gatatggcaa cagctgcaca tgacctctcc agcatggcag tctcagagtg gatatggcaa 108780
cagctgcaca tgacctctcc ggcatggcag tctcagantg gagatggcaa cacctacatg 108840
tgacctctcc agcatggcag tctcagagtg gatatggcaa cacctacaca cgacctctcc 108900
ggcatggcag tctcagagtg gatatggcaa cagctgcaca tgacctctcc ggcatggcag 108960
tctcagagtg gatatggcaa cagctacaca tgacctcacc agcatggcag tctcaggtta 109020
ctggtacttc ttaggtctca gctgaggact ccagtgcagg tgttgcaaga cagcagacgt 109080
agcactgctt atgtgtatcc tgaagtccca tgtgtatcct gaagtcccag aaagctgctt 109140
caagtagatt ccagtggaga agggagtcac caaggctgga cagtcattta tccatggcag 109200
gactagcaaa aaaatctgca ccatctctca tcgcacacac gtgggtaagg tttggactgg 109260
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
137
tatgatcttt ttccataatc tcattttcgt gatttcttaa ctgagaatat aatagtaaat 109320
accaatctca cagaattgtt atgaggaatg cagaaactta atcaaattac ttaattgtta 109380
ttttcatttc ttattaattt gttcccattg aaattaatgt tatgtctggt ctcattttaa 109440
attatttatc kttctgaatt tggatcccat cctcaagttt tcaatgcttg actttttatg 109500
aattcttgta ttatacctca aatttaataa aatcctttta atcttgtctt caccctagca 109560
ctgtctatac tgtcccctgg gtggaagttt cccatcattc taattacttt trtacacaaa 109620
tttgacttct ctctccagcc cctgtgagaa acatgtcctt tctgttacac agggagtagg 109680
tgaaggcctt tggacttcct atttttccta tatgaaactc tcttctttca gatatcagaa 109740
ttttcctctc tctctttcat tcagaactct gctagacaat catcttacca graagatttt 109800
tattcatcac cctgtgctaa ataacattgg tactatgctg ggctgagcta ctatttttcc 109860
ttgaatcctg ctgtaggctt ttcttcagac acttaccatc accaggcgta atgtgaatgt 109920
gtttgttcat tgcatgtctt ctccacgtga atggaaactt catgacaaga atgtgttcca 109980
gggctgggcg ccgcggctca cgtctggaat cccagcacat tgggaggccg aggcgggcgg 110040
atcacaaggt caggagctca agaccagcct gaccaatgta gtgaaacccc gtctctacta 110100
aaaatacaaa aattagcctg gcttctgtaa tcccagctac tcggaggctg aggcaggaga 110160
attgcttgaa ccctagaggt ggaggttgca gtgagccgag atcactcaag aaaaaaaaaa 110220
agaaaagaat gttttccttc acctctgaat ccctagtgta taggggagag cctggaacag 110280
agtaggggtt ccataagcca atcaaataaa tgactgaaaa agagttaagg gacaaggtca 110390
aacaaaaaga gctaatttaa ctgctaaacg attattctat ttaggccaat tggtaaccca 110400
tgactgcttg taaaattcaa tttcattgaa tgggacatat ttcaaacata aacataggtt 110460
tttttaatga atataactga actgcagatt gcaatcaaga tgttccctcc ctttctcatt 110520
tagatttctc atcttattag ccatcactga ccctcctcta gtggttaaat gcttagtttg 110580
ggacattatc tcagccatac cctcagaatg gttgattcag tggttcgttg cccatgtgtg 110640
ctgtgatgtc aacaggctgt tgaatgctga gggcaatctc atatttggct aatgatggtt 110700
cttcagaaag caacaccctt cagattagtt cagcagggtt caactttgtg gtgaccacag 110760
ttgggctgag caggctgcat gtcaggcaga gctgtcagtc tgctccagcc aagagtggag 110820
tgggcacttc ttgggatttg gataaggaaa catttgtctg agcagtttta ccaccttaat 110880
atgggtttga ttcttctatt tgtatacaga gtaagccaaa ttaaaaaatg aaaagaaaaa 110940
agaaccagtt catttaatca agacatgcta gtggttagtc atcttttata acaaccacat 111000
cgataattca cctttttcat tttcaaatta gtttttggtt gttttgtaga cagagagcct 111060
tagccataaa ttaaaagtaa tgataattag ccacatgttc ttcattatgt tgagggcttt 111120
gaacatttct tcacatagct attagacatg tcagccacat gtaggaaaag gaactataga 111180
atttcgtaat tttttttttt tttggaaaaa tgagcaacag aattttaagg cagaaacgtg 111290
aaatgcgagt gatggcaagt cccagtgaag tggagaatag catgctttat gtgaatgtct 111300
gatatttgtt ttctcagtgc ttttgatctc agaacaccta acaggactgg ggcagaagct 111360
ttttgctgac ttgttgcatc agtgctaaag atgaaaggaa acagtcttca tattcgccgt 111420
ggtgttgatt gccctataaa taggaaacta cccagttaac cttgcctgtt gtcatacgga 111480
gagttttatt aaaaaataaa cagtgcgtgg cgggtagcag aatgtgggat ttctgcttag 111590
atgcccgcaa ttctttcata tacttcatta aaatgtgcag gagaacttca gagccatgaa 111600
taaaaatatt gttatggaaa ctgaggcctg ttatcatagc ttcagtgatt tgcaatgatt 111660
atttaatgaa tgagtttatg tttgaaaata tcccctgtga taatatgaat ttatcgctcc 111720
cccctacccc tccgatttct tttattttga cacatatgga agatgctgtt ttgttttgac 111780
actcagagga gatgctcttt ttatcaaaaa tcactgaaca gtaatgagat tttagtgaac 111840
aatcttacca gacttcccga acataaagaa atctgatact gaggagtgca cagtgttcta 111900
taataagtaa tcttaggtgt gtgcatgctt ttcagtggca gtattcattt ttcacgagtt 111960
ttgtatttga tcttaccagg atttgatgta agaagacttg ggtagctctt gtgtagacac 112020
aaagaacaga gaggacatcc ataaagccat agagacagga tcccaaccac agtgtgagga 112080
gaaactgatg actatgccag gcatacagca ccatctcttc agcctaagag cagggggttt 112140
accaagctca ccaaaacaac ttaccattcc tctttccgcg tgattggaac tcatcttcct 112200
cctcagaggg tgcagagatg aatttagaag gaagtttgaa gagcccatgg tgtccagaac 112260
tcaggcctgc ttgcaaatga gtggctctgg gactgtcttt ccacatctcc aggagcctat 112320
tttccgggag gaaaatgaga gcactgttca gaagtactgg aaggaacctg ccaacattga 112380
gtttcttgag agtctctgaa gttagttctt ctaattttta gtaccctgac aatttcatgc 112440
aagttagtaa cttttgcata cttcagtktt ctcatctgta aaattggggt aatgataata 112500
tctaccaccc tcacagacac acccaggatt aatactttgc atccttcaat ccaatcaagt 112560
tgatactcag tattaactat cacatggtcc ctgaaaattt tattttattc tgatttggga 112620
ataaaaaagc tttctctttg accccgaaag tttttctctt tttgttaaaa tatattaaaa 112680
tatttatatg gatttctaaa atattgtgag ccccaggaac tctggttaat gtgcctgatg 112740
atctctgttg ccgtcagggt tggtttctca ttagggcact tctgggcttg tagagggcca 112800
ctttctcacc gtgtcccaga atggaccttc caagatctct ggtctccttt cctcttaaaa 112860
ggacaccagt cctatcagat tagagtccct ctcttatgac ttcatttagc cttaattatc 112920
gccttaaagg ccctatctcc aattgccttt ggggctagga aatcaacata tgaatcttag 112980
agggacacaa ttaactcaat aacagtgaca ttttaaaaac tacaaaataa gggaaatatc 113040
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
138
atagtttttt tctttacttt cacatagata ttacatcata ttaaaagata gatcatttct 113100
tcattttaat tgaaaccaga attatattgg aataaggggt gaccaatatg ggtttttcaa 113160
catttactct tatattaatg tattagcaga agacaagagt tcgatatttc ttaataattt 113220
tcctagaaat tgactaatat ttttattttt actttctcag atatattcgt tttaataaac 113280
tatttttgtt gttatctaat agtattcaat ttagacaatt tggagaacat ggatgcctat 113340
aaacatacat aagaatacaa atgtatcctg ctttcagcat cagagataat ttagggttat 113400.
tgcaattgtt tctgttttgg caaattggaa ggattatggt tgatgaactg aggtaagtat 113460
tctaggaaga atatttgctg ttgggtcagg catgctttca gtttttatgt atgtagagtt 113520
tgatagacca ctgagacatt taaaagatgt tcagaaggta ttgaactttt ggaaaggcag 113580
atcaaaatcc cacaagggaa gcctgacctg tgtacagaca tttgtgaatt gtctgcatat 113640
aggtggtatt gaagccatgg atgaaattgc taactaaagc atactcttgt gagaaaagaa 113700
gaggacaact tacccatcgg gcacattaac cacagttcct ggggctcaca atattttaga 113760
aatccatata aatattttaa tatattttaa caaaaagaaa aagaaaaact ttcagggtca 113820
aagagaaagc ttttttattc tcaaatcaaa ataaaattaa attttcagaa accatgtgat 113880
agttaatact gagtgtcaac ttgattggat tgaaggatgc aaagtattga tcctgactgt 113940
gtctgtgagg gtgtagccaa aggagattga cattgagtca gtggactcag aaaggcagac 114000
ccacccttaa tctggctggg caccatctaa tcagctgtca gcatggccag gatattaagc 114060
aggcagaaca acgtgaaaag cctagactgg cctagcctcc cagcctacat ctctctcatg 114120
ctgaaggctt cctgccctca aacatcggac tccaagttca tcatctttgg gacttggact 114180
ggctctcctt tctcctcaac ttgcagatgc cctattgtgg gaccttggga tcgtgtgagt 114240
tcatacttaa atacttaata aactcctata tacatatata tatatatata tatatacata 114300
tatatatata tatatatcta ccatattcgt tctgtcactc tagagaactc taatacatac 114360
aataaaaatc tattaaattt ttgtctgaaa cagaaaaaat aaaatattta acctttaaaa 114420
atgttcaatg ttgatatcaa tatgatgcca gagcccaatg aaaacaaaag tacttagttc 114480
ccacaaaagt tataatgaga ccctgatttg acctagtttg gaaatagcaa cctttaaaag 114540
gtttgagaaa aataaatacc tacacaagtg tttgaaaata tcccaggtgt ctaacaactc 114600
actttctcta tgtctttccc ataccccaaa tatcaaccat gacatttttc cgctgatctt 114660
tcagatctca gaaggcgaca tgaaggagat ccctctgctg tgagattgct attttcctat 114720
tgtacctcaa ttacatttat aaacttcttt ctttcatgcc agcctaagtg gtttttgaat 114780
ttattaactt taatgtttaa taaaccagtt tctatagcaa caatcctatg acagatgttt 114840
tgttaaagtc tctttaaagc acacacctct gtcaatatgt tattttgaac atttcaaagg 114900
ataaactctt gaaaaaggct gcacatatct caactttcaa gctcacaatt tgcattaata 114960
attataccct ctcttaataa aagaattatt taatagaagg ctgatgagct aattttaaga 115020
ataatacagt aaaaggtcaa aataaaactt accactctcg agaagaaagt gtaaggtcaa 115080
gaaataaaaa aaaattacaa catggactat actactttcc tcaatgttaa ttactttaat 115140
aaatgtgtga cgaatgatta ccaacatttt aaaatctatg tgcatttttc tccaatgagt 115200
ggcactggtt ttctttgcac ttttagagtg ctcagtcctg gcatatgtag gtcactgacc 115260
gggaaattac catctcaatt cactttcttt cttctttgct atttcttatc tgatctcgaa 115320
gttaaggcat tgaaactatt gcaaaaccct cattattttt tcccaaatta aaatggtaat 115380
atttaatagc tgcatatttt gatgcatgct tttggctctg gtttcctttt tttatgtgtt 115440
tttttttatt gttgttgtta tgaagggktt ttttttattg cttttttgtt aaagaacgta 115500
gcaaaaaaaa tgaagtatac taaaagctat ttcacccaga gaaacataat ttgttgggtt 115560
tttaaaaata tcattttcat ctgcttcttt gggaaacatc agaaataggc actgagggat 115620
ggcaaggttt atgctgaact ctaagtaatg catgttgtca cttgcagcca gtcactgaac 115680
tttctctgcc gtagcttcct catttttaat gtggactaag actccacttt tatatcacca 115740
cgtccaagtt tagacacgtg accctaagtt gctctatcag ggatctctag gccttcccta 115800
tgtgagacac aaggtgggta tggactgcag tcaaaggcaa gtgaggtttt tttttgtttt 115860
tttgtttgtt tgttcatttt ttgagatgga gtctcgctct ttcaccaagg ctggagtaca 115920
gtggcgtgat ctcagctcac tgcaaacttc gcctctgggt tcaagtgatt cccctgcctc 115980
ggcttcctga gtagctggga ttataggtgc atgacatcat gcactgctaa tttttgtatt 116040
tttagtagag acggggtttc accatgttgg tcaggctggt cttgaactcc tgaccttgcg 116100
atccacccgc cttggcctcc caaagtgctg ggattacagg tgtgagtcac cgcgcccggc 116160
tgcaagtgag tttttaatga atgcatggac ttgaggacag aagaggagcc cgaggtttct 116220
agtgggggct atgcacagtt ctgtgggtta aaggttgttc ttcctctttc cctgagctgg 116280
ggagctaggg caagctatgt cttatgtctc ccaagagtca aaacctttgg ctccttctaa 116340
ataccagcct agctcatact aacactggat gaatacattt ccacaacaga aactcaaaat 116400
ccatctgttt aaggatgcat gacaaatttc atttagaaca acagtatgag agtcatattc 116460
aaatgtgaag caagagtgag cacaaggctc ttatttgttc cttaagaaaa aaaaatttat 116520
ttcttagtga gtttaaatca tcaaccatgc ttcaggaaga aaaatgtagc ctggcctcct 116580
ttccatctct ttgtgattgt ggaaaagtgg acctttaaga tttcactgaa agattacaga 116640
cctgctcatt aattttacat tccaaacctt tgactggtga taaaatgaac aaaagaattt 116700
aaaataaagg tggaaaaaaa tggatccctt ttcatccgtg agggccctca ggctatatac 116760
aaacacaata cacaaaacct gcatcattta cctgggacaa tgttatgggc tactaagtcg 116820
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
139
atccttttag aagagcagtg agttaatgga ttgttttcct gacaatattt gtagtacagt 116880
aaaaaataaa atggggaaaa tatttttatc tggcttttaa atgttatgtt ttatggttgg 116940
gttaatgttg tggctgatca gctgttacat ggtgcatgaa tattgactgg attctccatt 117000
agggctgatg gggcatcacc gaccagctat gtgatctatg ttctcccact ggctcttgct 117060
tggcatgaga gatacatttg caggatgagg agcaggaatg agagctatcg attgtagaaa 117120
cagaatatag tagagctgat tgacctgttt caaaattaag aaatctgttg ccatatcttg 117180
cattacactc ttttatttta tattcttact ctgaattcct tcatgaaatg cacaaactcc 117240
accctgtata tacatatata tatatgtttg catttcctag cttttaaaaa tagtttaaag 117300
tataccttct ccaaagggga aatactttga aatatttttg gaagagaaat tgtattagtt 117360
tagatccata ataaataatt atattgtttt aaaagctggt gcaaagtaac attttcttat 117420
attgtagaac tctaagcctt ttggcttaga aaatgagagc aatattcttc tgcttttcat 117480
cacttacagg gatattcttg gtattattat ataaatttta ttttcattaa atataccata 117540
aaattccaaa tgtgtgtttc gaattactgg cagaaaaatg ttggtaattt tttccagtgt 117600
gacttaactg tcattataat taagtaattg tctccaccaa aatgtttgtt taggcaatac 117660
atttctgcat atttgaaaac ctaataaaaa gttttattaa agctgttcac tcaaaaatag 117720
acaactgtgc cccgctgagc agtagtttaa aaccaaatca atgaatttgc tattatgtag 117780
acaagaaagt gtcctatcat tgacattagt aatgtttcca ccaagttgaa cgtgatgagg 117840
gagctgttag ttgttaccct ggaaactatt caaaaggtct agagctgctg aaaaacagaa 117900
gactctgggc tcacccctgg gattccgctg cctttcagac catctaggat ccaaattttg 117960
ggaatgtatt ctgtatgtct gaacatgctt tactgccatt ttagactgat tgtatctaat 118020
tttaagttta tgatgccacc tctctttttc cctatatttc taaactttct ggaagacgtt 118080
ctgaaatcat tcaagtttat tctcattttt tatatctcag gactagtcac tcaatcttta 118140
aataaccact tttgatcaag agattactgt acccttctga tacaacttaa gatcataaaa 118200
acaagttgat ccaattcaat agctttttct tatattataa ttcatgccct ggccgaataa 118260
ttccaacttt ttcttttttt gaaatatatg ttaggttttc ctggttctca atcaatctac 118320
gtgagcactc attctttctg tattctggtt cctactacat cttttatcag tgtctctttt 118380
tgcattcatt gatcagtatc tcttttttta aatgcagaaa aaatagagtg tgcttataaa 118440
tgtttaacta ttagccagct atttaacttc ctaacactat ctgatatgct tgttattaaa 118500
tccaactcat tttctatgcc tttgattcgc cttatacact actaaggaca gaagagcaat 118560
ggagtcgatc taaaaccaga gaaccagaat cccttactcc cacagagaga ttgcctgtgg 118620
gctttaggca tcggtttact tgtctctaga gctcaagttc acaagcacca gtagccccat 118680
gggtagaatg tgaacctctg ttctatacag catgttgatg aatgcattac ttctgcctta 118740
gtcatgtcgg agcacagtaa atgtcaacta gcagtgcagc accggaacac gacatgcaat 118800
ctgctcacct gagtcatgct gctttcagaa gagaaggcac tggtttaaat ctgcatggca 118860
agcctgcccg agctagaatt cgatgagaac cctcaggtta atagctttgc tctttgagag 118920
agctctaagc tcttttcatt ccagaccaat ttcacattta catactacct gtcactaaag 118980
ccccaaggtc cttcgccaac aagaagcaga tatttactca ctaaagttaa tgtcccagcg 119040
ctttctagcc tttggacaca gtttttaggc aacaaggaaa ataatacata tgtataaatg 119100
gccatttgtg ttcctaaaat agcaaggggc tataacccaa agcctagaat tctttttcgt 119160
tttttttttt gttgttgttg ttgtttgttt gttttgtttt gttttgaaac agtcttactt 119220
tgtggtccag actggagtgc aatggtgcaa cctaggctca ctgcaaactc agcctccctg 119280
gttcaagtga ttctcctgcc tcaccctcct gggaacctgc aattacaggc gccagtcacc 119340
atgcccggcc agtttttgta tttttagtag ggatggggtt tcaccctgtc gttcaagttg 119400
gtctcgaact cctgacctca ggtgatccat cgtcttggcc tcccaaagtg ctaggattac 119460
aggtgtgagc caccacgccc ggccctagaa ttctttttct taaagacaat tataatggta 119520
attccgttta aaatgtcact ataaatctat ttcatttatt actgcatgat tttaatctat 119580
tattccactt aaaagaaaaa caaatcagag aaatcagcaa gggggcaata acaaatgtgg 119640
gttagggtac acagcccact ttgggaccat attcaatgaa gaataagatg agagaaagat 119700
aatgtgattt cttttattat tattattatt attatacttt aatttctggg atacgtgtgc 119760
agaatatgca ggtttgttac ataggtatac acgtgccgtg gtggtttgct gcacccatca 119820
tcctgtcatc tacattaagt atttctccta atgctatcct tgccctagtc ccccaccccc 119880
cgacaggccc cagtgtgtga tgttcccctc cctgtgtcct tgtgttctca ttgttcaact 119940
cccacctgtg agtgagaaca tgtggtgttt ggttttctgt tcctgtgtta gtttgctgag 120000
aatgatggtt tccaacccgg atgaagcttg atttattaag accaatagta attacagagt 120060
gtgccgtcca tgagtgagtt aggatgtttt ctgtgacatg tgagagaaag cccaattcaa 120120
tcttccttaa gcataaaaag atactttatt ggcatgtatg agtaacagtt caggagtaga 120180
tcctcaagag tggcttatct aaggcctcaa agatcataat cagagtctaa tttaactcat 120240
attatatgta ttgattaagc ttcatctatg taagctctat acttaagctc cagttcctac 120300
tcagaaagag ggtgacactt cctgatggac ataactgaaa ccccagaatg gggtcacaaa 120360
agccccgagt tagactaact tgtgaaagag cccaccttag aaccaatcat gatgcccaaa 120420
gacttggaaa gtgctgattt tgaagcccca tcatcgaagc agtgaaaagg aggcccggca 120480
tgactggccc cattttgctc ctaagcccac ctttaggtaa acggcttttg cttatctctg 120540
catgtaggcc aagctggcta cgggtggaat ttggtttata gtttcacttt aaagcaaggt 120600
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
140
ttgtaataat tccttcccaa aactaaccac ggaggaaaca agaagggcgt acacataatt 120660
aagaacatta ggttaaagat tataagagca ttgtgacctg accaaggatg aagaacttca 120720
cagtccactc cattggaccc tcattgctgc ccagatatat gtggtcattg gttgcctcgt 120780
gatttcaact ccttccctct ttcctcttcc ccaaacttaa atgttcctaa aattctatta 120840
ggatggttct ttaggacact aatcttccat cttctcagtt tgcttgtcct ccaaaataaa 120900
gtcagcttcc ttgctgcaac atcttgtctc ttgacttatt tgctgttgtg tggcaagcag 120960
tatgggcttt gaactcagct acatgtctcc aagtctgtga aaatgatgtc ctcttagagt 121020
ccttctgttc acacctgtct ccatctcccg gggctggaga tgtagtcagc ttgacctatg 121080
cagaggagat ggtgcgttcc ctcaagccat atgtgaattt cctgttgcca taagaagatt 121140
gatcctgggg ctaacaaaac atcaaagcct attatagata atatttaatt aaatctatgg 121200
atacttctag ttccgttagc ttccagccaa ttgtcaatgc cacttcataa aaattaagac 121260
aggagcacat ttttggagca cttagtatag actagatctt atgttaaatt atttagacta 121320
ggcagacatt tatcatagca gttgtgtaag taattataat tgtgtcttct tagagctgag 121380
gaaacatata ccaaaaaatt ttaagtaata ttgacaaacc cacatagcca gtgagaggag 121440
aagcaggagc ttagaaacaa gcttgtctga ctccagagac tgcagctttg cttataaaga 121500
cagaatagag aatgttgctt gaaaacatag gttcaaatat atgtttcacc acttagtagc 121560
cattcttctt tgaattctcc acctagattt gggatatttt cttctatagc taatgcctaa 121620
acacttaaaa gtattgttct tttaaggaca ggcaccttca gagcctgtca gaagttgcga 121680
tcaaatttct tccttagtcc tacaatttct attagcctct ttttctatgt cagttactct 121740
ggagtttact taagtcaatc aaccttcact tcaaaacttc ttccctggaa tctttttcct 121800
tttcctttca tttagcttag ctcaaagtct atgcagtctt ttttttcttt tttttgagac 121860
ggagtctcgc tctgtcaccc aggctggagt gcagtggcgc gatctcggct cactgcaagc 121920
tccgcctccg gggttcacgc cgttctccta ttctcctgcc tcaacctccc gagaagctgg 121980
gactacaggc gaccaccacc acgcctggct aattttttgt atttttagta gagacggggt 122040
ttcaccttgt tagccaggat ggcctcgatc ttctgacctt ctgatccgcc cgcctcagcc 122100
tccctaagca ggggtgtctt tatttattta tttatttgtt cattttattt tattgttttt 122160
tgagaaagag tcttgctctg tcgcccaggc tggagtgcag tggcgtgatc tcagctcact 122220
gcaacctcca cctcccaggt tcaagcgatt ctcccacttc agcctcccga gtagctggga 122280
ttacaggtgc ccgccaccat gtctggctaa tttttgtatt tttagtagag atgacctttc 122340
atcatgctgg acatgctggc ctcacgacct cctgacctca ggtgatctgc ccacctcggc 122400
ctcccaaagt gctgggatta caggcgtgag ccgctgcgtc cggccaaagc agggatgtct 122460
ttaatgccgc atcttcagtg cctaccatag agcccggcat gcaatagaag tgtgcgctaa 122520
ctcttccact tatccctggg ttaggcccaa ctcctccagc tatagtagta gagtcaagga 122580
gatcccagaa aaatctgttt tctctgcacc caggctttta agtcatcatg agcaagactc 122640
tgccttttct tagtttttcc aggtggtgaa gatgtggaac aggaaaaacc acataaaaat 122700
gcaatcacat gaataaatat tgcctacaat ggctggattc aactgaagaa cttacactct 122760
aaatcaggag cacagactca tgtttatgcc tttgtcccag gcaccaactt ctcttgaact 122820
tctttgctga ccctgcctga aagtggagtt aactaaatct tgtgtagatc tgtctcatat 122880
cactatttag cccatttgca gataggtatg atattgttaa aatgatgaaa atgccccacg 122940
ttggactcag ttggatattc tgctccggca gatcaggttc taactggaat cttggttcac 123000
ttcacttttg taggctaaga tattctattc gtacttgact gagcattgta ttgatgatcc 123060
ctgataatgc agctcttcaa atgtaataaa tttcttttgt aattgactgg ccatgcccac 123120
tcaagagata tatgtttgtt gcctgattga gtgtctaagt aaagaattaa atgaataaat 123180
gaaagagtaa cataagaaat aaacaacact gggacaatga actgagactt catttattaa 123240
gaagcaatta ttgataattt tgtatatgat tttagactat aactaatata ctccaaatgc 123300
aatagtagac aagatagaaa tggtcccttc cttcatactc gtggttgaaa tacattgtat 123360
tgctgatgtt ccatagcttt tttacacatg ttgttttcat ttgtttcaac taacggtaag 123420
gagtgtggat atttgaatcg gccagtgcaa aatgcagtga cttggaaaga gggaatcact 123480
gttagtgaat cataaacaat atttgaaggt ccttcagtgg tttattaact tcaaataata 123540
taactagatg agtctcggtt ttacaagtaa ccaggaagta atgcaagaat cctagcgagg 123600
gtggtatcaa aaacataaag tttatgtata aaaagcattt gaactcaaga atttgacata 123660
gaccttagtg aaaatgcagc tatttcttgt cagtttaaaa gaaataaata atttgttaaa 123720
ttcaaagcaa gggatcccta atcaacttag ctcacaggta atttcaaata aacataatgc 123780
ttattaacag ttccaatatt tgactttttg ctcaacctaa attcagcaat gcaatgtgct 123840
gagatatatc ccagtaaaga gcagctgctt ttgttttgtt ttattttgtt ttaatttatt 123900
tcacaaacaa gtttctgcat gagcctgaat ctttacaatg tgaaagctgt ttggattcag 123960
gtaggaaata cgtttgaact gatgcatacc aaatttccaa aagttcacct ttttatctta 124020
ctgcttagct gttgaataac acaacttttg cttagtcaag ccttctttca ttttcttgaa 124080
gatgaaaatg taattcttga gttacttctg aagaacaggt tggggaaatg caaataagag 124140
cattactctt ctagagtatg aaaagattac caaatttagg ttttctggtc agtaaaatta 124200
tattttccta acttgtttac taattacaga gtcatttaat tagattatca tttcttcttt 124260
ttccattgcc atctttttaa atgatgatat ttccagaact gctctattta actgttcagt 124320
gaaattacat tcatgaagct gacaattatt cagaagtaag tttcctatgt aactctccca 124380
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
141
ttcttcatat tctttgtttc taatttatat ttgggtctga aaattgataa agttactagt 124440
ttagaaataa ttaactgtga cttcttattt tcagaaacat aaatgagggt gcacttctcc 124500
gcagaacctt tttcacattc ttttaacaac caaatcattc ccaattttct ggtgtgtaaa 124560
ttccatgtga tcagtacaaa taaacaaact gacaagattt gggcagttgg aacccattgt 124620
tttacaacgt ctttgtttaa aatctttcat aattcatctt cagcaatggc cttcctagca 124680
attagttacc tttagtgtct tcattttcgt ttaaatgttc aatgatcagg ataattagaa 124740
ttaatttctc attgtcattt tatggtaatg aagcttctgc cacttatcac aagcatcctg 124800
caggcacagt gttaccacac aaatatgtga ctcctcactc ttcacacact ggtttatggt 124860
ccctggttaa agtggtaaca gtaggacctg gcctgattcc agtttaaatg tatgccatat 124920
tagatgaaag attgtgggta gtcatgctgg tattcttgcc ccttgtggat ggcattctat 124980
gtgcaactca gttctcctta agcaacacaa gagaattttc gtctccatta gtctgggtgt 125040
tttacagact gggattagtt ctacagttag aacaaaagga aatatctttg tgaatgaaga 125100
tggaaggcaa tgtcaattca aaactttata aaaacttcag atagaattca ggaaagcaaa 125160
ggttgaaaaa cttagtacca gaaaatctat gaagaagaaa gtgagtcagt gaattctcaa 125220
gctggaagag ccttcttgca ttatctggtc taggattctc cagccacaaa aaaaaaaaaa 125280
aagtaattgt gtattatcat ccccattcat tccctgtcat atctctgcct aagcaattgc 125340
agtagaattc atcctatcat ttgtatcctc ttccttactc ctgggaaaca tttagatagg 125400
gtaaaggatt tggttgagca gaaacctggg gtgggaaata gggagcatat ctaggtttgt 125460
caaagaaggt atttaaggct gccctgtgaa atcataccag tttcaaaatt agaaacttga 125520
tcttttttac agctgacttt tcttcaccac attttaaact tgttctttat tctgcatttt 125580
ctcaagaagg gatatgatat taccaagaga aatacttgct ctcaataacc ccaacctcat 125640
tttcttatga gtttgggtaa gttagaaaga aggtcaaact tagtagctta aagaaaaaaa 125700
cacattttct tttgcttata attgttgagg aaggaaattg gaaagggcta ggcagggcag 125760
aattggaagt tttcctgtgt gtctggcaga tgttggctag tgctgcaatt atgtggagtc 125820
tatttaaact ggccatccta tggcttcttc atgtggctgg tggtgaatgg tggctgttgg 125880
ctgggaactc agccggggat gacaagtgga tcacctccat gtgtctttgt agcacagcag 125940
tttcaggctt ttagaatttc ttccagtggc tggcatatac ctgaaagaat gtcccaagag 126000
agtctaaggc agaaatgtgt ggcttattta taactagttt tggaagttac aatgagacat 126060
ttctgctgca gtttactgat cacaagagag ttactaagat tgatcgagtc tctacccatg 126120
tgagggaggt gaatcaaaga acttgttgga caggttttag acctgtcata gagtgtaaaa 126180
aagctaagag gcttcatatt caagggaaga aatactttaa agttctccag ggatgaggct 126240
agtagtgatg attcagggca agaccagtga agtaagagag gctgggacat gcattgaaga 126300
agctcactga gaaagttctc tggtaatggg ctgcaatgtg ctggagttag tccacaatgg 126360
cttgcaagat ccagttactc acttgttttc tcaattccag ctctgagttc agtgatgtca 126420
ttgatagttt gaaaatgact acagtggaat atttacacca cattaattgg cagactctac 126480
aaataagggt gttttttccc caggagaccc agttgctgaa tagttaccaa ttggtaatgg 126540
ggcaacttag aaactacttt taggagaact ggactgtctc atagcaattc tatgttgtga 126600
actttggggt taaaaccact ctgcttttgt aaccttttca gtaaaatttg cgaggttccc 126660
tattgctttt gggtgaatga cattttgggg gataatctaa tgtgattctg aatttgagtc 126720
aacactggct gtttcagaac agcacatgtt gaagcaggag cctgatgcag aatacgtcat 126780
tagagggaaa gtgctggtaa ttagcagaaa ttacaggaag ctctgtactt caaagacttt 126840
aaaattgagt gtgtgaacca agcacatttg agtttccaga gaaggaatga agctccagtt 126900
gacactttgg ttatacaact gcatgataat ttatcattta cagtatactt ttatgtacct 126960
cataatgttt aaatgggtta tagatcaaat gcaaatattt aaatattttg catgacattg 127020
gacaagtcac ttaaattttc tgatactcag attcttcatc tctaggaatt agctgaaagt 127080
atctttatag agagttgttt cagtgagtgc tgtaagatta aaaagaaaaa taagagacca 127140
tcattagcca tgagtttagt aaatatttcc cagtggtgga acaccaattc caagtttatg 127200
taagttggtg ttgatgggaa ataagcaatg attaaacaaa ggaaaatcag gagaaagatt 127260
gttaacaaag ggcaatgctg tataagtgca aaaaaaaagg ggaaaaccac agttttttga 127320
tttcacaagg aagcagaggg ctggctttca ttcatgcccc actccagcct cagttccatt 127380
gcttcttgcc ggcaaagctt tctcgctctg acagaaggca agcaaacccc aagaggcccc 127440
aaggtggcct gtcagagggg gtaaaatata tagttttgca attgtataat attaatgttc 127500
ttatcagagt gagaatgtga gtagaaagca gagattttaa taatatgacc caaggaagtc 127560
aattttgaac attttacagt attaacaaaa atgtttagaa ctttagaata tatttaactc 127620
aataaaaaat aaatatattt tatgttatgt atgaataaca taaacaaatg tttggattag 127680
ttcagagttg atattttaaa ataataaatg ttttgttcta gtccatttaa ttatgggtct 127740
tgattggcaa ttctggaaag gactcagaaa gtaaaaaagg agagtaggga aagcctcaag 127800
cttagatacc acctaagtca tcattaatag ctattggtag aaatatgggt ggtgaagacc 127860
attctgatgt gttcccagat cctactgggg agaatgggat tggaaaatgg agaaaagtct 127920
atctttgtta tgaagtgtca cataacttgg ctgagttgtg ttcctgtcct gatattttgg 127980
ggaaggtaga acttgtgagt gatgaaattg tatatttggc tgcagcactt tctaaacaac 128040
actttgaaag agtagcctcc ttcctctttg ctgctcctag taaaatggga gaagagaaaa 128100
attattagag gatggaattg ttaatcaaaa ggaaagcaaa acttaaatat ctggaaaatt 128160
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
142
cttagtctat ccatattgta aaaaatgagg aagtatcttt gcaagagaag accaagggtg 128220
tgaccaaagg acaatctaac agaattactc agtcatttaa cagaatctag aacctgttgt 128280
ccnagaccat ggaaggataa tcctaaaagc aattcaaaaa ctatcagaac tgccacccct 128340
atcgcagacc caaaatgcaa aagtcggggc agcagggtgg tttccaattt aaagaaggga 128400
ccaccacgac cccgtgctgc ttcacattgt ggatctacct cccttactct gttaccatgc 128460
accttggtag ccccagattc agttctggtg aactctggca gggaattgtt aggggggcag 128520
agccaccaca gtgaacttct aataggccaa tgcccagcag agccacaaga gtagggctgc 128580
ccctgagacc tcagacctgg agagccacgg gcataaaatt cttggctgga agatccacag 128640
gcacacatct ccaatccatg agagctgcat tgtaagttgc atctggcaaa gtcatgtagc 128700
caggggttcc cagagccttg gaggtccaaa ctctgggggg caaagctaag ggagtaccac 128760
ccagggtgct cagaagggac ttttccccaa agtgggttgg aagggcagag catcaaaccg 128820
aagaagattg ttattgagac ttatgctata atgttttctc tgttgggctg tggacttagg 128880
gcctctttcc cctttcctct ttcctgtttc tatgttttag aatggggatg catgttctgt 128940
gcctgtccca tcattgtatt ttggaagcac ataacttgtt tgatttcata ggttcacagc 129000
tagggaacaa tttgcctcaa aatgaatctt accttgagtc tcattcatac ctaacttaga 129060
tgatatttag atgagatttt ggactttgaa ctattgagtt gatgttggac caagttaaga 129120
cttttggggc tactgggatg gaacgaatgt ccttgcttgt gagaaagaca tgaattttga 129180
gggctaggga cagaatgctg tggtctgaat gttcatgtcc cctcaaaata tgtataaaaa 129240
tttgattttc caaagtgata gtattaagtg gtggggcttt tagaaggtga ttatggtgga 129300
gccctcatga atgggattac tgcacttaca aaagaagccc aaggaaaacc cctttctcct 129360
tccaacatgg gaagatgtag gtgaaatatg acatgctttt ctgtgaacct aggtaaggat 129420
ccacaccaga ctccaaattt cctggtgcct tgatcgcaaa ccttttagcc tccagaacta 129480
taagaaataa atttctgttt ttaatgaagc tgtgcaattt atgatacttg gttatagcag 129540
ccagaagagt ccaagacgtg gtcctacaat gaagttagag aattttttta agtgtctgtt 129600
tattgttaca aatggcaaac aaaaggtcat tatgcttaca cacacaataa atgtgtacaa 129660
tgtgtatgag taagtttaaa acaacaattt tttttaatat gaaagtccca gttagtttta 129720
aaagaaaatg aacaactgag agtaataaaa cctttgttct tgttttgaca gtgatgggga 129780
agggttttca aaaataatga gttggcttca gtttggaatt agggaattac ctaccataaa 129840
actgtctttt agatatccta aaatatcatc tgttttgaga tacacaacat ctaaaggcca 129900
atgactttat tttcctgcac agagaaagga gacctaagaa ggattatttt aggtttggat 129960
tcagaaatgg ccattgtgta aagtatgtga gagcagattt gaatatttgc catagtgcag 130020
aaataattgc ttatagtacc tgattttttt aagttattat ttcatccata atatatcttt 130080
ttcttatatc tttaaaattt ttacaagata aaatgaaaat tgaactaact tagacaaagg 130140
ttattttcaa attataaaag tatatagatt tcaaaatgtt tattgaatac ttatgcacaa 130200
tggtcaaaac acttatattt ttatataata cactatgatt tttagcattc tgagcaaata 130260
tgtgaaacct tttagatatt tgcattattg ttaacaaaga agttagtgaa acatgtcaca 130320
tatatacagt ttttttatat tagcttgaat ttcttaaaat cagcctttac caggtatatt 130380
agtccattct cactctgcta ataaagactt acctgagact gggtaattta taaagaaaag 130440
aggtttaatt gactcacagt tcagcgtggc ttgggaggcc tcaggaaact tacatcatgg 130500
tggaagggga aacaaacacg tcgttcttca catggcaaca ggaaggagaa gtgctgagca 130560
aagaggggaa agccccttgt aataccatca gatcttatga gaactcattt gctatcatga 130620
aaacagcagc atgagggtaa ccagccccat gattcaatta cttcccaccg ggtccctccc 130680
acaacacatg gggataatag gaattacact caagatgaga tgtgggtgtg gacacgccaa 130740
actatatcat ttcatccctg ccctctttca agtctcatgt cctcacattt caaaacgcaa 130800
tcatgccctc ccatcagtcc ctcaaagtct taactcattc cagcattaac tacaaagtcc 130860
aagtccaaag tctcatctga gacaaggcaa taccctttca gctatgggcc tgtaaaatca 130920
aaagcgagtt agttacttac tagatacaat gagggtacag gcaatgggta aatacatcca 130980
tatcaattgg gagaaattgg caaaaacaga gaggccacag gccccatgcc agtccaaaat 131040
ccaatagggc agtcattaaa ccttaaagtt ccaaaatgat ctttgactcc acgtttcacg 131100
tccaggtcat attggtgcaa gaggtgggct cccacagcct tgggcagctc cacccctgtg 131160
gctttgcagg gtacagtccc cctccccgct gctttcatag gctggcattg agttcctgca 131220
gcctttccag atgcacggtg caagctgttt ggtggatcta ccattctggg atctgaagga 131280
gggtggccct cttctcaaag cttcaatagg cagtgcccca gtggggactc tgtgtggggg 131340
ctctgacccc acatttcctt tccacactgc cctagcagag ttcttcatga gggctccatg 131400
cctgtagcaa acttctccct ggatatccca gcatttccat acatcctctg aaacctaggc 131460
agaggttccg aaacctccaa tcttgtcttc tgtgcatcca ctggcccaac accacgtgga 131520
agctgccaag gcttggggct tgcactgtct gaagcaacag actgagctgt accttggccc 131580
cgtttagtca cagctggcat tgagccagtt gggactcagg gcaccatgtc ttgaagctgc 131640
acagagcaag ggggccctgg ttttggttca ataaggcatt ttttcatttt aggccttcag 131700
gcttgtgatg ggagcggctg ccatgaaggt ctctgacatg tcctggagac attttcccca 131760
ttttcttggt gattcacatt tggcttcttg ttacttatgc aaattcctgc agtgtgcttg 131820
aatttctctc cagaaaatgg gtttttcttt tttattgcgt cttcaggctg caatttttta 131880
aacttttatg ctctgattac tcttgaatgc cttgttgctt agaaatttat tctgccagat 131940
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
143
accctaaatc atctctctca ggttcaaagt tccacagatc tctaggtcag gggcaaaaag 132000
ctgccagtct ccttgctgaa gcatagcaag agtcaccttt gctccagttc ccaacaagtt 132060
cctcatcttc atctgagatg accacttcac tgtccatatc actatcagca ttttggtcaa 132120
agccattcaa caagtttcta ggaagttcca aattttccca catcttccta tcttctgagc 132180
cctccaagtc tctagaaagt tccaaacttt tccaagtttt cttgtcttct tctgagccct 132240
ccgaattgtt ccaacctgtt cttgttaccc agttccaaag tggtttccat atttttgggt 132300
atccttatag ccccactccc ttggtactaa tttactgcat cagtttgttc tcacactgct 132360
aataaagacg caccccaaac tgggtaattt ataaaggaaa gaggtttaat tgaatcacag 132420
tcctgaggct gggaatgtct caggaagctt acattcatgg cagatgggga agcaaacacg 132480
tccttgttca catggcagca agaaggagaa atactgaata aagagagaaa agccccttac 132540
aaaaccatca gatctcacga ggactcactc actatcataa gaacagcctg aggaaccacc 132600
cccatgattt aattacctgc taccgggttt ctcccttgac acgtggggat tattggaact 132660
acaattcaag atgagatttg ggtggggaca tggccaaacc atatcaccaa gatataaaat 132720
taagttgcct cactttaata acaaggttga gttacatttt aaaattatta ttaaagtata 132780
tatgtgtgtg tgtgtgtgtg tgtgtgtata tatatataca tatatgtctt taaagttatg 132840
ttaagtgttc catgtactac tgtattgagc acatagaggt gctcagtaaa tgtcaatgtt 132900
aggtgaataa atgagcggat aaaatatgga ccaacttagc tggtcagtga gtttatggtt 132960
acttatcttt gagaagcatc ttttgccttt ctccatattg agattgttta attgagctgt 133020
gtaacttttg tatatgttat tatatgtgtt taaattttgt atatattttg tctaccttag 133080
tagcaaattt tattgagaat atttttttct caaaatagca tccctttaaa ctagaaaaaa 133140
aaacagtttt tatagctctc ttttgaacta aatactaaag aataaattgg tcaagttctt 133200
tctctgatca tgaagtacct gcaaactgct tcccataaat ggcagaaaag gttaagagac 133260
attaccagga tggctgcccc aaattgttgc tggtatcatt aaaatagtca acaaaaatgt 133320
ggagcctaca gccttgtaaa aataggaaca tttaaatcca tactttagtc atttcctctc 133380
cctgatttat gttttcttgg ttgtttgcag gcgcagtcaa cagcagtgga agagctggct 133440
catgtgtggc tcaggctgac tccacaatca gagtgattat gtggaaatca atcagaattt 133500
tcttcttaga agatgtttgt tctgacataa tgactgacat tccagctaat ttttattcat 133560
aggcttctcc ttgcacaatg atctctattt ctctcaatgt tattctgtgt ctttcttgct 133620
tgcctgcaca ttctgaaaaa aaaaggaaag caattcccta cattttattt tgatacttaa 133680
tgttgtttgc taacatattc agaacacaat gcaactttat atattagagc acttataata 133740
tatattagga aaacatcaat taggtaccac cagttatttt agacaggtat ctcttaggta 133800
aaatgtggtg aaaatagagg ggcaatgata gaattcatat gtgaaagagt caattggcca 133860
tcattatgcc aaaattattt tgtggttcag gggacatttt aaactttaat ttttaagaat 133920
taaactttaa ttaaatttat tgtagtttaa atgcaatcac aaggaaagac tctgaactgg 133980
aaacaccaag ccaagctctt tcctagttct ggtcccctat aaaccctgaa agttaatgca 134040
attattgtaa tttttaaacc accgagttct cagggtgatt agttatgcag caatagatag 134100
cctgaaaagg accattcttt ctggcactga aaattaagaa gagtgattaa caacataaga 134160
atgtagtttg tgctgtctgc cacagattta tgttgtagct tcagtgattg cttcaaagca 134220
cccttactaa ttgccagcct attgctgata cctagctaaa ttagcatgtg ttagttttga 134280
taccactata ggcatttaaa ggatagctga tacattctat ataaaatata attattttcc 134340
tatctttagt ttatcctaaa gtagcagcta ttatattcgc ttcttgatta gctttataca 134400
taaccagaga aagtaaaata tcacagagta tatttgaaga cataaaagtc tttggacaaa 134460
gctcaagtaa tgaatcagga tgctattaca tcctccacat gacagtaaat atattttata 134520
ttcctaaatt ttaagctttt aacaaaagca aattttatac tggactattt caatttctag 134580
ggaaaggaaa ttatcattta ctgtctttga ggctataatc tatttagcca ttatttttat 134640
attgatcaat ttataataaa ggtaagagaa aatactacca catatatgtt gtttatataa 134700
ttttaacttt cataattaaa atactgggta tactgcaaga tgtcaatatt tataatagct 134760
tatatttgga aacaattata ctttatatac tcctaatcca ttgccttgtg tgtcattgaa 134820
gaaattgaag ttcacaataa tgactgaaca aatgctcaaa gctggtctgt ggcagaacca 134880
aaaatttcca tggcaccttt ctctttccat attggggtga tctgcctaat ttgactttct 134940
gcttatatgt ctagactcta cccctcattc cttctgctag tgtgttgttg aaccctttct 135000
attaacccac tctcgatttt tctgttgcac aatcaatctg tagcctgaat gttgagtccc 135060
aaatgcatga gctacctggc cgagtaatct aactagatta gcctgagtat atcactttaa 135120
ggccaatgta aagttatgtt gtaactacct catagttttg cagaggcaag aaatagaagt 135180
taaggaagag aagaagccaa tcttgaatca gttagaattt ccttggacat agaaaatctc 135240
tacaagcaaa aacccatttg attgaacaag caagcttatg cagttaaata tatcaaagat 135300
cttgtcacaa aaagtgtaaa gggaaagtaa aataaggagg gagcatgaag aagccagctt 135360
atattaaaga ttcaaagcag ggatataagg aaattcaagc caaaaataag gaagaattct 135420
tataaatgcc ccaagaatga attcgatgtt tggtcgatat tccaacagat ttagtaatgc 135480
tatttttaaa gtcaacaggc tgcccatttt tgcctcacac tctgactgca tgtaatctgt 135540
caagtactct gatgagttct ggagatgcta atgcaaaaaa gatataaaat ccttaccttg 135600
aaaatgtagt tcacaattta gccatggagt tatggcaagc atcttgtctt caattttagc 135660
ccctcctcca tccctctccc agacacccat tgtcctcttt ctcaccacat ccaccccctt 135720
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
144
ttttgtcctg tctttggtgc actatttata attcttctca tgtctaccac aactattttg 135780
ggtagtaaga acatcagtat ggagacccct taatcctaac taatatcaac tctatctgtt 135840
tggtattaat tcttgtttat tgaacttgag gcattgagta ctacaaaaat tataatacac 135900
tactggtgaa cattacttta ttaatgatta ggttccactt ggatgtttgt cattcgtatg 135960
tagctgttct ctccttgtag cctgtaaact ttctatggat gtcacaaaaa gagttttaag 136020
gattttgctt aaattaaaat taatacatca agaaaatact atgcctcaaa caaaaaataa 136080
tcagttaatt tagtttttag aaatctttta caaaaaacgt gatatttaat aatctttatg 136140
caaggatttt tgggatatta aaattgtcac agatttaata atacgtttta ttgtataaaa 136200
tttttctttt ctcttcaaag tgttgggaga gtgaattctc taagtaaaaa ctgaagagta 136260
agatgttatc attaaacatt tcagaaaatg cacactatcg tagactgcgc actgtgaaaa 136320
tgatcagcta gtagaggttt tggtgaacat atagtaactt ttatcaacaa gtaatgtgaa 136380
tatgtgaaat ctattgcttt tccaaaagaa agaaactttt acacttcttg gtaaagataa 136440
actttcatgt aagaaaaaat aaaaacataa ttttagcaat ccaaaccata ctaaaatcat 136500
aaacacttga ccacatgttt gagtacccca aaaattgttc ctgtgtggat tcttcttcta 136560
ggatgatcag tcctcatggc cttactactc tccatttctg tcccactgag gttagccaaa 136620
gttcacttgc cttgtcagtt aagtttctaa atcagatgag ttatgttttc tataattgag 136680
ttaaccacag ttaattgctt aatagactct gtctacacta actgaaaaaa aagaattaat 136740
tgcttggaga aaatgcatta tatattttat tcacatctac agtcatccag gccaaagtga 136800
caaaggcact ttcaacagtg gccagggcca atggcgacag cggggccagt gcttagctca 136860
gccatgtgtt caatctagta ctttgggatg tggatataaa gaaaatgagt tataaatgaa 136920
cttctcctta gagcttaatt cattattatt attattatta ttattatttc tttacataag 136980
aaaataattt taggagtgct ttggcaaaag tttaggtaca atttaagaaa atgccatttg 137040
taaaaaaaaa aaaaagacta gnnttttttt ttaattaagt ttttactttt aatgatttag 137100
atttaggttt taaaaatgta tttcctagcc aaggtctaac accaggtatc tgagattttt 137160
ctaaattttc tctgaaaaca tgagacgcac gtacagttat ttaaaatttg ctgcagccat 137220
ttttaataga ttttttatgt ttgaagagat gccaatcgct tattatagta agctatgata 137280
gcaatgccaa tgaatcctca attccattgc ttaaatataa gtgaaataat aaaggaaaag 137340
accagtattg aatatattgc ctcttcctgc tacactctaa catattcact acaataaatg 137400
gaaagttgca catacaataa aaacttaggc aatttattta tttacttatt ttttatttat 137460
ttttttgata tggagtctcg ctctgtcgcc caggctggag tgcagtggtg cgatctcggc 137520
tcactgcaag ctccgcctcc cgggttcacg ccattctcct gcctcagcct ccctagaagc 137580
tgggactaca ggcgcccgcc accacgcccg gctaattttt tgtatttcta gtagagacgg 137640
ggtttcaccg tgttaaccag gatggtctcg atctcctgac ctcctgatcc acccacctcg 137700
gcctcccaaa gtgctgggat tacaggcgtg agccactgca cccggccggt aatttattta 137760
agtataattg ataatcaggg caatatcaga aaatcttgaa taatttgtac tctaaaatga 137820
atttatgctt ttcagtgctg gaagcattat agaggttgtt tcaactatga aatcattttg 137880
tcaaacgttc tttgaagtct atgaccttaa gtaaagcatt taaaacccaa tggtttagaa 137940
acgtccagag aaacaagtat attggcaatt gtaaataatt tttgaagtat ttagcaaaac 138000
agcgaagtac aataagcatc ctattcacaa ttccaatgta aaaagagatc tggtcatagg 138060
cagaattata ctaagaaaaa ccctatgaag aaaataaagc ttgtttgtta cctccaagat 138120
ttcaccatct ttttcccgtg tccctgcatc tatgccctac tgtttctgct tcctcattaa 138180
tcttaaatcg acttaagtgg atactggttg tttaaatatt tcttatctgt atcacaagtt 138240
caacaaggaa aatatcttga taataaaaaa agccaaagga agcttttaaa aatttaccca 138300
tggattgtaa ttacccatga tccccatcct attcctttag aactgttaga taagagtttt 138360
ctacacttga aactttgagt gtttctaaaa atatttcctg ctttgagctt accaagttga 138420
tagataccgt ccagacaggg tgaactgaag caagagtccc tggctcgaaa gtgtgcctgg 138480
catgttctaa taaaacaaaa aggccgcacg ggtgctccta aaagggaata aagtcagcaa 138540
gtggggagag gggcatgtat gacttcttgt tgattattag aagaacattg agaaatgcaa 138600
aaccactttg tggttttgtg aatccactgc tgttttcagg atacactgcg aggggtaatg 138660
gcacaaaagg gaaatctcct ggttgatagt ttggtaatct agacagaagg tggtgttggc 138720
tagaatcaag gtaatagcaa gtcgagttat cagaaatgtg gaaattggtt ttatattgag 138780
aaacaagccg atggtgctgc tgagaattgc acgtgtagtg agggagaaca aagggactca 138840
agagtatatt tttttaacca aagcagctag aaagatgaca ttgcctttgt acccttcatt 138900
ctctaattgt attccccatc tctgccttca ttctctgatt acctttccca acaggtagct 138960
ttagcttgtc cacacctaac tatgcttctg tctagggcct tgacacttcg cgattccttc 139020
cacctggaat gcagttgccc aagatatcct catcaattat ctctcatatt tttcaagttt 139080
ttatttgaat gtcacctttt caatacaact tgccttgccc cccatcttag attgtatccc 139140
cctaaataca cttcctgtct accttctccg attcgttttt ctccatagcg cttatcccaa 139200
tctaacaaac atattttact tattttattt attgcctatt tccccagtaa aaaggcagct 139260
caataacaag gatgtctgct tgttttgttc actactctct ctccaaagcc tggaatagta 139320
tttggcatat aatagcacaa taaatatggg ttagatgcat gaattaatgc agggaattag 139380
ccaagctatt tactgtactc tggtctctga gaaaatttgc aagcaggaga aagattgctc 139440
tatggaaaaa cgtatgaatc aaagcaaaaa actccatcat ggtgtatcca gatgaaagtt 139500
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
145
gtttattgta atttagtttg tgataaagtc ttcatcataa ggaggatgaa aacaaaagcc 139560
ctagtagtat cagatcctca gagaagagct aataagctga gctccttaac atgactcatg 139620
ctttctctaa cttgggggaa tggttggccc caactctcac tgagtctgca cactgaggaa 139680
aactcctcaa aatctagcag cctggaagga tgaatgcaaa agaacagtaa caccaatatt 139740
ccctctaccc agctgacatt tctctcccat ccttcatttc cttaccataa ccctctgtgc 139800
tagcccattg ttcatggata atgtccaaga atgtacaatg atatacaaga tcatgataat 139860
tgaattccaa cttctgtcat ttttcttcgt gcccccccat atccagtgat tctgaactgc 139920
tacagttctg taaaccaaac atcccttttc cccaatttta taactaaacg cttttacttt 139980
tttattcttc ctagaatagc ctttcttatc tcatatcttt gtaaatttta attcatcctt 140040
taataatcat ttatagcagt tcttcattag tgaaattcct gatacatttc ccaccctctc 140100
tgaaaaatta attgctccct tattgatttc ccattgattc taatagttat gaaatatttt 140160
attacaatta ctggttcaca catctgaatt ctgcttggag ctgtgaagaa tctgaaggca 140220
agaaacatat tctactttct ttgtataaaa tggacttatc acataataat ggctcattag 140280
ggtgaatgaa tgattaatat taacaaagaa aattgtcaaa attaggtaag cttcttttaa 140340
aaagttgaag ttaaacatta gccatatgtt ttctggaaaa ctgagcactt tctgatgtgt 140400
ttgaaatcac attgagaaag tcgtctcttt tgctactttt gtttactgga atgaagggta 140460
actggaaaga tttcccagag aaaacaagac cacaaatgtt ttgaagtagg gaaaaatatt 140520
ttaattgaaa tagaggtggt acaaagacaa gaaatatgac atgtgataca gtagatataa 140580
gcgtatatga aatatatggg atgaacatcc atacaggttt cacaggactg aaaggtgcaa 140640
ctggtacaga gagtctggtt gttgaagtat ttaaaactca caatcaaagc tctgatagta 140700
ggatgcaatg tcaatgatta ctaatcgaga caaatttgct caagatcatt gtataattac 140760
acccaaattc caatttgtga atagatttac tcatcgtgac ctagctgata acatggaaag 140820
ataaacaagg cagatacaca gaacattttg cagactatgg tggctgcaag aatagctttt 140880
cgcttgattc aggctttaag tgttagcctg aacactcaga acgcgattta ttgttggaaa 140940
gggattaacg aagacattta tttcagaggc tactttgttg ttgttgacat ttttgttgtt 141000
gttgactttt ttgttgttgt tcttccctct catctgggat atttcccttg cccttctgac 141060
ggcttgtcaa tggggaggtg ttcgttcctg ctttatctat tgcatatctg tctgcttaat 141120
atgaatctat tacacagaat aaggaaatac atttagggct gactaatgta aaaatactct 141180
ttgatgagca gtacactgca acatagctca gagttttcaa atttattata ttggctcttc 141240
caaatatgtt attcatattt gctgagagtt gcttttataa atttctgctt tggagcatac 141300
agctcagtgg aaagatatgt gtttatctga attagctggc tctaatccca aatgaatatt 141360
tgtacaaatc tgtttttaac attgatatta atttattaga caattagaat atggcaaatg 141420
atgcaaagtt tggaacttgt ttcacatttt tttaatggtt tgtactcact cccctccccc 141480
atatacgaga ttttaaaagt ctatagggat atcttagtac atatttatgc agattacttt 141540
tttatttatg gaaggggatt gcttgatcct ccaggtggtt ataaaactgc tatttcattt 141600
tgacatgata taaattggtt tagagaaaac aaattattct aaagtcttta gaaaccaaaa 141660
tgatgctgtt ggagcatagt aataacgtaa ataaatctag aagatggaga tttttatatt 141720
tctagaacta gatgggtttg tcctggatca tgcctctgaa tttagtctct gatttttatc 141780
caggggtgat ttttgacttg tataaaacca tggaaaccaa gagccatcat aaagcaagaa 141840
tcggtttaca atctttggaa atgtgtattt acgtagacca tgaaataaaa aatattttgt 141900
tcaagaaaag ttgtttttaa tgctgctctg aacagcagac caaaaataac atttttaaga 141960
gcaagcaagt cgtttttgtg ttttacttgc ctgccttata aatatggaat gttggaccca 142020
gaagaatacc tgagtttagg accatacatt cttttaggta aaattttatt gaaaattaaa 142080
gtatatatag aaaagtgcac aaatcagaag cctacggctc aatggatttc aagtgaatat 142140
agccatgtaa ctagcatgcc aataaaataa cacattgata gagcattacc cgacccgggc 142200
cttctcatgc ctcatcccaa aggtaattgc tattctgcct tttaattatt acatattagt 142260
ttggcctatt ctcttgaaca caactcttca atgcttgtaa gttccatttt agaagatctt.142320
gcaagtggaa tttgccttct cccactagtc agtctttaac caggagatat caagatggaa 142380
tcagaggaaa tctaagcact ttaagtggtt ttgccgtgac agcatccttt gtgattactg 142440
aaagaaagct ggaagttgat aaagtgatcc atgttgaaag tacagattgt gctttgatag 142500
tggccatgtt gttcctgcca caatgtttcc ctgcactatt tttgcccaat attggattta 142560
acagtaaaag tttaagtaat gccatattcc actaacatat aacaaaaaaa tggaattaga 142620
aataggtagc aaattttaaa gatcagagaa aaaggaattg tgacatttaa gaattacatg 142680
tggttagaga tctttatata tcaacatatt gaaagaaatt aattcagtca gttcaggcat 142740
gacgtttatt tttaacaatt agtattctat tctctataat catgttccac agtttaaagt 142800
gcttaatgag ttcttactgg aaggggacta tttcgggaga gtataatggc ctttaatcac 142860
ttcactcaag ctattagcag gaaagattgt caggaaatat tgttactttt gttataaaat 142920
caattgaact ttcacttgga tgaaacaaga agtttgtcaa tatggtatat aacctccaag 142980
gtctttctcc cttttcctta tgctatttcc ccctcgtctt cgccatgtgt tattgattca 143040
tttgaataat ctatgattat tttccttctt aatagcctga gaagaaaaat agcttctaac 143100
taagcagcta ccaagtcctt aagctagatg ctatgtttat attatctcaa ttaatcccac 143160
tcagtgtagt cgatggtatg accctgttac aattgtgcaa aatggagttt caggaagata 143220
cacaatttgc tcattatcaa actctcataa catccacaga aaataattga aacacaaagc 143280
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
146
catatgactc ttaacctcta ctgaaagatg cttttatata gaatctaaaa tgttatgtta 143340
gatataatat attggctggt gaagttttat cttttccaaa acagaacaat attttagtgt 143400
tttctcagtg aaaatagtga acactattca gattcaggtg atgatatctt tgattatcct 143460
catgagagag tcagtgtagg tagttcagtg ggtctcaaag catagtacct ggacaagcag 143520
caacagtgac atctgtgagt ttgttacaca cacacattca tgagccctac cttaaatctc 143580
tgaatatcca agcatgcgat ccaggaaatt ctattttaat aggttctcga gatgattctt 143640
atatgcatta aggtttggga accactgaca tatttcttaa aagcacgaat tgcggaaaca 143700
gactgtgtaa gtttatattc atgttctgtg aaatactagc tatgtgacat tgaacaatta 143760
atttatcttt ctggatctca gtcttcttca tttatgaaac ttatacaata atcatatctg 143820
catcacgttg ttttcagaat tgttgaacac acatagaaaa gtgtcatgct agggccaggc 143880
acggtggctc acgcctgtaa ttccagcact ttgggaggcc aaggcgggtg catcacctga 143940
ggtcaggagc tctagagcag cctggccaac acggtgaaac tccatctcta gtaaaaatac 144000
aaaaaattag cctggcattg tggcagcagc ctgtaatccc agctactcgg gaggctgagg 144060
cgggagaatc gcttgaacct aggaagcaga ggttgcagtg agctgagatc gtgccactgc 144120
actccagcca ggaaacaaga gtgaaactcc atctcaaaaa aaaaaaaaaa aaaaagaaag 144180
aaaagaaaaa gaaaagtggc atgctcatag caagtactat gttagtgata gtaaatgcat 144240
ggatcttgtt ttcataatac aaattaatta atgatataaa gcattcatta aatatctcaa 144300
tatttggaac cttttctttt aataataaag tctagtaaat gttgttattg aatagaaata 144360
cacttttaaa aacgttgtgc attattttaa aaatatatga atcagaaaag gaaaggtgat 144420
ggaaaactca tacaaatata gtaaattgca ctgtttttgt gaagatgatt ttatgcagaa 144480
ttcaaagtag atgcaattag tgcttcaaat tagaaactgc aaatgatgaa ttcacaagca 144540
catgatttaa caaacaaatc agagaagaga aaaagtttct gatgaatttg agtttctaca 144600
tgtggatttc atcttgtgat aagccattct caggagaaag catgagatgt tattcgtcat 144660
tccagaaagt gggagaacat aaaagttgag aacagttatt gcataagcaa gaattatcaa 144720
tgaacacaat taatttaata catacacagg catttgactg tatgagaaaa agcatttcat 144780
gttatttgct ttgtagatac aatatcagtt tcgatgagat tcatgctgca cggatggtta 144840
cacctgtcac ctgtgggtgg gtaatcttaa tacctgtgat gacaagtaga ccacggggga 144900
ggactcgcaa aggatttgag tgaggagcca ctgatgctgt gtaaatgcca gagccgtgac 144960
cgtgcacttt tggggggatg tgcttaaata tcttcagatt tcacagaagt tagggcatca 145020
acggaaaata cttttgtttt ttctagctca tctgcacaag ttgaacacac attgttagat 145080
agtgtgtatg tcagagcata tgtgaacaaa tgaaggcgaa aagtcaatag ccatacattt 145140
gtatttgtat tgctctttat caatctaaaa aggtacatta aacaataaaa tgacaattca 145200
atttttaaca gcattctaga ctctagaagg tgttttctaa tccactctct taagccattc 145260
tcacaacagt acaagggaga atttcaatga gaccaggtca cccagcaata tggtgacaca 145320
gatgagacac ctcctcagat ttttgtttca aaatttttgt tctgcctact atgccataca 145380
tgctgtaatc atttaattag aatttatatt ttaataaatg aaaactaaag agtttttgca 145440
attgtgttaa cactcacgtg ttaaatttgt aattatgtcg gtaaataaaa agagtttaaa 145500
tccacacccc attagccagg cgtggtggtg cacatctgtc tgtaatcgaa gttttagaaa 145560
actgaagtgg gaggatcact gagcccagaa gaggtggaaa ctgaagtgag ctatgattgc 145620
atcactgcac tctagcctgg gagacagagc acgacccttt gtccaaaaaa agaggaaaaa 145680
aaaaaaaaag aaaacaaaaa ggcgcaacac agagagaagt gatcttatcc ttatccttat 145740
gctagatata tatttttttt ctggtcagag aattacaagt ctgtctaggt aggctcacat 145800
ttgagaagag aaaatcctgt tctattgact tagagagtta aagaccctgc cataagcaga 145860
gagggcacac gtgggactct gcgccaggac aggcacaact gtgggggacg cttcatagca 145920
gcttttgcag atctcctctg cacctgaagc gccgcctgta gaagctagat gaaacctcac 145980
aatgccaaag ggttgctggg cttaggaagc acgggctgca tagggataac tagatcttta 146040
tggatcctga agccactgcc ctttgtctgg atatctgtct ctttgtgtgg ccttataggc 146100
tgcatttttc ttgcctgtat gcctgaggtc ttgatttagt cacactggca gggtacaaac 146160
tggcctgact ctgccagtga cttcacagtg cagttgcaat gtcatttagt taccttccct 146220
tggaggaact gctactgttg atgaagagtg ctttggacca aatattttat gggcccaaag 146280
ttcatgtatt aaagccctaa ttcctaatgt gatgatgtga ggaagtggga cctctgggag 146340
gtaaataagg tcatgagggt agagccctta tgaatgagac tagtgtccat gtaagaagag 146400
atggaagata tgatctttct ctccaccatt tgaggacaca gcaagaaggc agccttctgc 146460
aagtcaggaa gagagccttc accaagaacc ctctctgtca gcactttgaa ctcagactcc 146520
ccagtctcca gagttatgaa aaataaattc ctgcatttta ggccacccag tctaagacag 146580
agaggtaaaa tatatagtgc ttgggccact cgtttgttat taaattcact atgtattcag 146640
cttcacttat atccttagaa aagtttgtga atgcagttga atgggtggag aacggtagtt 146700
gcagataatc agagaagaag agtagagaca gggtgcaggg gaaagtaggt cctttaaatt 146760
gaaaaatgat aacatgatcc attcatataa atgcactttt gttcaattct gctccagctg 146820
tattatccag cttctctaaa gaatggtgcc tgtacaggac agggtgatct ttaccctgat 146880
gaaagatggc tctccaggca gatagcagga gagacattcc taattgattc caggagggaa 146940
tgccaccacc atcaccacta tcatttatgt tgatatcaaa actgaaatgt caatgatcat 147000
ttctgttctc taacatttcc aatcagataa tttaaacatt ttactctaag agtttttcaa 147060
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
147
ctcaaatgtt atgcttcctg ttttgtgcat ttgtattatt aactctagtt tcatgggagt 197120
cccagttttt atacatcact gtatagcttt gatgttaaca tgattttgag ttaacataat 147180
ttttgccaaa gtgagtatta acctagtttg atcacacaat ttggttattc tttattctga 147240
tgctaaggga atccaatgat ttttgttgat agtaacccat caattctatt gactgtaaag 147300
agtaatctag aagaaattta aagaaaattt aatcagattt tacgttttct gtcgctaatt 147360
tggcatctta atagctgttt attttattcg aggtgcatcc tgagtcttgt aatgttcaca 147420
ttgcaatatt aaagcataac agatgagcct aaaatgttca gtggttaatt tgtacagatc 147480
aagatgttgt aattgcaata accttaatgt ggctaaccct tgaataacat aggtggaaac 147540
tatgtggata aatccactta tctgcagatt tgctgccacc tcggttaccc cagacacaga 147600
aaaaccaaac cctcctcttc ttcccccttc tcagcctact cagtatgaag acgatgagga 147660
tgaaaacctt tatgatgatc cacttccact tcatgaatag taaatatatt ttctcttccc 147720
tatggatttc ttaatagcat tttcttttct gcagctttat tgtaagaata cagaatataa 147780
atcatacaac atacaaaata tgtgttaact tactgcttgt tatctgtgag gttttcattc 147840
aacagtaggt tgtcagtagt caagcttttg aggagtctaa gttacataaa aattgctgac 147900
tgcgtggctg gggctggggg agttggcagc cataacctcc acattgttca atggtcaact 147960
gtataatttt ttagcggaag tgtaggaatg tttagtatga tacaaccatg gagaaatatt 148020
ttgtataaat atgtgtaaaa ttaagactgt agaactaaaa ataatacact tagttcatta 148080
gttattaata gctaatattg atttagctct gtgataataa attgacatgc attacctcat 148140
ttgtcacatt gtcatgagat caggattttt atttgtcttt catttacaaa tgaggaaact 148200
aagtctaaga ggagttaagt gatttaccca gtattacatg gcaaaaaaaa agtcagagtt 148260
taaacttaaa gccgagtctt tgcaattcta aagtccatgt tcttagctac tgcctttctg 148320
aacttattag tcaacctgaa ttctgaggat ctcacaaaaa gttacgtgct aattattttg 148380
gaagcattta tattatgagt ttctaaaatt acaaattctt ttatgtatga tagggaggta 148440
aaatcatggc atttagaggc aaacatattc tatttagttc ccatttgtgc tacttaacag 148500
ttgtgaacct gacgagtacc atttagtaac ctcaactgtt aaggtgtgta aacaagttca 148560
tttcatagag gtactgggga aagttaagcg agagaatata tgactaacaa aaaatatgat 148620
tttcattttt tccttgtgtg tatacttaag gggaaattta ggactgccta cttgttatct 148680
tccactgaaa acaaaacaaa acagaagatt aaaaatacaa acatgttgcc cttgtttatt 148740
ttgtctaact caagttgttc tgatatcatc catttctgtg taaccacaag cacagttggt 148800
aaagattgag ttagcaatgt tccctcaatt ccagattgcc ttctctacca tctaatttct 148860
ttcagtggta ccacaattct tccatgctgt aatagaaact ttgaaattat attttgctat 198920
ttttctcttt tgcatcatta ttttacattt tgttgtcaaa tatttatttt ctgcagaata 148980
tcttataatc ccatgcttct aatttctagt cagtgacttt cttgattctt attcctctaa 149040
tgtacaatcc aaataacact ttcttctctt ctttcattta acaagtaata atttaacgtc 149100
aacactgtgt catatctgtg gtgtcaccta tcagtatgca gaacaccaag ggattcccac 149160
tgtagtgtga ttcttcttct tgtgtattaa caccaatgct ttcttggcct cttaacgctt 149220
cctccttgat atttttcagt tccaggcact ctgccacaca ctctcatggc cacacacagg 149280
accttgttaa cacctggaaa ttctccatct ttgaactatg aaagattagt atctgcaatc 149340
agtaaatggc atcatctctc atagctttta ttccccaatg ccttctattc agccttgaac 149400
tttgtttttt ttctgcctgc tgcttcttcc ctcattaagc cagccacatc attcgatccc 149460
ttcactcaca gcattttcaa gaacatcccc tcttcctctt tttatcttca gtcactctgg 149520
tgtgaatatc ttaacaatta tacaatacac tttcagtgtt cctagactcc tgttgttaga 149580
gacagctgtg taacagaatg ccctggtgca gactgggggt ccctggatac cgagggtctc 149640
cagtttcagc tggcctcctc ccttaggtaa gagatagaaa caagaatctt agtattattc 149700
taatgttcaa gtatctggtc ttttctgcta tagttttccc ccataaatct tgatttttag 149760
ccatattaag tgtttttttc ctttaccaga taaacaattt tgtctccaga ctttctgcca 149820
ttttcacttt ttttacctgc caaacttttt gtgtctttac gtactcaatt taaaatcctc 149880
ctttatgaga tttcagcttt ttctcttgga ctgagattga gaacctctct ctgggctcca 149940
ataatttcaa atgtctgctt aaattttgaa gcataatttc attttatgag aatacataga 150000
tttcagacta ctaagcaata gaaatatgga tacaagacat acacgggacc acttggggca 150060
tagtaagtat tcaagaatac tgaatacttg gtggatattt ggtgagtgta ttaggccgtt 150120
ttcacaccgc tataaagaac ttcccgagac tgcgtaattt ataaagaaaa gaggtttagt 150180
tgactcacag ttctgcatgg ctggggaggc ctcaggaaac ttagaataat ggtgaaaggg 150240
gaagcaggca tgtcttacat ggcagcaggt gagacagaga gagagagaaa gaaaaaaaac 150300
agccacttat aaagctatca gatctcgtga taactcactc actgtcacaa gagaagcaag 150360
gtggaaacca ctcccatgat ccaaacacct cccactgtgc cccttcacca acaggtgaag 150420
attacaattt ggattacaat ttgagatgag atttgggtgg ggacacaacc aaaccacatc 150480
agggagtatt ataattggta aagaatgact gtccctagtg cattgaaatg taagtctcat 150540
ggaactaacc tatatttgtt taatgcaaat ttgaattcaa gatggcagac taaacatatg 150600
cattttttac ttatctttcc aagtctttgt taagttttaa acggattata taaaagagca 150660
agaagacaag aattaaaaaa gaagtagtaa gccacatggg aagtatgcat gagagttaga 150720
agctgaggaa gtgagtagta atctaaaatc tcagagaggt tttgggttca taggtgtgca 150780
aaaagagaat gagcattggg tccaaaaaac aaggcgaata atggaaggtg aatagttgaa 150840
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
148
cagttgcgct gatcagtcta gctttgcagc tcattgtcaa agaagagatc aagttggaat 150900
ttttggccaa atactatagg gttgtctgtg atatttaata gtaactgagt gagcagcctg 150960
agagtcaaga ctgttagcta tgttttgaga ccccaaagta aaccccttgc attttatcag 151020
ttgacagaag agaagtgctc tacatgtgcc ctgacttaag cttatttttc attcgtaagt 151080
gttaggtaat ttttagtaat atcattagcc ttctatatgt agagttatgt gagaattaaa 151140
ggtctctttc cctgcaatct cagacagaat tctactgtac atgcaaacat gtattatcaa 151200
gtatggacaa aatcaattgt actgagtata atgaagtcca ggttctctgc cttttatgtc 151260
ctctaattgt acacagcata aaatgttgac tcaagccaga gcacaaaata ctcaaaggac 151320
agaattcagc ttatcttatg gtcagatatt tgcactaaaa taattgaatc agtgattgga 151380
tacaaagact tggatgacat cacaaagtgt tcaggctctt gaacttccta ggtccttata 151440
accttctttt gaaacaatag aggccgggca tggtggctca tgcctgtaat cccagcactt 151500
tgggaggcca aggcgggtgg atcacgaggt ctagagatag agactatcct ggccaacatg 151560
gtgaaatctt gtctcttcta aaaatacaaa aattagctgg gcatggtggt gtgtgcctgt 151620
agtcccagct actcggaggg gtgaggtagg agagtcgctt gaacctggga ggcgggggtt 151680
gcagtgagtg gagattgtgc cactgcactc caacctggtg acagagcgag actccaaaaa.151740
aaaaaaagaa aaaaggaaaa ataggagtac atatggaatt ctaggcatct cacaaatctt 151800
taacgttagt atttcttcaa ttaaaatact ttttaaaaat tctaaccgct agaccactag 151860
agaaaaatac ttttggtttt attaaatacg ttatttaacc aacctctggt ctcatcagag 151920
agaaaaatag atggcatgtt tttacctttc cttgtttcag gcttctgatt agaattccta 151980
ctagtcaacc atttccaggg tgcacattct taatatttct caaaatttat attaggctga 152040
aacctacaaa atttattttt ttaagatcaa agaatgtcaa atattagcaa gtcacatggt 152100
ttatactgtt aaagcaaact aaatatggcc tgagaaagac tttgtacttc tgtatttgag 152160
accttgtgga tgaaccgcaa cctaaattaa taggcagaga aaattttaaa cttaacttag 152220
gagttagcac ttataacaat agctgggtct tggtaaatcc cagcagccat acttcagcca 152280
ctcatacacc gctgagtatt caaactgtgt tcaaataagg caaatgccaa tctgtaacca 152340
gtccagctgt ttctgtacct cacttctgat tcctgtatgt cacgtcactt tatttgtcta 152400
taaatttgtt ctgaccacaa ggcatccctg gagtctctct gaatctgctg tgattctggg 152460
ggctgcccaa ttcatgaatc gttcattgct ccattaaact cctttaaatt agtttggctg 152520
aaattttcct tttaacaata ccatctctcc tgggagagtc aaactcatat ggcaggtgag 152580
gattcagaga gattgttttc caaaagatag aaagtaaagt tgccattttc ttaaggtcta 152640
ggcagagaaa ctggtatagc tgtacttcta ccatattcta tcagttacac actgtcatgg 152700
agcaggctct tatgcaatgg aagaggacaa aggtggcctc atcttccctc catgctctgt 152760
tacaaatatc aatctgtctc cctttgcatg ccctgtcttt ccttggattt taggctattt 152820
catttccttg caatatcagc tctctgttgg attcaagaat agagatgatt ttgtagtatg 152880
ttccactatt tttcccccaa attattaagg tattagtaat gctctttcat gttccatatc 152940
ttaagtggaa gtggaacttt cttgctataa cttttgaatt agcaattcta gactctagac 153000
tccaaaggag tctgtatctg caaaagttct gagggaaaat aattgtgaag ttaaaattct 153060
aaaaaagaaa aaatccttgt ttaactaaat tatcattcta aaataacaaa aaatgatatt 153120
ttataattat aagaactaag gaaattgtct ttatataaat gtctggagaa atagatttct 153180
gagaatatat ttcagcaaaa caaggaaaaa ataacacggg gatatactgg gactgaagta 153240
acagtgcctc ttaccccaga gataagtgac atgaggtccc agaatcattt taagcaggct 153300
tagaagccga atgtataaaa tatatcatgt aaaatataac gtgacacaga gggcacttag 153360
ggtcattctg attcttgacc ttgatctgag tttcaatgac gaaaatagat tggccaaaga 153420
atgacatact agccacgcct ttattttcat tacatacact ttttactcca tactgcacag 153480
atatatacaa ttattttatc ttcctaacca ggcaataagt tacttgccca tcttcttatt 153540
aacaataatg tagataaagt atcttatgaa agtagagaaa tgtagtcagt tatttgataa 153600
gtgtgtgagt ttgttcatat ggtcttatag gaaataacaa acataattta aattggtaca 153660
ggttgtacac agaacattta aaaaagttct acctaatctt aaaaccatgg atttttactt 153720
aatgtttctg cattttataa tcattaaaaa caatggaaat tttgttgagc ttaatatgaa 153780
ttaaaatttt tatattagga tatcgtaggt tttgccaata gaattctaaa acttaaatat 153840
atctaatttg attactatgt aggttatgca ctgtgactca ttagaatata tgatgtgttg 153900
tttaaagtca taatgatcat cagatgaaat atggccatct ttaaagttat ctcatagatc 153960
taagtagtga ataaacgaga caagagtaat gtaaaaatgg ttgacattat caatgaaggg 154020
tcaatggata actgcgtggc tccggttctg atactcagaa ggaaaccaca tcacttaagt 154080
agtaatatga ggaaaatgaa ccacattttt aggaaacatc acacaaactg taaaccaaga 154140
acactttact attaaacttt ttttcaaata tgccaatgcc atgaaaaaaa acaaagagct 154200
gaggacccat tccagtttaa aggagactca agagacatta cgaccgaatc ctctatgtga 154260
tgtaacataa gctatcaaag acattaactt ggtcaattca taaaactgaa atctggaagg 154320
tagatcaaat aaaggttttc tatcaacatt ctgtttcctg aaacggtagc ttgtggttaa 159380
caaagaggat gcccttgtag ttagtactaa gggttgtagg gtccgtgtgt cagtgacttg 154440
cacttggcag tgagtgcgtg ggcgtacgag catgcacacc acacagtgca cacaggggtg 154500
atgcaacagt cagtacatcc aggaaaagga tttatggcag ctccgagtga gtgcgtgggt 154560
gtacaagcat gcacaccaca cagtgcacac gagggtgacg taacagtcag tacacccagg 154620
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
149
aaaaggattt aggggagctc tgagtgtgtg gatgtacagg cttgcacaca cacagcacac 154680
acggagatga tgcaacagtc agtacatccg ggaaaagcac ttatgggagc tctgtgtact 154740
attgttgcaa tttttctgta agcttgaaat tgtcctcaaa taaaagtgaa aaaatgttac 154800
cccaggaagg attggcacaa cattatttta gatgaatact tcgaaaactt cctttatttt 154860
ttgaaagtta ctggaacacg ctgattacac atttgggatt taacccctct gccttaagta 154920
taaacttaga cgtaagtgta agaacccagt ttaagttatc ttgagaagca caaaatttga 154980
gttactacac agtttccttt taaatggaaa tgaaatacat ttcaagtcat actaatatat 155040
gttggttttg aactacttgt agcccttcct tagaaaacta aaacaaaaac tctcttttaa 155100
tttcatgact ccttcaaata cggaaactat gaagatttat gtcttatgaa gtttatttta 155160
cacataagtt attagattct tttaaaatta ttattattat tatttatttt tagagacaaa 155220
gtctcactct gtaaccaaga ctggagtgct gtggcaaaat catatctcac tgcagcttca 155280
aattcctggg ctcaagccac cttcttgcct cagcctcctg agttgctggg attacaggca 155340
tgagctacca tgctgagcat acaaattatt tggtctgatg aaataattat tgataaaatc 155400
aacagaagtg atcattataa gttaaatatt tacagtgtga tttagagaac atacctgtag 155460
aaaggattga aacaataaaa tattattggc ttggaatttg tatagaattt tgcccttcaa 155520
tatagactgt catctaaaca ctcaaataga agacattcaa atttacaaaa tggtgcttta 155580
ttggccagcc tagataattt ttcttgcttc ctcagccccc tttttactta ctcctgaggg 155640
cttaatatca cagacaactg aaattcatct gcactctact tactatgtgt aaccagctgt 155700
gattttattt tctgatgcta ccacatgaaa aaaaawtttt tttcctgagc tatagatgtt 155760
aattggtgtc tttgtatctt gctaattaag ttctagcaac accttctccc tcttcctcgt 155820
ttgcacttaa tgagctcact tgttgtatta atttataaga taattagata aaacaaaaaa 155880
agttgaattt cttcaggagt ggctttggaa agtgcccctt aaatattcaa acatggataa 155940
aaatgtgtac attacaagac aaaaaaatca ctttaagaag aaatatactt aatgttagcc 156000
tgtagactca tactgacatt ttaaataatg tgatgatcag ggcttataca aaaaggaaga 156060
gattgattca aaagctcagg caatcacaat tattttggtg taagcaaaac aggatcacat 156120
atggtacaac atgatgctca taccagaaac ctttgcaata tttaagcaca acaaacaaat 156180
tagttaagca atgtgcccct tggactctaa ttaccatttt tatttgcatg ttcatttttt 156240
tctaaaattt ttttaagcca gtggccaggc agtattaaat tctttgctgt ttatcatgat 156300
accagaattt atttgacaaa aagtggaaaa atcattgacg tacagtgaaa ctgatcattg 156360
tttaatagta gaattctgtc gttcatcagc agttagggaa ttgtggaaat tgttttgagt 156420
gagaacatcc agatgttatt gattccaatt ttctggtcca actcaaactc atttgggcca 156480
ttagctttcc aacttgtcca atatcatcag aaaaggcaat ggcatctctt actgctctat 156540
ttttgtcttt ggttgagtaa tggattccac ttgactggca tatatattct ggctgccctt 156600
taggaaatct aagcatttga tgtcaaaaat acacatcttt taaaatactt cttaatattg 156660
aggtaaagca aacattcaaa attcaaaata tcaagctgta aatgttaata ctaaacagga 156720
acatatccaa tcgacattga aattgtatat aatgaacaag aaacaataaa ttaaagtgga 156780
aagtcataat aatatgcaat atttcaggta ttctttgata gatgtaatga cagaagctac 156840
taccttgcct gccccagtgt tagtaacatt gagctttcca gctaggatta gagcattttt 156900
atatgaatcc ttaaaaaatg caataactac tcctccagga gaggatgctg tccctgcttc 156960
ctgagggata gcactaatat ttccaggttg tctgctttac atcaagactt tgctttagga 157020
tggaaacagg attgtaggga gactgtgagc tcaacagtaa gattagtttg tctccatttg 157080
atcttttgat gaaatgcatt ggggtaaaac ctcttcccag tgtcattagt agctcatgaa 157140
ttagaaaaga taatttttct cctacatatt caagaagaat cagaaccagg taattgacat 157200
agccaactaa acctctatag ttattggttt tgttctgact caaatgctaa cttgaatccc 157260
ttatgactgt taagagcata aaggggaaga gaatgcccag ggaggcaact ggagagacag 157320
agacagcaga gctgtgagaa gactgtttgc agaaaatatt cttcccatgt gtggacttgg 157380
cctttgaagc agagaattac aacaggaaat taggaatagg ctggtgtagc ctcataaaca 157440
agtacaaaat tgtgtcagca caccaaaata tttcactaga ctgcccttcc cctaggaggt 157500
tcacaggtgg tataataaat gaaatcagca atccttctac atgtctcgct tatatggtta 157560
ttttggctca gccgaccatt agttatttgt aagctggggc ataaatacag acactagttg 157620
aatatttatg tacagctcca gaatccacct tcactaattt gtctacttat ggggaatata 157680
gctgtggggg gcatggaaaa tatttactct gggagccctt aaatgtaatg catgaatatg 157740
aatgtgctct tggcacggga ggtcctggaa ctcttggtag gtgttgggtc cctactgacg 157800
ctttatcatt ttcttttttc cttcaactga atataaaact gaaaagccgc ttttaacagt 157860
tagtaagtgg tgatactgcc agactcatcc tataagaagt tagctaaatt ttatccagac 157920
ataatatttt ttattagctt acttgtagag tccctcctca gagcccaact aaacgtggtg 157980
ctaaacattc ttttgccttt gtagaggaat aacattctga gactcctttg ttttttcacc 158040
aaacagtaaa attaaccagg tattgaattc atactctcat taaagtcatt gttaccattc 158100
ttttacaaaa aaaaatactc aaggagtaaa gaaacataaa aattgacact aaaacaatat 158160
cacctacgtt crtctttctc tggatgttag atttggaatg tatgcataga aaatggtctt 158220
agtgtcaaag atttaatgct gcaagagaaa tcatctccaa aagaatatct cctttaattc 158280
tgtcttctta tttatcaaat aatatctagc gaccgcactt ttcttttgtt ccttttgtat 158340
aagaaggaat tatagcggtt tgccacatta gagtacttta aaagtgcttc ctaaaatttg 158400
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
150
gtagagaatc ttcttaaaat tttactccac cctgcatctt tctggatatc tatcactcct 158460
gagatggttt ttccaggctt agattagttt tctaaatctc tcagctttct tttatctcaa 158520
gtgacacagc agttaaatta catcatgagt ttagcctgga ctctcttgag tcccccaaga 158580
aggaaaactg aaattctgca aaatgaccta tatttaaggg tgaaggaatt aagagacatc 158640
tcaagccgtc cccttattag aaggtaaact aggaatcata aaataatata tttgaccgag 158700
tgctcagaaa tgattaaatc caacaggctt gccaacagag ttgtaccgta gaattgccaa 158760
gggagttatc ataaagcaca gatactgggc tctgcctttg accttctggg tagataaatg 158820
ccagtgattt tgaaagtaat tccctgtgat tctactgaat ctccacaaat cttgtgtaac 158880
ctctcaattt taaaaagaag tttttttttt ttttcagttt aagccattta ttcaaagtca 158940
aacatgcttt agtgatggag aagaatctgc ttttaaatgt attaaaacaa attgatagga 159000
atcatgtttc ttattgtttt cctgtataaa gttagacaaa taggatattt ttgaagttat 159060
aaatcattta aataccctta aactgtttac aatatcgttt gttatatttt tatcttctgg 159120
ggtaatgtta tttaaattaa acgaggtact gagtgcttgc tgaaactaac tagaaatctt 159180
aggccttaaa aatagctatc tcatattttt aaaagaaaca tcaataattt ttatatattt 159240
ttaaatttat gagatggaaa gttagctttt actaatctta tcaggctaaa ctgagtaata 159300
atgaagaaaa tgaagagttt agaaatattt tttggaatat cagtgaaatc tctaaaaaga 159360
aaaaaaaaac cctcatctat atgtgtgagc gacataaagt cacactttgt tgaaatgcaa 159420
aatggccttg gaaaatttca tggaatgaaa ctaaatggca gcacatcact tttccagatg 159480
gggtcttgtg gttgtggctc agatcatggg ggtgatggca aactcttcca aaggaaaaat 159540
agtagcaatc cagtcacaag atagtaccaa acatagactc acagatgagt aatatgtcag 159600
tttcttaaaa gaaagagttg ttaggaatga gagtaaggat gtgcctcgat tacaataccc 159660
cagatacgat actattctga aaatggtgtg ggggttttgt gagggatgcc aaccacacat 159720
tgtgctagaa atctgcatcg ggaagaaata ttttttgcta catgttacaa atatgcctat 159780
agactgtgat tcaaataaat aatgtgttta ggccaggcgt ggtggctcac gcctgtaatc 159840
ccaacatttt gggaggctaa gccaggtgga taacctgagg tcaggagttc gagaccagct 159900
tggccaacat gatgaaatgc catctctact aaaaatacaa aattagctgg gtgtggcgac 159960
gggcacctgc aatctcagat actggggaag cttgaagcag gagaatcgct ggaacctggc 160020
aagtggagat tgcagtgatc tgagatagca ccactacact ccagcctggg tgacaggatg 160080
agactccatc tcaaaaataa ataaataaat aaaaataatg tttttataat tttttcatag 160140
aaaaataaac ctgaagttag gcagtgcaga cttgaatttc tcattctcaa ttcccattca 160200
ttttcctgtg tttttgaggg tttctcctgg aaagtaaaac aattcaatgc tttatcttct 160260
gcccttcaga agtcgggaca tcatcacatc attttacctt taagatattg gactggattc 160320
atagaggaat gagccatata caacatacat aggagtatga agaaagggag acagccttca 160380
aagctaattt agtaactaat attgtagttt aatgtaatga gaaataaaac tagaagatga 160440
ttgatagaat gcagagggca ctttaaatca gagagacgat ttgaaagaaa gaaatatttt 160500
tatatacctt gatttattag agatagatta aaaagttcgt ttaaaaaacg tgatcaagaa 160560
cttgcagtga taagttattc tttttcaaat atcatgacga taatgctgca taatcaccca 160620
ttcaaaaatt tcayggcttm gaacaacaaa tattactctg gagctctctg ttctgtggtt 160680
ggctgagttt tggctactct tgacttggct gagctgggag gatggatctg cttcaggctg 160740
caagctggct gagcttggct catcacgttt cattacgagg cacagactga agtgtttgga 160800
gaagcccagg cagtggcatg ttctttaaag gcactgagag gagcttatga atgaatgaag 160860
cttaactaca taagcwcact tgatgaagtc aaaatgcaag gactgggaag tacatgccac 160920
caaccatcaa gccatggtaa agctgtcgat gtactacggg ggagtggagt gctggtacga 160980
atcattcagt ctttcacaaa acactggcaa aatgcaggtt attcagacag aatcgttaaa 161040
tacaaaaacc tacttaaaac ttaagggtgt attagctatc tgtctccaaa tgtacttttt 161100
gaatttaagt tataaggact ttcactgcag aaagtatgca ataatgaaga agataattgc 161160
tttggtcatt gggaaagtgt ttttcaggta gaagtgaatg cagaaacaac cattccaagc 161220
aaaaccaatg acttccaggg taggctggaa agagaattct cttaatagaa aagaaagagc 161280
acttggaatt gagatagaga cgctaaactg agctactcct gttggggctt tgctgatcct 161340
tcatggaata cactcattaa ttatcacaga agccacctat gtactctgca ttcattggga 161400
tttgatgtat aattggttct taacttctct atgtttagca ttttgcttag aagttagcac 161460
ttatcttcag gtattataag gcttttaaaa tgacattttc ccctctagag gaagtatgcc 161520
tttgtttgtt tatttgtttg ttttgtcttg tttcttagag acagggtctt gctctgttgc 161580
ccaggctgga gtgaagtggc ttcatcatag ctcactgtag ccttgaactc ctggactcaa 161640
gccatccttc tgcctcagtc tcccaagtag ctggggctac atgcttggct aattttttat 161700
tttattttat ttttttagac atggggtctg gctatgttgc caaggctgat ctcaaactcc 161760
tggcttcaaa ctcctggact caagtaatcc tcccacctga aggtgggagg ccagcacctt 161820
gacctttcaa agtgctgaga ttacaagcat gagccgctgg ttacaagaca tggccagaag 161880
tatggggttt tctatgcttt cacatataat acatacttag gttttctcga tgatgaaatt 161940
atgtttgggt tacttttagt aaaccgtatg tgctttgaat taataaaaaa gttgtgattc 162000
atttattttc aactgctact tcccttctct tttggaggtg ctccgttaaa agattccctt 162060
tatgttgtgt cacagagtct gaattgacac aaaagcattt ccaggcatta ttcttgttcc 162120
cggttggctg acatagagcc ccactcactg atggcactgg ggaaggacag agcctgttgg 162180
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
151
acaaaccaac cctaggcatt agtatcaaat ggacaaaagg atcctaagac gtttagacaa 162240
ctgttgactt ttatgaaact gagacaaaaa tggtaagaaa tttagataaa tatttccttt 162300
tgtaaaaatg acatgaattg taagtttcct a.cactgtaaa ttagaaaatt taaattatat 162360
aaaactatat aaaattataa tttttttctt aatattggca tttttatgtg tactaaggta 162420
tttacctcac ttttagaatc tcgaattcta ttgggagtgt attattttca actcataaat 162480
caccttttaa acatttgatt cttataactt ttccttctca ggaaaactga acctatattt 162540
atagaatatg gatgctccag cagctggttc aaaaaatgat tccgtagtaa taatcacatc 162600
aattatatgg ttaaaatgtg aagcctgagt caccgaaaag ttaggtcatt taatttgttc 162660
aatgcagttt ctaaagtttt caagaagtgt attagattta aaagagactt gaaagggaat 162720
ctgatacaat gtcattacaa ctgagaattt tctcaccaga attcttgaaa gtactgaagg 162780
atgcaaccct agtgacattc tcattacaca tgtagatcag aaaccaagaa gtctatgagt 162840
aacgtttgga aagaacaatg tttaaatatg aaaaatgatg tgactcatga ttgaaaaaga 162900
aagtcatgta aattggaagt gcaaaaactt tacaggagaa atctatgaga ccaaaaatag 162960
gtagtaaaat aaaaatgaaa gtaaatatgg ttgcctaaaa cacattaaca aatgaaacaa 163020
atagataaaa ccaatgagaa tgggcagcac taagagtaac agagaagttt gacccaggca 163080
attttgatga attacttggg aaatctggta ataatcaggt aatatgggag cagcatgatt 163140
agttaataat tccactttaa aaaattcaca cagaaaagga cagagtatat atggaagaca 163200
tgcacagctt ctatattaat gtgacactgc tctgagtaat taaacaccgt ttccaggaaa 163260
gatttgttca gttgttccta gagggtgtgg atacatccag gacattcagc ttcatgactt 163320
ctcatttgtt ttagttttta tcttttaaat tgggggaaaa tgatgtgtta ttcactgatc 163380
ttttcttctg agatgccaat ctaaatctgt tatcttatta aacaataagc agattttgtt 163440
ctgatttagg caattaccat ggttagtaaa caagaaaatt accctaacaa tggaattagg 163500
ttttgtggac atgatcaggt catctttttg aggtatctgc cttttcctgc attcataata 163560
accactatta ctctgattac ttttatactg tccccataag tagtggagtt ctcacttacg 163620
caatgaaaac cagaattcag aggaaatgta accttctgaa ttcttattgt gcaaatttcc 163680
tcttcattca gtgccatgct cacctggaag aaataatttg tcaaatattc ttgccaacca 163740
aacagcagtc atattccttc agagaatttt cacactaaaa acaactatta gttttacgct 163800
gacagcacaa gtcaatccta atgtctttgg atcatgaatt tatctacaga tttcagaaga 163860
aacaagacaa acatttttgc caatgtcatc catcaatcaa gtggcaaagc agatgtgtgg 163920
atttcaatgc agatagtttc tgtccagctg tctgctctcc atcttggatg ttggttttgt 163980
tgtagggctg gctctcctca taaacttgag atggtcgcta gcaccttgta agggtatgca 164040
gttcttcctt ggcatccact gaaaaaagag tggatatctt tttcttagga aattcatagt 164100
tgggtattca gtcgcatgtg cattcttaaa caatcactgt tgccaataga aaacaatata 164160
ttaactggct cacctaggat cctatacttg tagacagttt cagccaaata caaagatctt 164220
aagaaaggga ggattggttc ctctacctca agaaaaatta aatcaatgtt gatgcaagag 164280
tgggaatgca tgttgagagg caaacagtaa acacaacaaa atgataaatc agatctgctg 164340
gccctcaata ttttcttttc tttgccatat cagaaaatct tctatgattc agagctcact 164400
cattaaatgc attgcccttg gataaaagcc attggtaaaa taaccaacaa gtcatcctcc 164460
tttgaacctt tagccatatt catgtctacc tacattatgt atatttcttt gcttcccaca 164520
ttccatcaga gtaaaatact tcgcaagagc cagccatgtt ctaggacata tggacatgaa 164580
cagatttata ggatgtggtt ttctcatccc aactcttgaa ggatgaatgg ggatcatcca 164640
tgcagatgat ggagaaagtc ttcaaagaga agtgaagatc aattctaaca agacgataac 164700
taaaacagca tagatgttca gagaactgca agaagcctca ttgcttaacc caaaagnatg 164760
agagagaaga ggcaatgatt ggtagaaatt agatcttcaa ggatcttgta ttagcacaga 164820
aaaagctgaa gatgtatttt atcacgaata gagtaccaac aaaataattt tcatagatga 164880
gcagcatttt taccttattt atatgagaat tccttctggc cagagtgtgg catatcactt 164940
gggaacagga agaatatatt attgccttta gtgaggcaat gctgaggcta ttatattatt 165000
gcctttagtg aggcaatgct gaggctatta ccaaagtcca ggctagaaat gaaacccaaa 165060
tgaagaaggc agaagtaggt ttcttgaggt gaaaacagag tcaggtcctc cttaatacat 165120
aggctcttac gactgggaga taattaaatt tagtggatgg ggaaatgaga agtgggggag 165180
catgacctgg ttttctgact tagtgtcata gtgtgtggaa atgcattaag agaaacagaa 165240
atcgtacctg aaggaaaatg cttgtagagg aaaagagtca ttttaaatat gataaatttg 165300
atgtgtacga gacatttcgg tgggcaggtc taacaggtaa cttacaatac atgtgtgcag 165360
agccctgtag aagaatctag gcattcagtg tctgctccag ggtcatcagt atgcacgtgg 165420
cagtcaaaac aataagagtg gctgagatca tccagggaga gtgttttgaa tgagaagtaa 165480
gcaaatagaa gacatttgga tgctgcccaa tatttaatga atgaattaaa gatacagagc 165540
ctgtcaagga gctgaagaat gaaaggtcag agaaatagga gcatatttga ggagaagaga 165600
gtgatcagcg gtaaaattga atgaacagac accaagaaag ccaaagccag ccatgtagaa 165660
gagcttcaaa ttagaaattt tttaagaggc attcttaaat gaagactgtc ctttattttg 165720
ttttgaaaga tgatttattg attctttaat cactcaatat tgcaactggg atttcttcag 165780
aggtctccaa gtctcctcta ttttcacaga tcaaaattct caggtgcaga gtatgtcagg 165840
acctattcaa ggttacacat ttggctgaca actgtgtcaa gactaaaatt tcatgatcgt 165900
tatttcagtt catctgaaat aaatatcctc caaacataaa ccataaactt tatgttttaa 165960
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
152
gagcacatac acctctttac atgaagtcct ccagctttgt aactcctcca ttcttatcag 166020
gtatcacttc ttcagacatc cctctcttca gtcattcctc tcttttcttc tcagcctgta 166080
tatcataaat acctatcatt tctctcttgt tgtataattg actccatcat cttttgttct 166140
tcatttctac ctggccctaa aacctacaca tcagatcaat cctatgttct ctctttttag 166200
gctccatcct tgtattgaac acaatgctgt aattatgtga attggtctaa tttgaattct 166260
tgccatctaa atccttcctg agcccacagt gctgtagaga aaatatgttt ctattctggg 166320
tcagcatttg acgtgctttt tctgtagggt tatacattcc ctgattatta aaagtttatt 166380
tccaagctct cctttcctgt gtattcagaa tatacctcac atgctgcttc acagagacag 166940
tcaatactat cagctagtag ggcatacaac tgtggccctg tcatgcctaa atcatatcaa 166500
tttacatcct cccttctcct tccactttat tccccttttc tttgtacaat gtcaatctgt 166560
ttcaaccttg gctactgctt cagacatctt gcattgtcag tcattatcct tctcttgtgg 166620
atctccaaca tcttacctct gccaaatctt ttcccttcat cagtaaccat aatcagactg 166680
tatttttaga tgatgtaaat ttctataatt ttatgttagc tctggcttat ccctctttct 166740
tcctactcct cctcttatag tcgtgtattt aggtcacaag tacactctta aacaataact 166800
gttgccagca gaaaacaata tattaacagg caattatcaa gtatgaactc cgaatttcca 166860
acagaatatc cttgatactc tgtgtatgtg tgcttgtgtg tgcgtgcgtc tctctctgtg 166920
tgtgtgtgtg tgtgtgtgtg tgtgtgaaga caagtttatg acaagaagga gagactcaca 166980
gaaggtcatc aaaagttaga aatttaaatg agaatacgcg tgaaagtaat tttctagcct 167040
gcacctgcca aagtgttttc tcatagttca tgtgaagaaa taccaatagg ttgttgtcgt 167100
tagtccacta cacagtgttc acctttaatg taggtggcat gggcctaaac aaggatggaa 167160
actgatatta acagagtgtt atacagcagg tgctgtacta agggctttat gaggaagggt 167220
taagttagtc atataataat atacttaaag ctttaatttc atggtgggat agttcactct 167280
catgccatca taattgttgt acaatcctga attaaagaac ttttcaagat gttattaatg 167340
aaaaatcttt actgagtgaa ttctatctga ccctcccagt caaaaggctt ctactcaaat 167400
ttggctaaac cctattagtg atgtgggttt ctgactgctg ccgtaacatt tatttggaga 167460
taagatgtgc tatatattac agatggactt tgggaagtga ctgagggtga cagaaattaa 167520
ttaaccacaa gcctccaaat gaaattttta tgctggtgag taagaaatac aaatttctga 167580
aacacagcgg tatgaaataa tgcagtatca atggttaagg aagcttccta ggttttgaag 167640
ttctatatta aaagatagat atgtaacaaa cctgcacgtt gtgcacatgt accctaaaac 167700
ttaaagtata acaataataa aactaaaaaa aaaaacaaaa aaactttgat aagagagtac 167760
atcttattaa tgatttcaca atgatgccta atataattta gtgtcttggt aatttaggta 167820
atgaataaat atgggatttc ttttcaaaaa atataagtaa tttttaatga aaataatatg 167880
cagaaataaa tacggggtaa agtttaataa ttaacaaata ttccagaagg ccagtagtct 167940
gcgttggtca gaatgaaact ttcacagagg ggagagtaaa agtgaagcag ataaagtaat 168000
gaaataattg atatcagtgt ctctaaagta agaccgagga atttgaattt tgtaggcagt 168060
gaggagcctc tgaaatcctg agaatggatt caacataagc aaaatcgtat tttggaagea 168120
gccagctggc atgcatgggt ggttggcgag aagtctccag tgagcaggtc attgcaggtg 168180
tttgtctcat gtactagttt aatgtgccgg caggggggtt gctgtgaggg aatttaagaa 168240
gcctgaatca gcagttctta gcaactacat gaggggatta agacatgtaa aagaaagtca 168300
actgtgactc caagatttcc ctgaataagt tatatcttat tccaacgcta ttttgaatat 168360
ttccagggtg tatat.tctga atatattctt gatatattca agattcaacc tgagtaagtt 168420
acatagacct gatgacattc agtattcgag gtcagataac aatgtaactg aattctcctg 168480
taaagagcaa aaatatgttt taattatttt acaagtactc aacatattaa ggaacttatc 168540
tagagtttcc tggaaactca agtcacggct gttgttgatt ttattaatta ggaagtttac 168600
atgaaccaat atagaactac actgctttat atgtataata ggtcctattt ttgaaatggc 168660
tgatacagct ttttaagtgg tttttaaatt gagacaactt gacatctagc ttttaatatt 168720
taaaggaatg aactaggata gctattcagg tcatttgaat attttgtgca aattctcaca 168780
ctcattatgt catgtctaca ttcttgctgt ttcatataac tcaaccctcc ttttgaatat 168840
catgatttaa gcactcataa aatattacta aagaagcctt gaggctctaa gtaacgcaat 168900
aattagccct cctctaatag cccaatagaa tacataaata attttctccc actatttcct 168960
ccccagatat tgaracctca atccgagttt taaaaactga cctatactag gtactagaga 169020
tctctattgg agatgctaat agattgtaaa ctgcatctag aaaacattaa accagtattc 169080
taaatggttt gagagtctta cttttattct gggtcagcca actttagatt cttttgtgaa 169140
tgcatctttc gtctgcactt ctgctctcca aataatcccc tgtaacagtt atttttttta 169200
atctttcaca cttttattct acatctaaaa ccttgacagg atttgttaat ttatcttaaa 169260
aattctcatt tgtaatattt atcaaaataa attagtttcr agtaactata tcttgatgtt 169320
ttttaataca ggtttctaac atgagactga aatctaaaat attatcatca tccaaaataa 169380
tctgaaaaac tgaaatacaa tatatacgca catataatat agttacagtg aataaaatct 169440
agtatttgat tgcgtaacag gtgacaacag tcgacagtaa tatattgtac attttaatag 169500
aactgaaaga gtataattgg attgtttgta atacaaagca aaaataaatg tttgtgatgt 169560
ttgtgatgat ggatatatgc ccccatacaa agtgctgtgc ctcatgcgtg ttatcccagc 169620
attttcacag gcagaggacg gtggatcact tgaggtcagg agctcgagac cagtttggcc 169680
aacatggtga aacccgtctg tactaaaaat acaaaaatta gcagggcatg gtggcaggca 169740
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
153
cctgtaatcc cagctgttcg ggaggctgag gcaggagaat cacttgaacc caggaggtgg 169800
agattgcagt aggtggatat tgagccactg cactccagcc tgggcgacag agcgggactc 169860
caccttaaaa atatatgtat acaaatatat atacatatat attatacaca catataaatg 169920
tatgtatgta tttatacata taaatacata tatttacaca cacagagggt cattatgtaa 169980
caacatgtct tcaaactgaa taattttagc catcttgtca tataaagcct ctaacaccac 170040
agatttaaaa tttcttcctg ggaagtaaat attaattaag gaaatcccaa cttcttttac 170100
aaatcaaaac ccatgttctc cataaattaa catcataaaa cattttttgt tcatgtcaag 170160
cggtcaggtg tctttgggga gtttagaatt acctgatacc tctgttcttt tatatcaact 170220
ccataaggaa atcccactgc attacttggt atgtgtttct gtaggcctct ttagtgtaaa 170280
atttaaaaga agggggaagt ttaagtaata tcaggattaa tgaaataatt ttcaagtaaa 170340
atatatttcc atgggtttac acaaagtatc ttcatctgtc agtgactctt aacagcagat 170400
gcgtatttct cactcccatg aaaagttctc cactggtcca ctgactgtga tctttgtgtc 170460
ttttaccctt ttggatccag gtggaaggag tcccctcttt gtgacactga agtttcccta 170520
gaaaaaagta ggagtcatat gatggttctt aaagtaatag acatcctttc tgctcacatt 170580
tccttggcca atgcaggtca catggtcaag cctgatgtca tcagggtggg aggtgtgatc 170640
ttcctatagg acaggggagc aaatactttc aatctgtcat aaaacctgaa tgaaatagta 170700
agatatctgt taaatctatg tttcttaaac acacatgact gtctayacag ggttcctttg 170760
tgcattattt gtaatgttaa tacataaaac atgaaggaga gtgtgtctcr ttctcatgat 170820
caaattttac ctgttatctt ttctctatta tcaaaatkcy ggtagtcttc taatgatctt 170880
tatttgttta tttatttttt agttaytgaa taatgataat ggtgtctatt tcagatctac 170940
aactttctga gttttaaagt catggaggaa aaactataat gaaataaaat ataattttat 171000
ctaaaaataa ataaatttgg tgttaaatcc aagcatattg ttmttaacag gtaatacttt 171060
tattgatttg ggtgttttag gagttttagg agcatagaaa tatatcatac ctgtgtttac 171120
tttattaaag aatcttttgt tagaacttcc cagacagcat ttttggagat ggtaacctga 171180
gatcatggtg tcatggtgtc cttactaatc acttttaata ggatatttaa accccctttc 171240
cagaaagaaa acaaggagct tccaacttcc catgtacccc atcacaaatc atccttcctc 171300
tggactgtag taacacatct accccgtcca acacatctac cccatcctct gaggtcattg 171360
tgttaataat gtaaccactt ctctcatttt tctgcagttt ttctccattc ctgtaagtgt 171420
ggtgtattag tcctttctca tactgttata aattaatacc tgaaactggg taattcataa 171480
agaaaggaag tttaattggc ttacgtttct gcaggctgta caggaagcat ggttggggcg 171540
gcctcaggaa acttatgatc atggcagaag gtgaagggaa agcagacatg tcttacatag 171600
tgggagcacg aagggtgcgt gaggtgccac acacatttaa acaaccaggt ctcctgagaa 171660
ctctatcaca agacaacact aaggagatgg tgctaaccat tagaaaccac ccccatgatc 171720
caatcacttc ccaccaggcc tcatctccaa cactggggat tacaattcaa cgtgagatct 171780
gtccctacac acagccaaac catatcatat gtcaatgttg ttctctccct gaaaacaaga 171840
acaaggctgg gcatggtggc tcacgcctgt aatcccagca ctttgggagg ccaaggcagg 171900
tggatcagga ggtcaggagt tcaagatcag cctgatcaac atggtgaaac cccgtctcta 171960
ctaaaaatac aaaattagcc aggcatggtg gcacgtacct gtaatcccag ctactcagga 172020
ggctgaggga agagaatcac ttgaacctgg gaggcggaga ttgcagtgag ctgagatcac 172080
actactgcat tccagcctag gtggcagagt gagactctgt ctttaaaaaa aaaaaaaaaa 172140
aaaaaaannn gagcaaaacc ttcccctgat gctctatatc catacatgtt tttggctctg 172200
tggaccatat ggactctatc acaattactc aactatgtga ttgcaatgaa aacagctatg 172260
acaatataaa aatgagtggg cataactttt ttcaataaaa ctttattcac agaaacaggt 172320
ggcccaatgg tggccggtag attgctgact cctctgctat agtctttctg ttaacctacc 172380
ccttactgtt tcttcaaaca atctgcttaa aaaaagtttc tatttctcat ggtttccaga 172440
ttcttacctc tgtttcatgc ttgaaaactc tgcaatttga cctttatacc caaagttttc 172500
tgacagcttg gggcaagagt ggctttctga ctgagtctga agcattatct gtgaattatc 172560
ttgggagtac atttccgttt ggctctcctc actttagact tcttacccca tggatactct 172620
cctctgttcg gtgaaactat ccacccttgg ttctcttcca gtatgtgagg tttcttctca 172680
gcatcttcat cgttaagaat gcatttaact gtaggagatt caaaaacgca acaataacca 172740
aaataaacaa gaattttttt cagatttcaa acctaacatc tggagttaag gagttcaagg 172800
ttggtgcagc cctttggcaa tgtggccaga ggtctaagca ttttcctatt tctgctccgt 172860
cttccatatc attttggctt ttgttctcat gtttgttgcc ttatgggaac ctcaggtttg 172920
aaatgccatg gacaatgctt gtgtgtctaa gacaaaaaaa aaaggacaaa attagtttgt 172980
tttttaaatt ctttattcaa tgaatcagaa aggaaaagtg tccctaagac cctggcagcc 173040
atgtctcctt aggtatcctt ggcctgaatt atgccagacc tgaactttgt cagttcagtg 173100
catgagagaa gctgggaagg ttcatatttc tagccagggg cactgcctgc ttctccaaat 173160
tcggttttca ttaggaagaa agatgagtta aatggatatt ggctaaacaa ttgacatgtc 173220
tcccagagtg acctgtgcag gatatttctc ctcccataac tcggtgttag tgttctagga 173280
atttatcttt cgacttcttt ttctgttaaa ctgcatgcaa ttcctgtgca gtctcattca 173340
ctatcttagc atgacacrta aggtgctgat gctcaaattt ttctaactca gattttagta 173400
tcctatatcc atctcctaag gggtttcacc ttctggtttc cccacgtgta tttcaaataa 173460
aagatagtct gaaagtaatg ctgtttcttt aaccggctat ttctcataca tctctacctt 173520
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
154
gattgtaact ataaaaatga taatcaagaa actgaaactc aacttctcct ctcactcctt 173580
caactgctat actcaatcaa ctgccaagtg ccatttacaa agtttcttaa catctcttga 173640
ggctattaac gtattttcat acccactgtc attctcatga ctagtttctt ggttaaaacc 173700
tgtattattt ctcactctgt ctattgaaga ttacattctc acctggttat tctgcttccc 173760
attaatactg ctatcagaac actctctctg aaatagaaac catttttcta ggttaaagcc 173820
cttcaacggc ttgtcataat taacagcagg taactcatac agtccctaaa caatcttatt 173880
tatcccaggg tattgctgag gacttcttaa tctttcactc agttcagact cactcttaca 173940
gctttatttg gtttacaaag gatatttacc tgatatctac caggtatctc aagctgcaag 174000
actgaaatca ttaccttcaa ataacctcca tatctatact ttgtccttcg tgttcccttg 174060
tttagaagat gttttgtcaa caactccatt cctcctagaa gttttgtagt aatcatccct 174120
gattttcttt ctcctctgct tcatcactaa ccagcctcct tttttctgat cagccacaac 174180
atcctattgc ttcaattctc ttaatgcctc tcaaatatac tcactcygct ctagtgtggt 174240
gattacagcc ttacttcagg ctactgtaat tacttgccta aaatatgacc agattctttt 174300
aatcttttcc atctgttcgt taaaagaatt tattctagag gttttatttt ctacaatgga 174360
gctacgatta tattattcac ttcttcaaat aattcaatat cttaccatta ccctctaaat 174420
gaagtccaaa cttcttacca tagtttagaa agcttttcca gagctggaca catctatcat 174480
agataatgct gcaggcaggt tgtatctgtg aacctgtcat cacctccctc tttgtactta 174540
ccacactgag gatgctgggc actgcatggc ttcccctatt accatcatca tggtcctcac 174600
tgtaactgta attggaagat tacatgtcct aatcctccac cctttcatca catcatgggc 174660
cttctgatct caaccatgat gttcttccta tgcctggctc tgtgtttggc aaatggtaag 174720
ggccagtctg tgcccttcca tgcatggatg actgattggg atgtcacctt tgctcctatc 174780
tctcatccca tcatccccca tcgctgcact tgactcacta gcgttttctc ttccctaaac 174840
agcagattca gtttgggtct tgaggccttt gcactttgtc ttctctctgt gtgcaagcct 174900
ctgcttttgt tacactgctt gaaggattgt cacctttcaa aacaggagac ttccgcatgt 174960
ctgagaaaga gctttaaggg ccgttgcatg gtttggctgt ctcccttttc ccttttgcct 175020
gagaacgacg tttcaaatag aagctgctct ttcaatctgg tgaaacggca tgaggagaaa 175080
aaccatattt aacccagagg tgaaatgcaa tgtcagtgag aaaaaagcta ccgtgagcca 175140
ctgagatttg gggactattc cacagcacac tccaacctag ggaaatctga caaaaacaga 175200
ccatcatatt tgaagatttg aattcaactt ctctctggtc tcttagcctt ctatcaatgt 175260
atgctagcag agaatgctac cttcttccca cagtaagaaa agaagaagaa atatcctacc 175320
ttctcctcag atgtaaatta tgagcttgga tttccttcct gtataagttc tatcagcttc 175380
aatgcatgca taggtctctt caaaaaataa aataaataaa atagctaaag atccttccta 175440
aatgctactt atcactccat ttaccatgtc cctagtgcta aacaactgtt tataatcagt 175500
ttaaaaaaat agttttgttc tctccattcc cattttgtga gctccctcca gcttctcaac 175560
ctttttcatt ttgtatttca tcctggcaat gcatgtaaac accctttaat gttattagtc 175620
gtatgtgtgt ccctaaaggc aacagatacc ctttccgttc ccaatttatc agaagactca 175680
tggatattca actttctgga ccattccaga ttttataaaa tgtgaccatc atttgacttc 175740
agtaactaca attgcatcat tttgctcttg ttgctttgcc tctgcttcag attgatctcy 175800
accctaaaat gttgctcctt cacaaattaa catataactg aatatgcaac attttcactt 175860
ggtgatctca agatacatct caaacttaac atccccaaaa caaaatatca taatttttgc 175920
ctttacaaat aaaaatctgt cactacaagt tacgtttcag ttttagaaaa tcataagaaa 175980
ttgaatttta gaatatgcat tctcttgtgt cgggctttga aagacacaat gttttgtgtt 176040
ttagtgtaat atttttaaga tttgtccaca ttgcatcaga tttgcccttt tttattgctg 176100
agtcataatt tgtatacaga tataccaact gaatccagtt atataaaatt catctacaat 176160
tattttgtgg acttatgtat ttatttttct tagggaaatg tttaacagtg gggttttctg 176220
gtcatgtggt atgcataaat tgaaatacga aatgcagaac tttctctaag cgactattgt 176280
tagggtctga gattttaacc tacttataag ctaacatgtt agtttattaa tgccttatgg 176340
atgcaagcag aagacacaaa acttctgggt cagagaaaca ggactttatt atccacagta 176400
gagcaatcag catgagcatc atgtttgact tggctttttg tatcgtccac gtcccacagg 176460
gatgacacag agggcccaga tgggtggctg aagattacag gagaggaaga gtgatcttgg 176520
ggaactcttc attttaagat aactggtgag caaacctaaa ctttgtcttg gataaaaaca 176580
tttcctcgtc cctcaaagtg gctcattgca atcataaccc tgagaaatgg cccaggttaa 176640
aaaataataa aaagtaggag agtttgatac tagatacttt tctagatatt ttgaagtatc 176700
cagaaaacgt gtggtattag gagagaccca tggaggacga tttcacaaca gctgagtaat 176760
tttacattcc cattagcaac ataggaaaat tatttaattt cagtaattct agtaggtgta 176820
tattaacttg aatttccttg aagaataatg gtactgaaca tcttttcttt tcttgcttat 176880
tgagcattca tatgtccttt tttgcaatgt gtatgttcag aattgtttct ttttaaattg 176940
ggttacatct tcttattttt cagttttaag ggttctttac atattattaa tacactttct 177000
ttgtcagata tgtgcactgc aaatattttt ctctcagtct gtggcttaca ttttcatggt 177060
cttagagaaa ccttttgaag aacaaaattt tatcttggtg aaatgtaatc ttttattttt 177120
tagcacttag tgcttttgta ttctaagaaa tgtttcccca ccccacaagt ctgaaatttt 177180
tatcttatcc tttcttttac aagtttataa tatgattttt gcttttttgt ctatatttag 177240
ttttgagtta tttttgtgta tggtgtgagg tggtggtatt taccttttcc aggtggaatc 177300
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
155
aacttgttct accaacattt atttaaaaga ttgtcctatt cctgttcttt tctgattgaa 177360
ttatgtttgt cctttctccc actgaattct gatatttctc aaaaatcaaa taataatatt 177420
tgtgcatttc cagttttggg ctctcaataa tgttctttct ttatgccaat atcacactgt 177480
cttgagtgct gaatatttaa attaagtact ctagccagag gtatttgatg ggttccaatc 177540
cattacattt attattatta ttataactat aataataatt attaatggtt gtttacagaa 177600
ggtaggctag tcctgtagca accattttgc cataactaat agtgtgatat tctgtttact 177660
tacaatttga tatttttctt cctttagtaa attggagatt gccagaaatt ccttactatt 177720
tctcccattg aaatagggaa gcaaattcac ctcaccttga atgtgggctc attttattga 177780
cttcttgtcc aacagaaggt gggacaaaaa aaaaaacatt atgttattgg acttccaaga 177840
ctaggtcata tgaatccttg aagcttcttt ccagctctct tggaacactt tctcagtgag 177900
acccgagatg ctatgtaagt ctaacaacca cctcactgct gtactgggga agacacatgg 177960
aggtgttctg atggacagtt cctgcctagt ccagaattcc agatttcctg ccaagatgct 178020
aagaaagtga gaatagccct cttggatctt ccagaccagt tcatctgccg ttagtgttag 178080
tgtgaattct agaaatacca tgttgaaagg aaagctccat gggtaaatac gcttctgcta 178140
ataagtggga taccagaacg gctgttagca gctgtcaggt ggaagtggtt ctcgtgtcag 178200
attccagtgg aagttttcag tgtctctttt ccttataggc ttaggatgtt tctctactgc 178260
tcccagcaga ggtgctcagc atactccaaa gaactctgac tttgatatcg tgccaatcag 178320
ggttcgaatt cacaaatttc catttataat ctgtataaca ttaaatcctg ttccaatgtt 178380
tctgtcattc agctttgtca tctctccata cagaaaaata cccacccaat gtcatcccac 178440
ctctgctgcc taaacactgt attaatgtta agtggcttcc ccatgctatg cactgtctat 178500
aaaataggga tagtatcacc ttcctctgga tgcattgtga aaagtcaatg tgaccatcca 178560
cgtaaaaaat ttgatgttag gcacagagga tttgcttaat aaatgttagg tattattcac 178620
atgaggactt gatgaaaaaa aggtaaaagc atgtatttat cacataaaag ggtcaaataa 178680
atgccagttt ccttcattct tttcctttta gggcactttg aaaatatgga aaactagtta 178740
caacacagcc tcaagaagct catgattcac tggttactta tacaagtgat cctaattatg 178800
gcttgagttg tagttgtttt acaaaatgta aaaattattg agataataat tagttattta 178860
caaaacaatt ttgctcgtag agattttaaa ttctgtcatt aaaaagaccc acaagcctct 178920
caattgcaaa gaagttagca tcaccttttt ttttttacca aattcgaaaa aagcaataat 178980
ctaactacag aataaaccat gggcggtaca gtacaaaaaa tgttcttatg tttttaaaag 179040
ttgtgcagtc cattgatcag gcaggcagtg gtggggagaa caaagccaaa cactgaatac 179100
acgttttgct acaaagaacc tagtctaatc agttccattt agaaatgcac tttcatttga 179160
ctatatttgc aaatcatcat ttttttttct ctaaaaataa tatggagtgt ggaaatgctt 179220
tcctatgcag aaaggttttt ttatttattt tgctgagttt caggaaatga agcttagttg 179280
ctaccttgca tagaaacacc aaactataga atgcacaaat ttagcacaga gtctgccacg 179340
tatggcaatt ttgataccgc tacctacaat tcacatttac tgcatccatc caattacacc 179400
catggtatca atgcacagca cttagagcag gctggcagtt cacaagagtg caacggatgt 179460
cacgcagtct gcatatcagt caatctgctt cctgatatgc tttaagaaag cctgttcctc 179520
agactcacct gaaatgcaaa gagagaggtg gaggacgatg gcccatgttt cctcttgtgt 179580
acctacactg cagttcttgt tgatgaccat ctaatgcaaa ctgtcccaca aatctttcaa 179640
agagagtaaa ggtgaagcca gtccctatgt taacaaacct caaccttatt tcagcagatg 179700
gtaaactttg attttgttta agaaccaaag cttcaacagc ttcaggaaaa catgtgtttg 179760
taattcatct ccattttaat gccacccttg catggacgag ctacatctcc tgctccaggt 179820
gaatgggttc ttacgttctg gacactgtgt cttcatttca gttattgata cctagagttg 179880
gtgagtttca agccaatctc taagtcaaga gtttatttgg gagttgggtt tccttttgaa 179940
atatactccc tggagcctca ggctgttgcc tgttcacctg tttccttttc agaccaaatc 180000
atggaaagga ccaggttatc tctgatccat ttggggtgtg taaatatcaa gaaggataag 180060
gtacctttcc tggacttgag aacttatagc ctaataagag aagacaggaa taaaaaaaga 180120
aaagttttag ttgctatgag actggcatat aaaagtacag ggacaggaca aagaaaaaaa 180180
tggaaaatta tcagaaatgg gtataaagat ggcttcatag aggaggtaaa ctctgtctga 180240
gaaattagaa aatgcccaga aagacatcaa agagaaggat aggctgaaag gtggaaggca 180300
taaatgctgt taaaaaaggc aaagagtcat gaaatagaca atgaatttct agaaactaga 180360
aaactggaca caatgggaca gggcatggaa tacaattaag tgacctctga tttaatgttc 180420
aagctagtat caaaggagat gctgtgaatt ctaatcttga aatagcacac ataaaccaga 180480
gctgccccag gcaaattgtg acatatggtc tccctaggca taaagttaat ggtatagtca 180540
gaaggttaat aacgtaggaa atgaattgaa atggctgctc tgacacacrc tacaaagttg 180600
gaacctgatg caatgtggta ggcagaattt tgttcactat gactttcacc cccggtgcca 180660
gctttgtgat tatgttatat gcatggcaga agggacttgc agttgtaatt aatgttgcta 180720
ttcacctgac tttaacagag ggaggtgatc ctgggtggtc caggtgggcc cagtgtaatc 180780
acacgagtct gtactagcag aagcagaagg cagacagatn agggaaagag gcaggacaga 180840
gatatttgaa gcctgacaag gacttgacat ggtattaata gttttgaaga tggcggggaa 180900
cataaggaag ggggtacagg tggcctctaa aagctgatga tgacctctgg ccaacagctg 180960
ttgacctgga gaagaatstg tgttaaacaa gtgtggatgg tgatgataat aatgaagatg 181020
attttgctta tatgctgaga agacatcatg ttaggagtga ttacagataa tgcagcaaaa 181080
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
156
aaggagcaaa gtgttgaggt agaggtgaga gaaggggtga gctcaagagg caggcaggaa 181140
tccttagtca ggcacagtgg ctatacattc cttttcattt ctccttggac ttgcagatgc 181200
gaaacagatt ccttttctca gatgcccatt cattaggggt ggccatgtga ctgaattcca 181260
gccataaaga tcacatgtgg cattttaagg cagaagcttt tcccttctcc cagcagaatg 181320
gaaaagctga agcaatagga ggagatgcac catacaatcg aaggaagcag agaccctcaa 181380
tatggaacaa cgagaaacat ccctgcagta atagttgaac aaaaacacac tcccattgtg 181440
ttgtgccctt tcttgacatt ttagactgtt cattttcaca gctggaccac tgcaaccatc 181500
acacatgtga gaagaaggtg ggtctagaag gaagaaagtg agggaagcta caaatattca 181560
tgtttgttag tggggaccat gaaggcgaga tagatttcaa tttcctcggc cgggcatggt 181620
ggctcatgcc tgtaattcca gcactttggg aggccaaggc gggcaaatca cctgaggtca 181680
ggagttcaag accagcctgg tctaacatgg tgaaacccca tctcaactaa aaatacaaaa 181740
attagccaag tgtggtgatg ggcgcctgta accccagcta cttgggaggc tgaagcagga 181800
gaatctcttg aacctgggaa gcggaggttg cattgagcca agatcatgtc actacactcc 181860
aggctgggtg acagagagag actccatctc aagaaaaaaa aaaaaaagat ttctattttc 181920
tccataaggt agtggaaatg ggatctgctg acctcctgag tgtgtaggag tggaggtgga 181980
gaatgggata cccaaaagca gaggagctca tggaggacaa gaactgtgag gactggaaga 182040
gaaagcatgc taggggtagg attgcagaat agagctcaaa cttccaggtc aatgatgagg 182100
gttcagcagg acttggacac tgggcatttg cagtgactcc atgtctcaat attgtctgta 182160
tagtgaacag atgctttgaa tgtgggagac tagaataaat gcatttttat aaagattttt 182220
gattaaggca ttagtaaata gcttcagtag aactgtttac ttctttctac tgcaaagata 182280
tcccaagggt ttctagcctt catcctcagt tgctttctta atagttacca tgaatatacg 182340
taaggccatc cataatttca cacctatact tatcatctca aggcaagcct tgttagacag 182400
gcataagctc ataataaatt acctgatcca gataaggctt ttttttttgt ttccccaatt 182460
acactcatca accacaaatt aagattaatt acatagatta cttggtctgt aaacatttaa 182520
ctaccatcaa tggtatgaat gaccatgtta aaggaatttc ctaagtgcaa tagcagagta 182580
ctaccattcc ttgagtatgg atagtcaata ttttgtaaag ctataaatac gggaatctgt 182640
aaagaatata ttctgtatgt ggagtccata ccaaatctgt tcaaaatgcc tatgttaaat 182700
gtaattagta tattctgatt tataatctac catataaact cattaaaaga aacccacaag 182760
cagctcgcca ttaaaaaaaa aaaactgtta aattgatgga aatctggtac ttatttttta 182820
ggcattatgc agtgtgcttc attattatac acagattctt ctcactatag tatcgtttct 182880
gttaaaagct gtgtgtgtca ctcatacagg atacttacag agcgttttta aagcagtaca 182940
taaatacatg aattatttcc aaatgtgagt taaattgcaa gtcacaattt agttaagtag 183000
attagtgaat agaaataagt gatttatttt aatagccaaa aaacaagctt aaagcaggtg 183060
aaaggcatag agcagacaaa ggctaaattt tatggagcat ttgcacattt gcaagatttc 183120
attaaatttt ctcaacacaa ttttcctctt ctagtaatat gggagactag atattctaac 183180
tggtctttct actaattaaa aacacctaaa aagtcttggg aaatttgttt tataaatgaa 183240
tcaatgcacc agaaagaaag taagaattct catttgaaaa ctaaatagag aaataaacct 183300
tgagaagaaa gaagaattct gaaacaggtt tgaatttgag gatatcaccc aaaaatcttg 183360
acttgcaaat ttgtttgcac agcctctcag agtgcaggaa acaggaggac atccaggtcc 183420
ctaaaaagat gtgagttgat cataagtact cttgatgagc tggaatgatg agaaggctac 183480
actcttagca tagctgtgag ccgaaactaa agacaactcc tttctccagc tgatacaagg 183540
taaattgtcg ataaacttga ccctgaatgg aaggtaaaca cgtaaataca cagagataca 183600
aacatacaca caaacctccc atcaaccctt taataagaaa gaaaggaaaa agctagacct 183660
ccctccaatt tacacttaac gcatggtaga tacagatata gacatggata tatatcacaa 183720
aaaacccaga gtttatttta taggcaattt acatacggca aaaagaatac aaatcttttt 183780
ggagaatttc agcttcatta ctaaactcat ctctagagaa tgttactaga aaaatgagca 183840
ctcaccagca gatttcacta aagaatcaag aaagaaagaa ccatgaggaa gaacttgcaa 183900
acacaagagg catcagaaag aaggctgttt agtaagaacc cgtaggaatg taatcacaca 183960
tggaatataa aatctatatt taatatcttt aaaggaatga aagactagtt ttaaaatatg 184020
atcatggaaa aagaaaacat aagaataaac atgatgattt ttaaaagaag aaccaagtag 184080
aactttcaga tataaaagaa ccagtggtcc tgggtatgac cacagcaagg acagagctga 184140
gtgccttagt gaactgaggg acctgaataa attacccgga aggcagtgca gacaagcaag 184200
gaaataagtg caatgaagga caacctagca caggtggaag aaagaatgtg aaggatgaac 184260
atatctctca ctggagttct gaaaacagaa gtggcaggaa aatataaaga ttgtaactga 184320
ggattattga tgactgatga atgatgacaa ttaatacatt catgaaaaca tataaatact 184380
aaccaggata gttaaattaa aataaaacac tcacacttta acacacctta tgataaaacg 184440
ggagaacacc aaagtaaaaa gagcattgta aaaatagtca gcaagaaaag acagattaaa 184500
tcccagagag tgacagttat atcaactgct aactttccaa gagcaaaagt gacattagca 184560
gaaagtagag tgatgtttgt tctgtattgt tctgaaagaa aataactgcc aacctacaac 184620
actattgcct gtaaaactta caagaggccg ggcgcggcgg ctcacgcctg taatcccagc 184680
actttgggag gccgaggcgg gcggatcacg aggtcaggag atcgagacca tcctggctaa 184740
cacagtgaaa ccccgtctct actaaaaaac acaaaaaaat tagccgggcg tggtggcagg 184800
cgcctgtagt cccagctacg cgggaggctg aggcaggaga atggcgtgaa cccgggaggc 184860
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
157
ggagcttgca gtgagccgag atcgcgccac tgcactccag cctgggcgac agagcgagac 184920
tccgtctcna aaaaaaaaaa aaaaaaaaaa aaaaaactta caagacagga gaaacccaga 184980
gattttgtcc aagtcaatcc tgattaaatt aaacccaaaa taggagtaga gaaataagaa 185040
cttagagagg actaaaatgg aagtggggag ttgagagcaa aaatctgttt acatgggtaa 185100
ataaaaatca aaataataca aaaataatca tttatcttgg gataaaacaa aactaaacaa 185160
gatagactaa attatgccat atcgatacaa tatagcctgg ggaaaatgtg aagataaatt 185220
tcctaaattc cctgtattgt ttagggagaa ttaccagttt ttaaattatt tttaaactta 185280
ggtaagttaa ctgtaataaa aaaattcctt gggtaaccga gtagttttta aggaactgaa 185340
tataatgaaa atacaacata taattcccaa aaaagtaatc acaaattaat gagaaaaata 185400
atcaaccatc tgaatctata agtaagaaca tcatataaag gtgggataaa tagaaataaa 185460
aactaatatt ctaaaaataa gtttagtatg tgaataatta gaatatgtat aaattaaata 185520
aatactccag gtaagaaatc atcgatatac agcctccagg gtcttagaag gaaacaaaca 185580
gcacacttaa ctaggacaac ctggtgacag tacaatagag aaaatatttt taaaagtata 185640
gatataccct gttttataac aataagaaga ttctcagggg agggtataca aaatatacca 185700
catgcactgc caatgaaagt gtaaactgtg taaactttct gaaaacaata caccccaaaa 185760
acctgaaaaa cgtaataccc ttaggtccta agaaaagtga cactaagaaa atatgtatct 185820
atagacatgc ttattattcc atgatttata attagcataa atgtagcaac tacttaaatt 185880
tccaacaaca tgaaaatagt atttaaaaaa ttcattaata gcatggggca atactcattt 185940
cataaggcat atgaatcaag aataaaattc aaagaactcc aactgattaa atagactccc 186000
cttggccaag agtatctcaa ggaaacccaa aaaactagtt cagaccacaa taggaagcgg 186060
ggttaaacat gcctccttat acccttccct ttggagttca ggcatacaac tgactgacat 186120
taatattaaa atagagatca gaagactgac aacacagact ttttgtaaca agaagatacc 186180
aaattctaac ctgagtctgg tatagcatca catgacagat agcagcaggc tttgaaggaa 186240
atcaaggtat atatagtata tcaaatgtat ttctttgaca tattttgaaa tgaccctgaa 186300
aagctgtttt ttgtagagga aatttgcagc ccgtaaataa tctccttccc ttactagata 186360
ttttctagag tctgacatcc tttaaggtat gataggaaat acatatgatc tattgtctct 186420
gaagcctgct acctggagac ttcatccaca taacaagaac cttggtttcc ataatccccc 186480
ttatcttaac tcaattgttt ctttcttttc ttttcttttt tgaatttcag gctaagttta 186540
ttttttattt tttttttatt ccaataggtt tttggggaac agctggtgta tggttacatg 186600
aataagttct ttagaggtga tttctgagat tttggtacac ctatcacctg agcagtgtac 186660
actgtaccca gtgtgtagtc ttttatccct caccaccccc tattctttcc cccaagtccc 186720
caaagtccaa tgtatcattc ttatgctttt gcatcctcat agcttagctc tgacacatga 186780
gtgagaacat atgatatttg tttggttttc tatgactgaa ttacttcact tagaataata 186840
gtctcaaatt ccatccaagt tgttgtgaat gccattattt cattcttttt tatggctgag 186900
tagtatatat gccacaaata tatacatata ctaaatatac atactatata tatatataaa 186960
tatagtatat aaatatatct aaatatagta tataaatata taaatataat atataaatac 187020
atactatata ttatatatac aaacatatat acacatatag tataatatat atactatata 187080
tattatatat atacacacat atatatatac acaccacatt ttctttatcc acttgttcat 187140
tgatgggcat tcgggctggt tccatatttt tgcaattgtg aattgtgctg ctagaaacat 187200
gcatgtgcaa gtatcttttt tgtataatga cttattttct tctgggtata tacatagtag 187260
tgggattgct ggatcaaatg gtagttctac ttttagttgt gtaaggaatc tccataatgg 187320
ttgtactagt ttacattccc accaacactg ttcccttttc actgcatcca cgccaacatc 187380
tattatgttt caattttttg gttatggcca ttcttgcagg agtgaggtgg tatcgcattg 187440
tgggtttgat ttgcagttcc ctgataatta gatgttgagc atttttccgt atgcttgtgg 187500
gccattttta tattttcttt agagaattgt ctatacctcc ccttaggctc cacttccaat 187560
attgggggtc acatttcaac atgaaatttg gagtttggaa acatgaagtt tggaaatatc 187620
caaactatat aagcaggatt atatagatac aataaagttc aatgtatttt tcaaggcact 187680
cattatttat atatttatat atttatatta tttatatata aaaataatat attatttata 187740
tatataatat atatattata tatataataa tatatataat atataatata taatatataa 187800
tataataata ataaatatta tttatatata taaatttata tatataaatt taatatgcta 187860
tataaatata aatatataaa taaagtatac tccacaattg cctaatacag atttctttta 187920
caaatccata ggacacctat aaaattgaca gatataaaat gtgtttccat ggtatttaaa 187980
agatttatgt tatgcagata actgcctctg aaagcagaaa cattaatttg caaataaata 188040
acaaaaggac aactagttta cagatcaatg aatgccctct taaaaaagtc ttgggtcaaa 188100
gaagaaccca aaatagatat tagaaaatat ttttaaaaaa tagataatga aaatatatat 188160
taagcctagt aacttacagt cagacagaaa tggatttaat gcagatatta gaaaagaaaa 188220
tactaaaatg aataagcttg gcatgtattg aagaagttat aacaagacaa ggaagaaaac 188280
ccaaagacag aagtaaatct catggtgaac tgtagttccc ataatcccca caactagtgg 188340
gagggacctg gtgggaattg aatcatgggg gcaattacct ccttgctgtt ctcatgatag 188400
tgagtgagtt cttgtgggat ctgatggttt tataaccttt gctctgcact tctctttgct 188460
gctgccatgt gaagaaggac atttttgttt cctcctcctc catgatcgta agtttcctga 188520
ggcctcctca gtcatgctga actgtgagtc agttaaacct cagcctcagg aatgccttta 188580
ctagcagcgt gcgaatgcac taatacatcc catatctcct taaaatgtac aaaaccaagc 188640
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
158
tttgcgctga ctaccttggg cacatgtcat caggacctcc tgaggctgtg tcatgggtac 188700
atccttaacc tttgcaaaat aaactttcta aattgattga gacttgtctc agatactttc 188760
tgttttacaa attacctttt gttctagacc actcacaaga gtgaccatgc aaaatggaag 188820
tgtgccactt actcagctag aaacgctcct tagcttttcc tctcactggg aatgaaagtc 188880
aatattctta ccttgacctg tcaggccctg tacttaagaa aagaacagca tgctttgacc 188940
taaaattacc tctgaatggt ctttgtctgt aaaatggaag agacatggag aggcgccggc 189000
acccgaggtg ctttctaaaa taaggggtgc cttaaaagtc gtgttgaagt ttgtcttcct 189060
ggaataggaa gtgggtggaa tattttaatt agggaggtga tgtgattgaa tttgtttata 189120
aaattatttt tggttaaatg taatagagaa ggaatttgat acagtgggta ataatgaaga 189180
ggaaacaatt ttaggaatat taaaatatcc caggcttgaa tgaacgtaga gatggagaaa 189240
tgtgtaaaga ctgaagaggc tgttgagagt tagatggaaa agacaagtgg acggattagt 189300
gttgggataa gaaaggaaga aaggagtcat tgatggggcc atgtttcaga aggtttaggg 189360
gtgaaggctg ctgcaattca ttgagaccag agcctttgaa agatagataa gcatgcttgg 189420
gtgcagtggt tcacatgtga aatgtcctac gaaacataaa agtgaaagga ggagacaaat 189480
ataataaaaa atatatattc ttgatgtcaa aactaaaata taaatatttt ggagactttt 189540
gtgtgtattt ggatgctatt ctcatgctct tttttctgga aaaaataata caaaacaaaa 189600
attatttcac gagttctcaa tttttgtcct tctgttttta tcagataaat gctaataact 189660
ttcatatctt tcttctcctg cagtttccca tgtcttccaa atttatttca catcattatc 189720
ttacttttcc tcaaggccgt tttttctctt gactacagca atgcagattt caattctgcc 189780
attgaattcc cagacatatt cgtcatcccc attttcatcc cccaccaccc tgccattttc 189840
ttcgtgttaa cttgttttcc tgactcacag aaatcacctt ttcctgtata catttttagg 189900
atgtcagact ttattctaat gatttctcct agttgccccc caaaattgta ttctacrgtg 189960
tgattttaaa gctgaatttt caagatgata tttcatatct atattttcac aagcttttct 190020
tctatgaatg ttattgtcag ctgtcagggt gtgagatggt acttgatact acattctttc 190080
caagctgttg cctgaatcgg tttaagacaa agtcattact aggctgtaaa ctgttgctct 190140
gcaaaattga gcagcacgta tttaaccact catacttctt agctctccaa cactttgagt 190200
caatagagta tacaaacacc tgtaatttcc agtgagcaca gctcccaggc tctctctctg 190260
tctctctctc tctcttttgt tttttttttt ttgcctcagc ctctcgggct ttatttgtgg 190320
gatttgcacc ttcaccttct gcatgcagtg tgccatggct agttcccctt acatttttgt 190380
catgattttg gtagaggcaa tgatttcctg gttgtagaaa aaagggcagc aacataggat 190440
tacaaaagta ttgctaagaa attgcaacaa gctacttgca gtttatgtat gattactcac 190500
agtttttgga tggtgcaacc cttaatttct gaaccagcag gtgaaagatg agagaagaat 190560
aagagacctt tctatagatc ttcaggcaga caggcttgtt ggcttcctaa tatttcggtg 190620
ggatactggg atgggttgga ggcaacatac tgtttaaata agtagacagt tttttaaaaa 190680
taatgaattg tgtctctaag atatattttt accagaatga tactatatag gaatatgcgt 190740
aaacccctgg actttgatct caagcaaaac cttttcccta ttatccctcc ctcttaagtg 190800
catgagtttg gtaaagtact acagaaattt gttctctcac agttctggaa actagaagtc 190860
tgcagtcaat gtgttggtgg ggttggttcc ctctggagaa tctgttctgt gctcctgcct 190920
taactttagg gcattgccgg caacccttga cttgtagatg catcacttca atctctgcct 190980
gctccacaag gtgttgtcca ctgtgtctgt gtccagtgtc tttgtccagt gtctgctttt 191040
tcttctaata aggacattag ctatatgcac tcaccctaat taagtatgat ctcattataa 191100
cttgattgta tctgcaaaca ccccatttcc aaataaagtc acttttccta gggttaggat 191160
ttgttttttt tttttttttg gtggagggag aaaggaagga agtgggcaca gttcaattca 191220
taaggaacca actaaatata aatgccactg tggtaagatc agcttgacca tgtagatttt 191280
taaatggtgg ttttctttgt ttctattgcg ttttttgctc atcttatcag aaaatttgat 191340
aactttagat aataaatatg aaggagtaaa tcattaaaaa tttaaagtga aggccaggcg 191400
tggcggctca cacctgtatt cacagcactt tgggaggccg aggcgggcgg atcacctgag 191460
atcaggagtt tgagaccagc ctggccaaca cgatgaaact ctatctctac taaaaataca 191520
aaaattagcc gggtgtggtg acaggcacct gtaataccag ctactcggga ggctgaggca 191580
ggagaatcac ttgaacctgg gagatggagg ttgcagtgag ccgagatcat gccactgtac 191640
ttcagcctgg acaacaaagc aagactctgt gtcaaaaaaa taaaaataaa aataaaaata 191700
aaaaaataaa gtgaatccca cagatttgct tatattcttt ataactagat taagtgtcta 191760
caacagggct ctttttgact aactttatgg ggatatacaa caggtgccaa ccactccaca 191820
ttccaaaaga aggcaaagac ttgctttgca ggacttgcaa agaggtgtcc aaaatgtttt 191880
cctggcctta ggctcagcat ccccccgaag gttatgaagg aagagctgtg gtctcccctt 191940
ggagagattg gatggatgct gagtgctcat cttcttcccc ttccctgaca gacaacttga 192000
tgtgcatccc tggacttaca gggacaaaga agtgtccgat ttattccaga aaatatttaa 192060
aggatgagag gcttgcaaag aggcccagag caaaatcaaa gaaggctata gcctgaaaat 192120
aattttattc ccccgatagc aggccagatt gcatctttct tatcactctc tggtggacat 192180
tgtgagacag agcttagcca gggattatct tagatcttgt caaagaaggc cctggccaat 192240
gaggcgatct ctgcagaaag cagctggaag tgcatcatcc cagatcccag gttgagagac 192300
cagcctcagg agaacagctg aggttgaggg attcattcta cctgggaaaa ctgcatgtga 192360
tggataacca ttcgtgggca gggatctcaa agaaccccca agtatgccct gaagaattca 192420
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gcacccaacc tcctattact ttcaaaggaa tcaaacaacg gtttccaagg gggcatgcca 192480
ataactttac tagtgccgtg ctctcccttt ctctgtaaca cctctcactt cagtcctccg 192540
tgagccatag tgtttcaagg gtgtgtgatg aagcgatgga agcctcaggt ctggaaatag 192600
gaagaaagtt tactacaagc ggcctgctga ttaaagtggg cccaaacttg tgaagaaaac 192660
ttggatcaaa gttggcatct tgattcttat ggagtacaca gaattgcaac caataaaaga 192720
gacaattctt gagaggaagg gtgattagag gacattttgt tacctgggag tgaacagata 192780
ctttatgaga aatgctctat atttgattaa gtaacaggga tttgcctctc aaagtggggg 192840
tggttttaag taggcagtct gtgggggcgg ggtaagaaaa tggatttctg attttatctt 192900
tgctcatttt ccaggttacg taaatattaa gaacattgtt aatttacttt aataaagaag 192960
ttcataaata gtccaatatt aaaagttgat taaataatac ttttggaaat acatgaattt 193020
tactgaatgc cctctagcct tactacaaaa agaatgcttt gcaaataata aaagctaaat 193080
aaaaataagc cagctccagc cactttaagt gacggaacac actctgtaac ttggggatgg 193140
ggacagggca ggaaatgaag aaattaaagg caagggcgcc tcactgaggt atatcaaatc 193200
ctattagacc aggtcatttc cttggctggc aactggacag ggctcctatt gtcttgtcta 193260
ctttggctga aatcttttat ttatcctcca catttgtttc atttgcaggt aattctattc 193320
ctgtttctac atttaccatg ctggatcagt tttttccctg attttatttt taagttacta 193380
tgatattcgt actaaatatg taaatgttta ttattgggtt ttagctgttt ctataataaa 193440
gagttgtagt tattgtaagt tgcatcgcac taagctttaa aaatgtattt ctccactgta 193500
gagaagtatg ttccattgaa atttgattgc acacaaagct tgacatgagg tttattctct 193560
ttgtgaaata aaccattcaa tctggactgc atccacattc atctgaaact tgaaggaaat 193620
aagtcatctt tcacttatgt tttaatatgc catatttcta ttaaattaat ggaaggttag 193680
acctaaagct caatgattgg acacttatta ttaatgattc tttgcacata gagtgcatgg 193740
atagctcaca agaaaatttc accaaagtca tcttatatat ttctcataat aatcctaaga 193800
ggtagggttg atagacatta gcattctgac atcagaattg gagacagatt cttctgtctc 193860
atttaaggga tttgccccca aattaatcag tccatgataa agccagctct ataatattac 193920
tctaaagaat attcaaaagg tcccgggcac agtggctcac gcctgggagg ccgaggcagg 193980
tggatcatct gaggtcagga gttcaagacc agcctagcca aaatggtgaa acctcgtctc 194040
tactaaaaat acaaaaaaaa aaaaaaaaaa tagctaggag ttgtggtggg tgcctgtaat 194100
tccagctact agggaggctg aggcaggaga atcgcttgaa cccgggaggc ggaggttgca 194160
gcgagccaag attgcaccac tgcactccag cctgggcgac agagcgagac tctgtatcaa 194220
aacaaaaaca aacaaaaaga atattcaaaa aggtgcatgg ggcaaggaga ggtcatttca 194280
catcctcttg aggaacacag gtgactccag accacaattc tcctagatgg ccgggggccc 194340
ctgctcccct ccttttggtt ctagggactt gattcctgaa gaggggtcat gcgccaacat 194400
ctagtttaga gtttttctat tacaccacct ggtctcttat attaatttgt ttccctgatn 194460
ttttttttta atctcctgga tcacaatata atcgtttgaa tttttgttgt tgtgtataca 194520
agggctccca agaaatgtgt aataaaagtg gttggtggga aaatcttgct aacagaatcc 194580
agtagattaa taactaagaa aataaggcac acacaacaaa aggttgtgca tggctgcaag 194640
ttcaagagtg ggaactgatt agagtggtag aataaataca tgtgcatgtg ttctgaatcg 194700
attagacata taaaaagata tctagattct ttgaaaaatt aataagaaac tttttttcta 194760
agcataaata tgaagttcaa gtataaactt accaaacaac agagaagtga taaagtgcta 194820
gcataaaaaa ttagcatcat gattattctg tattgtttac atagatctat caagtcaaat 194880
gttgggtcag agccattctt tattcagtta tcaaaatggt agagccattt ggatgagttc 194940
agagacttct tctttatgat aaaaaagata attgtaaatc aaaaaagagt ttaaaggcta 195000
tactaattaa acagctaatt ggaaattgga agatttgttt ctccaaactt ctactatttt 195060
ttattttctt ttctgtttgt ggaagttttg gaaagcaaca ttttattctg tgattagcat 195120
caaagagttt caggcatggg ttataggact ggaccatgca tacttgaagt gtacttcaaa 195180
ccataacatt ctatgagatt tcgtgagcaa ctacctctta ttgataaaaa gaattgctgt 195240
ttaaacccta ttttaaagta cttacttttt gctttctcaa atataaggat gatgtactat 195300
ggattagtaa tatcattacc tatggaaaca aaagatataa aaatttactg ttcactcact 195360
tctccttaat ttccaagaac attaatcttg aatttaagct taaacttact ttaaacatta 195420
tctttattat cttattttct atgaagaaaa taatccaacc tatctactag tatgccactt 195480
taaaaacatt aaaagccagt ggataactgc aaaagaaggg cttttaattt tatataaaat 195540
aataaaataa tttattctat tgataattcc aaactctcaa ataatatctt gctgcagtgc 195600
taaggaaatg gacaaaggaa gaaaaaacag cttttcatgc ctttcctgaa acaattgcag 195660
gaaatttttg tcacgctaca attattcttt gatcatgaaa aattctttta aagacacgat 195720
agccacaacc attttatctt ctgacttact aagcagtctg agggtgaata gagagtttcg 195780
attccaggtt atggttataa ttactaactg caaaaatcct attgcctttc attaagtagt 195840
taaaatattt aattgagact acagtgtgtc tgcacacagc gttgtaccat gcataattat 195900
ccctacacat acaggaacac tgagggtact tttaacaata aaacagatca tcaaaaaatt 195960
acatttttaa tttaagtttt gactttaatc ttctccgtga ttaaatacct atctctgcat 196020
tttttctgca aatgaggaca ttaagctaaa acaaatgaac cataaagtga cgggaaaaaa 196080
aactttgcac tgttaatata aatggataaa tctttaatat gtattaacca ttgcactatg 196140
tctttatttt ctaacagctt gtatgagaaa gaagaactgg tgatgcagaa agtcaaatac 196200
CA 02361408 2001-08-08
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160
cgccagctta gcgggtcagc atcctctcct cccacataag cagagatcgg agcatgagat 196260
aaaatacctg gatgcccttt gctccagcct cgtgctccca caactttgct tctgacagag 196320
tacttatctc tctgaccact gggaaactgc taaaagagag aaacttgaaa aggattggac 196380
ttttctgtgc aaatctcttt gaaaattgcc acctccaggt tagcttttaa gagaagccca 196440
atatattagg aacctgaaaa taaaggaaag tttgcacatt gaaacatcac ttgctaatag 196500
ttctattatt ggaaacggaa atatggaatt ctagaaaaag aaatgtcatt atggggttag 196560
gaattaacca cttgctactt atgttaatgt gacgtggttt aaaaaagctg caggaagttc 196620
ctgaaattat tgaaacaaaa ataaagtatt ttcccctgga atctaagtaa tgtaagtgaa 196680
attctttaaa cattctcttc aactttatat ttcaaaattg cttcacagta atttcttatg 196740
ttatccatca cttgtctaac tggaaggcaa gcatttttat tgttttagtt actatttagc 196800
tttatgaaca gcattcttgc tttgttgcaa ttacaaacat ttatttccat agggatggaa 196860
agattatgct ttgctctctc tgccaggtac caattgtcaa tagaaaatag agccaactag 196920
agtaacttta gctcttcaat caacacatcc agtattaaga aaaaaaatac attgatattt 196980
gagacgtaaa ttcaaatctt tattcaatac gcaagaagtg taattgtggg agattaggtt 197040
gggaaataat aaaaagctgt ataattagag tgtcaggatt tacaccctcc actggaagct 197100
actatatcag gtataactcc gcaaaattgt agatggttgg caactaatcc ttgctcacat 197160
ttratgatct attactatgt gccaggtgtt ctgtctgaaa cagcatggga agaggaatca 197220
gagacagaat tgccacctat gtggggcctt gctggggtgc agaaattttg tttctcacat 197280
ttttgaaatg taatactttg atctgaattt tactcctgct taaggacacc aagatgaaag 197340
cggatggcac cctgcccccc accctggtgt agtttgttaa gaaatgactt tagttctatg 197400
aaagtggatt cttagttata aacataaaga actatcaccg gctagtaaga aaggatttta 197460
ttgaaaagat gttgggagtt catttatctt cagggattct gcagatgggc agagagacta 197520
gaaaaccaag agcacgaacc aggcataatt caaacttcac aacagtgagg gtaccagaac 197580
agcttctagg gaacaacgcc aggcacgact gcctggaagt tgctggttac gggtgcttga 197640
ttgtcactat ttcctggcat tgccagctgc agaggcagct aactaacaga gccaggggtg 197700
catccggggc tctctttatg ggggcatcca cagtgggagg tagtgggttt tgatgcagga 197760
aattactgtg ttgtatcttg ggttttctca atttatacaa caaatgtata catacgttca 197820
gatggaagta agaagtacca catctgagag cggaagaggc actgtaatca cccatcccaa 197880
agaagatgat ttcttaggaa aagaagtgag tttgggaaat atattagatg tattctcctg 197940
tctcttccat attcttggga atttgagcca tcacttatct ctgatgtgcc ttgcttgaga 198000
agtggtttct atactatatt tgatgatgtg gatctgataa cacaatattc aaatattttc 198060
cagctgtgtt aactgagtct ctagaggcag atctcctgag aattgtcagt tgtgtttatt 198120
ttccagttaa gtctactttc agagagccat tattgaaaga gaaaagtttc aacagaaaga 198180
tgattattgt taatattatc gtggtaagac cacttaatgt gagatctatc ctgttagcac 198240
atttttacac acccactgtt gtgttgttaa ctataggtgc aatgttgcac agcagacttc 198300
aagagcttat tcatcttcca taataaaact ctgtaccatt actgttgaac agcaacttgc 198360
catttctccc tcctttcacc tctgcaacag aatgataaac ctggagagca ttatgctaaa 198420
taaaataagc cagttacaga aggacacata ttgcatgatt ccacttatat gaagtatcta 198480
aaataataac gcttattcaa atacacggtg ggatttttac tgggaaaaac gctcgctctt 198540
tttaaaaaaa aattgagaga gatttgcttt agttgatcaa aattataagc taccggaaac 198600
tccccaagat ggcatattgt tgaagccata gtgtgtgcac aggtgttgaa taggcccttc 198660
agagataaga agagtaaagt gtggtataaa aaagagaaaa agtgctagaa tgcagtcatt 198720
gcaacattaa aagaaatgct ttatcttggg ggagatcctt tggccaaact atttcaactt 198780
ggaaagatgt agtaatataa aaagatttca atacaaggaa ataaagaaat tgcatccgtg 198840
ctacttctca aaagagtaag aatttaactg ataaggttaa ttattataaa attaactttt 198900
accatctaca ttaaaattag gaattttctg agaatttgta ttctttttgt cctttcaata 198960
aagractcaa tatgtttaac tctattttaa acaggaatgg ctgcctatgt cttgcagttt 199020
gaatgcaaga ccctcaaatg ctcaggaatt atcaagtaaa gtttatgtta agaaactagc 199080
attctgttga atcactcaat aatggttatt atttaggata tgcaaaagtt aatcacaaaa 199190
acttagactg aaagatactg cttacaatta taggtgggaa ataccataaa atacaacctt 199200
tatttatttt ggaactcgtt ttaatgcaga ataatcctag cgctctattt agtaacaaga 199260
agaaaccaat ttaaatatca tgctgattta aatagtataa ataataaaaa tgacaatttt 199320
ttgttaattt tcagactcta catagctatt tttgtctctt ctattcttat gaaatattca 199380
gggaagatat tattactttc actttacaaa tgggataact gagaactcaa taaattgtat 199440
aatttatctc aagacacaga gctggttcat ggtagagcta tcatcagaaa tctcacgatt 199500
attagttatc cctttccaat tctgaagtcc tctgggaagt gtcagaattt acactcctca 199560
ctaggaacta ctattgcagt tggaactctg aggctttatt tgggagtttt tcctgattac 199620
agaaaatctc ttcttaagag aggttttaat aaacaaaata agtcggggat attaccagat 199680
agcccctata tcctcagagc tcccagcatc acacctttta taagaacagt atagaaaaac 199740
aaagttcctt ccctcctcct gccctgtgtt atttttccaa aaaacaaaca aacaaaaacc 199800
taactacaca ctaagtgtga aagtgattgg agtgggggaa ggcaagctgg ggctgtacca 199860
ggtcaagggt tgaaaagaat taggggatta ttacagttct agttcgaaga caaacacttt 199920
tcaatgtatg tcaatgaact ttattgaaca gccgccatat actagtaacc ctcttaggtg 199980
CA 02361408 2001-08-08
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tgttgtacac ttacacatcg aaaccagggt ttcccagatt tcttatgatg aaacagatag 200040
aaggtgataa tgctggcaca gcacacatgg acagtgtgac ggaaggagac caattaagga 200100
cgangcgggt ccgtatttct acacacctgc caccagctgg acggctgtgc tggaagtcta 200160
agccctggat gcttagctgt gtgatctgtg aaccggcagc atcagcgttc ccagggtgct 200220
ggttagaaat acacctctca ggcccaccca gacctkctga atcagaatct gctgtttcca 200280
aaattcccaa gtgattctca tgcaccttaa agctttagaa acactgttct aattagtgtt 200340
cttaaaatat tgctatggga tacaggcttt agtaaattct caggatattc taccatgtac 200400
tcaagtttga gaaacaggag atttaataaa tactgatgtt tggatcccat ccatagagat 200460
tctgttttga ttggtgtagg gtgtaatctg gcattaacat ttttaaattg cccctggtga 200520
gtttcatgaa tggcaatgtt tgggaacacc tgctttaagt taagccatga gctaattgtt 200580
cttcatcata ttgcagatgt gggaactgag acgttataag gaaatccaat ttgcgagtgg 200640
tagagccaga cttaagctta gacccttaac tcacttattc tcaaaactgg tctgtgctgt 200700
ttattatttt acaggagagt tctatattgc tatgtttaat acattagtat catttaaata 200760
tattttaata tatgcccatg atggataata ctgagtgtcc acttgattgg attgaaggat 200820
gcaaagtatt gatgctgttg tgtctttgaa ggtgttgcca aaggagattt gagtcagtgg 200880
gctggaatgg cagacacacc ctttatctgg gtgggcagca actaaatcag ctaccagctc 200940
ggccgggata taaagaaggc agaaaatcat gatggttaag caaactaaat atggcctgag 201000
aaggactctg tacttctata ggtgagtcct tgtggatgaa ctgtaaccta gcttaatagt 201060
cagacaaaat ttaaaaccta atttaatagt atgcactgta acaatggctg aatgttgccc 201120
agtcccagtg ggattcaacc actcatagac tgcttttgtt caaactgcgt tcaaataagg 201180
caaacgccga gctggaacca atctcactgt ttctgtacct cgcttctaat tcctgtacgt 201240
cactttacct tttttgtcta taaatttatt ctgaccacaa ggcacccctg gagcctctgt 201300
gagtctgctg tggttctggg gactgccgga ttcgcgaatc gttcatttct cagttaaact 201360
cctttaaatt aattcagctg aagtttttct tttatcaatg aaaagactag actggcttag 201420
ccttccagcc tgcacctttc tcccatgctg gatgcttcct gcccttgaat atcagactcc 201480
aagttcttca gttttgggac tcagactggc ttccttgctc ctcagcttgc agatgcccta 201540
ttgtggggtc ttgtgttcgt gtgagttaat acttaatacc ctctccttta tatatacatc 201600
ctattagttc tgtccctcta gagaaccctg actaatacaa tgtctccatt gaaaagaaaa 201660
gaaaatctat taataaactg atatagtcag agcccctcaa gaaaaatacc aaagaaactc 201720
caatgttgta gagaattatt ttattgctct aaagacatca aaataattac atgccttgtt 201780
tacgatgctt ttaagttgat cacattcaaa gatgtgtcct atccattcat gtacatacat 201840
tcaatttcat attgactctt gcctttttca.gcagtgatca gtaaaaatta tctaaaaatc 201900
aatcctgaag gttatacttt atttttccat tttgaacctt gcccttgaaa gatcatttat 201960
atattttaaa cacattttta aaaatgaatc tccagaagtc taatttctca tgctaaccaa 202020
attagagagg ttaattcgat gacgaactct tagaaacaat catcattaga acttgggtat 202080
tatttcaaac gcatctctct tccaaatctt agcagttgaa acaatttcac aggttaaacc 202140
agccagcttg acagcccgtg aatggctact cactaaaggg tccaagcaga ggcaaaatga 202200
tggtcctatc tcttaaagac agagcaacag aatatttgga attaaataga actggactta 202260
aatctcatcc cagtggacaa ctgggaaaac ttggaaacat taatcctgct gaatatttgt 202320
gcatcattta ataactaata catactgaat taagtagtta gcaggattta caacactgtg 202380
tataaggagc ctggcatgtg tttcctgatc tttggtgttt ttagagttaa tattatgaca 202440
gtgtgtaaac ttggtgtcga gaattaaaat ttgcttaaca gttctagtgt tctgtacact 202500
gttacctatg ttcatcgcct ccaactcatt gaggctcatg atgctaaggt gaattctgga 202560
ttgaaatcta ggtctgtctg cttatagggc ctttttccaa cttcagggtt tcctgctttt 202620
gctcaattga tcctttcaag gctccatcac gtttgagcta cagcaaatca tggtgtccac 202680
tgttcactga tgggctatgt tccagaagtt gcaagaaaag taaaggggga taaaagaaga 202740
gagagagaga agacccataa atattctgaa gtatatgact aatctagtat aatggaagct 202800
cagaaaataa attgtatttc caaatatata tttctgaatt ttttggtatt tgttattggt 202860
attctctgaa gggccacttt cttttctttc taatgctcta tgtccttaca aaggaatgac 202920
tattaattca ctggaataag aatcacacta attggcacac agtcccaatc tgcttggcat 202980
gtcatttaat gtgcagccat ttacctggtc aagtgaatac ttgaaaatta aacagttttc 203040
ttgtgctatg attgatggca atgcagtcta gggttaagtc ttaaacgtaa tcccttatag 203100
gatttcctag gttctccctc agagtttcta actccataga tttgggggtg ggtcccagaa 203160
tttccatttc taacacgttc ccaggcgatg ctgaagcttc tggtccaggt accacacttt 203220
gaaaactgct gttttaatgc ttacatgggg tagcatgagt tagttttgcc tggggctttt 203280
aattccaagt tctgctactt aacagctgtg ttataatgat taagttatgt gatgtctctg 203340
tagcttgatt tctttgtata atgaggaaaa taatcattcc cttttacata agattattgt 203400
gagaatttaa taaacaagaa atttcttata atgcctggta catagtaatc actcaataag 203460
ttatgtcaat tgtcaaagca catgtctgaa ttatagatga gagagaaata ttgtgaattc 203520
tatggcactt taatggcctg ttctctctac ccatctctag ccgtacctta cactggctta 203580
tcctgtgctc ttcctttcct gagggaaccc aaccacatat actgcctaaa gcactctttt 203640
ggcacttcta acataggtgc aaggaggaaa tttcaagaaa ttatgacaaa ctacaagact 203700
caaatctcct tttaaatttt aaaaatcaaa acatgtattc atatcccatg gcacatatgg 203760
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
162
atgaagatat tgtttttctc agttaatatt ttagttttgc ttttgtgcca gagccttcct 203820
ttttttttgt aaatgtccct tatcaggcta ctgcagaatt gcacaaatac tgaattgccc 203880
caaaatattt gcctttaatt tgtttcttta aagcaaatgt aaaactacaa tgggttatat 203940
ttacctagag gttttatcac catacgctta atttaaactc atataaaaat agaattagtt 204000
atatttagtc ttattttcat cattcactta atttaatata attcttagtc cataacttag 204060
atataacaaa aatttgtatt ttttctatcc tccatttgcc ctaaatctcc ttaaacaaaa 204120
caaaacccaa ggaaacaatt ttgcctggaa aacgtgaagt ttgattagtt ccacctacct 204180
taatgcactt taatttgggc cccttctcct cggtagtcta gaatataaac tttttttttt 204240
ttttttttta agagatctgt ttggaaaacc taccaaaaca agacaaactc aatgatttcc 204300
ttacagagag aagcctgggg aaagaattag caggaatttc tcaacgggtg ccgctgctac 204360
tagtttttta tgcatgagtg cttgtcattt ggcagaaatc aattgttctc tttacaccac 204420
aagagtggtg gaaatggggg taaaactgca agttaagact gctctgaatg tggattcaac 204480
acttcactgt tgtcctccaa catgcgccct caaagtacca cttggctggg aattaaaaag 204540
ggttgccttt agcaaagctt taatttaaaa tagtcacagg tgacagckct attatttttg 204600
cacgttcaga tgcagccaca gctgttttta ttgatctcag ctgcatacac acccatttgt 204660
tgtaattatt agtttctgat gtagctgaag atacatatct cgaatgccta tcaaggctaa 204720
attaaattaa ggaaatcgta cttttcacct tcaccctctt tggtcctgct ttgctgcagg 204780
aaattgccac aatgtaaaac tttgagcctc atttcatctc cccccactag gagtgatttc 204840
caaagttgtc ctaggttcct gatctattcc aatttaatag ttactgacat tttttccctg 204900
tatatttaac acactacaag caattaccat gtgrcaatta tgaatttaaa aattaaaaaa 204960
aacacaatta ttgctactac tgattaaaca ttgttaggac tttgaagaat aaaaaagtga 205020
attcaacctg ccctcggctt tctaaaaatt gcctttttgc tcttaaaaat gcatgtacag 205080
cttttttcat ataaaaataa tttcgagttt cttctatacg cataaaatat tttcagctat 205140
ttttgatttc aggaagtatg aaaaattaag tatacacaaa agaattgcgg catgacccgt 205200
tcgaactctg tctcagtgac agacagtttt ggattgtaga cctcactttg ttttgcgtat 205260
ttctgtttgt tgtttcacct gtggtccatt cactgtattt gatgtgttgc aaaacaatgg 205320
cataacggtg ttcccaccag taatgtaaga agaaacatgg aggaagcaag taagggtcta 205380
ggaaatttgg gagagaggaa aagagacata attaatgagg agagggatca agaagattgg 205440
caggattttt agaagggaat ttgatttgca aggtacccag aacatggcac acaaaattgt 205500
aagaaaaaca aatttttctt gaacatttat ataaagattc ctttgggaaa atagaacaaa 205560
tttggttgta gagtggtctg gggttgattt taaattggaa aaacacagtt ttgttttttt 205620
ttaatttgaa ataagagctg atatgcaata ttgtagggga gttggttgac tttttagtca 205680
gaatagtggc ttttacaacc atggtgacaa cattaactgt ggatcctctt gacgtcttca 205740
taagttcatt aatgctgggg gaaaatatgc atagcaacta atctaccaat atttgagaga 205800
attaggcaac ctctcaagaa tgtaggaaag aaatgtaagt caacaagctt atacaatgta 205860
aaaaccatga ataggcaggt aataaataat agaaattgat tttttctgtc cagtaaagac 205920
catgaaaaga gaaatattat aattttaact tgagtgctct agaatactgg gtttgttttt 205980
ttaattgatt aatatgattt taaaaaatta tcatgaattt aaaaatattt tctccattac 206040
tttgagttat cactttaaac ataggtaata tcaagatatg tttctgaatt atatatttaa 206100
ttatgaccac taaagagcac ccatgaaatg gaagtgttaa cagcaatgtt ctgttgtagg 206160
aagataatca tattggttat gtctgcttta tagtaawgtt attgttgatt gatttgcctt 206220
ttcctaactt aagtcttttt ggtcttttct tctatttgtt ctragagacc ctgttcaaag 206280
ggacatttta ttttcctttg tacaacagta tttgcctgac atttactctc ctctaataaa 206340
taatattaaa ctctagtcct aatacattta cttacctaag gaaatcggcc ttgtgatgga 206400
cccccggagg tgagatacat ttctggatga ggatctgttg agaagttgag catttgttca 206460
gctactaagt cactgccacc acctygttag ctaaacatac tctgtgctca ttccttcatc 206520
agtaaatttt ggttgggaca catggcaggt gataatagag gttattagct gcaatgctta 206580
ttaaaatatt tgaagatata ctttagcaca ttttaataat tattgagact gtcccttagt 206640
aacagtagct cttctaaatg aaagctttta aaattgcatg taagtcaaaa caaagcatta 206700
tttgttattc aactttatat aaaagctgtc cagtgatttc aaatatgtac taacatttaa 206760
tttcaattca aaataagtat ttttatgttt ttataaagtg attaaatcac tttattgaat 206820
tctatccctt tataaatgaa taaaggaatg aactcaagtt gtttctattc tattagcctt 206880
tacttttccc ttcccccaat taaccccaag caaaaatgta ttgactttga cctgagaaga 206940
gatacgtcaa ttttgttatt tattttgcct ctactcctat ttcccataca tatatgggac 207000
atatatatca gcacaaatta gcaggcccac caatttctta ctcttggatc cagtctgatc 207060
nnttctaact cgtgaaataa actaccatgc agcacggatg atcattcaaa ttacagctta 207120
gggttgatca taatgtcttc attttagtat cccctttagg ttgacattat ttattaaaaa 207180
ggtagttttc aatcggattt atggggcatt atcgatagta agtctacttg atacattgca 207240
catacctttc ttctgccaaa aagaagtgtt tacaaaaatg tatttgacca aatactttac 207300
ggtaaacatc acagtctgaa agggaactat cttctttgaa aggattaaag cctccagata 207360
gatacaaata agattttttt aaagtagaca catgttaaat catggaacag caaaggggat 207420
actttatgga aatgaattca caagataata atttgaattt gacaaggtga taattaaagt 207480
ccccagatag atttcttcca catctgtatg cctttcagta aagttggtta gcatattaac 207540
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
163
tactgctgga gaatacagaa aatattcatg ggatgtaaaa ctgcaaatta ttattcattt 207600
caatttgtat aataagtgta acaaaatgca gtgcatacag tgttacacaa gaggtaccaa 207660
actccattat agacattttt agagcaaacg tgggatcctt atatgacaat ttttgtcttc 207720
aaatattcaa gacatttaag tatgaattac cactttttgc aatttaaaag aaattttgtt 207780
tatcttcaat gctttctagg gctaacaaat tcttacttca aatgactaga atcattttta 207840
aatattatgt actaggatat gtggatatga acatatatat ttatacacaa atatatgtac 207900
acagccaaat aaacaaataa ttagtgtaat ctatatgtat taatattgnt atattttcct 207960
ccagagaaaa attgaggttt gctgaccaga gaagaagaaa gcatcaatgt gtgattaaaa 208020
aaaaaatgta tatatatata tatccactac atttctaatt tgaaatagtg atcctgcata 208080
ctaattctct tattcataat tgagtttcat agtacattca ttttaattta gacatttata 208140
tgagaaagca tgtttaatat gatgataaga aactgtatga aattttggga aagaactgtt 208200
aagtgtgccc acacactgta ggcactgaat gtcacacttg agaatgtccc tggtcctagc 208260
ttatctataa caggaatatt ttccgtcata tggaatttaa agataagaaa tgaatcacca 208320
cgcagagaga tgtgctatca catcccatct atggaaaaaa caaatgaaaa aaaaaaaaac 208380
atgaagaaag actttttgaa gtgcagcatc acctgcattt atgatatttt cagacatata 208440
aaacaaatat tattctcatg gttttgaata aaattgtcac ttttaaaatt tgacatggga 208500
tatcacaatg gacaatgcag ggacccttca gcccatagtc aacaggtgat caattgtgaa 208560
aactgatatt ctctattagg aaggttagct agagtaggag ataaaaaaca acatgattac 208620
aaaaaggagg atcatttgag accaacttta atgtgaaatt gtgtagaaat gggggaaaag 208680
atacagaaaa catcttcaca agtccacttg agaaactaag ttggtgcaaa agttattgca 208740
ctaattactt ttgcaccaac ctaattgtaa gttatgcttg aagaaactta aaaggagaga 208800
cggagagagt acacaactat aaaagcaagt ggaacaagaa gtgaaaatga ccaaagaaca 208860
tatttgttga acatggccat tttgacaatc aagggagaat agtaatttaa agtacaatgc 208920
cacaatctgg agaagactgc tcttgcacac aagtgaaagc tctcatcggt cctgtctgat 208980
gcaaattaca ggtacattgc tgcacaggtg tcagatcgca catagctggg ctggcactgc 209040
ctctcctctg gagaggaatg cagcacattc tccacaggcg actggaaagt ctggattctg 209100
tcatctagaa atacacctta gttatcccct tggcaaatta atggcjaaaac aacctcttca 209160
cttctgtgtt ttagaatttc tgttttatgc cttttcattg tttcatgcaa ttttattttt 209220
tcacgaggtc aggcacagct aactgttgat tttcaccaaa ttaccttgtt attggcttgg 209280
ctccatggag cagccccttc caagaaagtt tcccaagaaa ctatgtactt cttctacttg 209340
gactcagctg tgtacctatt tctctcgtca gccattagag tgttccacta atatagtcaa 209400
agcagaacat ctggcctatt atataaatga atattagttt tgaagaagat atctttggag 209460
acagtagaac aaaatggatt ttttttccta cacaggaact cttggttttt cctcactgcc 209520
cattgtcatt ttttctacct tactcagaac atgattttcc ctcaactgca cctttctgta 209580
actttgacct gtgccatcct tgtgaaataa gtgatatgtg atttatttta atttctcctt 209640
ctaagtgaac atgcagagtc cttcagagac catctgtgcc tcctgctgag tctctgtgtt 209700
ttctacccgg gctagcttcc tccagagccc agtctcaggt agatctgaac cacacatgga 209760
ggagatttta agaacaagtc ttgtgacact tcctatgctt tgggtccaaa aactattgat 209820
tttcttattt ccctgcaagt gtgtcagatt ctggcaaaac tagcttggag tttactgagt 209880
ttaatgatac tgaatgacat caggactcac tcttctcttt tcattttttt gctatgagtg 209940
ggaaaaaata taactgtata agcaatgtac tttttttctt aacgcaattt aatctttact 210000
aaaattaatt ttgataatca tatatgtaca aagtgtttaa ttttgttact ttttaattct 210060
tagacattga cttttaaaaa tcttaatcgt tgctattttc acccctgact ttatgcccag 210120
tgtctatatg cataaacaca aatctttcta ctcctatctg tttagcaaaa tgtaaataaa 210180
atgtctttaa tttatttcaa ttttgtgtat tttttttaaa tttacttgcc tgggttgagc 210240
atcttttagt atatatttca ttgtgtttta ctgaaaattt gacttaagac tcagtgtatt 210300
actgtcaaac tctcccgtca tgactatctc aggtagctga ggtatcactg acagcataag 210360
cagcgacaaa ccctcgggta atgcaaattg gcatatccga caaccccaag ctaacaagat 210420
cataaccagg gacttgcaaa catgttttta ggacataaac tcatcttaag gttttactta 210480
aagtaccatc catctcatct ttaaccagcc tctcctaatc tttgcagaat tgtccattct 210540
aatgcagtct ttcttcattc tttcacccgt ggctccatta aacgtttttc tgcaggtagc 210600
ctctccattg gagtaactgg actgaggatg gactcctttc ttaagaaatc-cagaaaagca 210660
acaaaaatct ttccagttac tactggaaaa tttctgcagt catcatacat gtatcattag 210720
gttctcacct accattccta gagtctatct atctatttac ctctgaggtt tcttagatta 210780
gccaaacact tttgcagctc tcgtatttgc attgtagggc cttggctgag actagatctc 210840
ccaatatttg gatatattga ggactggaag taaagaaaga ctgccacttc acacctatgg 210900
aaatactacc tttttccata gaggcagctt gaatacatga ttaggaattc actgtgactt 210960
tgggttagag gaaaaaaacc aaaatgggtt atttggttat atagagaagg aaggaaggaa 211020
ggaaggaagg aaggaaggaa ggaaggaaga aaggaaggaa ggaaggaaga gaaagatcct 211080
ttctttttcc ccccaggaac atggcagttt gagaaaatcg ggaataaaac aagtcttata 211140
atttgttaaa tattgtaaaa tactttcctt attgttagta gaattccatc ttggcagact 211200
atttcttcta ggaaaccatt tacccttctc cccttctctg ggcactacat ttctctttct 211260
ggtaagaaat ctgtcaaagg cacttcacca ggaatctggc tcttataaaa tgcagtaaaa 211320
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
164
ctgcaggcaa tggggaaatg accattactg aaactccttt ggagacggct tagcttatga 211380
agtttttgag cagttctacc tgatgaccag cttactatgc tcatctttac ttcctcctgt 211440
aacaggatga ctgacacgtc tcctctttgt catgtgacct tgcagagcct tcaggaattt 211500
atgtcgactg cacattttcc ttggccagtg gctctggtct tggccattga cttgcatcag 211560
tcaacagaaa tgttgcagac ctaacatgag cagaggctct aagtaaaygt gtgtgatttg 211620
gattggcctc ctgtgcttct gccatttgtc ggagcaacat tattcatgcc gccacaggtc 211680
cccaaatgag aagatgcatg cagctgatct agacttaagc tatagcctag aatcacatcc 211740
agcccatccc aacagaccca gagtgagccg aaatcttccc agcagtttca agagcaggga 211800
atggctgttg ttgcaagcct ttgggtttcc tggttatgta taaagcagca ttactcacta 211860
aaaacttcat aaatacaaag ctttctgcat gagtttctat tctgtgccct gcaagctttt 211920
attaaaggca tgtagagtga aagtctgatt ttacctgaat tttaggaggt cagggccaag 211980
gctggatgca gcctagcagt tgtgctgtgc catgggaagg gacagcatgt gcccccaaaa 212040
aaagtcagaa caaaaaaacc cacaaagttt gagtgtggaa aagtgctaca ggcttctgga 212100
atcagttggc tcactgaagt tcaagcagca actatgaaaa agttgtggga catattagca 212160
ttttataggg attcttagaa atacctaggg agagaaaccc cataaaaggc tagattttct 212220
gccataatac acaaagggac acaggctatt ggtatttagg cattaaaggg aagtttgacc 212280
cacccctgaa ggctgaataa gtgtgagaca cctggtttat atttatataa atttttgcac 212340
aggacaaatt caaccttcta agcacaatgc aaagtagcat atccaatcta ttaagcacca 212400
tgcctcttaa ctcataataa atagcatata gcaatcctgc cacaggcgct aacatttatt 212460
gagtttttct actgactagg ctgcgccaaa atatttttca ggttttaact catttactgc 212520
ttcatgagat aaattatttt actatcttga ttaaacaact aagtaaagtt ttgtttagaa 212580
gagtttagta gttacaccaa aatccagcag aagaaaatga ctgtaatttc ctatataaca 212640
atcctttgat agtttttctt tatcccttct ccttacatct gtgactaaca cattatactt 212700
ccttaaaata aggtgggagc cagcatttat aaaatatatg catatagaga aaactaacac 212760
atacattaag gagaggtgga gaaaaaaaga aagatcatat ataatcattt atttttatgt 212820
tcatttatgt aatttatcta tgtatataaa tgacttacaa taaaaatgag tgtattccta 212880
gaaataatag acaacaggga attgtattct tggggtgaag tctacaatgg atagatggaa 212940
tagttgtatg aataacattt ttgagtatat tagcttatct tcaaaatgtg cttggtcttg 213000
tcatttagat tatattatat ccatgtatat aaagaataat gatattaata tactcttact 213060
gctaaattta tacattacta aaaataaaaa gtgtcatata tttgagcctg aggacttatt 213120
tgaaagtctt acatgaagaa tattagaaac atagggatta cgtatcttga ggatgaaatc 213180
tgtataattt ctacttcagc aaatcttgaa aagcactctg atatgtcatc tattgcctaa 213240
taatgctgat catatggaaa ctggatcaac ttgcaaactg gatcaacttg caaactaata 213300
ttacatgtag taatattagt ttacttcaat tatctttcct aactctcacc ttgaaagtac 213360
tccactcatt aaactatgca tatacatata tatatatata tatatatata tatatataga 213420
gagagagaga gagagagaga gagagagaga gacaggatct agctttgtca cccaggctga 213480
agtacagtgg cacaaccttg gctcactgaa acatccgcct cctgggttca agcaattctt 213540
ctgcctcatc ctccccagta gctcagatta caggcatgtg acaccacacc aggctaattt 213600
tttgtatttt tagtagagac ggggtttcac catgttggcc acgcttgtct tgaactatgg 213660
aactcaagtg aaccggcctc ctcggcctcc caaagtgctg agattacagg catgagccat 213720
ggtgcccgga ctattcttgt actttgggtg tctttttttt tttttttgag tagtcataca 213780
gaattataaa gtgattcaca ccctcttatt ctaaatgtgt tcagtctaaa tgcaaaagtt 213840
ttagtataaa ttaattctgt atatttttat ttaattttaa gagtggagag atattagcta 213900
ataaaattag ctttggaaat aaaaagaaca gatacggtta tagttccttt ccccaaatgt 213960
tttaaactta caaaagcaat taagaagcag tatcacaaga tttaaagttt ttaaggatat 214020
tattttgttc cctaatagac tacacaccgt caatagttaa agttcactaa aaatccagaa 214080
gttgccacat taggctgaac tcacatttat tatttctgtt attagcttaa cttatattta 214140
ttataggagg gatgacttct ttttacaatc atttaatatg acaaataata tattacattt 214200
tgatttaatg acaactttgt gctttatcta aaaggtagca ttatttttgt gtgtgaatta 214260
atctatgttc caataaaact tccaacataa gtaaggctct gtatgtatgt tatgttcttt 214320
ctatatctct ggattatatg gatttacata cttgtatgcc agtacatatg tacatatgtt 214380
taagtataat atacatgtct gagtataata tatacattct tactgtacaa actatgcata 214440
tgcatatcca tattgcatgc agctatgtag atagactctg acagcataga aaaattttaa 214500
acttaagcaa agttgaatag ctctcaagta ctgatatatg tatgtgtcca atattatgat 214560
tccaccattg ctaatgcaca caaaaaaaac taccaattta tttttcttat ataattatat 214620
ctctgataaa attattgttt attcagaaac ctaatatcga ccattaatrt tccagtttca 214680
gaaaacaaaa actcctaaga gaatgaatag aaattttctt aaggaattat aaagaaccat 214740
ctcagaattt tactctgtta ctgcaaaatc tcatgcaaag atraccaagt acggtatgtg 214800
aacgtctctt cttctaaagc tcatgaaact gctctctgat tcctctagcg ttgacaraga 214860
atctggagtt cagtactcya tttcattcct ggacatttag cccattattc ttgtatccat 214920
atttcatatt ttcctttcat gggggwtaat tgtaagttaa aggtgaattt gttgactcaa 214980
accttataag gaatcataga tcaacctaaa gatttcctaa aaatatacct acatattgaa 215040
tacttgcttt gtctaagctg cttaacaaca acagaaaaaa acaagcaaac aaaaactcaa 215100
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
165
aaacaaaacc aaaccaaatg aaaacctgat ggcccaaact tgtaaagtgt attttcttgg 215160
ttaattattt aaataacaaa tatgaggaag aaaggcattc tagtgaatct gctttaaatt 215220
acataggaga gagtcttatg taaactaatg ataatgaata tgttcggagg gtttgtatgt 215280
ggagggcttt gtgttaagca ctgtgaatac tttgttccat ttaaacgcca ccttagactc 215340
tacaaagctg agagagatta tgacagttga ccaagattac acaatgagaa agtaagagat 215400
agaagtggaa cttgatcaca ggaagtcact tctaaagact caacatttga ccctggtctc 215460
taacgcattg attttgagcc cagcagcatg tgaatttatt cctatcagga taaatgaaat 215520
gcaagtaact tatttaaytt gagtctcaga tacatccaaa taaaaataaa tgccctcatt 215580
tatagcatca cattctcagt actaagtaag ctatctataa tgatacaatt ccattgaggc 215640
agaagacttc acttcatatc tacacgacat ttcattcttt ctttctattt gttttttcta 215700
gaagrattaa ctgaaattca tcccaagatg aggcatcttg gctgaggtga gatatgcaaa 215760
tcatctgtgt tgtttgacag tcacgggtag ataaatcata tcactaacaa aagtcagttg 215820
ttaaaacttg aagcacawtt aataaaaaga garattctcc cagtcacaca ggccaggtgg 215880
gtgcatagaa atggcatttt atcacttact gaccagagar ttgcaaatac aatcccatca 215940
cctaaaaaca aggaaacaaa acaataataa gaaaactttt ttttttaatt tttaatagaa 216000
agtcagtttt gcttctgagt aggtattkta aaataaactt atgggttctt ttaacttttt 216060
ttgctttacc ttactagaca ctgagttatt attttttgaa ggaaagtgaa ttataaatca 216120
gaaattattt tctctttttg ttaataacct taggacataa gaaatacata tttccagagg 216180
aatttataga aaaaataaaa gtaatgcttc cattattagt attctcccta aaactatagt 216240
tagaaattat aaaagtaggg aagggtccat caatagtatt gattgaaaat gtaatgttac 216300
atgtatcaga tacataaatc cataaatcca taacaatggc aaagggagac atcattacta 216360
tttggataaa ttaatatact tgaatatttt cccacataaa ttcactaact attcaaaaaa 216420
cttcacagga cttttgaatt tccgttgttt gttttactga ttatgacagc tcacaaagca 216480
gtatgtgtaa ctttcaataa taatttagtg atgaaatatt accaaacaag aggagagkat 216540
tttgattacc tatggtatta gtttatatca ttgtgtaaca aatcttcata aaaatataat 216600
tcataaaaat tatatttcat aaaaatattc ataaaaatat aattttataa aacatattac 216660
cacgtgttat cagctgggtc ccagacacag agtccgtcag aktccagtga agatgttggc 216720
cagactacat tgtcatcaga aggattggct gggaagaatc tgcttccaaa ctcattcagc 216780
tttggtagaa gttatttcct tgtggttgca tgactggtct ttttgctggt tgtagttgca 216840
ggtccacatt cgttctagag gctgcctgcg gtcyttagag gcctcatagk caaggaactc 216900
atagtttctt gccatgaaga cttttccaac atggctgctt acttcttcaa gcctgtaagg 216960
agatcyrgtc tcagttggcc aggtcttgtg aaaggtaacc tcatcacykg agtcaagtgt 217020
catcacmttt cccatgttcc attggttaga agtcccagct cctgcccaca ttcaagggta 217080
aggggttata caaatgtgtg accaccaaga agtcaagatt atgtgggtca cttagggtct 217140
aactgccaca actacatatt tggatataat ttcaaagaaa gactgtgaaa aagcataaag 217200
aattgtrgga attgcctgag aattgaggac gttcatctgc aatgcctgtm aggcttacat 217260
taaacaagtc tagcttactg agaaagtttt aaaaaatggg tttgtatgac tttacttatt 217320
gggagaagcc atttgacttg tctttgaggg gaaaaataat ttaaaaatac agatatactc 217380
tctctgcaaa acaattcctg gaatatgatc taacagaaaa gcccagcaga cctgattcaa 217440
acctgatgtg aacacagaat gctttgaaat gagtaaattt aattattaaa cctaattttt 217500
caggtgagga aactgaaaca ctggggttaa gtatcttttg cagggtcaca cagctaaaga 217560
attttggagc aggaattcaa attcaggcag ctggcttcag acctcatgct attaaacctg 217620
atattaaact tgacatccat cttacatgca aatgttactc tctctatcag gaaaataacg 217680
catttataaa agccagctca gatgttactt ccaaccaaca aatttcctgg acacactaag 217740
taatagagtt aatcacaccg tcctgtaagt actacccaca gtatccgggc tctaccacat 217800
tgtaatgcaa taggtgtgtt cacactgttt gtctctcctg gtgaatcgtt aattcatcag 217860
agcatgactg tgttgtgtgt cccattatcc ttagtaaata atgtagtgcc ttgtgcatag 217920
gaagaaatta atcttgatgg ctttcaagtt ccaccccaaa cagtcaagcc atgttgattg 217980
aaaagtatct tctcagtttg agagattacc atcagagtat ttgaaacaag attgtatcct 218040
tggggactcc atattgagga cattttcttc ataggattct aaggtctaat gacttggcct 218100
gatcctaacc taatccttta gaaggctaga gaataaaatt aaatatgttt ttcacttttc 218160
cagtggagta agcagggttt tattgtgctt cttgaatcat tgtcacacta gtaatctctt 218220
caaaagcgaa tttgttctgg aaaataatgg gttagaggcc tctgtggagg aatacagtag 218280
tggaatattt tgaaataatt gtaaagcaaa acagataatt gcgtttttaa gctctttgaa 218340
atatatacgt aagatgttat gtgcctgagg ttgaacaaaa agataaatag ttacagtcat 218400
tacccaataa tgtaccaatt acaaatagca ttgtgtgtac atgtcctcta ttataaaatc 218460
agaacgggat gaaaaagatt ataatcacgt taataatttg atttgcttca ttcatctttt 218520
gagttatctt ttcataaaat tagatactgt gttatttcct tctggaaagt acaatggtgc 218580
atgtgaggag aatgttttca tgttaatcaa tgctgacaag aatattacac ttaaaaaaca 218640
cagaaggcag gcaggttggg ggttggagga cagacaaatg aagaagacca gattgaaatt 218700
attagttgcc agaaatatat ctattgactt tttacatttt tagaagtacc tctgttagct 218760
tcccaaaata cagctgttta cagtgattga taagttcccg tgcttttaag cttattcaca 218820
tccattagtt ctgccttttt cccctgttaa aaatctgaag ctgtcacatt gaagtagcat 218880
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
166
gatcagctaa tgttcctgcc agattcaaag catgtcccca ggggtggcaa aagtattcaa 218940
aatctcaaag aaatggcttt ttaaatgttg cctgttgaca ttggtcactc catttgctgt 219000
atcagaaatg ttgaaataaa tatcaggcaa ttatagaaac aggactttga tgatcaattt 219060
tctataaata ttttatgttt agcccaaaca aaagaaggca tttggaattc actattttgt 219120
ataaaacttt tattttaaaa tagtatgtag tatattttca aaattggtta attaattttc 219180
tagttttcac ttcaaataat gattatttac tctattccct ctagcattag attattttct 219240
tgcaaaccgt tttttttttt tctttttttc tttttcctgt aatagtttta gagtttctgc 219300
cttaacacat ttaggtatat tttgtaggaa caaagggaaa aggtatcagg gagaggaaat 219360
gatttctaaa atgtaaattc caaagacagg gaatgttaaa agtgtttgcc agtcctgttt 219420
cttacagagc acagaactca gatgctctta taaagataca ggataaatca catcatttcc 219480
tgctccatca tcagaatatt attatatgat ttagatcact tttttaaaaa agaacatggm 219540
cttagtacag aacaacagca aaagcctggg gaaggagagg agtgcaccat gaggagtcaa 219600
tggggagcag aagccagtcc atttgactga tttggttcgt gtgcaaaata attgctaaat 219660
aattgcatat atgtgagact ccgggtattt tcaaaaccag ctggcaaaat tgtgttattc 219720
tctaccctct gctggctttc acgggttctc tgttctctct ccttttcctc cattctcctc 219780
ttaccctaat tcctgaccac tgtaatccaa taatctaagg ttttaggatt tggatgacta 219840
aggttaccca tggaattgtt tggaaatgta gacctgtaat ggagagggga gaaaatgaag 219900
aaatagaagc tgtacgaaaa tagtcaatac tgaggccagg taccgtggct catgcctgta 219960
atctcagcac tatgggatgc cgaagtgggc agatcactgg aggtcaggag tttgagacca 220020
gctgggccaa catggtgaaa cctcatcttt agtaaaaaat acaaaaatta tccaggcttg 220080
gttgtggatg cctgtaatcc cagctactcg ggaggctggg gcaggagaat cgcttgaacc 220140
tgggaggcag aggttgcagt gagccgagat tgcgccattg cactccagcc tgggcaacaa 220200
gagtgaaact ctgtctcaaa agaaaaaaaa aaaaagaaag aaagaaaata gtcgatactg 220260
agacctggaa actgagagcg ttcatgaatg ctgcatccaa agaatatttt gtactacgtc 220320
ttattcatga tacaaatcaa gcaaataagc acactctgtt gttcacatat gacactatat 220380
aggtcaacgg ggtgagagag ccacccagaa acagacacac aattttgtta tcagatattc 220440
tggagaggtt tctctgaggc agtggcatct gaagaatata cagatgttaa ccaaatgaag 220500
caggtgggtt tggggaaaaa agtattccaa ggagaggggc agggtgtagg acaactaaag 220560
agcaagggtg attagaatac tttgatgaag tgaaaaaaac actccaatga gtgagcgcgt 220620
atgaagaaaa gggtggagag cagattattg aggtccattt agatcatgtt ttagatcctg 220680
gacagcatcc ttaaaataat aaggagccac taaaagtttg aagaagggca atgacatgtt 220740
ccaatttgct tttttacaag atcactctga cttctgcctg gagtagcata taaagggact 220800
aagcacgata ccaggtggca cataggagct gaagtrgctc ttgtcaaaat aaggtgatgg 220860
ggatgggagt ggatttgttt cctaggctgc tacaacagag aactgtgaat ggagtagctt 220920
aaaataacag aaatctattc tstcccagtt tgggatggag gtttcagcag gacatgctct 220980
ctctaaagac tttaggggaa aatctgttca atgtccttct cttagcttcc agtgttgctg 221040
gcaatccatg gagctccttg cttgttggaa tatcactcca tcatcacggt gttcttcctg 221100
tatgtcttca ccttctcttc tccgtgtatg tctgcctctg tacctcttct cctcttccaa 221160
caaggacccc agtcataatg gaatagagcc actctaatga cctcatttta actgattaca 221220
tctgcaaata tcctatttct aaataaggtc atattcatag gtattgcaga ttaagactgc 221280
aatatatctt tcttggggat atagtttaac cccaaacagg ggattattga aaggaagtga 221340
gataagggtt agtggaaaga aaccatgtaa aggttttaaa atatattttt ggtggtagac 221400
tcaacaggac ttcatgatta agtctgagtt tagggatgga agcagagtcg tggttgactt 221460
ccaggtttct tccagatgat gatgccattt gttgagacac aaaatccaac ggatcaagta 221520
agtggtgggt tgagcatggg ttcatttttt tgacatgcca agtttgatct gtctgtgaaa 221580
tttttatgtg gagctgtaga tttggtggtt aaaaatgcct ttggaattca aatgagagat 221690
ttgagttgga gagataagtg tgggagtcat ttctattcaa attatcatca aagctatgca 221700
agtagataac tttcctcaac cagataatgt ttagtcagaa kagaagaaac cttgacatca 221760
acattaaaca ttttaaagaa caatgtggac tatttcagac taatatgaac aaaaaggacc 221820
agactaaccc tgccataaga aaaaacaaac cgtcaagaaa cagacaggac atttgaaacg 221880
atggttttag agacaaaaaa catcaggcag ccaaggacag aaaaataagc aaatacattg 221940
atcccaacaa ttgcctgaga ttacctaagt tcaggtaaaa gacaatattg tctgctttca 222000
atatttctat ttaatttgat attgaaattt gcattcatag tagtaagrca gcaataaata 222060
aaaggcatcc aaattgtata ggaggaaata aactggtttt atctgtagac aatatcataa 222120
actatataaa taactatgaa acatacaaaa aggtataaga gctaatgcat gattttagtg 222180
aggtttcaaa attcaaattt aatatataac attaaaatca cttgatacaa gagcaaagaa 222240
caatatgtaa ttgaatttta aaaaattgta cttataatag caaaaaatat aaaatatttc 222300
cagataaatc tgacaaaatt tgtgaaagtt tcacacagtt aaaaatagaa aacactaagg 222360
aaaaattaat gattacctaa ataaatgcag aaagatacat ttttaatggg ttggaagata 222420
atattcttaa gatgtcagtt gtccccaaat tcatctatag cttccctgtt atcccagcaa 222480
gctacattgt ggaaattgac aagctgaatt taaaattcct atgtaaacgc aaaagaattg 222540
ttacagctgt aacacttttc taaaagaaca aaactgggaa taagtatatt tttaagacag 222600
ttattagcat taagatagac aaatcaatag gataaaatag aaagtaaaaa aaaaatagac 222660
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
167
ctatacatat atggacaact gattttggcc aaggggcaaa ggaaacttgt tgggagaata 222720
gcaatatcat attttcaaca aatgaygttg gaacatctgg gtattcatta caaaacggtt 222780
aatctttgat ccatatttaa aatttaactc aagttgaatt atagatgttg gtgtaaaatc 222840
tttaactata aaattcatgg aagaaaacat atgagactaa cagtgtcaat tagcgttaag 222900
taaagatgta ttagatgcaa cagaacaaaa catgatccat gcaagaataa atgtgataaa 222960
ctggacttca taaaaattaa acaatcgcaa caacaaaaaa taacaaagaa atgaaaaaga 223020
gcttctgctc tttaaaaatc attattaaga aaattaaaag acaattctcc atggtacaca 223080
agaaaagatt tacaaaggtt atatctaata taagatttgt atccagaaag tataaagaaa 223140
cctcaatgtt caataagaga aaaaaaataa aaatgagcaa aagctttagc agaccactga 223200
aaaaaaatgg gtagagaata tgcatatgag aagatgctca atatcattag tcattaggaa 223260
aatgcaaatg aaagcataac aagatagcac tgccctcttt tttaaaagtc taaaactaaa 223320
aatgctgacc atatcaagtg ttggtgagaa tatggagaaa ctagaacact catatcctgt 223380
ctgtaggaat gcaaaatggt taaattactt tgaaaaacaa taatgaagca gattccttaa 223440
ataaagggtg atctatccaa ctactattag atctattcaa ttgatctagg tatttaccca 223500
tggaagtaaa agcatatctt cattataaga cttctacaca aattatcaca tctttactta 223560
cagcagctga aacctggaaa caactctaat gcccrtcaac agaggaatgg atggataaag 223620
aaactgtgat gcagtggaat acgactcaac gaagatgaga ctaaaaataa ttatactgag 223680
taaaagaatc caaacaaaat agagcaaaca ctgtgccatc ctgtttatac cttactccag 223740
taaatgcaaa ctaatacaca atgaaaaaaa ttacttattt gagaactggg gagaggaagg 223800
agagggaaag gggtagataa agaaaagagg agagattaaa aggagcataa gaaaacctca 223860
gagaataata ggtttgtggt aaacattacc gtggtaatgt ttttagggta tattcacatg 223920
taaaaactta tccaattata cattttaaat atgtacagtt tagtgtgtca gttatgcctc 223980
tgtaaagttg attttaaaaa aagttcctat ttccaagttc acaatttcat ttgaactctt 224040
aaaaactggc caggagcagt ggctcatgcc tgtaatccca gcactttgag gagcagaagc 224100
aggcagatca cgaggttagg agtttgacac cagcctgaac aacatggtga aaccctgtct 224160
ctactaaaaa tacaaaaagt agccagacgt ggtggtgggc acctgtaatt cctgttccag 224220
gaggctgagg caggagaatt gcttgtacct gggaggcgga ggttgcagtg agccgtgatc 224280
gcaccactgc actccagctt gggtgacaga gtgagactcc atctcaaaga aaaaaaaaaa 224340
aaaaaactta caccaaggtc aaagcagagg agctggcaaa agagactgag aaaaagagca 224400
gagtgataga gaataagaaa tgagagctcc cacggaagct aagggcagga accacacagt 224460
ccttcctcat gctacttaga agttaaaaaa aaaaatgaga gttaaaaaag gccattcgtt 224520
tcagaagtaa cattatggac taatgaaaag gaatttagtt aaataaggca tgagacaaaa 224580
gaaagtaggt tgactgagaa atgatgaaat agaggtagca agtaatatgg tttggctgtg 224640
tccctaccca tatctcatct tgaattgtag tttccacaat cccacgtatc atgggaggga 224700
ccctgggagg taactgaatc atgggggcag gtctttcctg tgctgttctt gtgatagtga 224760
ataagtctca tgagatctaa tggttttata agggggaatt tttctacaca ggctctctct 224820
cttgactgct gccatataag tccctttgct cttccttcat cttctgccat aattgtaagg 224880
ccttctcagc catgtggaaa tgtgagtcaa ttaaacctct ttcctttgtc tcaggtatgt 224940
ctttattagc agtgtgagaa cagactaata cagcaagtat aaaaaacatt aaatgtttgt 225000
cttctaaggg aagagaggag agtagagaga gagagattgt tagctgaagg gtaaagtatt 225060
cttgttatta agatatcaga gcctagaaca tatttaaata ctgatgagaa ggatacaagg 225120
gagagagaaa atttgaatca atagtttgtt tccactacca cagaaaagga tgagatccag 225180
aggtttgata gaggaatgag ttttcctcat tggagagata agagcagatg ggtttgaatg 225240
ctggatccta agggtgggat attaagggag tctgtttttt atggctttta ttttctcttt 225300
gatcttggca gcaaggatgt ctgccaagat ttaagggttt ggacaggagg atcatagttt 225360
taatgaataa aaacatatat gaaatagcca cttcagagag tggggcagac agtatgtgtt 225420
ttagtttaga ccagagtccc tgragttata ggggtttgaa ttcaaatcct agctcctcca 225480
ttcacctgtg gtactgtgaa caatgacaga accaagttaa gaccccaaat cttctttaaa 225540
gtgggatgat aatggcatgt tcaccataga cttcttggga gtaataaatg aaatacttta 225600
gttcaactat tttcacaggt cctgacactg ggttttgaat aaattgtgcc caggactatt 225660
gctattataa agcaaaatga aaaaacacaa tggcccaatt aatatgtttc caaggagttc 225720
aatactaaga agaaaagtat tgttggaaat ggaaatccac attactagat taacatgtgg 225780
agaacttgct caaagaggag gctggtttag atgctgtgat aattttagat gtcaaatgga 225840
ctggattatg gaaataccca gagaactggt aaagcatcat ttttggtgtt tctgcgagga 225900
tgtttccaga agactttggc atctgcgtca gtggactgag tgaggaagat ccctccttac 225960
cgtgggcagg tgccgtctca tcagctgatg gcccagatgg aataagatag aggaaggaat 226020
atgtgtttct ctccttctta gggctggaac ttactcttca ttccctgctc ttggacaaca 226080
gaactccact ttttggactc taggtattac actagcaccc cacttcccat agccgagttc 226140
ttactcctta gatcttggtc tgagagttac accattggct tccagggcca cactactcca 226200
tgccaggatc tccagcttrc agatggcttg tctggaggct tttcagtctc tataatcacg 226260
agccaattct cctaacaaat gctatctatc tatctatcta tctatctatc tatctatcta 226320
tctatctatg tatctatcca tccatccatc catctatgta tctattatct atatctatcc 226380
tattggttct atctgtctgg agaaccctaa tacagatgcc agcaaaccaa aaccaagtgg 226440
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
168
caaatgtcta ccattgacat tcctctcctt ccttaatgac tcttagkaac caaaaacaca 226500
tgtaaaattc catgtaatac acaagccaga aaaggtaaaa tattgtatct gctagttcac 226560
acagctcatt tcactaccac aatctaccat tattcaaata ctgatttaga aaatgacagc 226620
ctccaaaaga ctaaaatcat cagtttttac ttagaagaaa aagaaatgaa attttaatga 226680
cagggaattt taatcttact atttcaattt ataagatgtg actggctgaa tattgttatg 226740
tactaaaatg ataaatacta tgtgttatta aatattttgt cattgaaaaa tgacctatta 226800
ttctgaccta ttttattttc aggggtactt ttagataaag gagtttataa aggcttctgc 226860
taaagaagay atcagagaaa atgtcttcca attgatttat cttgctttgt ttctgagcat 226920
cttgactcca actgtattgc aatgaaaaat aattttttta aatggcagag actctgattt 226980
gtcctakgcc ccttcttcta aattccaaga gtctatgtga actctttcta tgagtttctt 227040
aaaattcacg aaagtagtct ctactggttt aaatggtgtc ccctcaaaat ttatgtcatt 227100
tccagaaccc cagaatgtgc ccttatttgg aaatagggtc attgtggatg tacttagtta 227160
agatgaggta atactagagt agagtgggct ctacatccaa tattgctggt gtctttctag 227220
gaagaggagc agagccacag ggaatggtga ccatgtgaag acagaggtag agattgactg 227280
atgtgcctgt cagccaagga aggtggcgca ttgccggcca ccatcaggaa gtcggagaga 227340
agcctggcac agattctctg tccagtggga accagcctgt gtgttaattt cagacttcta 227400
ccctccagaa ctatgagaca ataaattgcc taaaactgtt ttaagccact cagtttgcaa 227460
tagtgtatta tgtcagccct aaaaagctaa tacaaagccc tagagaattt caataaaggt 227520
gtcaggaaat atagatcaca gacaataatg ataggacctt ctagcattct tacacttctg 227580
taatgtttkt tgctctttcg gtctctccta twtgctttta ttgtgattgg caaaaatccc 227640
ttgaaaaaac caagaaacaa tacgaacaga aacaaagcta tgtacttgtt ttgggaagca 227700
acctcaaatg gaaagatggg ggctgtgttc taaaaggtga ggagaaattt atagcgaaga 227760
taaagagata aagataaatg gtcctgtgca ccactgaatt ctgagaactc tgaacaaaac 227820
ctaagtatat gttagtgccc agtgaatagt tgttgaatga atggatgaat caacaaataa 227880
atgaattgat gagataatca atctgtgaga caaaaagcaa cacaaatgag tagacaagag 227940
tgggttagtt tggctaaaaa ttgaagatca cccatttttt cagccaagta ggcaggcatc 228000
tgctayttgc caggcatggg tattggtgtt tggcataatg aaatagcaaa acaaagtcct 228060
actgtcargg aacatagact cttggaattt agaagaaggg gcatgggaca aatcagagtc 228120
tccgccatta aaawaaaatt atttttaatt gcaatacagt tggagtcaag atgctcagaa 228180
ataaagcaag ataaatcaat tggtttaaaa tatctttcac actacmcttc catggaaggt 228240
gcagagaagg ttcyagtcta aatgtaggca actggagact cccttttcct atattccttt 228300
aaaccctatg ccccaaaatg tgtaatcaag tctattcttg aacagaaaag aacacagtgc 228360
cctttctctt tggaatttta tataagcccc taagaaaagc tgctattgtc ctagtttgta 228420
aaagtacaaa tgggtgagta tgcatctgct ctgttcagtt ggaaaattag tacaggtttc 228480
agcactcctc gataccaatt gactattgaa tgcgtactaa gggaagcttc tgtacagacc 228540
agtaaaccac acaattgcag aaatcctcta attaaagaaa cacaccataa tcttcctggt 228600
gaatctgaag aaaaggtttt ttagaaaagt acatctgtat aaggtacatt tgtgtaaaaa 228660
acaatcattt ttcattgaag tgcagctgta ttgttagatg ttgttctaag aaaactcagc 228720
ttaaaatttc ttataggctg ctttggctta aaataattgc ctaactggat ggtcacaaat 228780
gaccaagaaa ccaaatatat ttcatagtat taactatcat tacagagtgt taaataatac 228840
tgcacagtag agatcttttg aaaaatattt taaatgatag attctatttt ggtttgaggc 228900
aaagtcttaa acataacaag ttaaataaat ttttaatgaa attttacaag tgaaataatt 228960
aatgttcaag acatagaatc atgccttttg gaaatgactc tcatgatatt ctattatttt 229020
aaaaactatg tgcctatttt taggaattaa attgctctgg tagataccyg ataaatatct 229080
atctcacaaa tcatgttttt ctgtcatatg taaatttttt aaatgtttta gtttataggt 229140
tgtttggctc tgtcacccag gctggacwgc agtgctgtga tctcggctca ctgaatactc 229200
tcctttctgg gttcaaggga tcctccctcc tcagcttccc aagaagctgg gactacagrc 229260
atgcaccaac atatctggct aatttttwaa ttctttgtag agatggcwtc taggtttccc 229320
tggttggtct tgaactcctg ggctcaagca gtycycctac tttggccttc caaagtatgg 229380
gattacaagc atgagccact atgcctggtt agtttctaat ttttacattc agttyatttt 229440
tatgtgactg gcatttgtgt aggattattt ttataaccaa tatgtwttag gtatgtaacc 229500
cagaagtaaa tcactaatta atctgcaccg gaggaagtat aatttaggga gagtagaaac 229560
tctatctgat agactgcact gmaggtragg tgtcacagcc ttraarmrcc tcagtgactt 229620
tgggaaaaac aagcaccaag actgaccttc cagatccaag gtctggtakc argayggttt 229680
tsatttccat ctgttggagg tctcagcttc tgacataaag gcctgcttta tacaaaatga 229740
gcctgattga aagatgtaag csaccaggtt agagggagaa ctacaggagg cagacaggag 229800
aaagtaagag aagagtgacg ttgttcttcc actagcttgt ggctactaac aaatttcatc 229860
agaaagttgc tgaggattcc tcagaacaat ttacagagat aactgtaagc tgcagagggc 229920
tatgaaaacg ctcatgggtg ctgacaggag cccctggtgg stggtgggtt gggaatacag 229980
gggctctgta gggggtgaag gaactgtgct tgacaccaat caatgggagc ctggagaaac 230040
tgaggcaggg actggaatcg tgctgagact caaacgtttt gagttagagt actcaccagg 230100
tactctaact caatcatatg ccttgggtat aaggaaatta ggaataattg gaactgtggc 230160
tggccccaaa tttcatgccc tatttatagc cattcatcaa atttagaatg aggtaaagga 230220
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
169
aggattcttt ttattatytt ttaaaatacc cacctyattt tttayaccca catcataaat 230280
caccgagagg gagaattagg cctgtggacc tccctttttg tagtacctca taygtaattt 230340
tttttttktt ttttacasat tcatgttttw tggtacaagw gaacgtttta taayraaaag 230400
gcttttttgt tgttgttttt attctctata amaatacmtc trggtgmaaa ttgttaagaa 230460
agctaattat tgtatcttta catgactcta aatttggtct atttaaaaag tcaaaayata 230520
grcatttgga aatgactttc tcctytcakt actgaagttg agagggagaa ggaaaaaaag 230580
tgagaaattc cagtgcctgg atgwtcccag gctaatttct agacaagtga gttttgataa 230640
gttcaagttt cagatgagaa tttctttttt cttctctcat tggytttccc acatcgtgar 230700
ttaaaatgtc tctgaaagag tctgaaaaaa tatatatatt aatgtggaga attayttaca 230760
taaaatttta ataaactaat atgagaatga gaccctccaa taaatattgt ttagagttat 230820
tttaatagtc ctctccccta tcataaccca tttaaaaatg tgggtatata tatatgtgtg 230880
tgcattcata aaaatttagt gtgcagttct tagtttttct ttatgcaaaa cacacaaaat 230940
aaatgtgaat aattgaagcc attacacaga catttttcct gctaagttct gtaaatagat 231000
attccaataa agacactacc aacatcttac tttgtcttaa atataattga gagtatttcc 231060
atattaaack ttttaaataa aaatgattgg atttcaaatt gccttaaaga ttcataaygt 231120
aatattcttc accytaaatc acccagatta tttctaattg tttctttatt ttgccttcat 231180
aaatacagcc tttgattaat ttagcggaat ttatcaatct gagatatttt taccttccca 231240
cattacagca tgccatggaa tgaaaactta ctttgttgct caaatgtatc aaacacagtt 231300
tctgtggtca agttcctctc cttttctaaa tttgcttaga ggatctcata aaacgtaact 231360
cctctgacaa grgaaccatt ttagcaccaa cactgcaaaa gcttctgtgt tcctaaggga 231420
aagatccttt cctgaattaa atttaacctc tttagtactc ccatttagcc acctgataaa 231480
tccacttgag ctatcttttg ggaagagaga ggtatctggg aacaataaca cttccttttt 231540
gaacagttta ataaagcttt gtgagatttc aagatgaaag ataatgtgta atgctgatag 231600
tgccctccaa ggctctgcat tcatggatcc aattacgttt tttgtcatgg taaaagccac 231660
agtggataya ttaaatraga gtgtggttta agaatgaagg cccaggagtc tggagatctg 231720
gtttctaagg ctgacttcac ttctgctttc ttatctcact aggggtatgc agcttawcat 231780
ctttacctca gtgtctcctt ccataaagtg yccagcaaat atctgagaaa ttcttttaaa 231840
atgacagtgc aaaytgccat ttagaatcam cttggaatgt ctagaaaaaa atgaggtgaa 231900
tgttcgttca gaacgggaaa tacaatctts tgcttaattt cagatttatc atcaagtttg 231960
tcttttactt tttaaaagtc atgagatttc cagaagagga atgacatttt caaagcctta 232020
aggacacttg tgaaaacact ccttcaacta ttctttattt ctcaccaaaa ttttgactct 232080
ggcttttctc caacttcctc tcttccccaa ttcccaattc caacttgaaa agagtaattg 232140
caatcttaac tttttccatt ctggagtatt ttcttgcagc cgatttgttt catataattg 232200
taaatttatg catgtcagat tttgttttag atgcacgttt gctggcttta gtcagtcaat 232260
ccccaaaccc ttaaactgat taatttcacc gtgaaataat tgattacgaa tttgtagcay 232320
tatctgactt tattttaaaa tgcaagttga tagaacattg tcatttattg attaatctat 232380
tgccctttgc cttgagataa ttttgaagaa gcagaatagt gccattagta agacaatatc 232440
tatgtattac aaatgatcat gttcttaaaa tacacaygca cacacacacg cgcatgcaca 232500
cactcacact ttctagtaat aagcagtgtt ttgagtaaaa tcttttgaaa gatgtttagc 232560
aaatcgaaac aatttctgtc ttcctatgtg atgcctgcaa ttatatggtt tagatattta 232620
ttgaaggact tgggaaacct catagtccca ttggcattat tctcaacata tcaaagattc 232680
attcagtata aataaataat ttcattactt ataataataa aagttatcat ggaaaatttt 232740
ataacctagt aaataggatg tcatagaaat attcaacacg gataaataaa atatatacat 232800
agtttaaatt agaacacctg ttatagaatg gtacagtcta actctctggc caggtaagct 232860
tctagcatga aacttcacac aatcatacct acaatatrtt cttgcctaat tccttgttcc 232920
aaaggaaagt ttgataagga agttgaataa tttagcttcc ttttagagat ggtagagctt 232980
atttaagtag ctttcctkta gtacaaaaag attaggcagc tctgattgga actctagatt 233040
gaaaatgagt agaaataacc tcttatagaa cacgtctaaa tttaactttg cttcacaccr 233100
ataaactata gcctctacta ctttatagac agattatagc tcatcagtag gactaaaaat 233160
cactgtggaa ttactctgca atagtcctgt tgctatgtct ataaatataa tttcagtgag 233220
tgacttttcc attttctagc tgcttggcta tacttttttt gcgtggcaaa ctaaagggct 233280
ttaggaatat ggtaaatgac aaatttaaat agcctcagat aaaacatgaa agtcaacatt 233340
aaattatttg gttaaacatt attttcagaa caattttaaa aaataatatt ttgcaactga 233400
ttttaactta atgtttatac tattctaaaa aggtaaaaaa aatgcaatgt tgyttattct 233460
cgttaagcct aacatgaaaa taaaagcatt atttagggga aaaagtccca tttaattatg 233520
tgaacacata attaaataat tatcataaga ggcaaaaaaa gatagatagc atcagatatt 233580
gtagcttggt agagcttcag tactaggggg tcaaacagtk gaaaataatc tgggaaacag 233640
ttttaagtgt tttatattta aaacacctac acacacaaac acacacacac acacacacac 233700
actctcacgt aggcagtgtg aaatttacat tgttcctttc ccatgttatt gttgtgtatg 233760
ggcaggctta tttttcacat atttccctct caatagcctt ggggttctaa agagagacac 233820
aacattatca cccaagatgc ttgacaaaga tgggtatttt gagggtgatc cagatttact 233880
gatgatatga ggcctggaaa tctgaaaatt taacaaactt tcctagtaat ttttataaaa 233940
aacaaaattc aagaaaaact actgcatgaa aaaatgtgaa gaagccagtg gatactttta 234000
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
170
aaaaagtgtt aaaatggttc ctatgtaata gacaaataat ctctgagcta gataaaagtt 234060
caacatgaag tataatctaa tattaaaaag cccagagaag ttgctttcgt aagttccaas 234120
attagcattt agctttctcc tggttaaaag tttaaaatga agaagataca tactctgcat 234180
agggctgagg aaggtaagag acccaaggac ataatgatct ctgtaaatgc ctctgtgcca 234240
tttccaaata gccgtcctca tgccttctct tccatcyttc tttccttgtt accgtctctc 234300
ttccttmttc tgtctccttt gctgcaacag tatttaagtg gatatataat acatattaac 234360
tctatcacat cttttaacat acatgttggt ttaatgactg tggagcgatt gtaggaattg 234420
tccattttac ttaatttttc agaggttttt ggttaagaca aaattccctc agagactcaa 234480
atgtcatctg ttgattgaaa tatacatctg tgttttgaga ttaagcccaa acgaagggtg 234540
gcttctctct ctggatcgga ctatactttg agtcatttag ttacagtaaa acaaaaatat 234600
caaaatggca cgaaaaaatt aactgtggtg cctaattctt tgttcctcat gaaatggatt 234660
gcctatacca tacttaaata acatgtgcat agcctttcca aagctccaaa cctcacgatg 234720
aaatagtcct ctcgtccctt ccctgtgtga stgttgggaa gattcctttt ccctgtcaag 234780
gggcctttcc tccggtgttg accacaaggt agttttttga ggggatctta agttgtatta 234840
gtattttatg agttcttaga tagggttaaa taattcctct tactttggcg tggaaagaga 234900
atggagtgtg atagtgaatg tgggaaaaag ttgtgaaaga ctgtgaaatg agctgtaaag 234960
attactaaat cacctgacta gcagagtctt ccaagatttc tctgcctttc atcatctttg 235020
agctattttg caactttgta aaattttaaa aatatgatat aaatgcaatt gactttcttc 235080
cagaaaaatg caaagagagt gtccagtgaa aatgctaagg attattgctc tgtgaatcga 235140
ccagttttac ctgtagatga ttttaaattt gcctttgaat tggttgtaac atcttattgt 235200
ttctcttatt aatcaagtaa aatctttgat tcatgttcat gatacatctg tatgagctta 235260
ccatgtcttt aaatgcctta tcatgttaac ataacctact ttctagacaa atagsactcc 235320
ctttcttatt ttcaagtaag tagcaaacac ttatttgaaa ttctgagccc atcaatttat 235380
tttttatatg aaaggatgaa catttcctag aagccctctt ggtatcatct aggtaaactt 235440
catatcaaat ctgtgctaat atgttatttg tcctggaact ggttcttagt ccaaatttta 235500
taccatttat tcgactctta tatccttcac cttgatcaat ataaagtgca tttgccacac 235560
attcggtttg accaatatta ttctctgtat agtggcttta actcaattat caaactgtat 235620
tttaaaaatt gaatggccag gtgtggtggc tcacatcttc tataatccca gcactttggg 235680
aggccaaggg gggcggatca cctgaggtca ggagttggag accagcctgg ccaacatggt 235740
gaaaccctgt ctctactaag aatacaaaaa aattggccgg gcacggtggc tcatgcctgt 235800
aatcccagca ttttgggagg ccgaggcggg cggatcacaa ggtcaggaga tcaagaccat 235860
catggctaac acgatgaaac cccatctgta ctaaaaacaa aaaattagcc aggcttggtg 235920
gtgggcgcct gtagtcccag ctactcggga ggttgaggca ggagaatggc atgaacccgg 235980
gaggcggagc ttgcagtgag ctgagatcgt gtcactgcac tcgagcctgg gccacagagc 236040
gtgccatcaa aaaagaaaaa agaaaaaaga aaagaaaaca aattagctag ttgtggtggt 236100
gtgtgcctgt agtctcagct gcttgggagg ctgaggcagg agaattgctt gaacccagga 236160
cgcagaggtt gcagtgagcc cagatggcac cactgcactc cagcctgggc aacggagcaa 236220
gactctgtct caaaataatt taaaataaac aaataaataa aaatagaata ttttggttgg 236280
gtgtacatgg gtgagctgct ttattttatg tatgtagaat ttctaaaata attgtgcttt 236340
taccgtctag cttctataat ttataaatat gtaataaata gtagataatg ttaatgagtg 236400
tgttgtttgg cattttgtta gttggcttaa aaatgagaat gataaaaaag gcatggtatc 236460
agggcatttt aaaattatta gccatggggg taaaaaagaa aaaggaaagt gagacaagtt 236520
gccagcatgg ctacacagag aaattccagt ttccccaaaa ctggaaaaga atagcatttt 236580
atatgaggac agtgtgctta atacataaca aagatagctg ctatatatta gaaattatgt 236640
ttgttattcc ttaagcagtt atttttaatc ttgatagttt attctggtta gatatataac 236700
aagaatataa ctctagtctc ttcttgcaaa aaaaaaaaaa aattccaatg agcaagatga 236760
ttaatccagt aaagaaacat gtccagcctg gggacaaaaa aaaagtagat caaattttgg 236820
ttaggaagat taaccaagta aaaatccatt agctggaatt tattgtaaaa gccaataaga 236880
aatcatccaa gaaataaaaa actaaaaata gccctcaata tggaataaaa aaagacatag 236940
agtgattctc tttgcattca atagagactg agaaaacaca actgtcagaa tattaaatat 237000
tgctttggaa agtttggaaa tatgatgaaa gtaaattaga caattgctag aaaaatatcc 237060
ttcagttggt tccccacaca tcacaaaatt cagcttgata ccattttctt tttcttgaca 237120
aatttagggc ttttattagt gctatgacag aaagaaggaa tgctaccaaa aagaccattt 237180
gaatttactt taattatttc agagtaggga aacgataatt ggaaagtagt ttataacctt 237240
gagtttgtaa aatctgtaaa ctctcacaac gatgtgaagg cagagaaagt atcaaactca 237300
gtcccctata ataagctcat tacttcataa aatatatatc cccttcatct atgtgtcaga 237360
aatgtttaaa attttcacca ctggtacatt atttttgggc cttacatttt tgtggatttg 237420
gtgaatacct gaaagaaata aaataggatt ggataatgtg aatttctttt acactcattg 237480
tcattattag aaaataaagc ccaaataaaa tatgacagag cagaattagt tttaatacag 237540
gaaaaatttg caagttgaag aggagaaaat gcagccagga actaacggta cacacctagg 237600
tggttaagac agtgtggatg gtgataagag aacataagga aaattctgcc ctccagctac 237660
tttgaattta gtgttctgcc tagtatgaat attattgaac cctatggtat ggtacttaac 237720
tatctaatga gatgataact ctctcctacc tgtagaaaat gtagatgcct tgtctacttc 237780
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
171
tgcttatata catgctgaaa catactgatg tctgctgtct tcttaatttt acactaattt 237840
ttaaagtaaa gattgatttg ataaaaaata tgcacttgga aaaattattc tgctattccc 237900
acatttcatg ttcatgtcta tttacagcta acaagactag cacgcaaata gatatatgct 237960
ccaagatctc gcttcttttc atgtctggct tctccctgtt tacccacaat tattttcata 238020
atattttact gtgattccac aaaccagaga caaatctctg aagggaatag tgttccaagg 238080
catggccatc attagaagac aataagcttg ttttccttcc aacattctta gctttgttga 238140
aggctaagtg gaagaaatta acatactgca tgcctttcaa tgaaaattgt ttctaattat 238200
tttgcttctc aaattattcc acmaggcatt gattagactt tttaaattca tttcatatct 238260
gtcactctca gctaacattt gtaatttttt aattgttgtt aaagagaatc tattaattga 238320
aatataatta tcctctttaa taaaagtaaa taaaattact tgggtagcca acatattcaa 238380
gtaatcatca atcttggtca gaaattaaaa gtaagatgag catctaaact tggcactcaa 238440
agactgacca tctgcacctt tgaggcaaaa taaaattcag tttaggaaaa ccttatgaaa 238500
atcaatgttt taattatgct atcaagggct gtggtaggca gaaacttctt tgctccaccc 238560
cccaaaaatg tccagttctt aatcctgaaa acctgtggaa tcttgtgtaa caaagggact 238620
tcatagatgt aattaatgtt aacgaccggg aggtggagag tgacctcggt tatcctggtg 238680
ggtccaaggt agtcacaggc atctttataa tcagtgaagg tctccctgct gtgcttagag 238740
agggggatgc tggaagaaga gtggtcagag aagcaacatt gctgactcya aagacagagg 238800
gcaggccacg agccaaggca tgcaggaggc ctccagaagc tggggcaggc aagagaatgg 238860
actcagccct ggagcctcca gaaggcatgc agccctgccc attccttgct tttagccagg 238920
taagatgtct gtcagcctga tgagaactat gaaataatga atgtgcttgt ttttttcacc 238980
actaaatttg tgcttatttg ttatagcagt gatagaaaac taagacaagg ctatatcttg 239040
gcatgtcaga ttttaagtta tctgctatag tttagaaaag cccanagaag gagctgcaat 239100
ttgtctcttt gaaaaaaaaa aaaaaaaaaa ggatcacctt ctaggggatt aaacattaat 239160
gggctgggtg ttgtggctga cacctgtaat cctagcactt ggggaggccg aggcgctgct 239220
gcactccagc ctgggcaaca tagtgagacc ctgtctccag aaaaaaaaaa aaaaaagaaa 239280
aagaattaaa cgttgacaga ttattaagtg aggcactgtg tgagacctag cttgggtttg 239340
cgcctataga tatttaaaag ttgatccagg ttttcacttg aaagcagaac tactgcctta 239400
aattcccact tcacaaaaat aaatcatgga ttgagggaaa aatttacttg tttgctttat 239460
aaaaagagat atcgatctct tcataagtta tatatgtttt acaaggttgc actgtttgaa 239520
ctgtaagtgt gaatggttgc taacactcca gaaaccaaga ggtacatttt aactggaaaa 239580
attttcttcc tgtatcttac aaattaattg aagtttgtct acgcttgaaa atatgtcaaa 239640
agtattatgt agctttacca cagttttatc taacttctag aagaatttaa attcatataa 239700
agataaagag taacatacca atagagttta gagagttttc agatttgctc agaagaatgc 239760
tcytttgaaa acctatgaag tagattttac ccaatgtata tctggatcta aaaattaaag 239820
aaaatatcag tcgtgttcag attcctttat accctgcaga agaragaaag aataagcaac 239880
atcartggag catataacat gtatggttta gcactttcat atttttaatc ttaactattc 239940
agccaaatay gtcttatttt tttattttta tagatgaaga tattgaggtt tgcatttttt 240000
ttttataaat tgctcagtca tacagttggt aaatagctga cagragagtt cactccaggt 240060
cttactggct ctcaaacctt tgctttttaa aaatctccaa actagcgcct ctccctttta 240120
actgcaaaat aagcacaaag ttatcccagt tctacacagt gctaaacaaa ttcctgtgag 240180
caaacaatta gcacaggcag atggagtgag ggggaggtgg tttataacaa tggaaagctg 240240
tctgcctgct gtggattaaa gattcaaact ctttgatcct cctcccaggg ataggtgagg 240300
gcctatgtct cctcctcatt aacatgagtg atccttggct aggttctcct ttgactgaca 240360
gaatatggga gaaagtaagg ctgaaccata tactgggctc aggcttccaa ccctgacatg 240420
ttccacttcc tgtctccagg aacattcacc ctgggagctc tgtgctgcca tgcaaatgtc 240480
acattgcact gaggccrcca tgctgtaaaa aaccccaagc tacctacctg aaaagctgga 240540
gakaatcagc acccatcagc ttttccagca ttttgggtcc tcccagctaa atcatcrgca 290600
ttgtgaagca gagatgagac ctcctgccat gccctttcca aatcctggac caacagaatc 240660
atcatataca ctagtaagct tttactttaa gccactaatt tggggtgtag ctcttttgca 240720
gcaaaagatc atcagaacac tgccatgcag gagctgataa acttgctcac tsttatgtat 240780
gtatccaatg actactcaca cacacattac ttgcttcact ctactttctg gctttccatt 240840
cagcaaattt taagaaayga aaatgttatt cgtgggaaat taactcaaga tcaatattgt 240900
tgtagttaat ctctttgtaa atggtaaaat attaaattat tgtgagtcat ttttatttaa 240960
agaagtttgg ttctttaaat gaaagaagtt tgggtctttt gyggatactc tgcatataga 241020
cattctagac atgaaagaaw gttgaagaca aagaatgttg aagaaatata gacatgaaag 241080
actgttgaag tttggttttt tgtggatact ctgcatatag acattctaga ctggagtgat 241140
acatcttgtt caggtttcta tgtttttaaa atgataactt gacacgccta ccaatgccaa 241200
tttttaggat atatatytgt atatctgtgt gaactaagga aaattcagga atgattaaac 241260
ytacatattt tgccaggaga gactggataa tgtaagtctt tatatttttc acaacttcaa 241320
gtttatagca tccaaatgag caattgctga catacctagk ggatttctct gcaggttcaa 241380
gtctgatctg gcctgagggc aacactctta ctgagtgtgt tcctaggcac tccttggcag 241440
ttggctccag gccacaataa agagccctga tgattctctg agcaggccca acttccattc 241500
acattcrtgg gaatatgagg atgacttgtg atcttcagga cttagataga ctctttcagt 241560
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
172
tggtgtaggg taagctcagc tcatctctag agacttccca cagtggagct catgcatgam 241620
tctgtgcagg tggcacagga cagccagaga caggcaccta aggagtgcac taccagcagg 241680
tggastctcc actgagggag gtagacaagg gagaaagcca ggtgtccaca tggagcaggc 241740
cttactcagg grgactgaga ttttgctcta cacatcataa aacgtggagg tcattaatgg 241800
aatttttcac aggacatgac tgccatagcc atgatagggt ccctggctaa tctttcaatt 241860
rtgatagcat cataagataa ttttgaatat gaggagagaa gaataactct agaactgcaa 241920
tatccaatat ggtaacccct agcaacctaa ggctacttaa actaattaaa attaaaactt 241980
tagttcctca gtgccactag ccatatttca agtactcaat aaccacacac acttggctac 242040
catgttggac agcactgaca tagaccattt ccattactgc agaaagtcct cctatttgac 242100
agtccacctc tggaaccaat ccggagtctt tagggaccta aaagactgag gtgctaaatc 242160
tcagagcagt actctgctta atgcttagtt aaaagacttg ctaatctata tagttgatct 242220
agagaacttt aaaggcagct agttcgtagc aactatgttg ctggaccttg aaactgtatg 242280
tcaggaactt ggtgttctag tggtgacttc tcttttatct accatgttca cacttttcct 242340
accactcatt tatccattca gaaagtattt cagaagtccc tatgatttac caggtgctat 242400
tkcagacact gaggcactgt ggggaacaaa acaaacaaag tctcctttct cagggatctc 242460
acattccatg tggtgatgca gactgtaaaa attcacacac agaagatact ttcatacagt 242520
aggaagtttt atgaagaata tttcaaaagg ggtgtggggt gggagaggtt gatgttcagg 242580
tgtttgcttg agaatgaact gttcatacaa agaatcaata attcatttgt tccacaaata 242640
tttattgagt acctgttatt agcaggctac tttattaggt tgccagagca gggttttctt 242700
agcacaatta aaacacaata acatttgtta gaaattcaaa gacccatgtc cactcttgca 242760
taatgaatca gagtctcgag gttatggtcc agagactggt gtatttaaaa atcactgaag 242820
taattttaag gtatagccag aatagagagg acaccggcat tcttcctgaa actcaacaca 242880
ctagacaatg agaaatcatt aaaatgaagt aaatattttg attgagattg ttttggcttc 242940
aaaattaata atagcttgga gaggaaagaa ggtaaattat aaaagacaat taagaatctc 243000
ttaaatgtat ttagataata gttacagagg gacaaaaatg agtaggatct gtgataacag 243060
aaagaataaa aataaacaaa aggacttaaa aaagtaagaa taagaaagaa gtcaacagta 243120
acccagaaat tttcaacctc atgtctaaga gaatgatgat gctatttagc aatatatcca 243180
aaccaaaaat actacgagaa gtaggttgtg ttcacttgtg atgttgtaaa tttataatta 243240
ctttttcttt attttggatg catgcttttc ctttttctga agttctgaga catacaaaaa 243300
caataaagaa aaacatgatt ttatgccaga aaataagata ggaacaattc ctcatgctca 243360
atataatttt agcctcccac ataatccaaa atatatgtgc agcaaattgt gggagtttcg 243420
aaattagatc caacttctta ttacagttaa agataaaaag aaaacaaggc tttgtctttt 243480
ttaggatctt ttttggaact tgcagtataa aaatactctt tcaaaaaaca taactcaaca 243540
tcaaagtcca ataaaacagt aaactggact aaatatattc gtatattagc ttgacctaag 243600
tctgggaatt gagccagact tttcaaatta tactatcatt atttacagaa aaaggaaatg 243660
ttaactaaca ttattaaata aaagcacata tacacatgca taacaggaaa caaaatgaat 243720
gttaatgtta acaaatgttg aagatgtgtg tgtgtgtgtg tgtgtatgtg tgtgtataca 243780
aagcagataa gatattctct tgagcatgat tggattggaa atagtagcta tgccagggga 243840
aattttatgc aatccccttg gctgtgggct acacatttat tgtgttatac aaatatgcca 243900
aaaaaaatgc catttacaca gttgcctaaa acaaaattga aattatacat tagtgtttaa 243960
agtttttttt tttctttcgc ctccttttct taatgaatgg cagataatga aatttaggag 244020
tttgcaaaaa caaacgtagt ttaaattgta ccttagttgt ctatgaaata caaatacatt 244080
ttatatattt atggaaacat ttgtgtgtgt tcagaaagtc catattttgc attcaagatt 244140
gaccctgttt taagtcatat ttcatttgct acactcaaat tgactaaagg cagatacttt 244200
ggcattcact ttttgattca ttattaaggc attattttga ttgattctgc ttaaggtagt 244260
tttcctgatc agagtagacg tttaggccac ctatctagac aaatatccca ctwtcctatc 244320
tgaaatattt gatctctcct tacccattct agggttttgt gcatctctaa gatgatcatc 244380
ttggtgtggg gtcctgatct tcccagtgac ttagcagcac agtaatttgg ctgaaatgtt 244440
gatgagttca gacaagaaga aggtgatgat gacaagagag cgtcacgggg aaattctgcc 244500
ctgaggaagg aatagtttga ggctggagag atgtgctacc cccgccactc tttctcaaat 244560
ggtatttatt cttgaaagac agtgtaaagt gtctgaaatt gcagaagcaa agtggttgct 244620
gtagaaatac ataccatgac gtgcttcaac tcgtttcctt aaaggttaaa gaaagaaaaa 244680
tgtgcatctt gaagaaaatt ccaaaccctc attgtgagga gtaatccaat atttcaattt 244740
agaaattcag agggttttaa ataagaagca attattctag gcaaaaagca aatataaatg 244800
ccagcagtca aaaaaccagt gaaaagatat gattaaaact gagatgtaaa aaatagatat 244860
ttatctgaag ttcttgactt ttaaagtcca caggcatttt cccttaagaa aagaataaaa 244920
acattaaatg ttaaagaaaa acataagaaa tattataaaa aagataatta ttcagaaaat 244980
attagtattt tgttaccaac accaaagaca aacagagtat ttttcaatga ctggaagcca 245040
gtttaagtga ggaaaaaaaa aaacacgtta ttattactgc tattatccat tatttttatt 245100
tttacttttg gcagtgttat ttgctaatca gctaacgcat ggtagtggac ttgatctttt 245160
atgtattata aaggttgtat cttctcattt taagggaata ttttaactac attgtccaat 245220
tgtacactat aaatgcagca agaccaggtc aagtgaaact tcagtgggcg agtctctttc 245280
ttttcttgtg tgtagggctc tccctcccac ctgctacctt gactttttag attccctgtt 245340
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
173
cccctggtct gtgcttgtat aatatacaag ctgtccttga catagcacgt tcctcttttt 245400
tccttcatta tttttaaatg gttataatat actcttaaaa acaaatttga atattactaa 245460
tagattctaa tattatctta ctctctgaaa ttaagtagtg atgtatattg tgttaaacgc 245520
ttgtctatgc tgatgcaaca tatgggcagg tctctctctg ggcctatatg tatttgtttc 245580
atatcgttgt acacagattc attcatttct ttaaatgggt atataatatt tcagtgtata 245640
aattaatcac tcgtaagtgg ctagtaattt aatttgttgc tacttcctcc caagatgaac 245700
agtgctttag tgagcatcta gccatttctg tatctgtcta cttattgatt tatgcatata 245760
ttcaccacct tcttcttcca caaatagact acacatcctc ttcatgagag tctacacaaa 245820
aatgttacaa ataacatttt taacgcaata gttcccttaa gctcacactt gtaatgtttc 245880
tgcccagact taagccagcc aaatgtgtgg aaataaattc catttgtgta ttaaatatca 245990
aagataggga acattcataa caaatgtaaa catagccaag gattcattga aacatttcca 246000
cataccatct ctccaaatct ggttttaaag agattgtaac ataatttcag gaataaagac 246060
cttctggaat tgagatttat ggaaaagaga ttatagctcc acaagattct agggatgcaa 246120
aaggtctgga ggagcctcca ggcacaggca ctttgtttcc atgctgaaga ttcaatgtgg 246180
gttctgaaaa tgctgcttta gcaagcacac atttgttcca ctggtgttgg attttctatt 246240
gattaatagt taccattttt ttcttctctt aggaaagaca acctgtaggc acagaaatca 246300
ttgctctgct tacactgaaa tctcctgctg actttgagag ctgagcattg gattttgatg 246360
ggagagtgaa acttagtgaa gaaatgattt gaacctttgt tgatctaata cttctgtgat 246420
acagttatct aaacagaatg agtctaaagt cagtataaag acctgtgtct ctccatgttt 246480
tgctgcttat aattgcagag gaacattttg agatagaaaa ttttatccct ctttcaagtg 246540
actttttata aaacataacc ttttaagaga ggtcattctt ttgaaaaatt gtctgaatac 246600
aaaaaagtaa ctgaacagca agggattgta gccataatgt tcttgaccac tttagattga 246660
caaatagtat ctcaaaattg atcaggttct ggagaatcta ttgaggttgt atggagtaac 246720
caagtgatgg aagaggttgg aagtgaataa ttttatgtgg tattatgtga ttttttttgg 246780
tgggggtagt gtctggagct gagcatgatg gagcctagat ggggcagcct tctaatgctc 246840
ccagtatttc gcaaatcata tgtcacgtca aaattgtaat gacaaagctc acagcagctg 246900
cctacgccag gtttggtgcc agctctaatt agagcattga tcatttctct ccccttcatg 246960
aatgcacatg agtgcacatt ttcatatata agggcaaagg acatttcaaa gtttggatgg 247020
aatctttcct acttagaagt aataaaaaac aatactttga aatcttacca aatgttaaac 247080
aaatagcaac aatttttcca tttgaagatg tgtgtcttaa ggtctgttgg atctttcaaa 247140
tttctatttt ggacatggaa actacagatg aaatttaact tactcaaagt tacacagaac 247200
tcctggctga tctcttttac ttaattcttc taaaatctaa agtaagaata attttgaaat 247260
tttattggta atgcttaaat aacaaaagtt actttaatat gttacatgtt tgaagtttca 247320
tttatactta atatctaatt taacgcttgt gaaaatatta ttcagtattt ttttttcttt 247380
tctaaaatga cttgttcagg gctccttttg ggattttaag tgagaaaaac tctatttcat 247440
aatattgtta ccatgctcat ccaataacac ttcatagatg gttagccatc tctaaaatta 247500
aattttgtag ttgaggagca ttgaaaatat cacctatatt tggatttctg tttaacactt 247560
caaaatgcat tttatcataa tttaaaattt gatttaaata caaacctctt tatagaaaac 297620
ctgataaatg tagttttatt tgtttgcttg cttttttttg cagggaggga tattcccttg 247680
ataccactct gtctttatga ctcatcggtt atttataaat gttatcatcg tttttctgat 247740
ttttaaataa gtttcagaat taatacattt aactgaataa atcaaccaat aatgtcaaac 247800
ttaaaatgtg tttgtaacaa gagtcagcac ttataatgaa aaatataatt aattaagagr 247860
ttayaaaact tataagcaga gtttactctg cttacagaag ggcaaacatt tgttatttga 247920
tacaacatat taagtattta tcccatgcaa tcactgtcct aggctttgag tttatagtga 247980
tgatcaaaac gatttacagg tttcaagaac cctgctcaca tacagcttac aatcctatgt 248040
gggaaaatga taatagtgaa ataattacat taattaatat atacttgatt caaatgtaaa 248100
taattattct gaaggaaaga cacctacatc aagagagctg gcttaaattc ggggatcaag 248160
gaagcctttc caaataattg ttgatgggat tgaaagacaa ttgtgggatg agatgaccac 248220
ctgggcttgg tatgggggag atacaactgt cagtgggaaa gccctggaga tggggaagaa 248280
gaacttcttc aatggagaga agttcctgag tgagkagaag gcaggtgacc acagtgtgaa 248340
gtgatgctat agaagccaac cacgtggcta tgcaagcaga aggaatttat ccaaaaagaa 248400
agggggaggc attagaggga tttagtgtgg agagtggtgg tgacaagatc agatttgcaa 248460
cttgcaactc tctctcaggt tgcagcatgg gggatgatgg gatgagccca gagtggactg 248520
acgcatttcc agtagtccag gagagtggca tgtggcatga actgtgtgag gaagggggag 248580
ctggggggaa gaagtggggt aacaacaccc tatttgttgt tttgcttctt acactttgaa 248640
aaatatttca aagcaggaat gctattccag acatttaaca cctggaacag gaataagtac 248700
caaccaaata tcgtgggaga ctgacgaatc agaatgaaca tcagctctgc atggcagtat 248760
ggttttaaaa cactttcatg tctatgtaaa caaagtaaaa atgttaaaag attattttac 248820
gcctttggtt atcagatagt cagactttta gtagtttata ttttattgca gtctgatgag 248880
gtctgctttt aatagtagtt ttctcttctt cccccaaccc cattacatta aaatggcaaa 248940
tgatactttt ccttgttagt aagcaaggcc aagttaggat tatcagaaag tcaataccta 249000
aacacaaaga atagtgcagc caaacccgga aaatattgtc tgttttgcca agaggaagca 249060
tctcactgag tatctggaaa gctcattgtt tctcaattat ggttatttta ttagttgcca 249120
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
174
taactcagct atagtcataa tgtaactgac cagcaccgat gatgaaatca ataaccacta 249180
caacagagta aatgctgttt ggggtgcaag aaacatcatt tttatctaag tgaaagtaca 249240
tctcatttaa atgtatttca agttgacatt ttgtatatat tgttaataaa cttcaatttt 249300
actaaaatct ctgcaatatc taatcaatat actgaatgat atgctctccc cttttgtgct 249360
caaataggat ctgtttatat tttagttaag aaatgctatg ccattttatt atattagaaa 249420
aatatttact ggtaggaatt tggtttaaac tctccctgtt attcagctgg gaagtatatt 249480
acaagtaagt ctttaaagac tacaattgga gaccgggcac ggtggctcat gcctgtaatc 249540
ccagcacttt gggaggccaa agtgggtgga tcaggagttc gataccagcc tggccaacat 249600
ggtgaaaacc ccgtctctac tgaaaataca aaaattagcc aggtgaggtt gcaggcgcct 249660
gtaatcccag ctactcagga ggctgaggca ggagaatccc ttgaacctgg gaggcagagt 249720
ttgcagtgag ctgagattgc accattgcac tccagcctgg agaacaagag cgagatttcg 249780
tctcaanaat aaaaaaaaaa aaaaangaaa aaaaaagact aaaattggag agtttaacgt 249840
atcaaattta ggagataaat ggtaaataat atgtttgtat atgaaaatat tttaatacaa 249900
tatttgaaat gaagaaactg agatcacaca actttttgag cgttgagttt atacatttat 249960
tttctttctt tctttctctt tctttctttc tttttttttt tttttgagat ggagtctcac 250020
tctgtcaccc aggctggagt gcagtggcac agtctcagct cactgcaacc tctgtctcct 250080
aggttcaagt gattctcctg cctcagcctc ccgagtagct gggactacag gtgtgtgcca 250140
ccacgcctgg ctagcntttt tgtatttttt tagtagagat agggtttcna ctgtgttagc 250200
caggatggtc ttgatctcct gacctcgtga tctgcccatc tcggcctccc aaagtgctgg 250260
gacgtgagcc actgcgccca gcctattttc tttcttttac ctatatcatt tcattttttt 250320
attgatacgg aatattttac atatttatgg agtacatgtg atattttgtt acatgcatag 250380
aaggtgtaat tatcatcacg gttttgggga tatatatccc cttcagtatt tagcattttt 250440
atgttttaag aacatttcac attctctctt ctcgctactt tgaaatatac aatacattgt 250500
tgttaactat agtcactcta ttctgccatt gaacattaga acttaaaata ctttccagcc 250560
aggtgtggtg gctcacacct gtaatcccag cactttggga ggccgaggtg ggcgggtcac 250620
ctgaggtcag gcgttcaaaa ccagcctggc caacatggtg aaatgtttgt atttgtaaaa 250680
ctacaaaaat cagctgggcg tggtggtggg cacctgtaat cctaactact caggaggctg 250740
aggcaggaga attgcttgaa cctgggaggt ggatgttgta gtgagcccag attgggtcat 250800
tgcactccag cctgggtgac aagagcaaaa gtctgtctca nagaaaaaaa aaaaaaaaaa 250860
gaacttatag cttccaacta actctatgtt tgcacccatt gatcatcttt tcttcattcc 250920
ccactctcag ccatacacac ttcccagcct ctggcatcta tcattctact gtctacctac 250980
atgagatcaa catttttaat tcccatgtat gagtgataac atgtggtgtt tgtctttctg 251040
tgtctggctt atttcactta acatagtgac ctccagttcc atttatgttg ctgcaaatga 251100
cataatttca atgntttttg tgcacaatta gtattccatt ttgcttatct atttgttaat 251160
tgatggagat ataggttgat gctatatctt tgcaatggtg aatagtgcta cagtaaatat 251220
gccagtgctg gtctcccttt ggaacaccga tttattttcc tttggataaa tacctggtag 251280
tcgaatttct ggatcatatg gtacttctat ttttaatttt gctcagaaat ctccatagta 251340
tttgttcata atggctgtac taatttacat ttccaccaac agtgtataaa agctcctttt 251400
tccctgtacc ctcaccagta tctgtcattt ttttgttttt tttagtaata gccattctac 251460
tggggtaagg tgatatcaca tagtggtttt gattcacaat tccctgatag ttagtgatgt 251520
tgagcatctt ttttatatac ttggtggtta tgccatttgt atgccttttt ttgagaaatg 251580
tctactcatg tcctctcatg tcctttgcct actttttaat aggattattt gtgagatttg 251640
tgaggttgtt ttttgtttgt ttgtttgttt gtttgttttc ttacagttga gctatttgag 251700
tcccttgtat tttctggata ttagtcacct gtcagatgaa tagcttgcaa atattttctc 251760
ccattcaaca ggttgtttgg agattctctt taaaatagct gcaacaaaca aacaaacaaa 251820
caaacccggc caagcacggt ggctcatgcc tgtaatccca gtacttaggg aggctgaggc 251880
gggcggatca cgacgtcggg agatagagac catcctagct aacacagtga aaccccgtat 251940
ctactaaaaa tgcaaaaata ttagcctggc gtggtggcgg gtgcctgtag tcccagctac 252000
tcgggaagct gaggcaggag aatggcgtga acccgggagg cggagcttgc agtgagccga 252060
gattgtgcca ctgcactgca gcctgggtga cagagcgaga ctccatccaa aaaaaaaaaa 252120
aaaaaaaaac cctaggaata aatgtaacta aggaggtaaa atatacctac aagttgcact 252180
aaaacacact gacaaaagaa attgaagagg gtgcaaacaa atggaaagat atcctatgct 252240
catggatgaa gagacttaat atgattaaaa tgatcgtatc atccgaagca atccacacat 252300
tcaatgtaat ccctatcgaa ataacattat tttttcacag aaaaaaattt aaaaatcctg 252360
aagtttgtat agaaccaaaa aagagcgcaa atagccaaaa ctatactgag caaaaaggac 252420
aaagctttag gcatcacact acctaacttc aaaatacaag gctatagtaa caaaaatagc 252480
atggtgttgg tataaaaaga cacatagaga ccaatggaac aaaacagaga atctagaaat 252540
aaaaccccat atttacagct agctgatttt tgacaaaaat gccaagaaca tacattgggg 252600
aaaggatatc ctctttaaaa aatgtttgca ggaaaattgg atttccatat gcagaaaaat 252660
gaaactggac ccctacctct caccatacac acaattcaac tcaacatgga ctaaagactt 252720
aaacgtaaga cctgaagcta taaaaccact agaaaaaaac agggaagaca cttcaggact 252780
ttgttctagg caaacatttt atgggggaga cctcaaaagc acagaggaca aaaacaaaaa 252840
taaataaatg gggctgtatt aaactacaaa gctgcagagc aaaggaaagt attttcttaa 252900
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
175
tccttactgg ttcttaaaaa gttttggatg ttgaccaaca catctattat gataattaaa 252960
tgatttggac atgtcaagct tgtcaggata tgcgcaggtt gcccccttta ggaagagcac 253020
agtgactctt tctaattcta tttttctatt tcttaaacat agctgactat aaaattgcaa 253080
agaaatttgt gtatgagcta gggaagatgt tgggttgggt tgagattcaa ggaaggagtt 253140
ggactttaaa atggtggaat caccagtaga ggacaacacc gtgtaccaaa aacgttcaca 253200
ggacaagcca ggttgtacac catgatatat gagttgtgat gctgatgaag gacatagtaa 253260
gcttccaata atgggtcaaa aaaaaaaaaa agaaaaaaag aaaagcatta atattaggca 253320
atgtattttg gtgcctataa tttatattct tatcaatacg gatagctcca tattgatctg 253380
tttatatata tctatttgtt tatatcattt gattaaaata tggcattgac cattggaaag 253940
gtacatctca aattatcctg gttaaatgtg aaagtatgaa gaggctgtga ttataagcat 253500
ttaagtttca atcaagtagc aagtgctgtc aagatggtat atccaatcag atattgtgag 253560
ggacatgtga ttgctataga ttattctgct gtcttaagag ataggctgtg gatattcara 253620
ttgtgatttt ggagtttaag agggcaaagt aaattgcctg ctgaactcac agtcatgttt 253680
gagagagact gacaggaaaa ggtaaaaatg aatcatcatc tacaactggc tggattggac 253740
ctgacggaat aagatccagc aggaaaggtg tgtgactacc attcctggaa ctgggttttg 253800
ctgaatcatt ggacagtttt gctgaatcat tgagcataca agttttgagg gatacatgtg 253860
catttagaaa gtaacgaata agaatattca taattatctg ctacttttca tagcccatgt 253920
attaacacca aagcaatttt agatgagcta tcaataaaaa tattaaaaaa gaaatcacag 253980
tctatttatt taacacacat tggttatagt caacaaggta atgtgttgtg ctgcaataat 254040
acaagtaaac atccgtctaa gaatccattg tttagtaggt attactgtac gaatttttaa 254100
caaagctgct ttaaacacta taccaacagt tttaaataca aaagcccagt ggtcaagctc 254160
taatataaat gaataaatgt ggccttctgg aagaccctag agagacaaca ggacacagag 254220
tggagcacag gaaagaaaga agtccacttc ctgcataaat ggcggcggca actctgtttc 254280
acctgacaga cgcctcctcg aaatgcagtc ccatttaaaa cattttttga ttgttttaga 254340
taaaacttat aacattgttg aagaagcaac taattctaga tatttttata attttaagct 254400
gccagaaaaa gtaagtccac aattggaaat ggcccaaggc ccccaggatg taccttacct 254460
atgccaatat tgagaagatt attccagtgc aaaaggtcca tgtaactttc attaacacta 254520
tggtttgttg gaaacacact aaaccactgt tccataattc cttttttttt ccagttactc 254580
aaagcaaaaa taccagaatt ttatgtttac aaatgtgagt ttttaataga aacatgcaca 254640
gtgtatactt tatatattgc cggaattgac ttatcgaatg ataatttaac aagattgttc 254700
atttgaagtt tatgcccact tttataaata aaagaatcat tttggttgtc ttcctctctt 254760
tctctttatt tttcctttct tatttcagtc tacaactact cccccttctt ctggcccatg 254820
tggagatatc ccatttccca acctgctccc tgttcagtta caaggaggga gggaagacat 254880
ctggcagagg aagattccca gggaactatg aaaggagata gtgactactg cagagcttgt 254940
tacaataaca gactattaag gctggtgcag tggctcacgc ctataatccc agcacttcag 255000
gaggccgagg agtgtggatc acctgaggtc aggagttcga gaccagcctg gtcaacatgg 255060
tgaaaccccg tctctactaa aaatacaaaa attagccggg tgtggtggtg agcatctgta 255120
atcccagcta cttggaggac tgaggcagga gaatcacttg aattcaggag gcacaggttg 255180
cagtgagcca agattgtgcc actgcactcc agcctgggcg acaagaggga aactccgtct 255240
caaaaaaaaa aaaaaaaaaa accacaaaaa acaaacaaca acaacaacaa aacagactat 255300
tagcactttc tcatatccct tgtttgctta agaatagtat ttgaataata taacggccta 255360
tattttatct acctactctc tgacttcctc tggtttggag gggggtgaat catcagaggt 255420
gttgttgcac agtatgtgtg tgggtaaata gggtcccttt tctctactca tcttttctat 255480
gcaaaataaa gccattggtt ataatgaaga ggaaatcaga ggggaagagg tctattttga 255540
atttttgtaa ccgaaaaagc tcatgatttt atgtgaatat tccattggct gcttagcttg 255600
cctacttact tgaatttgga gtttattccc aacactgcag cttacatgca ccaaggtttg 255660
ggaacattct gtaaaatttc cttgaggaca aatatccgct ttgttgtatt ctttgttatt 255720
tatccatttt gccaaattat ctgcaagtag aaatatcgaa ataagaagct ctttagcaat 255780
ttactttgga tattggtttt cttttgaagg acagttatta aaatagcttg taggattact 255840
cattttcrtt tttcttcttt ttaaatataa agcaatgtca tcactttttt ccctgtatta 255900
tatttctcct caataattga tatgctacat taaaggaaca caaaatggtc ttaattatgc 255960
aataatgatc aaggcaaaga gtgtttcctg ggaactaatg gttgcctgag aggaggtgat 256020
ggcttgaggt ccagctggtt attaagccgc aggaaatgct gcaggccaag atttgtatta 256080
tttctctgag atgaaaatga acccaaaaaa aggcaaaatg ggtttttctc cactaatggg 256140
taaaatgaac tcattttgga tgcagaagac ctttatgtag aaggaatgta ttccataaaa 256200
gcaaaatcaa aatgttcagt ggtctctgct ttttgtttaa aatatagtat agcacaaata 256260
atagtccatt attgatttta aatcttgatg caactaaaaa tatcatgcaa cacttgagtt 256320
tttgtctagt tctagaactt ccatagaata ttatgtccaa caattgtttt gatagctttt 256380
gtaagctaag aatatatttt gtatgcattt aacattgaaa atggttactt ctgaaaatat 256440
tcagaaaaca gctatctcat aacaaaagaa tacaggcatt attttctttt ttttctggag 256500
ttcattcaaa aaatattggg gaaaggtgtc tcattaaaag atgcgttgag atttgtggtc 256560
tctctgcatg attagagatg aatcacttaa ccttcttaaa gaaactgcct aatcaatttg 256620
taaagtagtt agtatagctg cccccatctc tgatttgtag taggattatg caaagcagag 256680
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
176
tattttgtag atattaatat tactaatata aaaatgtagt tattactata tttactttac 256740
catcttaacc aagtgaaaca atatatttta tcatattttg ccatttttgc cacccctgtg 256800
acatggggta tgtcacaggg catagtagac aactgaaaga gctcctaata gtcaaaactg 256860
gaaaagtttc agaacaaaat taaccagtag tattagatta taacccaaaa tacaaaataa 256920
atgtttctga attcattttg atttaaatga atgacagaat acataagtca atgggggaga 256980
gtttattctt gcatgcagaa gaatccagat aatttatgtg gatgccctgc cttcaaagag 257040
gcagagccta actctcattc ctggacagca cagagtgact tccttccaaa gagtacagga 257100
ccgaaagggg tgaccaaaag attgaagaaa gatcaagcag ttatcatgag taaagcaaac 257160
cttgacaagt ttatcgcaat gtttagaatt ttgttatatt caatcgagga ctttacaaaa 257220
ttgtgttaaa ctttatgatg gatatgggtg tccttcttaa tagagaaagt tcaaaagccg 257280
ggtgctttgg aggaaacatt atcttttgtc tgccactata aatgtgacta aaatagtacg 257340
taataagcat atggccacaa acttaaatgc attatgttgc caagaaaata tgttggcagg 257400
tgtgtagcag gccttgcaga agatttgtag gaaaaatcat aaaacaaagt acatagtgtg 257460
agatgtttgc tatacatgag gattttttaa aaagcagatc tagtagaata tgatttactt 257520
agagaagatt tgtatctctt gtgttcagct gaattatagc atctaacaca gcctgtgcca 257580
cacagtagga actcactcaa tttttgttga aattattcaa cgaatatttt attttaggct 257640
tttgcaagat atgactttgg taataaatgt agcacactta attcattgaa cactaaagga 257700
aacaaatgct aaagaaacta gtttccaggc acaaatgact tgcttaatag cacaaggcac 257760
atggtgggga ggggaggtaa ctacaagatg ccaccctgaa ggagtcactg tttcatctgg 257820
agcactagag atagtgggtg ctattgatgt tatctagcaa gactgagggg ccaactttct 257880
gagttcaaac cgtggttttt ccacctgtaa atgaggaaca acgataggac tggcctcaga 257940
gataacccat gaggactaag ttggttaatg tagagtactt agatagctgc ctaaaactat 258000
gtaatcatta tgtaaagata agctattatt aattttaatg gtcataattt aaatgaacat 258060
tctaggatat agttgcagac attgcaatac accaaagtca tttatgttat aatttatatg 258120
ctatccagga gagaaattgc aacacagatg tgcaggcacc ccactatcac cccaaattaa 258180
tattatggtt attaattcaa gacctataaa atagcatgtg tcatttataa aactctcaaa 258240
tgtccatatt taaaaacttg cttaaaattc ttaaaaatca aaaagttaat gggttttgaa 258300
gtctcttgtt aaaaaaataa caaatcagtg taaatgaatg acagtttaat atcaaaaaga 258360
tgaaaagttg atagccaagt aacaaatgaa attgttaagc agggttgaaa aattaccaag 258420
tgcaatggaa aaattaacac agggatttta tatttgtaat tattgattaa cttcttctat 258480
taattcttat tttgacaata tttaaagcca aatattggca tatattaaac tgagaaccga 258540
atccttaaat tgctgtatct cagggtacta aaycaaaatt ttctaaaacg ttgaaacaaa 258600
tttcactcac ttgggcttta ttgaagatat tattgcttta tcctttagtt agaatgatgt 258660
tattataatg ttgtttctga agaacatacc ataattaatt aatgttaatt ccccatttct 258720
tttatcattt agatttctac ttttagtgta tttcatgaag gacatgaaac attactattg 258780
aatgacatat acaaaaagtt gaagatgtgt taatgttctt ttattaggct gatggaagta 258840
atcaaacata tttattattt atcttaggtg aagtttaaat aataaagtct tgtatactat 258900
taaactatat attactttta cttgtcacca tcttttctct aagcctggtt tagaggtaaa 258960
aatcttttca aattgtgtgg cttcaacttc caacttgctc accttctctg ggtaagagtt 259020
gaccatattc tatcaaggac acaaatactg tattccttct tcccagggca tttatatagt 259080
cacagggaag gccttagcct gccttttgga cttccctatg ctttaagatt tttttcttta 259140
tgtacgataa gtagaagagg aagaaataca tcaaaagaag tttcgctgca attcaactac 259200
cttattgacc ttaacttcct caatcaacta aaagtatctt tctacatcat tcatttcagc 259260
atttttcctt ttttcttatt tatttgtttt tcttttttct tttctatcat ccatttgact 259320
tttgtcacag atagatttta acagcttgca ttgtatgttc attttcctaa aatattagag 259380
cttctattaa aagattggtg taaagaaatt aggggtccag gcggctcatg cctataatcc 259440
cagaactttg ggaggccgag gtgggcggat cacgaggtca gaagattgag accatccttg 259500
ctaacacggt gaaaccgcgt ctctactaaa tatagaaaaa tttagccggg cgtggtggca 259560
cgcgcctgta gtcccagcta ttccggaggc tgaggcagga gaatcgcttg aaccaggagt 259620
tgcagtgagc tgagattggg ccactgcact ccagcctggg caacagagca agactccatc 259680
tcaaaaaagt aaataggata attatattct tatattcatt aacatatttt gatggatccc 259740
ctgacatgaa taagggcaga gacggtagca agttaagatg ggccagttgg atttcatgcc 259800
ttcaaggacc tttcattcga gcataggaag aaaaataaga gtatacatat ttataataca 259860
aggccaaatg tttgaaatcg tgaaagcttc cttctgtatc tcaaagagca atcaactctg 259920
gcacaagtga tctacagtga ctttgtggga gcagttggca tctgaaaaac atcttaaaaa 259980
acagtctata acttgtattt gtttcttttc acttacatgt tatgaaagaa gagaaataga 260040
gcctatgtct gctatctcct ggaccctccc ctagtacatt tttccattgc taactttart 260100
ctacagcctt tcactgtaat aaaccattac taagagtgtg ttagtgtttc taaattcttt 260160
gagtcctttt agctttcact gaatctaata tttgtgttag gaccccccca cacaccccta 260220
aaaaagaggc tctagagttc gtcagctggg acattcaagt ggccaggccc aatatattca 260280
gaaatgctga cttccttaca aaaactaaaa gctttataat tttcaaaaaa aaccccaaac 260340
ctagtttgaa taacacataa caagttttga gtgaacgctt agcactgtct caccatgagc 260400
tcatggattg gaggacagtg gcagggccac acacgtgccc tccctgtagc caaatgtagg 260460
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
177
ccagtttaca gacatcagga agttgccact gcgatgcagt cattcttgac ctctgtgaag 260520
aaattcttcc agttaaaaat ttatttatgt ctacaagcat cctctttcaa atgcaaccac 260580
cccgtggaat attttaagtc tcacagaaaa gtcaccttta ttttagcatg aaatggctta 260640
aaaatcagat tatttttctt caaacatcag atataatttc cattaaggaa atagaagtct 260700
ttatagtgat tgatggagag aagttatttt ggcataaaag gaaaatgtgc ttgggtggaa 260760
taccagagca gacagctatg agctgtcaga gagaagaact tgtggggagc agaggagagg 260820
ggaccttgaa agctgggaga gaaaggcaca aaaacagcaa tgcaagaagt atattttaac 260880
cactttcagt ttcactacta gctgccccta cagagtgatt gtgattaaag aaactcttac 260940
taaccgattt ttaacccgcg ctgagtcttc catgtatctt agcttgattt tttttgccct 261000
caatcacgtg tctacactag atcaagtgca ccatctacca aatcaaacac tcgtttttaa 261060
gtagggtgta aactgtcact aaggaatgtt tgggtcaatg tccacctata gatactgctc 261120
tcactgtact tgaggcagta ttggagaact tatgttttct atggaagact tagagcatta 261180
ctggaaaaga gacggctttg tttcctttca tattaaatgt caaggagagg cggtaaagcc 261240
tctcctctgt ttttctatag aacccagttc agggctgtgt ctcatcactt actatcctgt 261300
gtattattaa tgatcaattc atctactcct caccagactg caaagttttt gaggaaagaa 261360
ctccttcatt ctccactatc tacacagact acgtataaat taacaatgaa taaatgaaca 261420
aatgccttct tcatatatct tgactagtct atatgttgtt agcattatat ttaaatacca 261480
ctttttcata agagttgtgg attagaaaac tgtgaaggga ttgtttgttt gtttgtttgt 261540
ttgtttgttt tccttaaaaa attaatactt gcggccgggc gcggcgggtc acgcctgtaa 261600
tcccagcact ttgggaggct gaggcgggcg gatcacgagg tcaggagatc gagaccatcc 261660
tggctaacat ggtgaaaccc cgtctctact aaaaatacaa aaaaacatta gccgggcgtg 261720
gtggtgggca cctatagtcc cagctactcg ggaggctgag acaggagaat gacgtgaacc 261780
cgggaggtgg aggttgcagt gagccgagat cacgccactg cactccaccc tgggtgacag 261840
accgagactc cgtctcacaa caacaacaaa aaataataat aatacttgga caggaagacc 261900
acagctatca cttctagatc taaacattct tcaagatgag tggagacaga ggtagagtgt 261960
gtgctggatg gatataggag tggacttact tggttgtcat catacggttg taccatttct 262020
ttttaataat gactgaagat gacattggga ataaataaac atagaccttt gagtttcata 262080
gccacttaac tccctagttt tgtttttcaa attagttgag aggtgatact tatagccata 262140
actttaataa cattaccatc atcatctcaa ttgtggcagc tacaatgtca agaaactcac 262200
aaagttaaaa tgtgaagaaa ctttagaggt ggtttggtgt ggagaagatt gatgttgata 262260
cgattcatgt atctttcagg attccatggg attgcactct gtcatcaatt tgctctaagg 262320
actaagtctg aaaaaactta ttgtgtgtca ttactgaaat actcagcagt ggtttggttt 262380
ctgaatactt ttaaagcatt ctctctcttc tccgcattat accataaaat atatcttagc 262440
atattattgt tttcacttgc catttgttta atatatgaga atatattaaa gcatatgcct 262500
tgaatcaaat gctaaccaga ttaaactata tctaagagag tgtgtctttt caaaacagat 262560
tgtgaagttg tgttctggtt cccatattac tgccattgtt caatattttg ggacttctat 262620
tttggaaatg cattcagttc caacttgtag cccctaagaa atgctcccta catctaaagg 262680
ctaagatgcc ctcctttatt atttttctga tcaaatattt aagaaataag cttcaaatat 262740
ttgttaaatt tttctcaaaa gtaaaatttt tatgtttaaa atatgacaat ctaattgtca 262800
tctttaatgt attaaaatct tttatatcca gtttttattt tattttattt acttatttat 262860
ttatttgaga tagggtctca ctctgtcacc caggctggaa tgcagtggca caatcttggt 262920
tcactgcaac ctctgcctcc taggcccaag tgatccttcc accttagcct cccgagtaac 262980
tgggactaca ggcccacatc actgcgcctg gctaattttt atatttttag tagagacggg 263040
gtttagccat gttggccagg ctcgtcttga actcctgacc tcagttgatc caccctcctc 263100
agcctcccaa agtgctggga ttacaggtgt gagccatata ttcagttttt agaagatcat 263160
tagaattcaa atgttgccag actttaagtg tgggtcacta tctgatggag ggcttctctt 263220
agaagatgtc cccaatggca gggccttgtt ataaaggttg gaagagagat aatcctctga 263280
ctaagaggcc agagaagcag aagatttttt ttcatcagat ttcacgtcag taggaagaca 263340
gaaaggagaa ggaagagaag gcatgaacag catatgtgtg aagtagaatc ttaatagtgt 263400
gcatctttta agtcaggatt ccgtctactg ttggccaaaa taaatcatta ttatctggtg 263460
gttggaaaaa ataaggacat tccttggttt tctccaaaaa cttattttgg tgtttcttaa 263520
ttacccttag gagaccttaa tgatcaacac tgtatcaaca gagaaagtgg aattttattc 263580
tcttatagaa cagtgatgtt attatgcaat gtattcacat aattatttac agttcttcag 263640
ttctagatga ctgatactac agaaacctga gataatccct gcttccatta gtttgggtgg 263700
aacttttgtt gagagacttg agtcatactg aataccttga attactgcca agagctggtg 263760
atcatcaagc ttgagttaat atcaatgtta tgttgctatg gagaggataa ctgcaggaga 263820
acaatcatca tgtggtaggt tttaccacgt ggcctgctga actccatgct caaactccaa 263880
ctacttttaa gtaatgacat taaaaatcat attttccatt tatctgtgga agctagtgag 263940
taaagaataa gatagagtct actgaaccta tagaatgtta ctaagtatta ggtgttgtat 264000
ttaatttcca gtttgtctaa tgctggaggc aattttacct tctcctacca gtgaaaaagt 264060
ttatgccagt aagacttgtg atttttgttc tcccccaaca catgcttcta tataaattta 264120
ttatgggaaa agtgatatta ataaaaactt tctggaacaa ttatagatag agtgtggtct 264180
ggtgtgacag atattttgtt tcttcacaac attcattctc tgagtattca ccatggatca 264240
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
178
gatattctgt agtttctgta gtagatacaa aagctttaca aggtgtattt ttccacaaag 264300
aggttagcta gattaatagt gagaggatac atcaaagaac atggaaatga tttttagaga 264360
aatgagagca aatactaaag tattgaatta agtaaaacaa gaaaaatagc tcctcccacc 264420
ttcaaaaaca ttggtgagac caggattgtg gagggcacct tggcaatggg ccttgtagct 269480
cagtgaatgg ataaaatgtg tacacagtga gaagagaaga aagtgtctac acagaagtta 269540
gtttttgttt aatttgatat tttctcttta cctcgttcta gtcaagatga cctgaagcct 264600
tctagtgaag aaccagccag gcaagttcca cttcttaggg ccgttaaatc ccttctctta 264660
ttaatgatgt taattgcatt tggatctcca tccagatatt tgccctacct taatttcatg 264720
ttaatgtgcc atgggctaaa gaggcagtat tttttaaacg catctgtaag tttcatttat 264780
gacagaattt ctgtaataaa agtgtagtca agagtgttga tggaaaatta gggtgacata 264840
aatacgtgag aactggaaaa tgtataatct taaacagtac acattatttt tattatctct 264900
ctttcccaca ggctgatgag gcctgggata ctaatatnaa aaaccaaaat tagaaacttc 264960
tcctctgtgg tgtttattgc ttcgcctgca gtgcatgaca tcttaattct aaagctctna 265020
actcacaaaa tctgacatcg ttttaccctc tgacacgtca aaatcagggc ctaattgntc 265080
ctgtggttgt gaattatgaa caaatatact ttctaagaag atggattttt catttaattt 265140
tccttttcag cttcacaata tgtacatata cagaggttgc ctgcgatttt aatatgctca 265200
cacctacaaa aacacacaat acacacaaac tttcaaacgt aagcacacag atctgtaaac 265260
atacacatga agatttgttg caacacaatt cattctcaaa tctatttcct gttatgctta 265320
tgattaagat ctataacttc tcagggttga tttatttgtt ttgtacgaga ctgagtaaag 265380
ctaaagacca cgaatatgat gggtgttgct aaaataaact tctcaagaga catcaagttt 265440
taatctgcca tatttcaaat attccctgtt gaaatataaa cataaaggaa ccattaatta 265500
tataaaaata gaaatacatt tgtgactttc agagctgtca ccgaatagat attggaaggc 265560
aggttattta gaggactcat gtaagacaga aaagaactac gcacagatca ccgatgatga 265620
cacagttatg tggagaaagt aatctgccac aggtcaccca gacagggagt gggaaagtga 265680
tggctccgtc ctcgatcact tttatatccc tttcattcca aagccaagca tgttctataa 265740
aagcagaaat ctctgtactc ttttgacatc ctaactcctt ctgctaccct catttaccct 265800
catacatgtt ttatacagat gtgggcttgt cagaaaaatc acaaaatttt aatgttagaa 265860
tggaccttat catgctattt tagttatcag ctgctgagct gttttctatg tttgagttcc 265920
cttctctcta aaaaatatac aaaaatcaat agaactttca gtgcacttgc aggtgggttt 265980
tacctttttt aggccttgat ctcacagcct gatccttaac tcatctactt tccaatactg 266040
gctgacagag catccaccat ccaaaggcag cgtagacaaa ggttcaatga gtaggaactc 266100
ttaattatga cataatgaca ttaataactt ttaccttatg ttttatgttt ttggagacaa 266160
aataattcca aacttattat tataaccata aacataaata tttgtatcat taataacagt 266220
gtaggacctt aatttatagt ttaaccattc acatttgagt ctttaatccc tgctcaattc 266280
caaatgtata catagtttta ggggtccatt tttatttctc tccacatgta gtgatttatg 266340
tttctctgta ccttctacta agtaacctgg ccttattcca ttatatattt agtttccata 266400
tatacataca tctgtctctg aggactttta atttcatttc attggtcaat gtatctgttc 266460
ttgctgttgt aacagactac tgctactaat actactgctg aattactatt attattatta 266520
ttacttttca gtatttctaa agagcttttt aaaaatatgt cattaagtta ctgttttaag 266580
taaaacattt tatatagaga ttcatataca tattgaactt atgtttttat tttcttgcat 266640
gtatcttaag tgatcttgaa atcaacatta taacaacctg ataaaataga gtgaaggttt 266700
ctgatctttg ctcatttgca ggagcacctt atataagatg taaattaggt aaacgtttaa 266760
catttgggag aaattcacta tacaacaatc tgattctgag actccaaaga tcgtttttta 266820
tgtttaaaat atctatttct ctattcaaac tttcatttta tttgccgcat ctaatatctg 266880
acacatttcc aaataagtaa aaacaaaatt caccaaatct tgtatctttt aaaatgtatc 266940
tttgtttcct gtcttctatg ttttgattat ttcttttaaa tttttaaaat aaatttgtgt 267000
ttagttttga accataaaaa taactcattc aaagtcatca aagtaaaagt aatcatctct 267060
taggcatata gttgtcagta atctgatttt aacccaacag actatataca tatttaagac 267120
agggtctctc tctgttgccc aggctggagt gcaatggcac aatcatggct cactacagcc 267180
ttaacttccc aggctcaagc gatcgtccca agtagctggg gactacaggt gcatgcttcc 267240
actcctggca aatttttgta ttttttgtag atgtggggtt ttgccataag acgaattgtt 267300
gagtcaagat gtagatggca cattagttca cgttatttca gttaaggttt cctgagcctc 267360
tactttgtgc catgatataa gcaaggtgct aagtctgtgc tgcaaacagc agtcatccta 267420
tccaaaccgt acacttacaa gtgaggcaac aaaggtatat aggggttcgg gaaaaactac 267480
ggaaagcgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtatc aggcagaaaa ttatcctcac 267540
attttcctac gagtatccta gttgatcctc tgccaccatg ctctttccat gggtgccctt 267600
tgctgtgtcc tttccacccc acccttccag agggatctgg atgtggatgc ctatgctgag 267660
tgtaatgaag cctgagatgt tgttagaatt taatgaataa ggccaagtat gctaacattt 267720
tttcaatcca caaaacgaaa attagatctt gacctacaca aaatgtggct agctcctctg 267780
ttgagaaacc ctgacaccag atctattaat acctttccta tggtcacttt atgttttgaa 267840
agtttgctac tatttggtga tgacaccacc aactaggatg aatataaatg ttcattttca 267900
aagatgttaa aggcatcatt ctcttatttc taataattaa ataataaatg tggagataca 267960
cacacacaca cacacggttt ccatagtttt tttttcaggc aaattcgcta aaatctcata 268020
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
179
aacattataa ttattattaa ctcctaggaa taatatctac atttaaggaa agagtaattt 268080
taatttaagt agacacattt aatgatgcaa gtatggatac ctcatgcaaa caaatgcctt 268140
tatacttact cagaataaat aatgggaatt ccacatggaa gcttatgaga aggtctttaa 268200
tgatcttatt ttgctttggt tttagctttc tgagtaaaca agcccctaca cactgagtat 268260
tagattcacc tggaggtctt atttcataat gtatccaggg ctttagccct agacatgctg 268320
attaagactg gggtgggctc aagaatttgc atttttcaca aattccaagg tgatattgat 268380
tttattctta gtagatcttc tcattaaaaa taagtgtaac cctctgcaat taacagaata 268440
aagtcaaaat ctctatcgca ggattcaaca gagggatgac aatctggccc aaccaccttg 268500
catagctttg ggacctaaca ttactcttgt tttacagcag tagttctgcc attcgtaagt 268560
gaaatgtggt ctgttctctg aatataccat tctctttggt atctttgcac tttgatcttg 268620
ctgtattttc tggccagaaa gcccttccac ctttacagtt tagaaactgg ccacttaccc 268680
ttcaaggcca agttccaata aagtttcttc taagaagagt gctgcctatt tccaaattta 268740
agtatataaa attgaggatt gaggaaatcc caaaattcca gtacatttgt ttcataatgc 268800
aatctaagat cattctgtta atgttccacg tgcttccaac ggctccacga agtggtatga 268860
gactcaagtt gaattttgaa tcacaaagtg tattcattgt ccacctgaca tcttttttta 268920
ttttatacca tgatttttat gtaatacatc atttgtgtct ctaagagttt ttcacgtgga 268980
ttttaataat gtgccaattc acaaaagaat ttgacttaac acttctgagc attattcatt 269040
gatacacagt tgaaatacag atagtttaga taggaggaaa agtcagtata aaggaatgaa 269100
atttttttta aagctcaaca tttcctagag attttacttc tcatatctaa tggtgtaatt 269160
ctctcttatt aaaaaatgtg ttaatttaaa ctattataat tttatcagat gctgatttcg 269220
tgtgtgtgtt ctgtgtgtgt ttgtgtgtgt gtgagagaga gagatgatct gatgtgtatt 269280
cctaagttta caagattcta aaccttttca cttataaata gatagttcag agggtgacat 269340
ttttggtaga gaaatcttaa tgaagcttaa aatgcaagtt tctgtgtaga ggtaccatct 269400
ggttaatctg cttcaaatga tggtggatgc accatcatta cccaaatggg tgaaagcctg 269460
gctgcctata gtctccctta aaggttaagg agtgatatat gggtgctaaa gaaaggctta 269520
tcaggctact gtacatcaga gcactgacaa aacttcctca ggaaatcacc aaatgaaaca 269580
aggacctatt cagaaatgtt ggtttataga tatgccatta caatggaact catctaaatg 269640
acagcatggc ttaagtgagg aatttttact cccaggtcag gaaattctaa ggcaggaact 269700
aatgcctatc ttaactcttg agatgtggcc agaattcagg ttgtttttct actgtgtgct 269760
ggttttctca gacatgtgaa tttggggaga taagaacaga atagcatatt agctgcaaca 269820
tgtggcactt gtcagattaa caaaaggagt gggaggcttc atacaagtct ccattttccc 269880
tgatagagtt tcaagttgag aacagtataa tgttcatatt ttacatcctg atgggaaaat 269940
gggtaagaat aaaaggtgtg tgagccatag aaacagaatc tgtttctttt cactttttat 270000
agcaatagga gctaaaggca ctctaaaagc tcacttgaag gccacaaggc cttgcttttg 270060
tcttttgttt tcattttaac tttctgcttt tttacaaaaa aatctatatt ttgtcccatt 270120
atttaatggc aagttgcctt taaaatgtat ctggcctcat cacagaaata ctaaggtatg 270180
tgattttgca taaataatca cagagaatgg catttcttaa gttaattgtg tctttctcac 270240
taattcccat caagagcgtg aaagctacaa tttaggtgat ctttcagacg attagtgtag 270300
tcatccagga agtctctttt gttatctaat ctaagtcact ctagctataa ttcccccttg 270360
tttttttttt tttttttttt tttttttttt gagatggagt cttactctgt tgcctaggct 270420
ggagtgcagt ggtgtaatct tggctcactg caacctccac ctcccgggtt caaacaattc 270480
tcttgcctca gcctcttgag tagctggatt acatacacgt gccaccatac tcggctactt 270540
tttttgtatt tttagtagag acggggtttc accatgttgg tcaggctggt ctcaaactcc 270600
tgacctcata atccaccacc cccctcagcc ccccaaagtg ctgcgattac aggcatgagc 270660
cgctgtgccc agcccttgtt ttgttaggtg agaaaatgag cctgtttcca catggagggc 270720
agtggtggtg aagttgtatt atgttttgaa aaatactgaa agcaaacagg gagggaagca 270780
gattaacatg tttttaatca tttatgcact aatattgtat acaatgtgtg tgtgtgcctg 270840
tgtaaagaaa gaatacactg catgtaacac agtaaggtat tgtatttata tattgctcag 270900
gcagaagata tttaaacagc ctggattaat tcactcatct tgtttgtact aagaaacaaa 270960
gactgaatga gttacaaata aacaagttcc ccaaattgta ttattgtggt ctcatttgag 271020
tgtctcataa ttgtatatgt attgcattta tcacaaaagt tatatttgaa cacaaggtgg 271080
acagttataa cgtgcatgag caaaactata gtgagccata tctagcgatt tagctttcca 271140
ggtgaaacag ccactctagt tatgtaaagt gataggaaat aaatcaatcc catcttagcc 271200
taggacgaca ttgacatcag catcagttat tccaataact gcataatcaa tatttatggg 271260
cttaatcaag agagacatga cacctggatt cgctgcatgt gagaagggag ggcaatgtca 271320
aggtggattt ggtgaagtcc aggtggggaa agcagagtaa atcagcagca aagtcaacaa 271380
gcaatctgct cacagatcca caatattcgg ctgctttata gaacacagct ttattctttg 271440
tctgtgatgg aatatcaatg cttccatttt gggaaaagtc taacgaattc tttagctttt 271500
taaaattaaa aaaatatata tatagccagt ttgtattttg tattttttat aaaaggcata 271560
taaaaatgca aagcatagtt tctgtctttg agaagttttg aatcttgttg gtgagtcaag 271620
aaatgtagaa gaagcaatta taagcaggat ttgaatccta cctgtatcac taatttgttg 271680
tgttgtacaa atcaattctt gtgcctaggc caaaataaag caaaaaaaga ctacactggc 271740
tccacattcc aagtaaattt actaattcaa tggtactata aaatgtcaat gaatatattc 271800
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
180
cagaaaataa gagtgaaaaa tttcaagaat gaaggaaaag aagagtcaga tgtggtgaaa 271860
gaaggcttgg attagcaagc atttgattga tattaaaagc aaggataaga atttgctgaa 271920
tggagaggtg gggaggagtg agggttatta tagaaaaaaa atgaagagaa taggaaaaca 271980
aacacaggtg aaaaatgagc atgaggggat cacctgggat tgagaagatg acatcaactg 272040
ctggaaatgg aagttttgca tggagagcat caggtcagtt tacagaacgc catggacact 272100
gaaataacag ggctgggttt gaagctgttg aaaatttcaa tcaggaatcc tttcctatct 272160
gactcagaga aaaggggtgt ttggaaaatg ttcatctgaa gcaggggggc ggggcgggga 272220
gcaagattaa actggtagct atcatttcca gatatgaccc agtccgtaga atgtttgatt 272280
attaaacaaa accaaatgct aacatcagca ggtccacaac aaacagaaga tttacaatct 272340
cctgaaattg caaagatctg gtagaataga tttcacatgg caatagttgg cagaagctaa 272400
gttgcttctg ctttccatgg ctctccttat ctccacattg ttgtgactga agctggcctg 272460
ctccccattg tcagcctgga acagaaaggt gtttgcatca gagatcacta ctgtagggac 272520
catagatgga caagtgcttt aggaaactac taccgaggtc tcatcctgag atgagaaggc 272580
tctcatttag aacaaacatg gaaaggaagg attgtatgtg agttttgttt tgaaagcaga 272640
atcaatatac taataattga gactgagtga actagtctag gaggcaaagg agaggaacta 272700
gcttacacac gaggaagctt aaaaatattg tttgtgtata ttaaaaataa aataaatgcc 272760
taggcatggt ggctcacacc tgtaatttca gcattgtggg aggccaaggc gggagaatcg 272820
cttgaggcca ggagtttgag accaacgtgg gtaacatgga gagactccat ctctacaaaa 272880
aatttaaaag ttagcccaat gtggtggtac ttacctataa ttctagccta ctagagagtc 272940
taagatggga atcacttttt tcctggagtc taagactcca gtgagctgtg actctgccac 273000
tgtactccag cctggatgac aaagtgaaac cctgtcttac tccaaggaag aaaatgaaaa 273060
taatactttt gaaagtcctc agatagaaga ctcttacctg cttcatttta ttagtataat 273120
atatgacaaa ttaaaaatat taaatttaag tgtttatttg ccacttactc aaaattttag 273180
gtatacacag gttgacccag aaaagaaaca aatgctaaat ccaaaaatat tgtcgtgctt 273240
catgcctaca ttacttttga gtacacatat ttcttctgta acccattata aggagttttc 273300
aaaatataat atgttcttaa taacttacat taaataattc agtggtaaat acaagttata 273360
atatattgaa tgttgactgg tcaagagttc ccttttttca taaaacagat ttcaattctc 273420
atgttagttt ggccaactga aagtaaatat gcttggtaga aaacagtcta agtgagacat 273480
tattaatgaa ataatatgtc tgaaggtctg gtactaatgc tggatcacga atataatttt 273540
tgaacatgaa gagctactaa atgtaactga gtttagactg ggaaactttt ccagtgatcc 273600
actaggtact agtttagttg catggctgaa tgacccagct atttgccaga ggagagggaa 273660
atgatatgta gctgactgtc aaatcatatg ctatttatta tagttatatt ttgtttgttt 273720
taactcttaa gtgaattgtg agtttctgca aatcagaaaa ttgtttatta atgtttgttt 273780
gtactgctgt gcttaattca aaaccaccta atgagtgatt tttgaaatca acccaattca 273840
tacatgatgg gtagatttaa aaaatagttt tacattgttt cttatttcgt ttagaactgc 273900
aatcccgaga taggaagatt gcttcaaaaa ctataacaga tttctgaaat tgagtaaatt 273960
tgcttcaatt gtctattaaa agttttgaag tataataaac aaaaaaatat attaagtaaa 274020
gcaaggttca aaatcacgtt tccagtaaac tttgcatttg cagtacattt atgtagacaa 274080
aacaagtcca caatagttta aacagacatt cacagcaggt gattccaaga ccatgggaag 274140
gatttggttc ctgtttattt tctgagttgt cttggatgct ctccttccag ttatgtcttc 274200
ttctctttct catgtatcat gtcttatttc aactattctg acagcatgtc aagcattagc 274260
agcagaataa tctgtatgca cagtgggaga gagaggcaga ccaaatacac attgaataag 274320
gaaaaagaag tttccagcgg ttgatacatt attctcccta gcaaagggct agatttgcta 274380
agcatatgga gacatgctta aggatcaata gggagaactt tgaaatatat gcccatcctg 274440
tgaaaattta tatcttgact gaggatatgt tttgatagta taagtaatat tctcataaaa 274500
tttttggagt gacacatgag aaatggagga aaccataatg taaaaagcac atgttaagtc 274560
cttgccaatg attaagccat ccttttgcct tataaagaca ttgattttca ttctatcctg 274620
atcttttaga gtagttgggn ttctatatat cttgagaatt cctatgagaa taaaacacag 274680
ctaaaattag tgtaatgagc ttaagttaga ggaaagcaag ataccctgga tcttggataa 274740
atatacttgg tttaacgaat ttcttaagat atatccatga ggatatcatt ttccttacca 274800
aaatataatg catatcttta tttatttgtt tttttaacct cagagcttct agggtagact 274860
caaaaaagac attctgctag ccttatgttt tactatgttt ccataaatgc taacatttct 274920
ttcaaatatt tacccccaag gcttatttta gatgtatcag ctaagggaga ggagtcagaa 274980
agatacctta taatgaagtt tcctcttctt tttcttatat tcgtaacaat ccgataaatg 275040
gtttctgaat tatcgagtag acctctgaga actcagcagg tgattccaaa tcaaattcac 275100
aaccttccaa gatgacattt tccttagaaa atcccagtat ctaaccttac caactggatt 275160
aaaatcaaac ttctttatga aaaaatatac atcattaaat tgtgaaatca aatatagctc 275220
tattaattaa aatgtaatgg taggaatagg aaaaagtgtt agtgtgcgtt gtaatagaaa 275280
gagatgacaa gtgcgcacag ctgaggaacg ttccttatat ttccaaggtc tctgtgtcag 275340
aagttcgata tcaccataac cttttgatgg gtcttagtta ataaatagtt cgttattata 275400
ttttattcat actgtaatat tgcttttaaa ttcgtcctct tcattcatgg ctgtctttaa 275460
atcaatagaa tcagttaaaa tatacagaat ataaagtaga aaatacagcg tattttctgg 275520
ttagaatatt atgttgattt aagacttaat tgcattctgt gaaatttagg tttaatcatt 275580
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
181
ccacaaaaaa acacttttag aagcaaaagt gatgattaaa gtattcaaca aacataattt 275640
aataatattg gtttagttga caaaataaaa tgttgttgtg aaagcctttc ttacccttgc 275700
tctaaaaacg gaaaataagg ctgggcatgg tggctcactc ctgtaatccc agaactttgg 275760
gaggttgagg tgggtggagg atcccttgag gtcaggagtt tgagaccagc gtggccaata 275820
tggcgaaact ccatctctac taaaaataca aaaaaattag ccaggtgtag tggtgtgtgc 275880
ctgtagttcc agctgctttg gaggctgagg catgagaatc acttgaaccc aggaggcaga 275940
tgttgcagtg agccgagatt gtgccactgc actccagcct gggcaacagg gaaaataaga 276000
acaaatgtaa tcacataatt tttttagttg ccatagtggg tttattacac aagcatgtgg 276060
tgatttatat ttaatcataa tttattgatt atattaaaaa atagagacac aatggtctca 276120
cagagaggga atgaacatat attattttgg ctaactatat tttatgagta actgcattta 276180
catttccttg gttttgaact tagccatgct atgaacaact gaataatctt tattgttata 276240
gtttcaaaat atttgaaatt atctaatggc tcttagatta tacaataaaa attataaaac 276300
attatattga aaaaatgtat taatattaca aaaccttaca ataaaacata ataatacagt 276360
gttgttttgg catgtgtctc ttttatataa aaatcagaag gagaaaatcc agttatttgt 276420
tctttttttg agattttact aaattacaat gccctcaata atatgaagac atacaattta 276480
ccaacaagtg gccgggcgct ctgtctcacg cctgtaatcc cagaactttg ggagccgagg 276540
tgcgtggatc acgaggtaaa gaagtgaaga ccatcctggc caacatggtg aaaccttgtc 276600
tctactaaaa atacaaaaaa ttagccgggc gtggtggcgg gcgcctgtag tcccagctac 276660
tcgggaggct gaggcaggag aatcacttga acctgggagg cggaagttgc agtgagccga 276720
gatcgcacca ctcactgcac tccagcctgg gagacagagc gagactccgt ttcaaaaaaa 276780
aaaaaaaaaa aaattaccaa caagttgata atttcctaca gaattaacgt caccctgaag 276890
tttacccctt tggtattaca gctgtttatc atgtacataa ctcccttttt attttgagag 276900
gggttaaagt taattcgtat ctataattta tagagtaaaa ttatatttgt taacaaaata 276960
aaaacttttt ataatacttt aatgaaaggc ttattcacca aagaaaataa taaaaattac 277020
agtatctcat caataatttg gcagatatct caactcttat tttttctcgt attttaagac 277080
tataaattat ataaaagtaa cagtattcat tgctaaacag taaaacaatt tttttctgtg 277140
tttacatcta gcttactgtt ttagtaataa aaatgttctc aattttcatg cattgcagtc 277200
acatccttaa aaaatctgag atttcttgat tttctgtaaa tttggcattt tagtctgaat 277260
tattaaactt aagtaaccag gatgtaaact tttatcgctt ttttttcatt taaaattaag 277320
aatgacatct ctctgagttt ttatgtccaa aattctggat acttctaaaa ggatgtgagc 277380
attactgcag ggtagatggt aatcctagac tttggaatac aaattaaatg agctgttcta 277440
tctgaccatt ctctgtaaca cagtttcagg gacttgaacg acctgatttg aaaaacaagt 277500
atgaacagtt agacataatg tgatctaaag gtagagtatt tatgtataat cttaagttac 277560
aaaattattt gctgaaaact ttaaagtcat atcgtatctt aatatatata accttattta 277620
tatatttatt atttagtcat ctgcctttct ttccaaaaat gctgaaaaat aagtcagtta 277680
tcttttcctt catttgggga ccatgagaat tttctctttg agaaatatgt gttttttttt 277740
ttttgttttg ttttgttttt ttttttttgn ggcagctctg tgagctcaaa tttcttaggt 277800
ttaatctaag aaattccagg agcgttactc tcaaccatga aagctttttg ataggagtga 277860
actgcagatg atctggcttt ggaacattac cagtaacttt caaagaattt tcttcatgaa 277920
agtcagaatg tcagtgctgt tgctaaaatt tctggtttaa acatgtttct ttttcttttt 277980
tttttttccc cagctgaaaa tacaaggcaa acactgccgt tcaaaaacat taaaaatcct 278040
tgcttttatt ctcatattag ggttcaatat cagtggatgg aagtaaaata gtgtacacat 278100
cactcaaaat aatcaatata ctgagagctg gtagccttac tttgagttct cacttctgct 278160
tttatgtaag ccttgttgcc tatttggaat gtttttctac ctgatacagg aaatgagaag 278220
gtgatattcc ttccagttgt aatcatccac gtttctatgg tgtaaagtca ctgtattcct 278280
tttaccccca acttttacta cgcatcaact gcatgccagt tactggctga gttcttcaca 278340
ttaacaatga cattaaaatt tcaaaatacg catttgagat agggataaaa atggcagaga 278400
aatcaagcaa gttcccaaag gtcacagagc ccaataagaa acacaaacag aataacatag 278460
gagtcagatc agtagccaag atttgatttg tgtgatcacc ataatataga tcttaaacca 278520
aaactgatgg ctacttaact taattttgtg aaaagaatga acacagagag aaagatgggc 278580
ctcatacaca cacacacgca cacgcacaca cacagcatat ttaactgcat tctactaaac 278640
agatactctt tcaggtgaca attggctagc ctttttaaaa ttacttaatt aattattatt 278700
tctttttaag cagagtcttt ctctgaaacc caggctggag tgcggtggcg ggatccggac 278760
tcactgcaac ctccaccccc ggggttcaag cgattctcat acctcagcct cccaggtaac 278820
tgggaataca ggcatgtgcc accatacgtg gctaattttt tcagtaaaga agaggtttca 278880
ccatcttggc caggctggtt tcaaactcct ggcctcaagt aatccgcttg ccttggcctc 278940
ccgaagtact gggattaaag ccttgagcca ccactccagg actggctggc ctttcttgat 279000
agaacagtta agttttaaaa gcaaatgaga aatactctct ttttaaaact ttccctttgg 279060
gatgaaattg tgaaattata gctaactacc attgactaga caaaactcca actgtgtttt 279120
tggctttgca tttgttatat ttaatacttg actcaagaaa accttgtaaa gtgtcttttg 279180
ttattacaga atctagaagc cctaagcaaa tatatcactc tttttctata tattaggaga 279240
atccccattt gccctatctg tattttcaaa ctttggggct tcaaatgttt gaagtaaatt 279300
aatatttgta ttttaatatt tacctagtca attttctaag aaattcaact tactaaatgc 279360
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
182
ttaatgtcaa tgtcattcaa acacaaagta tatatactac acttaattaa ggattcattt 279420
acagagagtc atggaaaata taactcataa tttataattt acaagtctca acattttgca 279480
tatttttcaa aagggaaata tatatacatg tatacataca tacacacaca tttagatatg 279540
aggtactaaa ataaatataa tgtaacttac taataaaatc aatgtattgc atgaattgtc 279600
aaaattctat atttttgcta tactaattca actcttttgt gccacattat gttagagtca 279660
cttatttctt tatggagctg tcagagctag tttactcagt aaaatactct gtatgtttac 279720
agcctttata tgatattata cttaaatcat atgcaatata attcatatta tgtgcaatgt 279780
aatccaaayg tattctttga aacatttgta atgtgtattc agtaaaaata tactgaaata 279840
aaaggtaggc acctggcaca atccatctct tagcccttct cacgttgtat tgaaatgatt 279900
tctatccaag tttcattgac ctttagtcta agctcctatg gggaatttca taccatgctt 279960
ctacaactaa aatttaaccc catactgata aataattggt ggtcaataaa tatttgtttc 280020
agctggctga agaagtaagc ctttccaatt aataataaaa attaaaattt tatgggattt 280080
tccaaataat tagaatcaga ggaagagcga gagagagaga gagagactga gatctcaggc 280140
atatcaacct tgtggataaa tagagggtta tagaaatgaa ttgacaaacg tgctgtaaat 280200
tgcttagctc tgcgaatctg ctaattctca ggagagtaga aaagacttga catttatcaa 280260
gtgtgtgtca tgtgaaacac ttcgtgcaag gtaattttca ctctttattc cttttagtac 280320
caataggtat cagatatcac tgcacagtta gctgcaccta attatccagc taatttttct 280380
acttatactt tgaaatacgt cactatatga caatggtaaa ctgtagcatt ttcaaatttt 280440
accgtatgac ggttgtaaaa atgaagttta ctacttttaa acattccatt ttaatttata 280500
tatatatatt tgttttctga tatttattat cgcatatgaa tgattttata tgtgattaat 280560
ttatataaca aagtacacca ttgaacttca tgaatatgaa atcataatct ggtatacata 280620
gacttttagt aatataacag cattttagga ggaattatat tatgagctga gtggcaagga 280680
taacaaattc tgtcctgttt taattattta agtcacagtt ttactagtag tagaaacaat 280740
tctgaaaaaa aaaaaagaaa aagaaaaaga aaaagaaaaa caaaagatct ggtcagatgt 280800
gatggttcat gcctgcaatt ctaataccct gggaagctaa ggttggaggt tgtagaattg 280860
ctgaagacca ggagttggac ctgggcgact tagtgagacc ccgtctctac aaaaaataaa 280920
aataaatttt aatttgaagc aatggtctga gaaagtgaga aattgtcgac ttgtaccctg 280980
gataatttta tgcctgattt tgatttttct aacatttctt actttaaaaa ttatccttga 281040
aaatttcaga agtggcttca cacttaattt tcatgatcat tttcaatgtt tcttccaaaa 281100
aatgatctac atggtaatta ttttatgtgg cataattctc tagttgagga gacacgatgc 281160
ttttactccc caaataaaat atggatatat agctctttgt catatgagca catgttgcaa 281220
gaatcatttg atatgtttat gctgaaatag aaccttaatg actcatttat atttccttac 281280
atccaatttt attctgcatt acgaagtgtt taaataatat ggtataatat attgtttgag 281340
tctagcctct aacatcctgc aaactggcat cagaataatt tacttttcct aagatttaat 281400
agtcacaaaa atattcatta aaattaaaaa cattacatct ggaaatacaa ctttgctgtt 281460
taaactgatc attgtactct actttccttt tttgtaatcc gaatggtaag gtataattta 281520
caagttatat tttataagtt cataaatgag gagtaaattt tgttttataa aaacaaacaa 281580
taattgttaa gttagtattt atcacagggg gaaaggcctt gattcaacaa tccctgccaa 281640
gttgcaagtc tcaaatccta cttagatata tattacttgt ttgcgtactt ttaaatgtgc 281700
cttccttcac tacagagtat atatgctgat ggctttattt tttagcactt acattcatag 281760
attcctgcca tatgattgca ttttacagta taatacgaac atgttcataa agatttcatt 281820
tgaatctatt cacagttttt atatatactc catgaaaatg ttatactttt aatatcaatt 281880
atgtgatatt ctcaaattgt cattgattat tctggtccat tgttgagaga tgttcctcac 281940
tcttagtaac agtttctaca tcctggaatt cataataata acaagagaca tttagatagt 282000
gtgatggtta atagtgtcaa cttgattgaa gtatgcaaag tattgttcct gggtgtgtct 282060
gtgagggtgt tgccaaagga gattaacatt tgcatcagtg ggctgggaaa ggcagaccca 282120
cccttaatct gggtgggcac catctaatca gctgccagca cagccaggac attaagcagg 282180
tcgaaaaaaa tgtgaaaagg ctagactggc ctagcctccc agcttacatc tttctcccgg 282240
gctggatgct tcctgcactc gaacatcgga ctccaagttc ttcagctttg ggacttggac 282300
tggcttcctt gctcctcagc ttgcagacaa tctaaagcgg gaccctgtga tcatgtgagt 282360
taatattctc taataaactc tcctattatc tatctatcta tctatctatc tatctatcta 282420
tctatctata ttctattact tctgtccctc tagagaaccc tgactaaaac acatagtaac 282480
ccacagtatt atttacccac atatagtaac cattagctta tttaagccat accacaaacc 282540
tatgatgcag ttgttatttt ccctcatata aacgagaaat ctgaggatga cagaagttaa 282600
gccatttgct tgagagtttt tagctaataa gtgaccagga cagaaattaa cttatctcta 282660
taaaatgtta tttttgttaa tattgaatct cagctatagt aaacaggata ttttatgtac 282720
agactgggat atatgtgaaa tgatttaccc ttatttatat tccaggaaag aagaaaaatg 282780
attacgttct tctcaggttg ttacttcata aacggtataa ctttttattt tgggatatta 282840
tgacaagaat atttgggctt tggctgaagt ggaaggactt gggactacat gtcaaatttt 282900
attttgatag taaatattgt gtccaagggt gcccatcctt taaagtatgt aaattcaggg 282960
ttacccctct gtgattatag aagacttata tcctgtactt gataatggga aattaactaa 283020
atgattttcc atataatgac cattagcttc tcaaaggaac taaaaaagtg ttaatgagaa 283080
aacacacatt tttattgact acaaaccata atttttgatg gtctcataat caatttaaat 283140
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
183
atagaggcat atttataaat atcatttgca tttgttgttg gatttttatt tgatatatta 283200
tttattttaa tttttttatt tcaatagctt ttgggataca ggtgtttgtt ggttacatgc 283260
atgaattgta tagtagtgaa gtctgagatt ttaacacacc agtcactcaa atactgtaca 283320
ttgtatccaa tatgtcattt tttatccctc accaaacctc cctcttctga gtctccaaag 283380
tccattatat tactctacat tttgcatacc cagagttccc acttacaagt gacaacatac 283440
agtatttaat tttccattcc tgagttacct cacttagaat aatggcctcc agctccgtcc 283500
aagttgctgc aaaagacatt atgtttatgg ctgattagta ttccatggtg tatctatacc 283560
acattttctt ttcttttctt tttttttttt tttttgagac agagtctcac tctgtcaccc 283620
aggctggagt gcactggcac aatctcagct cactgcaacc tctgcccccc gaggtcaaga 283680
gattctcctg tctcagcctc ccaagtagct gggactacag gcacctgcca cctcacctgg 283740
ctaatttttg tatttttagt agagacaggg tttcaccgtc ttgcccaggc tggtcttgaa 283800
ctcctaacct cgtgatccac ctccctccct cggcctccca aagtgttgag attacaggca 283860
taagccaccg cgcccagcct ataccacatt ttctttatct actcactggt ggatggggac 283920
ttagaacggt tccatatttg caattgtgaa ttgtgctgca ataaacatac acctgtagat 283980
gtctttttaa tataatgact tctttttatt tgggtagaca cccagtagtg ggattgatgg 284040
attgaatagt agatcccctt ttatttcttg actaaatctc tacactgttt cccatcgaga 284100
ttgtactaat gtacattccc accagcaatg tttaagcatt gccttttcac catattcaca 284160
gaaacggcta ttgtttgttg actttttaat gattgcattt ctgcaggagt gagatggtat 284220
ctcattgttg tcttaatttg cattttcctg ataactcata tgtttgttag ccatttgtat 284280
ttcttttttt gagaaatgtc tgttcatgtc atttgcacac ttttgatggt ttttttttct 284340
tgctgatttg tttgagttat ttgtagattc tagatattaa tattttgtct gatgcacagt 284400
ttgcaaatat tttctcttat tctggagatc gtctatttgt tctgataact atttctttgc 284460
tgtgcagcag ttttttagtt taatgtgggc caattaattt attttgttta cgtttgcatt 284520
tgcttttgag gtcttattca ttaattcttt gcctaggcct atgtccagaa gagttttttc 284580
taggttaact tctagaaatt tatagtttca ggtcttagat ttcagtcttt gatccatctt 284640
taatggatgt atgtataagt tgagagatcc agtttctttc ttctacatgt ggctagccag 284700
ttttcccagc accatttatt aaacagtggg tactttcccc aatttatgat tttgtacgtt 284760
ttgtcaaaat taagtcagtt gtaagtattt ggatttattc ctgggttctc tatactgttc 284820
ctttggtgta tgtgtctact gtatactggt accacgttgt tttggaaact atagccttgt 284880
agtatagttt caagtccagt aacgtgatgg ctccagattt gttcttattg catagaattg 284940
ctttttttcg ggctcttatt ttggttccat atgaatttta cgtttttaaa aagtattgta 285000
aaaatgatat tggtattttg atagcaattg cattcaattt gtagattgtt ttggtcagta 285060
tggtcatttt catgatattc attcttccaa cccatgagca tgggatgtga ttccatttgt 285120
ttgtttcatc tacaattttg ttcagcaata ttttgtagtt ctccttgtat agatctttca 285180
cctccttggt taactatatt accaggcatt ttattttttt atttttgtat gtttgcagct 285240
gttgtgaaag gggttgagtt cttaatttga ttctcagctt ggttgttgtt ggtgcatagc 285300
aatgctaatg atttgtgtac aatgattttg taaattgaga attcactaaa tttggttatc 285360
aaatctagga gtctttcttt atgatgtaaa agagaagcaa aggccaatgg agtgtcaccc 285420
tctaagccta cccttacatc ccagttacgt tgctaactca gaaaaatcag ctgaagggca 285480
cttggaaatt ccctactctg acccagatag tcttttgatt aaaatcatat ggttattagt 285540
ttttattttc cagatggaat aaatgaagac caaaagaatg tttatgtgga aactgtgttt 285600
ccccaaaccc ttctgcagta gtcttttcac tgctgaaatc gttgatatac taccattata 285660
aacaaacaca ctctttattt gttcacctaa cctgcatgcc tttattcctt agaagatttt 285720
caatatttta ttttaaagca tactggaaag aacagaagca ttaaagaaaa aaaataaata 285780
aagggactcc ccccacctcc accaacacac acaggtatcc tctttctcaa ttcatcagtg 285840
aggacgcttg gtcagtaaag gaatttctca tgatccctcc tcctttctct acagggcata 285900
gatttgcaca cgtgaagcca ggcttcacat gactgtattc cataatagca caccaaaaac 285960
actgtcaaaa tcaatgaaaa cttcacaata taaagaatat agctagaatc atggtaatga 286020
tcagttgatt gatataatat tagataagtg caggatggta acttttataa actaactttt 286080
caaatggctc agtgaattgt ctaacattcc atggcaaatt tgtatgaaga ctacctggaa 286140
ctcagctatc tacaatttgg ttggcagggg aactaggttt gtgagtttgt ttcccccctc 286200
tatgttctaa tgctcagcaa actgtgaaat tttccatgaa atataatagt tacgtaaata 286260
taaaaaagca aaactttttg gtatgttaat tattgcacca acttgtgttg tttgactact 286320
attaacaata aactaaaaca attctacctg cttgattgaa gcaaaaatgt caatgtgtaa 286380
ggatgatggg tagatcacaa aatcaaagaa acagctacat agtctgactc agacaggaca 286440
tgtcaaacag catccctgta aggaacttag tctacagact cacataggcc ctgcctcagg 286500
aataaataag ctgcacgtgt gttttgcttc cttgtattct ttgatgtcag ggtcagatac 286560
tgggaaagag actcagggca aaaaaagagt atattgattg acagcttcct caagacagcc 286620
cacaatagaa aagacatttc ttttcaaaga aactgagtat aattgtcaaa aaagaaaata 286680
gatactggtc atcaaagcaa gaccttatac tttgtcaaag tttactttaa atgtcacctc 286740
ctccaaaaag ccattttctc attcccctaa atcattctca gtatatctca gctttcatta 286800
aacaagcatg ggccatgtat ttaagaaaac agaatttacg ggaggacaag acagaccaga 286860
ccttaatttc agggaacata aattttgcca aagatgatat tgccatacta ctatttctgt 286920
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
184
gattctctta ggatcctgat gccttgtgtc ttagttatgt tttttcttaa tcagaagttt 286980
aaaaagtata ttatatttta ttttaagttc tgtgatacat gtgcaggaca tgaaggtttg 287040
ttacataggt aagcatttgc catggtggtt tgccacactt atcaatccat cacctaggta 287100
ttaagcccag catgcattag ctatttatcc tgatgctctc cctccccaca accccgaaat 287160
agaccccagt gtgttgtttc cctccctgtg tccatatgtt tttattgttc tgctcccact 287220
tataagtgac aacatgtagt atttggtttt ctgtttttgt gttagtttgc tgaggataat 287280
ggcttccagt tccatccatg tccctgcaaa ggacatgata tcattccttt ttatgggtgc 287340
atagtattcc atgatgtata tgtaccacat tttctttatc cagtctatca ttgatgggta 287400
tctgagttga ttccatgtat ttgctatggt gaatagtgct gcaatgaaca tatgtgtgca 287460
tatcttaaac aaatttgtaa gaaaaaaaca aacaacccca tcaaaaagta ggcaaaggac 287520
atgaacagat acttctcaga agaagacatt catgcagcca acaaacaaga aaaaaatctc 287580
aatatcactg gttattagag aaaagcaaat ctaaaccaca agataccact tcacaccagt 287640
cagaatggtg attattaaaa agtcaagaaa caacagatgc tggcgaggct gtggagaaat 287700
aggaacactt ttacactgtt ggtggcaata tcaattagtt caaccattgt ggaaggtagt 287760
ggggcaattc ctcaaagaca tagaaccaga aataccattt tactcagcaa tcacattact 287820
gggtatatgt ccaaaggaat ataaatcatt ctgttatcag gaaattttaa agcttctttg 287880
tgatgtgttt tattagttaa aacaataatt tattagttaa aatgttgtgt ctttcctaac 287940
acttaccaca tggtgtatca tgcaatgcac actaatgaac gcttcaaaat tagccttaaa 288000
tgcacartct cctcacttgc actctttgct tatcttgtgt ctgatggctc ttctgcatga 288060
acaggaaaat ctgaattctc acaattattt ctaaagcttt tattaccttc ccttaaccca 288120
agcccagttt tattacctgt atgacactta gacagtttac attgtaatcc caccctctaa 288180
tggatttaaa ctcattttcc actttggtat ccccatattt agtcattatt tgtacttctg 288240
ttattgcaga cccactccac cttgtgttgc agtgtgtgta tctgtgatcc cctgtagagt 288300
gtgagttcct agagtcagag tatccaggga tagctctctt taaacatcta atgggattct 288360
atgaacataa tgaaataaca tttatgttag ctaaatgtat aaagagaaaa tatatacttg 288420
cccctttatt aaagttgttg tttcatatta ttatatgcca acaccatact agtcctattg 288480
acagagagtt atatgtggta tttgtattac ctttaaagat attagagcat aaaataattg 288540
gaataaactg ttaggacaaa ataaagaggt acaatacaga cactgaaatg ggattggcca 288600
attctactta gctggacaga aaagctttct agaatagatg aatctcaaag gataaacgga 288660
ggcataatcc ttgcagacaa gaagaaaagt gctttccagg tgaaagaagc agtggtacaa 288720
cgaacaaata tacaaaggat gaggaaggtg gagcatccaa tttaaggatc aaaataacaa 288780
ataattaaat taggttattt agaaggtaag atcatagata aacacacaca tgcatgtgtg 288840
taatggaatt taaaatcatt ttttaggtaa gaaagattcg ttggaatgtt ttagagggaa 288900
gaattaagta attctataca cattttagaa agctcattct gatatcctat aaagaatgtg 288960
tcaagtgtga aaattagtaa gatgaagagt cagtaatagt gaatctaaaa atgtgaatga 289020
gcacaagaga ttattacata tatatgtgtg tgtgtgtgtg tgtgtgtata catatatata 289080
tatttttaat ccaaagcata tggtaactga taacaggcgg gagtattaga aagggtcatc 289140
caggttgaat ccaggatttc atgggagata gaaggaatga acagtgtttc cagacactga 289200
gattaagaat gtgagaaaag aagcagttgt aagtgtgttg aacttttgac gtctatacaa 289260
ggagtctact ggttactaga aggtttacaa agagacctag gtggatatta ctagtctttg 289320
tgacattata gtgtactggt ataactcttg gtgctatttg gggttgctaa aaatgaaata 289380
aggaagggaa ggggacagaa gataaaaatg gagggaggat aaaggggaga acatgagagt 289440
ggcaagttaa aagtagggca ctagagcaga agacagaagg aaagcgaggc atacaaggta 289500
agggaaaggt aagaaggagg cgagaagaga acctgtgtga tttccaacat ctaagtgtgg 289560
acaggagaga ttgtctgtaa aagggagaag acatggtcac gaggaaaggg ggtgctagca 289620
aattttcatc atggaagcct aaggtaaaat tttcagagaa ggatgtttaa tgtaagtgat 289680
atctaaaatg gccaagatca atcatgatga taagtgaaca ttcagataaa gtttcagaac 289740
agataaaact ctgtaatggt gacagcagcc atcggagtgg ttacatggta tggcctgggg 289800
agggatgtgg ggaatcctgg ggtgttgaac atggcctatg tctcaaagtg gtgaccaatc 289860
acattaccgc acttcatgtg ctttgctata agcaggtcat ccctcgattc aaaatgtgtt 289920
aaaatgtaat acgaaattaa tataacacct aagagggtaa aaaatattag tggctttctc 289980
ggattacctg ggtaccatca gctgaaggat tcaaaccaaa ctctgttaga ctcagatgcc 290040
ttagctgctg accgctgtac tactctgctg tcaaatccaa tccttgccaa gcctctccat 290100
tggcatgtta aatggactta gtctctgttg tcccttttag tcttattttg aaggcaccta 290160
cctattctac caactgataa attgaattgt tattactgtt ttacagtaag atttggtcag 290220
aagctttggt tagaccataa ttttttgtca gatctgttgt tctgaactct ccattaagga 290280
actgtttaga tattacatat acttttgctg aaattcagag gtactcataa atttgacgac 290340
ttttaaaaaa atgtactatc agcagtggta aatgataact aaaatggtat aatttatctt 290400
aacagtatct tgagcttaac aaagcttcag ataaaaacaa gattgcattg aatatcatgc 290460
aataaaagga aatacttaaa gcaaaggtat ttatatgttc ttatgtgtat gttcttacag 290520
ggatggaaaa gtctattttc ataaaatcta attttttaat ttacaatata gagccctttg 290580
cttcttttcc tgtttaggtt aagatctttt cttctcttga aagattatgt atattttaat 290640
atgattaatc ttattttacc tttacagaag tactgtgaat tagcagggca gatattatga 290700
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
185
catctcctta acatatgaat taattgtggg ctgccaaata gtacatgatc ttttactgga 290760
acgtagatcc aggtggctca aatagatatt taagggcaga gcacctaaac tgaccagcca 290820
atgtaagcag ttcatcttcc gagcagattt atttttcact gtaaccaaat gtatttacat 290880
gctcctggaa aaagtgttct cccgtgagct ttgttagtgt gttttcacca aggaactgct 290940
atctgggttg cccacactgt gtagagtttt tgtcctgaaa agctaaagtc catatattga 291000
agaaaaccta ccacataaag atgtttccta gaatacccgt catgatcaaa ggtttgcagc 291060
tgtagtggaa ctaactaatg gatgcttcat tttagtaagg gcctcttttc ttccattgat 291120
catagttgaa tattgtggtg tcagtttaag atgagtccat gtgtgacatg gatttaaata 291180
cccaaatttc agtggtttga taaaaattat aagaaatact gcaattatct caaactaaaa 291240
cttgtcaaga tttgtgtaat atcatagaat gtggacaaag tgattaaaaa atatattcta 291300
ttgactctgt gacataattt tagcagatac atctttatat tggccaacct ttctttgaat 291360
taatcttgac ttacgagttt agaatagtgt catgtctgga gagaaaaaga cttcatgtga 291420
aatataaaca ctctatgtac tattttagta ttaattttag aaagatattt ggcacacctt 291480
gaaacgtgat ctaatatcac tttcaattct aagtctattg catcatcaag cagaattata 291540
taaactattt ttaaaagttt atcaactgga ttttatgtta ttagcaatac atgagatgtc 291600
atggctttaa aaggatggct attttattat gtagtatcct tcaaatatta ttttagtagt 291660
tttttgtact aaccataggc caattaatga ttcagaaata tatttaattt ctattttata 291720
aatcttatat tcatggcaat atactacccc tcactgattt ttgcttggct ttattaaact 291780
gagtttctgt tttatctctg caaaatataa taaaaaataa aaatatgctc aaatattaag 291840
caccccataa atattaggtg gataaataaa tataaccaaa ctgctcttgc aaaagtgaaa 291900
aagttttaaa tatagagatt tcattccatt ccctttaatt tttcaaaata ttagatgata 291960
caaaaatcat gtgcacaatt cagactcata gctattttta gaaactataa tttttgattc 292020
aaaagaaatc tgcaatcttg caaaaatgag actcagttta acagtgtatt tccaaagaaa 292080
ttgtagctgt tattcttgcc tttcttctta gacaagagac ttgtgatggt atctcttaat 292140
attccatacg taacaagaaa aagagcagaa aaagccatgg gaactataaa tataggcagt 292200
gatattgtgg tattgtggtt gaaaacatta tctggaagtg agaccacaac aggttctcgt 292260
tctagctctc catctaactt ccatctctag agatgtgccc ttgacaaaat gattttttcc 292320
tctggacttt aatttcttta tctggaccag gtaagctcaa agatctcagt ttagtatttg 292380
atttttccag attaaaatct aagatgtggt atcagataca cttttctatt tttcttttat 292440
ttgtcagaca aacaaggtga aaatgtgttt aaaaactagg tttatccatt tttttcctgt 292500
acagtgttcc taattcaaca ctacattttt ctatatactt ttagtagaaa gtgaatcata 292560
agttacttca gtaggatata tctgttgttt tgctcttgta ctcttccttt actattacta 292620
ttatttcata acataaataa tgttaagaga tctgggtcta aatgtaggat ttaattttty 292680
aagtttttac aaattctatg aattccctac agtttctttg gccgtcacta tttgtctggt 292740
tgtttataga agccgagaag cagaamccct atggctgaag actggtcctg atagagattc 292800
ttcttctaat cttctcaaac caggaaggtg ttcaggtcac tctgtaaatg attcaaagac 292860
agatactatg taaagwtaca tttttccttt aaaatccagt ctgtaagcaa attttatgcc 292920
ttattttaaa taacaagata tgtagctttg gcaacatgtc atcttatttg gataggctat 292980
gccaacagga cccaaccaga gcaagccaaa aaagatcttt gaatgacaga cagcttaaga 293040
agaacagaat ctgttagaga aaataagaga aaaggagaaa tgtactgagc agaccaaaaa 293100
aataaaataa aatagaataa aaggagcttc cacacaaggc tgttgggttc attcaccaca 293160
taccaaggga acactaccaa gtaaatatta taaataaaat acttgctgga gaaactgaat 293220
atccacctgt aaaataatga atcagaacac ctacttcact tcatgccata tacaaaaact 293280
aacccaaaat agatcaaaga tctaaattta ataagtataa atataaaact cctagaaaga 293340
aacataggtg aaaatatgca aaagttttta ttagggaatg agttcttata tatgatgcca 293400
aaagcacaag caaccaaagg aaaatcgata aattagattt tatcaaaatt aaaaactttt 293460
atgcattaaa ggatactatc aagaaaatga aaagcaagta acagaatagg agaaaatatt 293520
tgcaaacata tgtctgacaa gtattaagta tctagaatgc ttcaagaact cttacaaatc 293580
agcagtaaaa acacaattca attaaaagat gagcaaagtt caatattaag ctattcccca 293640
gagaagatac acaaatggcc aataagcagt gaaaagatac tagcattagt cattagagaa 293700
tgcaaatcaa acctacaatg aaatagcact ttgcacctac taggtggcta taattaaaaa 293760
ataagcaaac agaaacaaaa caactattgg tgtggatgta gagtaatcgg aatcctcata 293820
cattgctagt aggaatgaaa catggtacag ccactatgaa aaaagaaatg ttttcagttc 293880
ctcaacaagt taaacataga attaccatat gacccagcaa ttccgcagct aggtaaatgc 293940
ctgagagaag tgtgttagtc cattttcaca ctgctgataa acacatcccc ggggctgggt 294000
aatttataac ataaaagagg tttaatggac tcccagttcc acgtggctga ggagggcctc 294060
actcacaatc acagcagaag gtgaaagaca tgtcttacat ggcagccagc aagagaggat 294120
gagagccaag tgaaaggggc tttgccctta taaaaccatt gagatctcat cagacttatt 294180
cactaccatg agaacagtat ggagaaaacc acccccatga ttcaattatc tcccaccatg 294240
tcctttccac atgtgggaag tatggtaacc acaattcaag atgaaatttg ggtggggaca 294300
caacaaagcc atatctgaag taagacaaat tatctcacaa aactatacac caatattcct 294360
agcagcatat tcattatagg taaaagaaga aaaaaggcac atgtccatta tattcataca 294420
atagaatatt attccatcat aaaaaggaat gcggtagtgt tacatactac atgatgaacc 294480
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
186
ttgaaaatat tatgctaagt gaaacaagtc tgacacgaaa gaccacataa tgtatgattc 294540
catacagaag aaatgttcag aacaagtaaa ggcacagagg cataaaatag attagtggtt 294600
gccagtggct ggcgggagat ttccattaac agctaacatg tacagggttt ctttttgggt 294660
tatcagaaaa ttctggattt catatttatt gttgcagagc atagtgaata tactaaaaca 294720
aacaaacaaa acactaacat atactcttgt aactggtgaa ttttgcttat gtgaaaaata 294780
tgtcagtaaa aatgctaaag taaaacaacc tgaagagttg actatatata tttgtagata 294840
tacacaagta tgcatttagc ttttataaac aatgtcttgt taaattatta ctagcaattt 294900
tatagtcagt taagattgaa tacatgttta attcctgcct ttattgaata ttcattctgc 294960
aactacttgt gctgggcact gtcctaggtt caaataattt aacaataatt aagagagaca 295020
tgcttcttct agaaaagatc aatgatttga aaacattttt atttcaggac acttttatac 295080
tcttgaaaat tattgaggac cccaaagaac tattttttat ataggataca tccatcaata 295140
ttcactttat tagatattaa actgagaaaa aattttaagc atgtgttgaa ataataaact 295200
attttaatat aaataatgca tttattaaaa tattttctat tagaaacatt ttagagaaga 295260
gtaaaattat ttcatatttt tgcaaatatt ttgacatctg actgaagaga agattttcag 295320
atttttacat ctgctccagc atttagtcta ttgcaggctc ttgttttggt taaaatgtat 295380
gaaggaaatt ttgccttgca cggatatgga aaagagagga gtatttcaat taccttttca 295440
gaaaattgtg aatatatatg tatatatatg tgtgtgtata tatatgtgta cagatagata 295500
gatagatgat agatagataa ctacatcagc actaaacaag tggtaatttc ttacatgttt 295560
gttgcaatgt gtaatccgga actgtatcag tgaaattctt ataacctgtt acattaaaat 295620
tgattggtcg ttctttcact ttgaagagat cttttaatca aaagtgattt tgcagaattt 295680
tgcattggtc atttggaaaa ggtttgttca tgaagstttg cagattttcc aattgttgat 295740
acattttatg atacaaataa cacttgttaa taccaccact gttctcaaaa ggagttttaa 295800
gtgtggaagc cgtaagctgc caagctaatg gtggcacaca cacgttttcc gaaattctgc 295860
ttttcacttg aaagctagaa ttttataatg aataacaagt actgtcagat gtttccctta 295920
gggtcacttt gttcatgttt gaaaaagaaa agtctgccaa atgcctactt atgaattacc 295980
atggtttgtc agtcattctc tcaattagaa gcgaagagct accaaaaagt rggcagcgaa 296040
ctctcactcc aacgaccgca tgagcgcycc ctgccgtcaa ctgtcacgct gccgtgcagc 296100
agaagtgctg gatttcatct gaggatgtga aaaaggcatg tactcaggat ggaaattcca 296160
cataatgaac acttttcgct gcttcatcaa ggacgtgctt aactaaaagc agcatcgttt 296220
ttggttgttt gtttacactg.ggtgtgtagc agtgaagact tcagtggcac ctagtgcggt 296280
agctcctcga ttcttcatct gcactttcgc cattgatgcg ccactagttt tgctcccctt 296340
atgcaatgtt agcacagtga aaaagacaaa tacatttcgt tttgttttgt tttttttgag 296400
atggagtctc tctctggcgc caaggctgga gtgcagtggc gtgatctcgg ctcaccacaa 296460
gctccgcctc ccgggttccc gccattctcc tgcttcagcc tccctcccga gtagtgtagc 296520
tgggactaca ggcgcccgcc gccacgcccg gctaattttt gtatttttag tagagacagg 296580
gtttcaccat gttggacagg atggtctgca tctctttacc tcgtgatccg cccaattcgg 296640
cctctcaaag tgttgggatt acaggcgtaa acgtttctta atattatggc aataaatata 296700
gttttggctc cagagtcccc ctaaaagtgt attgggacac ccagagacct gcctgagcac 296760
cataactgga taactgctgc tctagattct aaaactttct ctgagttgct ttatcaattg 296820
tccttttctt gttttcttac acatgggaga ttcttcctca ttgtctctga aaatcctcat 296880
gtttcttatg gttattttat atggcttcat gatgcacaca cacatcctta tatatatttt 296940
cttccgaatc ttctctaaca tgCCCtCttC ttgcctatag atcatgacag tattctacgt 297000
acatattttg aggagttttt attatgttca ctctgggaga gctttcgctc ctcagggtac 297060
aggagacttg tgaaccccag agtcagtggc agtgcctgca ctccctagct tgctgctcac 297120
atcggtagct gaaatgcctt agtcttgctt cagttatttc ctttaaatag atgctaggtc 297180
gaataggtgt tgtggcctct tagtaactga gtgatgggag aggtcatttc tttgcttata 297240
agaacacact gctttctaag tgagaagagc ccagcttcct gacagagcac cattagaaga 297300
accctccact gtccttgtta ggttatagtg cttatcaatt tctctccttt acagggccca 297360
atccaatgag tgacctgttt tgggaagcaa acatgttaaa agaaacccta cttgaaagtt 297420
aaagactaca attgcatttt agaatataga ctagtgctac caattgtgat tgtcctcctg 297480
aacgctatgc ttttgtgaca gttaatggaa tttaaaaagg aaaagtaaac gtatctataa 297540
cctaactttt gtaatggaaa ggattggatt ggaatggaat cctaatacat tatttctctc 297600
agaattaagt ccattgttct taacctgtta ttcttcagtg acctcgcagg actgcaagct 297660
acctaaaact gaatgtaaga ttttgtgagt tttttttttt tttccctgca tgatatatag 297720
acatatatac actggggaaa gaatatcaaa aggtacattt gttttattca ttcaaatatt 297780
aaatatccaa atatttctta tatacacagg tataggtatt tagttattgg atggtaaaat 297840
atatatattt ttatatgtat gttttggtca tttcacttgg taaaatagag catcagtgtg 297900
cactatggac agaagcagta ccatagtttt ttcctcttat atcaactttt cttctcattc 297960
cctctttttt cttctgatcc atctccttcc cctccctcaa ttccagtttg tttttctctt 298020
ttaaagttgg ctatggacag caaagacaag tgaaatgtaa tttaaaatac gcacatttaa 298080
catattctat attataaatc atgctgctat aaagacacct gcacacttat gtttattgcg 298140
gcactattca caatagcaaa gacttggaac caatccaaat gtccaacaat gatagactgg 298200
attaagaaaa tgtgtcacat atacaccatg gaatactatg cagccataaa aaatgatgag 298260
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
187
ttcatgtcct ttgtagggac atggatgaaa ttggaagtca tcattctcag taaactatcg 298320
caaggagaaa aaaacaaaca ccgcatgttc tcactcatag gtgggaattg aacaatgaga 298380
acacatggac acaggaaggg gaacatcaca ctctggggac tgttgtgggg tagggggagg 298490
ggggagggat agcattaggc gatataccta atgctaaatg acgagttaat gggtgcagca 298500
caccagcatg gcacatgtat acatatgtaa ctaacctgca cattgtgcac atgtacccta 298560
aaactttaag tataataata aaaaaaaatt cttcattgac ttacatgcaa tgaataattt 298620
ataattagcc tatgttacta ttcattttcc ttttattttt ttcttgcaaa attatgttag 298680
aactgtgact gaaatgtatg agtttctcaa tagatgctat tgattgagtt attttgaagc 298740
acaaaaataa attgaattgg ttaatataca ctttgtaggt caaaactggc cctgggaatt 298800
attttttaga gctattccac attattcaac ttcgtaagct tactgttggt tatttatata 298860
tttttaattt ttgaattata atagaagcag tttaggactt aaatataaaa atatgtaaaa 298920
tgtaaataca ctcatttttc attttaaaca catgctttca tgtcataayg gatcccaaaa 298980
taccaaagat attaggggaa aaaataaact gttgttgtct taaaatacat tcctttgttg 299040
aattcatcct gctaaccctt tagggtattg acagcctatt atttttcata tgtgccatct 299100
ttatctagaa aactgagaga acaactaatt atatcctttt gcaaatgagt gcaacagaat 299160
ggcttttgtt caacacaatt tttaagtctg ttgaacagga ctgttgaatg gcttaaaaat 299220
ttgccatggg gtgtgtgtgt gcacatatga gaatatgtat gttaatattc agccacctta 299280
gtgtcatgga aagcgtggcc tggggatttg attatacatt gtgctttgtc ataaatttaa 299340
tggtttcttt gcaacattat tggagggagt atgcctctat gtctttcatt tagcttgtat 299400
atttttggta tgatagacat ggtaattact gctcttaaag tttgtgcaaa tgccactggg 299460
aaaggggata ggagtaaaga attaaagtga aggtcatgaa ataaacctat taacaaaagc 299520
agagtgattt cttgaataat cccttcatct ctccccatgt cataatcctt tctcataaat 299580
aattatacaa gcaagcctag acacacacta gtgttgaaga attgtgctgc aaaatgcatt 299640
tagctgcatt aaataccaag agaagccttg agttccaaaa cctccttaaa gtggaattct 299700
cagttgtttc cagagaagag gcaagttata gtacatataa tctattatga acgtatctga 299760
gtagaacacc atgcaataag gcgctattga attgggaggg aggtatcaga gctaaagagc 299820
acaaagacgg gccatcgaga tattagagga gatttctctt catatgtaat tctgctttac 299880
atgtttcctc aatcttattt cctttctccc taccgcctct ttttttttta gccacaaatc 299940
attgcgtttg tacagattac aggaaaacac tcaaatattg ctcgaagaag cataatcttt 300000
cttctgcagt tggtaataaa tgagatctac ttgtaaaaat tagtgtcatt gtctacaaca 300060
ctttcagatg actctcatgc caccaggtca atattcctgc tagggatgag ttagttctta 300120
cacttgggtg atcaccaaga atgtgggact cataagggca atggatgatg caggcgcata 300180
gtgtcctttg atgttactgg aggtgtaaaa tgaaggtttt ttttcattct aaatcaaagt 300240
ttaatggtat agtaagtatt tattatcttt atcctggaag ggattttatt gcttttgaca 300300
tttttaaaaa tgtcaaattt taattttaat ttaattgttt aaaacaattt ttaaactttt 300360
atatrgtttt acaattcagt ggaattctct cttctttata ttattgtact tgcattaata 300420
atattttaga tgttttcaat catgagttat tgtcactatg ttttattaga aatatccttc 300480
tcactatgag ataaagggac gaaatgagtg ctaatgtaat tctacagggg tcagatagca 300540
tttccatggt tacattgatt cactagcagc atgtcctgaa taactcctgc tgtattgcaa 300600
accccttgcg ggcagggtct agtatatttt taatgtttct gcatatagct ccaatttagc 300660
tccaattttc ttcctacatt gtagtactag atcaaaaaat acttattggt tgaacctata 300720
atgtatgcta cttaggcagc tctggcatga ggcatgacat tatattttaa ataaagaaac 300780
acattccagc attccaaaat tctcaaagca taaccctgtg taaaaccata gttaaagttt 300840
caaaatttga aacacgaaaa ctgacttttt aaaatgttaa ccatacaatg actaatgcag 300900
tgtgctcttt gcacgtgcat aaacaataag aaacattatt aaaataaaat atttatattt 300960
taaagtaaac atacactatt taaaatactg agcaaacatt tatataagta ggggatttat 301020
ataaaatctg aatgatgaaa gtacttaaaa agtactaata gtaactaatt tattgaatct 301080
ttgtggcagt cttcatatga ataatttaac caccagaata gttacggaag gtaggtacaa 301140
atgaataacc catttgtata ggagtaaact gatgcctaga aagagaaagt cactaattca 301200
agctcataca acgtacaagt agaaaagtga ggattttagc acaggtaatc ttgatacaga 301260
atgatttcca ttatttttaa ataagagtaa tacatgtatg tatatgaatt caaataatac 301320
agaatgataa aaatggcaga atacggagcc cccttttcca cccctcgagt tccttctccc 301380
caaccaatat ttatattaat agcttatttt atttatctta aaaatattat attttacact 301440
cattatttct atctatatct ctatatagat atatatcttc atcattataa aataagatat 301500
acagtgataa acctttctct taatatgaat ggatgaactg atctaccata tattattagt 301560
agctatattg aattccgatg tatggatggg cctaattatc ttttttatta ataaaatttt 301620
agtttgttta tatcattaat attctcatat tttgctattt gcaaaatatg ctggaataaa 301680
caagagttaa ttttatttct atttactgta aattgtgtca ttattactga agtaaaagga 301740
ttgagatgac ataatgccta tcagtgcctt taaaatattt caataacaac aaaaaagaaa 301800
cctctttcaa gtgtgcaaca tcctgataat taacttatct gggtaatgag tgtatgaaag 301860
ttcattataa atgatatttc tatgtgtgtg tgtatttaga atttttacaa tagttttgtc 301920
aaaagttatt ttttaatgaa gcatctgatt tttagggagg gatctaagct ttccacacat 301980
gcttctattc tccatagtag tgtaagaatt tcaaatgtgg acacgttaaa gtatttctag 302090
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
188
aggaggatta agtgatatga atgaaactgt tggggacctt acattttatg tgtaatgaga 302100
gctgaaaggg ggttctacaa agaagtgtga taatagagga cagatttttg gaatgaggta 302160
atgtcattcc aataaggact atatttatct agggatattt tgaaagaaac tggtgatgag 302220
gagaatgaag agaaatagtc attagtgcaa acatgtcaag aaagaaaaca tattacttct 302280
ttggagatat tttCtCtCtC tCtCtCtCtC CCCCtgCCtt CCCCtgtCCC tCtCtCCata 302340
aggctctatt tatctatcca tcatctctgc atatgtcttt atccatactt atatctccat 302400
actcatatct ataccgatat ctatatttat atctgtaagc tgatcttagc ctactcatca 302460
tggtaacata tggcagattt gtgtatacct gttatcagtt cccaaatctt tacacacact 302520
tctctgtcat catgattaag gggagtaatg tgctcttacg tttttgagaa ttgggcccaa 302580
tggggacagc tatttttctc tgttataaga ttccatagat tgtggcaaca atggcaccat 302640
gatgacttct aaactcttga tgggagactt gcttctgtga cttaatggat tattagccct 302700
gcaatgggaa ctacacaccc aaaggccaag aggaacatgc aaaggcaaac agagagacaa 302760
gagagcccat caatcacgag aagatggcag gaagttgtgc cgttcccatt gcagttattc 302820
ggacagctta agattgaaat ataatagaaa gttatatgac gtactctaca gacaagttta 302880
tattttatta ttattattgt tttgtaatgt agaaaacatc tacccctaaa aatctgtgga 302940
taataggtta ctagattttg taactaaata agataataga caaaatataa tagatataga 303000
aaaagtcaga aatgatcctc atccatttta gaaacccaat caatttcaat ttaatccaaa 303060
tctcttcctt cttcaacaag gcactacgtt atcctcatcc ttccagcttt ccttcccaca 303120
gctttgatca ttcagggtta gtcttcattg cccatacttg ttcctatttg ttttaaataa 303180
agtcttaata aattcttcct attgggtggt aataagatat attcaataag gtgaaatgtc 303240
taactttaat tactgaacaa tgaagcatgg tagaggttta tactttaata atataattta 303300
ttaattatac atcatggtcc aagggctcta ctttaattaa tattttccac tagcaaaaaa 303360
taactatcgg tgtacaaagt cccacagatt agacaccaga accttaggca ggtagtaagc 303420
ccccagtagt tcagtggcta aagtgggctt taagtaccta aggtttatct ttattcatgt 303480
gaaagttttc tggctagaga gttaacagct gagtgcattt ttagtaaaat actgcaggaa 303540
atggctgata aaagtatcaa tgttgtatat ctgcttaaag gagatgcata tctgttcttt 303600
ctcaaaccac tgttaagctg tcacccatag acttattgta gaaacaatta tctcacagta 303660
gttttatctc cagacatttt tctgcccaga caaaagaatc tatggaagta gtcatttctc 303720
tagtttgttt tagggaggat tgtgttggtt ctcctatgag aaatcacttg cacattatgt 303780
tcaggtatac aaacacgtga atgtatttgc tatacagagt ccatttctta cacacagcaa 303840
ggtatagttt caaattgctg aagccaaata aaccaaatgg gaagaaattg atggtaaact 30390'0
ttgtcagaat gttggttctc tctcatattt atgaatctgt caaaggatag actttttgta 303960
aactaatagg tttttatatg ttctaattat gcaaggaaat ctatcctgtc ttagcaatca 304020
agtggtaaga gagaaacata tggttagaga tcagggaaga atatgttaag tgaataggac 304080
actgaaaaag tctgctgtga atacagtggt gggcagccat tgtgagatta agtagtaaat 304140
gcccatgcaa acagaaaaaa aaatggaatt gtaatataaa gtcacaaata taatttgttg 304200
attgacttac acggattaca aatttggtat attgagcttt ccgggcttag tgaataacat 304260
cactctttgc atttttttgc tacatcatct ggccacaaaa ttttaaagac tatttatgaa 304320
agtcaagtta atatttaaag tcacaaagag tcctagaaat tttgaacatc acactgactt 304380
cgtacctgtt gtactatggc atatgtcttt agtcaactaa ttatttttct cgttaacaaa 304440
aaaaaaggaa ataaaaaatc ccaaaaaaca aataacccaa taaaaataat gagtaaaata 304500
tcagggttga tattcctcaa aagaagacat acaaatgaag agcaagtata tgaaaaaatg 304560
ttcaacatca ctaatcaaaa atcaaaacca cagtgagata acagctcacc ccagttagaa 304620
tggcaattct ccaaaagaca aaagataacg tgtttgcgag gacgtggaga aaagagaatc 304680
attgaacatt gttggtggga atgtgaatta gtatagcctt tacgaaaaac agtatggaga 304740
ttcctcatga aaacaaaaat agaagtatca tttgatccaa cagtcctact actgggtaga 304800
tatccaaaga aaatgaaatc ggtatgtcaa agaagtgtct gcgcttccat gtttatgaca 304860
gcattattca caatagccaa ggtatgaaat caacctaagt ggacatcaat ggaaaaatgg 304920
ataaagaaaa tgtggtatgt atacacaatg caatactatt caaccataaa aagaatgaaa 304980
tcatgcgaca acaccaatga acctggaaag cattatgtta agtaaaagaa accaaacata 305040
ggaaaacaaa caccgcatgt ttcactcatg tggaattcaa atacattggt cacatgaagg 305100
tagagtacaa tggtagctgt cagaggctgg gtgtttaggg gagaaatggg atggagagat 305160
gtcggtcaga gcatacattt acatttgata gaagaaatga atttcaagag atctattata 305220
tagcaaggtg actctaatta atgaaaatat gattctattc ttgaaaaatg tagaatgaat 305280
gtaatatgcc atcaccacag aaattgtaac agtgcaaggt aatgcatttg tgaattagct 305340
agatttaaca agtcaacaat gaatatacac tttataacat catgttgttc atgataaaaa 305400
acatacaatg ttatctgtca attaaaaaaa tatctaggaa gaatctgtac agaagattgt 305460
gggtatttat aaaatgcata tttactttgt aagtcaccaa atttgtgaat aacattattg 305520
gatttatttt gcttaataga atagaataaa taatagaata aattataatt aaatatttaa 305580
agtgatccct ttagaccttg atgattttat aaatataggt gagatgctag tttgcttacc 305640
ctaaatatct attttctgcc ccagaaacaa tcctttaata gaacacttta cctttcctta 305700
acttccatca ccaaaattgg caattaagaa tattttcaca cagaaaaaac cactattgat 305760
atgtgtgtat ttttagcaag aaagccagtt ttttgagctg tatgatggag ccttttcact 305820
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
189
cattagtgat gcaactgact tctgcacacc atcctacaga agaagaaact catgttcgta 305880
tataagcaaa atgacatatc attacacata ataactcatt gtggtgggtt ctaagcaagt 305940
gaagcagtac tggctaaatc catcagtgta gtattggctc tctattctac ctgttcttaa 306000
aaccagtaag gtagagttcc cgctccttga tataagaata aggattccac cttctcctgc 306060
ccctcccaac tagaattctc aaatgtgttt gtcggtggct catccaatat tgcccaagga 306120
aagtgtgttt tattagcttg ggattccatc tgtgaagact ggcatttcta tcttactaac 306180
agatacagaa catatgaaga atccctgagt tcctacatag ctgtcaagaa gtaaatgaac 306240
tgatttgact gttattccct tcactcactg gaaaaatagc tcttcccaga atcaagtatt 306300
gttgactctg ttccaatcct cagagcaatt cttgccaaac ttcttttgag aggtgctgcc 306360
ttgagaaagc atgacctatg aaaatgagtt gaagctccaa accagcccat accacgtgat 306420
ttgcatagta caagcctcac tgatgatcac tatccaccat atcttagaga tgggatttag 306480
aagttactca tctctggaga ttgtatccca gggtctagca caagtctcta cacaagtggt 306540
actcaaagct agcacttgca ttagtattag ctgagaattt tttaaaaaaa aatcggagaa 306600
cgaagcaatg aagtaatagt agaaaattcc tcttcatgtg aaattcctgc taacatgttg 306660
tacagcatgt taggatgggg accacacctc ctttttactc acccattata gcccaacgat 306720
ggaacacagt gcctgacaat aagtatgtgt tgagtaaatg aaccgctgtg atcctcccac 306780
tgcatcaccg caagtacctt tagaccccaa agagcataat acagatatgg tttggctatg 306840
tcctcaccca aatctcatct tgaattgtaa tccccagttt tcttactggg ttcagaaaga 306900
gaagtatttt tccccacatg tggaagaagg gacctaatgg gtaactgaat aatgagggca 306960
gtttccccca tgccgttctc gtgatagtga gttcttacaa gatctgatgg ttttgtttgt 307020
tatttgttag tttgttttga gacacagtct tgctctgtca cccaggttgg agggcagtgg 307080
tgtgatctcg gctcactgca acctctgcct cccgagttca agcgattctc ctgtctcagc 307140
ctcccgagta gctgagacta caggtgtgtg ccaccacgcc cagctaattt tatgtattct 307200
taatagagat cgggtttcac cgtgttagcc aaggcggtgt cgatctcctg tcctcgtgat 307260
ccgcccacct cagcctctca aagtgctgag atgacaggtg tgagccacca tgcccggctg 307320
atctgatctg atggttttat aagcatctgt catttcccct gcttgcactt ctctctcctg 307380
tcgctgtgtt aagaaggttc ttgcttcccc tttatctttt gccatgatta taagtttctt 307440
gtggcctccc cagccacgtg gaactgtgag tcaattaaac ctcttttctt tataaaataa 307500
ccagtcttga gggtatttct ttatagcagt gtgaaaacgg actaatagac aaagaaagcc 307560
tcaaggaaag aaaggtacat tgtagaatat caaaatatct cagtaattct ttttcatagg 307620
aaacgtggct tgatcatgtt tgttcattga gaacccactc tattggcttt gtatcttgct 307680
tcaagttgtt ctagaaattc caactattat tgaggcattt gcgtattaaa ttacttttta 307740
gaaatcttta cagtgaaggt gaatctggta ataatacgta acaacattat gctaaccact 307800
ttaatgttct agatgtattt gataagaacc ttattctcag tattctgagt aaactcgggg 307860
cctggaaaac atttagcctg tacaaagatg tatatttgtt atatttttct taattgaaag 307920
acgatatata ttttgaaaaa aacatttagt ctcctaaaat tataaaaaaa tcattgttta 307980
gagaatgcaa ctaatctcaa aattttaaat aaataaccag tgcttatagt gtagttgtat 308040
tatccattca taaaattgat tgcaatatgt tagtgctggc agcttagtat aacacatttt 308100
cccccgaacc acaaaaatgt gtttatttat ttattcattt taaaactact ttatagtaat 308160
atacagatta agtaaacatt ttagtaatga gcttacagat tttatacgat catgcggttt 308220
tggttttctt actgggttca gaaagagaag tatttttcag tggggattgc ctagctgcaa 308280
ccttgacatt ttcactgtct tgctgcaggg agttcaggag catgtataag actattctat 308340
ttaatttagt tttacaatct cattgtatct ggcaatttaa gacatagaaa agtaactttt 308400
ccttaattaa aataaacttt tggtatttgg atagcaggat aatgaatacc cagacaggca 308460
gtatgtggtg atgagtagtg catgaacttt ggaattcaca gaccttggct tagatttcag 308520
attctccaat tattagctat gtcagttagg gcaaattgcc ttaattcttt aaactcaatg 308580
tattgatgtg gaaaaagggg caataaatcc tatcattcaa agttgtaatg agcagtaaag 308640
tatatgaata tgtaaaaatg actaggctag tccctgacta tgggacatag catttatttc 308700
catgtgcact ttgtgtgagg gagtgtaata tccaatttct gtattatcat actgcaacta 308760
tgaatatgga cacaaataca gatacatctt taccatttac agactacttt tccatgtaca 308820
cacacatagc cctttgctaa aatgtgatca tggaattagg atttcataaa attgaattat 308880
aacattggaa ggccatgtag cttaagatta aaaacataga atttgcagac agacacaatg 308940
agctggaatt ctattctact tgtttcctgt cctatcttga gcaagccact caacattttc 309000
agtctctttc tttttcatgt aaatgtacat atccatgtca tagatttgtg atgtctatta 309060
aggaagatgt atgaaagcac tgtcacaatg accaataaaa ggagaggatt caataaatgg 309120
tcattgtccc ttaacagatg tctttaaaaa tatattaaat ttgaaacatt gtttcagagt 309180
gtcttattgg atgaaatgat aataactgta cacatgggtg aagattagtg attggaagtc 309240
aagaattttt gcttcagctc cttgaccttg aggttgaaat ttaagcctcc tcatctagtt 309300
tttttaaaaa acgtttctaa cagaaatata ctttgtggat cattatacct cattctaatc 309360
cagctccctc aagcttaatc tgtatgaact ttggggaaaa gataagcact gtgaataagt 309420
tggcatgctt gaacattctt tgaataagta gaaaatattg ctctttcatt ttattgacag 309480
aaagattatc ttgatagctt atacttctgt ttttaatgta aataataggt atcaaattct 309540
aaaattgaat aatgttgacc aatttaatga gtgtctgtaa taaggggaat ttataaatgt 309600
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
190
tttgcactaa ttgcagtttg taaagttatt gaacttcctt ttatacttag atgataattt 309660
attatttatt tatttatttt tgagatggag tcccactctg ctgcccagag tggagtgcag 309720
tggcccgatc tcagctcact gcaacctctg cctcccaggt tcaagtgatc cttctgcttc 309780
agtctcctga gtatccggga ttacaggcac gtgccaacac gcccagctac ttttttgtat 309840
ttttagtaga gatgaggttt cactatgtta gccaggatgg tctccatctc ttgacctcat 309900
gatctgccca cctcggcctc ccaaagtgct gggattacag gcgtgagtca ctgcgcccgg 309960
accaattttt tatttttatt gacaatgctg ctttggataa agaaagttac tgaacgcctt 310020
ggtcaatgca actgtggtaa agagaacaga aatgatcatg cacaatagca agatttcagt 310080
taaggttctt ggttgcaagt gataaaaatt taaagcagga aaataatcta ttagaaggct 310140
atggaataga tgtcagagac aaatgttaag gttctgaaat tgggcaataa gcaaggaagg 310200
aaagacctca aaggcattaa cctgcagtgc ttctgaacgt gggctctgga gctgaagttc 310260
caaatcttcg ctccaccact taatagaact ttgtgacttc gggcaagtga cttaaccttt 310320
gtatgtccca gtattcagat cttcaaaatt agactaccct tacagctaac tgagttaaca 310380
cgtgaaagac acataataga tcttcaaaaa tgtccagaaa aaaataaatg tggccagaac 310440
aatggccatc acattataca ccatggactc cactggacgt ggttatggaa aactaatctc 310500
gctgtccttt tgaatttgca tacctccaca aagttcctga cctatattgg attttgcctt 310560
ggttgagagg agaacagaag ggatgaaatt tctttacttt ttctctaagt gaaaggtata 310620
attccctgaa actaagaaga ggagggattt ggatgttaaa cagccacaca ttttgaaaat 310680
gtccactaca gttagaataa ccatatatcc tagctacctt gagaaagtcc cagtttacaa 310740
ctgatatccc acatggttaa acacaccttc gtggcagaag tgtcacaatt tggatgataa 310800
attatggtca ctgtgattgt cattcactcc cttttgctgc taaaatgtgc atatattctt 310860
cttcttatac ttactggtcc agtgaaaaaa gaccttaata acaaaattaa attttcattt 310920
ataaaaacaa taatgcattt attcttttca gcaaacaaaa caaaaacaca acaacaacaa 310980
caacaaaaaa ccagaaagtc caaaatacta ttattctgct atctctaagt cttggatatc 311040
tgtggactat tttttgactc taattttttc taatcctatc tcagtatttc atcacctaca 311100
gagtaaatta gcatcgtccc cacaacaata ccctacatac ggtatctata tctatttata 311160
tacatgtata caaatatata cataaatata tatatgcata tatacatatc tatatgtata 311220
tagatagatg tagatatatg aaaggtatat ctatatacag taggcctcca ttacctcaga 311280
gacacatctc aagaccctca gtggatgcct gaaaacgtgg atagtgccga accctatata 311340
tactatgtat aatttttttc tttgtcacca tttcacagat aaaagattca ttttgctgta 311400
tatcttagca acctcagcat atgatttttt tccctttctt tattaagtca agaacttgca 311460
tcattttcct taatggaagc actttacagc ttctgtttgg catagccaaa tggccagtat 311520
cactgctttt gtgctttgag gccattatta agtcaaataa ggatgacttg gacataagca 311580
ctgaaatagt caatctgata gctggggtgg ctagtgagtg actaatgggt ggggagcaga 311640
gacagcctgg agaccctgaa caaatgaatg attcatcccg agtttgatgg agaaagagca 311700
caaaacttca tcaccatact cagaacagca cacaatttaa aacttatgaa ttgtttattc 311760
ctggaatttt ccacttaata tttttggacc atggtttact gcaggtcatt gaaacctaaa 311820
aaagcaaaac tttgaataag gagaaactac tctgtgtgtc tacatgcaca tgtataagta 311880
gtctctcttt cacacacata tacacataca ggaaaggaag agaagacatg tggattctag 311940
tttcctcatt tccatacttg attatgaggc caaattgagt atttatgact tgcctccttc 312000
atgacccagt acatactccc tctactttcr gggaacactt ctgtaatatg ctagaatttt 312060
catgcctaaa gattctaagg gtttttcttt ttacatatag aatgaaaaga gtctttcatt 312120
aacttccaat taatgaacat gctggttctg tacaccatct accacccaga acgctgatct 312180
ttcaagatgt tgtttcccat ctggcactat agtgagtttt ccatgaatca tccagtattc 312240
cacaagggct acacagtaag aaccttgaat cctatgggaa taagctcaat gcctaacatc 312300
gtttgcatta tattctttgt ttagtagcaa tgatatataa aagttgtggt tatagagttt 312360
gttgaaaata tctgaagaag gtacagacag caaaggcaga cacagaagaa aaatatatca 312420
attttttaac agcagctgtt ctactgaagg caaatcactg cactctccat gattcaagaa 312480
atcaactacc acccccccaa cccccccctc accacacaca cacgcagtac tatttgctag 312540
catcagtctt gctcctctat cagggcctct aggttgtgct cagtatgaat gaattagaca 312600
ctcaggggtg ccattagctt ggcaacctgt ccattttacc atgtcctagg catgtttcta 312660
tccataagac ctttgtcact tgacttaata aggagacaca cagtggccag gaaaagagat 312720
atttcatcac agaacctgct gccatgttgc ttagaaggag aaggagctag atatgtgact 312780
atgtgtccat tcttgagccc tggcacttgg gttgtcttga tggtcaggaa cttggaagga 312840
agacaattga aatattgatg acaagaaaat ttggggaaga gacatgtggc tataactctc 312900
agaatgaacc aaaacttgaa gatatttttg gatgtttaaa aaaggatgac ctcagaatag 312960
gaggatttta acaattaaaa gaataggatg acttgttttg tgggtgccag tcagcctctt 313020
tactcagtcc tccctgtcac ttcccattgg gctcatgact aaaatagcca ttgtgtcagg 313080
gatggaggtt acgcatgggc tcagctacat ggacttacac tcaccaaggc tgccttccta 313140
ctatcagtct accagctgta gagaccaaca ctgtgcaccc aatgtgacac tattccccag 313200
gggatcaggc atctacctgg tggcaggcag atcacagtgg acagcctcca tcatggaaag 313260
ggaagtattt tgtttctact ggataagatt ttggatgtgg atgtgtctgt cctgaacaca 313320
atgcttctgc caaacacgga cttacagact gccttatgca ctgtcgcagt attcctcacg 313380
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
191
gcatggcttc tgatcaagga actcacttca cagaaaaaga agagtgccaa tgggccatgc 313440
tcatgggatt caccggtttt atcatgttcc ccaccgtcct gaagcagctg gcttgataga 313500
atggtaaaat gaccttttga agacagctct agccccagct aggtaacttc acagggcggg 313560
ggcgagggtc tctagatggc tgtaaatgct ctaaactaac tatccgatat atggtgtcat 313620
taatttttat ccaaattcat cttcttcacc tgtgtattat caatagaaaa tagcttaatt 313680
tgtcaatcta tcttgggtca aagtttacca taaagctttt catgaatttt agtttcaaaa 313740
atttacatct tatgtaatag tgtgtataca tttatatagt aagaaataat atagtaaaga 313800
aaatcttaaa cacatggcta agtttggcag aatgtcataa agatcacatt gtacaacaaa 313860
tgccagaaat tatagtgctg tccataattt tgtttctttg agactgattc cactggtttt 313920
caaatattgc tacagttgaa acaaaattaa aagaataaaa actcagaatg atcacataga 313980
gtggctaaat taatgatatt caagttctgt ttcttcatct ttataatcac ggtgttataa 314040
ttgtttattt caaatcaacc gctcaaacac aggaatccat agcaccaaaa atttttgata 314100
cagaaacttc actgagggca agcctaaatg atcccaaatc tctatgaacc ttttcttgaa 314160
atgaatgcat gtaactgagt ccgtgtttgt caaggccatt tgtaaaactg gaagttctct 314220
aatttaacat ccatgtaaaa tacaatattt ataaaacaac ttgtaataaa tgtatgttaa 314280
tttgatgtta catatatatg tatatatnca attacatata tatatatata attaaattca 314340
agagaaacca agtgattgtt taggactgag accaataaaa tatttaataa aatatttttg 314400
gagggaggac ttgtaatcac gaactggggg gaatatccac gggcaaacca tgaaccagat 314460
tcaggacaat gtcgttgtcc tctgaatccc aggtaagtcc actttgactc ttaaatggca 314520
gaaggactct gggttttcaa aacccataag cctgttatct aacgtatttt cgtttcacca 314580
gtgcacagct cctcttgttt atggatgcag atgcctttcc agaaggctag aaattataga 314640
aataacattt ggtattttca gagtctgtat atggaagtac ctacctacca tgtttttatt 314700
taaagaattt tgaatatgtg atttgactca aatttgggaa ttgtgtgagg aacaaaacta 314760
ttttggtggc ttcaattagg tctatatgca atagaacgtg aatacttttc aaaaacagaa 314820
atagaacagt gcctacgtga gctagcacca attatggtcc ttggtactcc atggcctatt 314880
tacagctaca ttaatccatg agtcttataa ttcaaatggc tccagtggct ttgatgttca 314940
ttagggacac aacagccctt tgccttccct ggagaagtgc tgtgttttgg gttctaacaa 315000
cataaatact ccccagtccc agtgttttta tggagcccaa ttcaatgtac gatctccccg 315060
tggcatcacc tacctataat gattaaggat ttgggagatt catttagtga attttatcaa 315120
gataacaatc ttaacaaaca ctgtagcata tgcacactcc aaaggctttc cctctttcta 315180
cgttaaatcc aatggattcc tgggactgtg tctcttatag gcttttactg ggcctaaatt 315240
ttagccaata agcttgtcaa acagctagaa acacattaaa ctcttcaagc ttacctactc 315300
tatccatgct cttcgggtaa gtgtccactt tgaaattcac cccaatgcaa tcttttatct 315360
tggttggatg cacaccttca gaacctattc ctaagaaatt cttgcatata ttgttggcat 315420
aaatgtcttg caattctgtt gttatatcat tttttttctg agtatatttg acccctattt 315480
aatgcttagc tcttgctcaa gttctaggac tgcaggcaat gaagactggg taagtagggg 315540
ttaggatgag aattatcttc tcagtctgag gtaacttcct catatgtaaa ggctactaag 315600
gcaggtttgg aaatgggttt atatatgcat ttccgaatat cctaataata tttggctgct 315660
tacattagta aaaatcatta aagttgcttt cactcaaaga ctgtaagata taaagaaaag 315720
ttatttaaaa tgtaaagcat tgaacagaaa acaatcggaa actaatcaat gaaatgggta 315780
tatataggag gattccaaaa attcggagac tctaaccagt gaatccagcc ttgctagtac 315840
atccctgcag ccagatacag ttgcacttgc tggaccacta caacatcggg tgccaatcta 315900
accactgaat ccaacctcct tgtacatsac tgcaaccaga tgcagttgca cttgctggac 315960
cactacaaca tcgggtgcca atttaatact ttcttctttt cactctctac cccrgtttca 316020
gtatccttgg cagtatgcta tgttcaactg actttgagat gtatgattct attttgacac 316080
caacaggctt agaaaagagt aaactgaaca ctctggcttt tgtagggaga agtagaactc 316140
cgtgtagcac gaagtcttat gcaaaagtag gaagcagtgt aggaggattg gcagaccaaa 316200
aaatgaaaag tgacaaatat ttatatacag ccagataatt ttgttataag tcaatactct 316260
agatttttta aatctcccat ctccaaggca atttaggcaa cagcaagtat cttataaaat 316320
tctctttttt tagaaaatat agatgaatta tttaagatgg attatcatta tttattgtgt 316380
atttagtata ggtttattta tctcacactt ctttgtcttt ttccattatt ttcagctgtt 316440
caaaaattct gcatttgtaa caacttcctc aatatgtaaa tttaaaaatc cctcaatatt 316500
tgccatctta ttctgaagtg tttaccatct tactctaaag taatctgaac accacatgca 316560
ttattgttgg agttttaaaa cattagtatt tatctgatcc taatgtttta ttgtaattgt 316620
atagattttt tcactaattt tggaagggta aactattgtt tcatagatgc aataaatcct 316680
ggaaacttgt ttgcaatact tttaaaagca gttttcaaaa tttctcctct atcacacagg 316740
agacacactg taatgactac tatttcctct gatttctttt aggtgcgttt cttttgactg 316800
tattttcatc agtctcatca tttttctgtg tcatccattt gcgctgggac ttgtgcctac 316860
tgatggtttt caagtgtggc tgcaatttgg ttcccttgaa ggtattttaa aatatgctga 316920
tgcactagta ccattcccaa accaactgaa acacattctt caatggcaag gtcatggtgc 316980
tggtatttaa aacaaaaatc ttcctaagtt attttaatat acaactacaa catattcact 317040
ggtatagata atattgaata caaaaaaaac ctatatgatg actcgttcct tctgtgagag 317100
agcaaagtcc acaatttaaa aaaattaata atactgttaa ctcagaggga tcagaccagg 317160
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
192
tggaaagcac gaatatgcac tctgcataat gaagcttatt tccagtgtac aaatctacag 317220
caagcagaaa aggatacttg gtgcrgtttg ctctagatac acagctaaca cagcgagcca 317280
tgcagtgggg cctccaccta gaggaactga ttacaggaag aggaagtttt gatttcaacc 317340
ttgttaggct ttccttccag ttagtaatgg tttcaagctg aatggatgac acaacatgaa 317400
aaattcaact acttaagaat agcatgcgcc aagtatattc tataactttc tgttaagatt 317460
catttcactt aataattttc tatataaatc tctattaatt taagtttctg aataactgta 317520
gggtcaacaa catatttggt actctcctac tttgagcttg gttgaaccac ataatttgaa 317580
agaggatatt ttataaagtt aaaatcctga taactttaaa gactgataaa tttctgtttg 317640
cattcagaat atagtggcag aaaaaaatat tcctttctaa attataatga ttaaattgtt 317700
ttgatggtat tatgttgcta taaataattt cctagagata ttaaggtata cttacataag 317760
atttattcac atttatgata ttttaggctg accttaaaaa ttatttatga atttaattgc 317820
ttatgcatat gtgataaatg ctaattataa tatttacttg gctttaataa atatttccag 317880
ttgcaatttg ataggctaac tgtatgtaaa aatttcataa tattgtctag aatagttttt 317940
ctttattctg atccttttta gttatagtct tatagatatg gccttagttc aaaagcacta 318000
tacactcgtg aaacatttct aagtcaatgt aaaatattgt aatgtgatgt cagaataaaa 318060
tctttttgaa gatagagatt ttcatggttt ttttccaaat cagagtttaa agtagtcaat 318120
ctcatgattt gtcagacttg aaaagttata gaatgaatat tttaacataa aaataactta 318180
aatgaatatc cttagaatac aaatcaactg tatattcact cgaggcactt aaaatattct 318240
atatgccaaa aactgcatat ctctttccaa tttttaatac tgctttctct ctctctctct 318300
tagtttacaa atatttctca atatttaaac ttttagaact gaatcatgtt ggggaaatga 318360
agtctttggg gaaataattt attatgaaaa atttttatgt agttattaaa aaaattctaa 318420
ctcagttaaa caatattata tggaaatgcc atagtttgaa aaattgtcaa ggttaagata 318480
aaacaaaaaa atatttttga cttttttttt cttttctttt attattatac tttaagtttt 318540
agggtacatg tgcacattgt gcaggttatt tacatatgta tacatgggcc atgctggtgt 318600
cctgcaccca ttaacttgtc atttagcatt aggtatatct cccaatgcta tccctccccc 318660
ctccccccac cccacaacan gtccccagag tgtgatgttc cccttcctgt gtccacgtga 318720
tctcattgtt ncaattccca cctatgagtg agaatatgcg gtgtttggtt ttttgttctt 318780
gtgatagttt actgagaatg atgatttcca atttcatcca tgtccctaca aaggacatga 318840
actcatcatt ttttatggct gcatagtatt ccatagtgta tatgtgccac attttcttaa 318900
tccagtctat cattgttgga catttgggtt ggttccaagt ctttgctatt gtgaataatg 318960
ccacaataaa catacgtgtg catgtgtctt tacaacaaca tgatttatag tcctttgggt 319020
atatacccag taatgggatg gctgggtcaa atggtatttc tagttctaga tccctgagga 319080
atcgccacac tgacttccac aatggttgaa ctagtttaca gtcccaccaa cagtgtaaaa 319140
gtgttcctat ttctccacat cctctccagc acctgttgtt tcctgacttt ttaatgattg 319200
ccattctaac tggtgtgaga tggtatctca ttgtggtttt gatttgcatt tctctgatgg 319260
ccagtgatga tgagcatttt ttcatgtgtc ttttggctgc ataaatgtct tcttttgaga 319320
agtgtctgtt catatccttt gcccactttt tcatggggtt gtctgttttt ttcttgtaaa 319380
tttgtttgag ttcattgtag attctggata ttagcccttt gtcagatgag taggttgcga 319440
aaattttctc ccattttgta ggttccatgt tcactctgat ggtagtttct tttgctgtgc 319500
agaagctctt taatttagtt agatcccatt tgtcaatttt gtcttttgtt gccattgctt 319560
ttggtattta gacgtgaagt ccttgcccat gcctatgtcc tgaatggt 319608
<210> 2
<211> 995
<212> DNA
<213> Homo Sapiens
<220>
<221> 5'UTR
<222> 1..253
<220>
<221> CDS
<222> 254..304
<220>
<221> 3'UTR
<222> 305..995
<220>
<221> polyA signal
<222> 971..976
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
193
<220>
<221>allele
<222>53
<223>99-16050-235. polymorphic base or C
G
<220>
<221>allele
<222>228
<223>8-135-112 polymorphic base T
. C or
<220>
<221>allele
<222>282
<223>8-135-166 polymorphic base C
. A or
<220>
<221>allele
<222>388
<223>99-16038-118. polymorphic base or G
A
<220>
<221>allele
<222>447
<223>8-137-152 polymorphic base T
. G or
<220>
<221>allele
<222>477
<223>8-137-182 polymorphic base G
. A or
<220>
<221>allele
<222>693
<223>8-130-220 polymorphic base C
. A or
<220>
<221>allele
<222>659
<223>8-130-236 polymorphic base G
. A or
<220>
<221>allele
<222>831
<223>8-131-199 polymorphic base C
. A or
<220>
<221>allele
<222>894
<223>8-132-97 polymorphic base
. C or T
<220>
<221>allele
<222>961
<223>8-132-164 polymorphic base T
. C or
<220>
<221>allele
<222>976
<223>8-132-179 polymorphic base T
. A or
<400>2
gtagagtgaa atg tgtgtgtgag tagtcattgg atacatacat aasagtgagc
gcaagta 60
aagtttatca cat ggcagtgttc tgatgatctt ttgctgcaaa agagctacac
gctcctg 120
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
194
cccaaattagtggcttaaagtaaaagcttactagtgtatatgatgattctgttggtccag180
gatttggaaagggcatggcaggaggtctcatctctgcttcacaatgcygatgatttagct240
gggaggacccaaa atg gaa aag get gat ctc cag 289
ctg ctg atg tmt
ggt
Met Leu Glu Lys Leu Gln
Leu Met
Gly Ala
Asp Xaa
1 5 10
ctt ttc gaatctga 344
agg gta acacgactga
taa ag tattttcttt
aatttttaga
Leu Phe
Arg Val
15
tccagatatacattgggtaaaatctacttcataggttttcaaargagcattcttctgagc404
aaatctgaaaactctctaaactctattgcaaaggagacagaakaaggaagagagacggta464
acaaggaaagaargatggaagagaaggcatgaggacggctatttggaaatggcacagagg524
catttacagagatcattatgtccttgggtctcttaccttcctcagccctatgcagagctt584
gaagaagtaagcagccatgttggaaaagtcttcatggcaagaaactatgagttccttgmc644
tatgaggcctctaargaccgcaggcagcctctagaacgaatgtggacctgcaactacaac704
cagcaaaaagaccagtcatgcaaccacaaggaaataacttctaccaaagctgaatgagtt764
tggaagcagattcttcccagccaatccttctgatgacaatgtagtctggccaacatcttc824
actggamtctgacggactctgtgtctgggacccagctgataacacgtggtgatgggattg884
tatttgcaaytctctggtcagtaagtgataaaatgccatttctatgcacccacctggcct944
gtgtgactgggagaatytctctttttattaawtgtgcttcaagttttaaca 995
<210>
3
<211>
1035
<212>
DNA
<213> sapiens
Homo
<220>
<221>
5'UTR
<222>
1..253
<220>
<221> CDS
<222> 254..304
<220>
<221> 3'UTR
<222> 305..1035
<220>
<221> polyA signal
<222> 1020..1025
<220>
<221>allele
<222>53
<223>99-16050-235. polymorphic base G
or C
<220>
<221>allele
<222>228
<223>8-135-112 polymorphic base C or
. T
<220>
<221>allele
<222>282
<223>8-135-166 polymorphic base A or
. C
<220>
<221>allele
<222>388
<223>99-16038-118. polymorphic base A
or G
<220>
<221>allele
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
195
<222>447
<223>8-137-152. polymorphicbase G
or T
<220>
<221>allele
<222>477
<223>8-137-182. polymorphicbase A
or G
<220>
<221>allele
<222>621
<223>8-142-132. polymorphicbase C
or T
<220>
<221>allele
<222>700
<223>8-142-211. deletion TTTG
of
<220>
<221>allele
<222>743
<223>8-138-218. polymorphicbase C
or T
<220>
<221>allele
<222>759
<223>8-138-234. polymorphicbase A
or G
<220>
<221>allele
<222>839
<223>8-119-38 . polymorphicbase A
or T
<220>
<221>allele
<222>894
<223>8-119-93 . polymorphicbase A
or C
<220>
<221>allele
<222>898
<223>8-119-97 . polymorphicbase A
or G
<220>
<221>allele
<222>921
<223>8-119-120. polymorphicbase C
or T
<220>
<221>allele
<222>926
<223>8-119-125. polymorphicbase A
or G
<220>
<221>allele
<222>996
<223>8-119-195. polymorphicbase G
or T
<220>
<221>allele
<222>1001
<223>8-119-200. polymorphicbase C
or T
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
196
<220>
<221> e
allel
<222>
1005
<223> -204 . ymorphic
8-119 pol base
G or
T
<220>
<221> e
allel
<222>
1011
<223> -210 . ymorphic
8-119 pol base
G or
T
<400>
3
gtagagtgaagcaagtaatgtgtgtgtgagtagtcattggatacatacataasagtgagc60
aagtttatcagctcctgcatggcagtgttctgatgatcttttgctgcaaaagagctacac120
cccaaattagtggcttaaagtaaaagcttactagtgtatatgatgattctgttggtccag180
gatttggaaagggcatggcaggaggtctcatctctgcttcacaatgcygatgatttagct240
gggaggacccaaa atg gaa aag get gat ctc cag 289
ctg ctg atg tmt
ggt
Met Leu Glu Lys Ala Asp Leu Gln
Leu Met Xaa
Gly
1 5 10
ctt ttc gta taa gaatctga attttcttt 344
agg ag acacgactga aatttttaga
t
Leu Phe Val
Arg
15
tccagatatacattgggtaaaatctacttcataggttttcaaargagcattcttctgagc404
aaatctgaaaactctctaaactctattgcaaaggagacagaakaaggaagagagacggta464
acaaggaaagaargatggaagagaaggcatgaggacggctatttggaaatggcacagagg524
catttacagagatcattatgtccttgggtctcttaccttcctcagccctatgcagagaac584
acagaagcttttgcagtgttggtgctaaaatggttcycttgtcagaggagttacgtttta644
tgagatcctctaagcaaatttagaaaaggagaggaacttgaccacagaaactgtgtttga704
tacatttgagcaacaaaactctttcagagacattttaaytcacgatgtgggaaarccaat764
gagagaagaaaaaagaaattctcatctgaaacttgaacttatcaaaactcacttgtctag824
aaattagcctgggawcatccaggcactggaatttctcactttttttccttctccctctca884
acttcagtamtgaraggagaaagtcatttccaaatgyctatrttttgactttttaaatag944
accaaatttagagtcatgtaaagatacaataattagctttcttaacaatttkcaccyaga1004
kgtattkttatagagaataaaaacaacaaca 1035
<210>
4
<211>
1158
<212>
DNA
<213> sapiens
Homo
<220>
<221>
5'UTR
<222> 7
1..18
<220>
<221> CDS
<222> 188..520
<220>
<221> 3'UTR
<222> 521..1158
<220>
<221> allele
<222> 1
<223> 8-140-108 . polymorphic base G or C
<220>
<221> allele
<222> 66
<223> 8-140-173 . polymorphic base G or T
<220>
<221> allele
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
197
<222>179
<223>8-140-286. polymorphicbaseC
or
T
<220>
<221>allele
<222>326
<223>8-141-161. polymorphicbaseA
or
C
<220>
<221>allele
<222>425
<223>8-141-260. polymorphicbaseA
or
G
<220>
<221>allele
<222>469
<223>8-141-304. polymorphicbaseA
or
G
<220>
<221>allele
<222>577
<223>8-144-127. deletion GTATCCA
of
<220>
<221> allele
<222> 646
<223> 8-144-196. polymorphic A or
base T
<220>
<221> allele
<222> 684
<223> 8-144-234. polymorphic A or
base G
<220>
<221> allele
<222> 828
<223> 8-144-378. polymorphic A or
base G
<220>
<221> allele
<222> 914
<223> 99-16050-235 C
. polymorphic
base G or
<220>
<221> allele
<222> 1089
<223> 8-135-112. polymorphic C or
base T
<220>
<221> allele
<222> 1143
<223> 8-135-166. polymorphic A or
base C
<400> 4
stccacctgc ggctgtcctgtgccacctgc60
tggtagtgca
ctccttaggt
gcctgtctct
acagaktcat gatgagctgagcttacccta120
gcatgagctc
cactgtggga
agtctctaga
caccaactga gtcatcctcatattcccayg180
aagagtctat
ctaagtcctg
aagatcacaa
aatgtga atg gtt ggg cct get aga atc agg ctt tat 229
gaa cag atc get
Met Glu Val Gly Pro Ala Arg Ile Arg Leu Tyr
Gln Ile Ala
1 5 10
tgt ggc ctg cca act gcc aag tgc gga aca tca gta 277
gag gag cta cac
Cys Gly Leu Pro Thr Ala Lys Cys Gly Thr Ser Val
Glu Glu Leu His
15 20 25 30
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
198
aga gtg ccc tca ggc cag aga ctt cct gca aaa tcc 325
ttg atc gaa gag
Arg Val Pro Ser Gly Gln Arg Leu Pro Ala Lys Ser
Leu Ile Glu Glu
35 40 45
mct agg gtc agc aat tgc ttt gga tat aaa gaa gtt 373
tat tca tgc ctt
Xaa Arg Val Ser Asn Cys Phe Gly Tyr Lys Glu Val
Tyr Ser Cys Leu
50 55 60
gtg aaa ata aag act tac atc cag ctc ctg aaa tat 421
aat att tct gca
Val Lys Ile Lys Thr Tyr Ile Gln Leu Leu Lys Tyr
Asn Ile Ser Ala
65 70 75
gta rgt atc att cct gaa tcc tta cac aca ata car 469
tta ttt gtt gat
Val Xaa Ile Ile Pro Glu Ser Leu His Thr Ile Gln
Leu Phe Val Asp
80 85 90
ata tat cta aaa att ggc ggt agg gtc aag tca ttt 517
atc att cgt tta
Ile Tyr Leu Lys Ile Gly Gly Arg Val Lys Ser Phe
Ile Ile Arg Leu
95 100 105 110
taa aaacatagaa acctgaacaa tcac tccagtctag ata 570
gatgta aatgtct
tgcagagtatccacaaaaaa ccaaacttcaacagtctttcatgtctatatttcttcaaca630
ttctttgtcttcaacwttct ttcatgtctagaatgtctatatgcagagtatccrcaaaag690
acccaaacttctttcattta aagaaccaaacttctttaaataaaaatgactcacaataat750
ttaatattttaccatttaca aagagattaactacaacaatattgatcttgagttaatttc810
ccacgaataacattttcrtt tcttaaaatttgctgaatggaaagccagaaagtagagtga870
agcaagtaatgtgtgtgtga gtagtcattggatacatacataasagtgagcaagtttatc930
agctcctgcatggcagtgtt ctgatgatcttttgctgcaaaagagctacaccccaaatta990
gtggcttaaagtaaaagctt actagtgtatatgatgattctgttggtccaggatttggaa1050
agggcatggcaggaggtctc atctctgcttcacaatgcygatgatttagctgggaggacc1110
caaaatgctggaaaagctga tgggtgctgattmtctccagcttttcag 1158
<210> 5
<211> 894
<212> DNA
<213> Homo sapiens
<220>
<221> 5'UTR
<222> 1..253
<220>
<221> CDS
<222> 254..304
<220>
<221> 3'UTR
<222> 305..894
<220>
<221> polyA signal
<222> 879..884
<220>
<221> allele
<222> 53
<223> 99-16050-235 . polymorphic base G or C
<220>
<221> allele
<222> 228
<223> 8-135-112 . polymorphic base C or T
<220>
<221> allele
<222> 282
<223> 8-135-166 . polymorphic base A or C
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
199
<220>
<221>allele
<222>388
<223>99-16038-118. polymorphic base or
A G
<220>
<221>allele
<222>447
<223>8-137-152 polymorphicbase G T
. or
<220>
<221>allele
<222>477
<223>8-137-182 polymorphicbase A G
. or
<220>
<221>allele
<222>602
<223>8-138-218 polymorphicbase C T
. or
<220>
<221>allele
<222>618
<223>8-138-234 polymorphicbase A G
. or
<220>
<221>allele
<222>698
<223>8-119-38 polymorphicbase A
. or T
<220>
<221>allele
<222>753
<223>8-119-93 polymorphicbase A
. or C
<220>
<221>allele
<222>757
<223>8-119-97 polymorphicbase A
. or G
<220>
<221>allele
<222>780
<223>8-119-120 polymorphicbase C T
. or
<220>
<221>allele
<222>785
<223>8-119-125 polymorphicbase A G
. or
<220>
<221>allele
<222>855
<223>8-119-195 polymorphicbase G T
. or
<220>
<221>allele
<222>860
<223>8-119-200 polymorphicbase C T
. or
<220>
<221>allele
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
200
<222> 869
<223> 8-119-204 . polymorphic base G or T
<220>
<221> allele
<222> 870
<223> 8-119-210 . polymorphic base G or T
<400>
gtagagtgaagcaagtaatgtgtgtgtgagtagtcattggatacatacataasagtgagc60
aagtttatcagctcctgcatggcagtgttctgatgatcttttgctgcaaaagagctacac120
cccaaattagtggcttaaagtaaaagcttactagtgtatatgatgattctgttggtccag180
gatttggaaagggcatggcaggaggtctcatctctgcttcacaatgcygatgatttagct240
gggaggacccaaa atg gaa aag get gat ctc cag 289
ctg ctg atg tmt
ggt
Met Leu Glu Lys Leu Gln
Leu Met
Gly Ala
Asp Xaa
1 5 10
ctt ttc gta taa 344
agg aggaatctga
acacgactga
tattttcttt
aatttttaga
Leu Phe Val
Arg
tccagatatacattgggtaaaatctacttcataggttttcaaargagcattcttctgagc404
aaatctgaaaactctctaaactctattgcaaaggagacagaakaaggaagagagacggta464
acaaggaaagaargatggaagagaaggcatgaggacggctatttggaaatggcacagagg524
catttacagagatcattatgtccttgggtctcttaccttcctcagccctatgcagaactc584
tttcagagacattttaaytcacgatgtgggaaarccaatgagagaagaaaaaagaaattc644
tcatctgaaacttgaacttatcaaaactcacttgtctagaaattagcctgggawcatcca704
ggcactggaatttctcactttttttccttctccctctcaacttcagtamtgaraggagaa764
agtcatttccaaatgyctatrttttgactttttaaatagaccaaatttagagtcatgtaa824
agatacaataattagctttcttaacaatttkcaccyagakgtattkttatagagaataaa884
aacaacaaca 894
<210> 6
<211> 863
<212> DNA
<213> Homo Sapiens
<220>
<221> 5'UTR
<222> 1..25
<220>
<221> CDS
<222> 26..76
<220>
<221> 3'UTR
<222> 77..863
<220>
<221> polyA signal
<222> 839..844
<220>
<221> allele
<222> 54
<223> 8-135-166 . polymorphic base A or C
<220>
<221> allele
<222> 160
<223> 99-16038-118 . polymorphic base A or G
<220>
<221> allele
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
201
<222>219
<223>8-137-152. polymorphicbase G orT
<220>
<221>allele
<222>249
<223>8-137-182. polymorphicbase A orG
<220>
<221>allele
<222>413
<223>8-143-232. polymorphicbase G orC
<220>
<221>allele
<222>420
<223>8-143-239. polymorphicbase A orG
<220>
<221>allele
<222>423
<223>8-143-242. polymorphicbase C orT
<220>
<221>allele
<222>426
<223>8-143-295. polymorphicbase A orC
<220>
<221>allele
<222>511
<223>8-130-220. polymorphicbase A orC
<220>
<221>allele
<222>527
<223>8-130-236. polymorphicbase A orG
<220>
<221>allele
<222>699
<223>8-131-199. polymorphicbase A orC
<220>
<221>allele
<222>762
<223>8-132-97. polymorphicbase C T
or
<220>
<221>allele
<222>829
<223>8-132-164. polymorphicbase C orT
<220>
<221>allele
<222>844
<223>8-132-179. polymorphicbase A orT
<400>6
gatgatttag g gaa aag ctg atg ggt get gat
ctgggaggac ctg 52
ccaaa
at
Me t Glu Lys Leu Met Gly Ala Asp
Leu
1 5
tmt ttc agg gta a aatct ga acacgactga tattttcttt
ctc ta agg 106
cag
ctt
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
202
Xaa Leu Leu Phe
Gln Arg Val
15
aatttttagatccagatatacattgggtaaaatctacttcataggttttcaaargagcat166
tcttctgagcaaatctgaaaactctctaaactctattgcaaaggagacagaakaaggaag226
agagacggtaacaaggaaagaargatggaagagaaggcatgaggacggctatttggaaat286
ggcacagaggcatttacagagatcattatgtccttgggtctcttaccttcctcagcccta346
tgcagagctcattttgtataaagcaggcctttatgtcagaagctgagacctccaacagat406
ggaaatsaaaaccrtcytgmtaccagaccttggatctggaaggcttgaagaagtaagcag466
ccatgttggaaaagtcttcatggcaagaaactatgagttccttgmctatgaggcctctaa526
rgaccgcaggcagcctctagaacgaatgtggacctgcaactacaaccagcaaaaagacca586
gtcatgcaaccacaaggaaataacttctaccaaagctgaatgagtttggaagcagattct646
tcccagccaatccttctgatgacaatgtagtctggccaacatcttcactggamtctgacg706
gactctgtgtctgggacccagctgataacacgtggtgatgggattgtatttgcaaytctc766
tggtcagtaagtgataaaatgccatttctatgcacccacctggcctgtgtgactgggaga826
atytctctttttattaawtgtgcttcaagttttaaca 863
<210> 7
<211> 603
<212> DNA
<213> Homo Sapiens
<220>
<221> CDS
<222> 2..310
<220>
<221> 3'UTR
<222> 311..603
<220>
<221> polyA signal
<222> 588..593
<220>
<221>allele
<222>27
<223>8-135-166 polymorphicbase A or
. C
<220>
<221>allele
<222>87
<223>99-16038-118. polymorphic A or
base G
<220>
<221>allele
<222>146
<223>8-137-152 polymorphicbase G or
. T
<220>
<221>allele
<222>176
<223>8-137-182 polymorphicbase A or
. G
<220>
<221>allele
<222>289
<223>8-145-138 polymorphicbase G or
. T
<220>
<221>allele
<222>311
<223>8-138-218 polymorphicbase C or
. T
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
203
<220>
<221>allele
<222>327
<223>8-138-234. polymorphic A or
base G
<220>
<221>allele
<222>407
<223>8-119-38. polymorphic
base A or T
<220>
<221>allele
<222>462
<223>8-119-93. polymorphic
base A or C
<220>
<221>allele
<222>466
<223>8-119-97. polymorphic
base A or G
<220>
<221>allele
<222>489
<223>8-119-120. polymorphic C or
base T
<220>
<221>allele
<222>994
<223>8-119-125. polymorphic A or
base G
<220>
<221>allele
<222>564 -
<223>8-119-195. polymorphic G or
base T
<220>
<221>allele
<222>569
<223>8-119-200. polymorphic C or
base T
<220>
<221>allele
<222>573
<223>8-119-204. polymorphic G or
base T
<220>
<221>allele
<222>579
<223>8-119-210. polymorphic G or
base T
<400>7
g gaa aag 49
ctg ctg
atg
ggt
get
gat
tmt
ctc
cag
ctt
ttc
aga
tcc
aga
Leu Glu Lys
Leu
Met
Gly
Ala
Asp
Xaa
Leu
Gln
Leu
Phe
Arg
Ser
Arg
1 5 10 15
tat aaa atc tac ttc ggt caa arg agc att ctt 97
aca ata ttt
ttg
ggt
Tyr Lys Ile Tyr Phe Gly Gln Xaa Ser Ile Leu
Thr Ile Phe
Leu
Gly
20 25 30
ctg c aaa gaa aac tct cta tct gca aag gag aca gaa 145
ag tct aac att
Leu Glu Asn Ser Leu Ser Ala Lys Glu Thr Glu
Ser Asn Ile
Lys
Ser
35 40 95
kaa a aga acg gta aca agg gaa tgg aag aga agg cat 193
gg gag aaa rga
Xaa y Arg Thr Val Thr Arg Glu Trp Lys Arg Arg His
Gl Glu Lys Xaa
50 55 60
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
204
gag gac tat ttg gaa atg gca cag tta cag tca tta 241
ggc agg cat aga
Glu Asp Tyr Leu Glu Met Ala Gln Leu Gln Ser Leu
Gly Arg His Arg
65 70 75 80
tgt cct gtc tct tac ctt cct cag gca gaa tcc aak 289
tgg ccc tat cat
Cys Pro Val Ser Tyr Leu Pro Gln Ala Glu Ser Xaa
Trp Pro Tyr His
85 90 95
act ctt gag aca ttt taa ytcacgatgt agaag 340
tca gggaaarcca atgag
Thr Leu Glu Thr Phe
Ser
100
aaaaaagaaattctcatctg aaacttgaac ttatcaaaactcacttgtctagaaattagc400
ctgggawcatccaggcactg gaatttctca ctttttttccttctccctctcaacttcagt460
amtgaraggagaaagtcatt tccaaatgyc tatrttttgactttttaaatagaccaaatt520
tagagtcatgtaaagataca ataattagct ttcttaacaatttkcaccyagakgtattkt580
tatagagaataaaaacaaca aca 603
<210>
8
<211>
593
<212>
DNA
<213> sapiens
Homo
<220>
<221>
CDS
<222> 8
2..35
<220>
<221> 3'UTR
<222> 359..593
<220>
<221> polyA signal
<222> 578..583 .
<220>
<221>allele
<222>27
<223>8-135-166 polymorphicbase A C
. or
<220>
<221>allele
<222>87
<223>99-16038-118. polymorphic or
base A G
<220>
<221>allele
<222>146
<223>8-137-152 polymorphicbase G T
. or
<220>
<221>allele
<222>176
<223>8-137-182 polymorphicbase A G
. or
<220>
<221>allele
<222>301
<223>8-138-218 polymorphicbase C T
. or
<220>
<221>allele
<222>317
<223>8-138-234 polymorphicbase A G
. or
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
205
<221> allele
<222> 397
<223> 8-119-38. polymorphic T
base A or
<220>
<221> allele
<222> 452
<223> 8-119-93. polymorphic C
base A or
<220>
<221> allele
<222> 456
<223> 8-119-97. polymorphic G
base A or
<220>
<221> allele
<222> 479
<223> 8-119-120. polymorphic C T
base or
<220>
<221> allele
<222> 484
<223> 8-119-125. polymorphic A G
base or
<220>
<221> allele
<222> 554
<223> 8-119-195. polymorphic G T
base or
<220>
<221> allele
<222> 559
<223> 8-119-200. polymorphic C T
base or
<220>
<221> allele
<222> 563
<223> 8-119-204. polymorphic G T
base or
<220>
<221> allele
<222> 569
<223> 8-119-210. polymorphic G T
base or
<400> 8
g ctg gaa c 49
aag ctg atg cag
ggt get gat ctt
tmt ct ttc
aga
tcc
aga
Leu Glu Lys u
Leu Met Gly Gln
Ala Asp Xaa Leu
Le Phe
Arg
Ser
Arg
1 5 10 15
tat aca ttg aaa atc tac ttc ggt tttcaaargagc att ctt 97
ggt ata
Tyr Thr Leu Lys Ile Tyr Phe Gly PheGlnXaaSer Ile Leu
Gly Ile
20 25 30
ctg agc aaa gaa aac tct cta tct attgcaaaggag aca gaa 145
tct aac
Leu Ser Lys Glu Asn Ser Leu Ser IleAlaLysGlu Thr Glu
Ser Asn
35 40 45
kaa gga aga acg gta aca agg gaa rgatggaagaga agg cat 193
gag aaa
Xaa Gly Arg Thr Val Thr Arg Glu XaaTrpLysArg Arg His
Glu Lys
50 55 60
gag gac ggc ttg gaa atg gca agg catttacagaga tca tta 241
tat cag
Glu Asp Gly Leu Glu Met Ala Arg HisLeuGlnArg Ser Leu
Tyr Gln
65 70 75 80
tgt cct tgg tct tac ctt cct ccc tatgcagaactc ttt cag 289
gtc cag
Cys Pro Trp Ser Tyr Leu Pro Pro TyrAlaGluLeu Phe Gln
Val Gln
85 90 95
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
206
aga cat aay tca cga tgt aaa rcc gag aga aga aaa 337
ttt ggg aat aag
Arg His Asn Ser Arg Cys Lys Xaa Glu Arg Arg Lys
Phe Gly Asn Lys
100 105 110
aaa ttc tct gaa act tga atcaaa 388
tca actt actcacttgt
ctagaaatta
Lys Phe Ser Glu Thr
Ser
115
gcctgggawcatccaggcac tggaatttctcactttttttccttctccct ctcaacttca448
gtamtgaraggagaaagtca tttccaaatgyctatrttttgactttttaa atagaccaaa508
tttagagtcatgtaaagata caataattagctttcttaacaatttkcacc yagakgtatt568
kttatagagaataaaaacaa caaca 593
<210>
9
<211>
649
<212>
DNA
<213> Sapiens
Homo
<220>
<221>
CDS
<222>
2..49
<220>
<221> 3'UTR
<222> 50..649
<220>
<221> polyA signal
<222> 634..639
<220>
<221>allele
<222>27
<223>8-135-166 polymorphicbase A C
. or
<220>
<221>allele
<222>133
<223>99-16038-118. polymorphic or
base A G
<220>
<221>allele
<222>192
<223>8-137-152 polymorphicbase G T
. or
<220>
<221>allele
<222>222
<223>8-137-182 polymorphicbase A G
. or
<220>
<221>allele
<222>335
<223>8-145-138 polymorphicbase G T
. or
<220>
<221>allele
<222>357
<223>8-138-218 polymorphicbase C T
. or
<220>
<221>allele
<222>373
<223>8-138-234 polymorphicbase A G
. or
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
207
<220>
<221> allele
<222> 453
<223> 8-119-38 . polymorphic base
A or T
<220>
<221> allele
<222> 508
<223> 8-119-93 . polymorphic base
A or C
<220>
<221> allele
<222> 512
<223> 8-119-97 . polymorphic base
A or G
<220>
<221> allele
<222> 535
<223> 8-119-120 . polymorphic base
C or T
<220>
<221> allele
<222> 540
<223> 8-119-125 . polymorphic base
A or G
<220>
<221> allele
<222> 610
<223> 8-119-195 . polymorphic base
G or T
<220>
<221> allele
<222> 615
<223> 8-119-200 . polymorphic base
C or T
<220>
<221> allele
<222> 619
<223> 8-119-204 . polymorphic base
G or T
<220>
<221> allele
<222> 625
<223> 8-119-210 . polymorphic base
G or T
<400> 9
g ctg gaa aag ctg atg ggt get gat 49
tmt ctc cag ctt ttc agg gta taa
Leu Glu Lys Leu Met Gly Ala Asp Xaa
Leu Gln Leu Phe Arg Val
1 5 10 15
aggaatctga acacgactga tattttcttt aatttttagatccagatata cattgggtaa109
aatctacttc ataggttttc aaargagcat tcttctgagcaaatctgaaa actctctaaa169
ctctattgca aaggagacag aakaaggaag agagacggtaacaaggaaag aargatggaa229
gagaaggcat gaggacggct atttggaaat ggcacagaggcatttacaga gatcattatg289
tccttgggtc tcttaccttc ctcagcccta tgcagaacattccaakactc tttcagagac349
attttaaytc acgatgtggg aaarccaatg agagaagaaaaaagaaattc tcatctgaaa409
cttgaactta tcaaaactca cttgtctaga aattagcctgggawcatcca ggcactggaa469
tttctcactt tttttccttc tccctctcaa cttcagtamtgaraggagaa agtcatttcc529
aaatgyctat rttttgactt tttaaataga ccaaatttagagtcatgtaa agatacaata589
attagctttc ttaacaattt kcaccyagak gtattkttatagagaataaa aacaacaaca649
<210> 10
<211> 733
<212> DNA
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<213> Homo sapiens
208
<220>
<221>CDS
<222>2..49
<220>
<221>3'UTR
<222>50..733
<220>
<221>polyA signal
<222>718..723
<220>
<221>allele
<222>27
<223>8-135-166 polymorphicbaseA or
. C
<220>
<221>allele
<222>133
<223>99-16038-118. polymorphic
base A
or G
<220>
<221>allele
<222>192
<223>8-137-152 polymorphicbaseG or
. T
<220>
<221>allele
<222>222
<223>8-137-182 polymorphicbaseA or
. G
<220>
<221>allele
<222>336
<223>8-145-138 polymorphicbaseG or
. T
<220>
<221>allele
<222>352
<223>8-145-154 polymorphicbaseA or
. G
<220>
<221>allele
<222>395
<223>8-145-197 polymorphicbaseA or
. G
<220>
<221>allele
<222>441
<223>8-138-218 polymorphicbaseC or
. T
<220>
<221>allele
<222>457
<223>8-138-234 polymorphicbaseA or
. G
<220>
<221>allele
<222>537
<223>8-119-38 polymorphic
. base A
or T
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
209
<220>
<221> allele
<222> 592
<223> 8-119-93 . polymorphic base
A or C
<220>
<221> allele
<222> 596
<223> 8-119-97 . polymorphic base
A or G
<220>
<221> allele
<222> 619
<223> 8-119-120 . polymorphic base
C or T
<220>
<221> allele
<222> 624
<223> 8-119-125 . polymorphic base
A or G
<220>
<221> allele
<222> 694
<223> 8-119-195 . polymorphic base
G or T
<220>
<221> allele
<222> 699
<223> 8-119-200 . polymorphic base
C or T
<220>
<221> allele
<222> 703
<223> 8-119-204 . polymorphic base
G or T
<220>
<221> allele
<222> 709
<223> 8-119-210 . polymorphic base
G or T
<400> 10
g ctg gaa aag ctg atg ggt get gat 49
tmt ctc cag ctt ttc agg gta taa
Leu Glu Lys Leu Met Gly Ala Asp Xaa
Leu Gln Leu Phe Arg Val
1 5 10 15
aggaatctga acacgactga tattttcttt aatttttagatccagatata cattgggtaa109
aatctacttc ataggttttc aaargagcat tcttctgagcaaatctgaaa actctctaaa169
ctctattgca aaggagacag aakaaggaag agagacggtaacaaggaaag aargatggaa229
gagaaggcat gaggacggct atttggaaat ggcacagaggcatttacaga gatcattatg289
tccttgggtc tcttaccttc ctcagcccta tgcagaacattccaagktga ttctaaatgg349
cartttgcac tgtcatttta aaagaatttc tcagatatttgctggrcact ttatggaagg409
agacactgag actctttcag agacatttta aytcacgatgtgggaaarcc aatgagagaa469
gaaaaaagaa,attctcatct gaaacttgaa cttatcaaaactcacttgtc tagaaattag529
cctgggawca tccaggcact ggaatttctc actttttttccttctccctc tcaacttcag589
tamtgaragg agaaagtcat ttccaaatgy ctatrttttgactttttaaa tagaccaaat649
ttagagtcat gtaaagatac aataattagc tttcttaacaatttkcaccy agakgtattk709
ttatagagaa taaaaacaac aaca 733
<210> 11
<211> 1009
<212> DNA
<213> Homo Sapiens
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<220>
<221> 5'UTR
<222> 1..267
<220>
<221> CDS
<222> 268..318
<220>
<221> 3'UTR
<222> 319..1009
<220>
<221> polyA signal
<222> 985..990
210
<220>
<221>allele
<222>136
<223>8-144-378 polymorphicbaseA or
. G
<220>
<221>allele
<222>242
<223>8-135-112 polymorphicbaseC or
. T
<220>
<221>allele
<222>296
<223>8-135-166 polymorphicbaseA or
. C
<220>
<221>allele
<222>902
<223>99-16038-118. polymorphic
base A
or G
<220>
<221>allele
<222>461
<223>8-137-152 polymorphicbaseG or
. T
<220>
<221>allele
<222>491
<223>8-137-182 polymorphicbaseA or
. G
<220>
<221>allele
<222>657
<223>8-130-220 polymorphicbaseA or
. C
<220>
<221>allele
<222>673
<223>8-130-236 polymorphicbaseA or
. G
<220>
<221>allele
<222>845
<223>8-131-199 polymorphicbaseA or
. C
<220>
<221>allele
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
211
<222>
908
<223> -97 . e C or
8-132 polymorphic T
bas
<220>
<221> e
allel
<222>
975
<223> -164 . ymorphic se C
8-132 pol ba or T
<220>
<221> e
allel
<222>
990
<223> -179 . ymorphic se A
8-132 pol ba or T
<400>
11
ccaaacttctttcatttaaagaaccaaacttctttaaataaaaatgactcacaataattt 60
aatattttaccatttacaaagagattaactacaacaatattgatcttgagttaatttccc 120
acgaataacattttcrtttcttaaaatttgctgaatggaaagccagaaagtagagtgaag 180
caagtaatgtgtgtgatttggaaagggcatggcaggaggtctcatctctgcttcacaatg 240
cygatgatttagctgggaggacccaaa ctg gaa ggt get 294
atg aag gat
ctg
atg
Met Leu Glu Gly Ala
Lys Asp
Leu
Met
1 5
tmt ctc ctt ttc g gta taa ggaatctgaacacgactgatattttcttt 348
cag ag a
Xaa Leu Leu Phe g Val
Gln Ar
15
aatttttagatccagatatacattgggtaaaatctacttcataggttttcaaargagcat 408
tcttctgagcaaatctgaaaactctctaaactctattgcaaaggagacagaakaaggaag 468
agagacggtaacaaggaaagaargatggaagagaaggcatgaggacggctatttggaaat 528
ggcacagaggcatttacagagatcattatgtccttgggtctcttaccttcctcagcccta 588
tgcagagcttgaagaagtaagcagccatgttggaaaagtcttcatggcaagaaactatga 648
gttccttgmctatgaggcctctaargaccgcaggcagcctctagaacgaatgtggacctg 708
caactacaaccagcaaaaagaccagtcatgcaaccacaaggaaataacttctaccaaagc 768
tgaatgagtttggaagcagattcttcccagccaatccttctgatgacaatgtagtctggc 828
caacatcttcactggamtctgacggactctgtgtctgggacccagctgataacacgtggt 888
gatgggattgtatttgcaaytctctggtcagtaagtgataaaatgccatttctatgcacc 948
cacctggcctgtgtgactgggagaatytctctttttattaawtgtgcttcaagttttaac 1008
a 1009
<210> 12
<211> 897
<212> DNA
<213> Homo Sapiens
<220>
<221> 5'UTR
<222> 1..46
<220>
<221> CDS
<222> 47..97
<220>
<221> 3'UTR
<222> 98..897
<220>
<221> polyA signal
<222> 873..878
<220>
<221> allele
<222> 21
<223> 8-135-112 . polymorphic base C or T
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
212
<220>
<221>allele
<222>75
<223>8-135-166 polymorphicbaseA or C
.
<220>
<221>allele
<222>181
<223>99-16038-118. polymorphic ase A
b or G
<220>
<221>allele
<222>240
<223>8-137-152 polymorphicbaseG or T
.
<220>
<221>allele
<222>270
<223>8-137-182 polymorphicbaseA or G
.
<220>
<221>allele
<222>408
<223>8-130-83 polymorphic G or T
. base
<220>
<221>allele
<222>426
<223>8-130-101 polymorphicbaseA or C
.
<220>
<221>allele
<222>427
<223>8-130-102 polymorphicbaseA or G
.
<220>
<221>allele
<222>468
<223>8-130-143 polymorphicbaseC or T
.
<220>
<221>allele
<222>469
<223>8-130-144 polymorphicbaseA or G
.
<220>
<221>allele
<222>545
<223>8-130-220 polymorphicbaseA or C
.
<220>
<221> allele
<222> 561
<223> 8-130-236 . polymorphic base A or G
<220>
<221> allele
<222> 733
<223> 8-131-199 . polymorphic base A or C
<220>
<221> allele
<222> 796
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
213
<223> 8-132-97 se C or
. polymorphic T
ba
<220>
<221> allele
<222> 863
<223> 8-132-164 ase C or
. polymorphic T
b
<220>
<221> allele
<222> 878
<223> 8-132-179 ase A or
. polymorphic T
b
<400> 12
tcatctctgc ttcacaatgcygatgatttagctgggaggacccaaa ctg gaa 55
atg
Met Leu Glu
1
aag ctg atg ggt cag ctt agg gta 97
get gat tmt ctc ttc taa
Lys Leu Met Gly Gln Leu Arg Val
Ala Asp Xaa Leu Phe
10 15
aggaatctga acacgactgatattttctttaatttttagatccagatatacattgggtaa157
aatctacttc ataggttttcaaargagcattcttctgagcaaatctgaaaactctctaaa217
ctctattgca aaggagacagaakaaggaagagagacggtaacaaggaaagaargatggaa277
gagaaggcat gaggacggctatttggaaatggcacagaggcatttacagagatcattatg337
tccttgggtc tcttaccttcctcagccctatgcagagagctgggacttctaaccaatgga397
acatgggaaa kgtgatgacacttgactcmrgtgatgaggttacctttcacaagacctggc457
caactgagac yrgatctccttacaggcttgaagaagtaagcagccatgttggaaaagtct517
tcatggcaag aaactatgagttccttgmctatgaggcctctaargaccgcaggcagcctc577
tagaacgaat gtggacctgcaactacaaccagcaaaaagaccagtcatgcaaccacaagg637
aaataacttc taccaaagctgaatgagtttggaagcagattcttcccagccaatccttct697
gatgacaatg tagtctggccaacatcttcactggamtctgacggactctgtgtctgggac757
ccagctgata acacgtggtgatgggattgtatttgcaaytctctggtcagtaagtgataa817
aatgccattt ctatgcacccacctggcctgtgtgactgggagaatytctctttttattaa877
wtgtgcttca agttttaaca 897
<210> 13
<211> 777
<212> DNA
<213> Homo Sapiens
<220>
<221> 5'UTR
<222> 1..46
<220>
<221> CDS
<222> 47..343
<220>
<221> 3'UTR
<222> 344..777
<220>
<221> polyA signal
<222> 753..758
<220>
<221> allele
<222> 21
<223> 8-135-112 . polymorphic base C or T
<220>
<221> allele
<222> 75
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
214
<223>8-135-166. polymorphic A or
base C
<220>
<221>allele
<222>135
<223>99-16038-118 G
. polymorphic
base
A or
<220>
<221>allele
<222>194
<223>8-137-152. polymorphic G or
base T
<220>
<221>allele
<222>224
<223>8-137-182. polymorphic A or
base G
<220>
<221>allele
<222>362
<223>8-130-83. polymorphic
base G or T
<220>
<221>allele
<222>425
<223>8-130-220. polymorphic A or
base C
<220>
<221>allele
<222>441
<223>8-130-236. polymorphic A or
base G
<220>
<221>allele
<222>613
<223>8-131-199. polymorphic A or
base C
<220>
<221>allele
<222>676
<223>8-132-97. polymorphic
base C or T
<220>
<221>allele
<222>743
<223>8-132-164. polymorphic C or
base T
<220>
<221>allele
<222>758
<223>8-132-179. polymorphic A or
base T
<400>13
tcatctctgc cccaaa atg ctg 55
ttcacaatgc gaa
ygatgattta
gctgggagga
Met Leu Glu
1
aag get gat tmt ctc ctt aga tcc aga tat 103
ctg cag ttc aca
atg
ggt
Lys Ala Asp Xaa Leu Leu Arg Ser Arg Tyr
Leu Gln Phe Thr
Met
Gly
10 15
ttg tac ttc ata ggt caa agc att ctt ctg 151
ggt ttt arg agc
aaa
atc
Leu Tyr Phe Ile Gly Gln Ser Ile Leu Leu
Gly Phe Xaa Ser
Lys
Ile
20 25 30 35
aaa tct cta aac tct gca gag aca gaa kaa 199
tct att aag gga
gaa
aac
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
215
Lys Ser Asn Ser Leu Asn Ile Ala Glu Thr Xaa Gly
Glu Ser Lys Glu
40 45 50
aga gag gta aca agg aaa rga tgg aga agg gag gac 247
acg gaa aag cat
Arg Glu Val Thr Arg Lys Xaa Trp Arg Arg Glu Asp
Thr Glu Lys His
55 60 65
ggc tat gaa atg gca cag cat tta aga tca tgt cct 295
ttg agg cag tta
Gly Tyr Glu Met Ala Gln His Leu Arg Ser Cys Pro
Leu Arg Gln Leu
70 75 80
tgg gtc tac ctt cct cag tat gca agc tgg ttc taa 343
tct ccc gag gac
Trp Val Tyr Leu Pro Gln Tyr Ala Ser Trp Phe
Ser Pro Glu Asp
85 90 95
ccaatggaacatgggaaakg cttgaagaagtaagcagccatgttggaaaagtcttcatgg403
caagaaactatgagttcctt gmctatgaggcctctaargaccgcaggcagcctctagaac463
gaatgtggacctgcaactac aaccagcaaaaagaccagtcatgcaaccacaaggaaataa523
cttctaccaaagctgaatga gtttggaagcagattcttcccagccaatccttctgatgac583
aatgtagtctggccaacatc ttcactggamtctgacggactctgtgtctgggacccagct643
gataacacgtggtgatggga ttgtatttgcaaytctctggtcagtaagtgataaaatgcc703
atttctatgcacccacctgg cctgtgtgactgggagaatytctctttttattaawtgtgc763
ttcaagttttaaca 777
<210> 14
<211> 823
<212> DNA
<213> Homo Sapiens
<220>
<221> 5'UTR
<222> 1..46
<220>
<221> CDS
<222> 47..97
<220>
<221> 3'UTR
<222> 98..823
<220>
<221> polyA signal
<222> 799..804
<220>
<221>allele
<222>21
<223>8-135-112 polymorphic base C or
. T
<220>
<221>allele
<222>75
<223>8-135-166 polymorphic base A or
. C
<220>
<221>allele
<222>181
<223>99-16038-118. polymorphic base A
or G
<220>
<221>allele
<222>240
<223>8-137-152 polymorphic base G or
. T
<220>
<221>allele
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
216
<222> 270
<223> 8-137-182 . polymorphic base
A or G
<220>
<221> allele
<222> 408
<223> 8-130-83 . polymorphic base
G or T
<220>
<221> allele
<222> 471
<223> 8-130-220 . polymorphic base
A or C
<220>
<221> allele
<222> 487
<223> 8-130-236 . polymorphic base
A or G
<220>
<221> allele
<222> 659
<223> 8-131-199 . polymorphic base
A or C
<220>
<221> allele
<222> 722
<223> 8-132-97 . polymorphic base
C or T
<220>
<221> allele
<222> 789
<223> 8-132-164 . polymorphic base
C or T
<220>
<221> allele
<222> 804
<223> 8-132-179 . polymorphic base
A or T
<400> 14
tcatctctgc ttcacaatgc ygatgattta gctgggaggacccaaa atg ctg gaa 55
Met Leu Glu
1
aag ctg atg ggt get gat tmt ctc cag agg gta taa 97
ctt ttc
Lys Leu Met Gly Ala Asp Xaa Leu Gln Arg Val
Leu Phe
10 15
aggaatctga acacgactga tattttcttt aatttttagatccagatata cattgggtaa157
aatctacttc ataggttttc aaargagcat tcttctgagcaaatctgaaa actctctaaa217
ctctattgca aaggagacag aakaaggaag agagacggtaacaaggaaag aargatggaa277
gagaaggcat gaggacggct atttggaaat ggcacagaggcatttacaga gatcattatg337
tccttgggtc tcttaccttc ctcagcccta tgcagagagctgggacttct aaccaatgga397
acatgggaaa kgcttgaaga agtaagcagc catgttggaaaagtcttcat ggcaagaaac457
tatgagttcc ttgmctatga ggcctctaar gaccgcaggcagcctctaga acgaatgtgg517
acctgcaact acaaccagca aaaagaccag tcatgcaaccacaaggaaat aacttctacc577
aaagctgaat gagtttggaa gcagattctt cccagccaatccttctgatg acaatgtagt637
ctggccaaca tcttcactgg amtctgacgg actctgtgtctgggacccag ctgataacac697
gtggtgatgg gattgtattt gcaaytctct ggtcagtaagtgataaaatg ccatttctat757
gcacccacct ggcctgtgtg actgggagaa tytctctttttattaawtgt gcttcaagtt817
ttaaca 823
<210> 15
<211> 836
<212> DNA
<213> Homo sapiens
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
217
<220>
<221>5'UTR
<222>1..46
<220>
<221>CDS
<222>47..427
<220>
<221>3'UTR
<222>428..836
<220>
<221>polyA signal
<222>812..817
<220>
<221>allele
<222>21
<223>8-135-112 polymorphicbaseC or
. T
<220>
<221>allele
<222>75
<223>8-135-166 polymorphicbaseA or
. C
<220>
<221>allele
<222>135
<223>99-16038-118. polymorphic
base A
or G
<220>
<221>allele
<222>194
<223>8-137-152 polymorphicbaseG or
. T
<220>
<221>allele
<222>224
<223>8-137-182 polymorphicbaseA or
. G
<220>
<221>allele
<222>338
<223>8-145-138 polymorphicbaseG or
. T
<220>
<221>allele
<222>354
<223>8-145-154 polymorphicbaseA or
. G
<220>
<221>allele
<222>397
<223>8-145-197 polymorphicbaseA or
. G
<220>
<221>allele
<222>484
<223>8-130-220 polymorphicbaseA or
. C
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
218
<221>allele
<222>500
<223>8-130-236. polymorphicbase A
or G
<220>
<221>allele
<222>672
<223>8-131-199. polymorphicbase A
or C
<220>
<221>allele
<222>735
<223>8-132-97 . polymorphic
base C or
T
<220>
<221>allele
<222>802
<223>8-132-164. polymorphicbase C
or T
<220>
<221>allele
<222>817
<223>8-132-179. polymorphicbase A
or T
<400>
15
tcatctctgcttcacaatgc ygatgatttagctgggaggacccaaa ctg gaa 55
atg
Met Leu Glu
1
aag ctg ggt get gat tmt cag ctt agatcc tat aca 103
atg ctc ttc aga
Lys Leu Gly Ala Asp Xaa Gln Leu ArgSer Tyr Thr
Met Leu Phe Arg
10 15
ttg ggt atc tac ttc ata ttt caa agcatt ctg agc 151
aaa ggt arg ctt
Leu Gly Ile Tyr Phe Ile Phe Gln SerIle Leu Ser
Lys Gly Xaa Leu
20 25 30 35
aaa tct aac tct cta aac att gca gagaca kaa gga 199
gaa tct aag gaa
Lys Ser Asn Ser Leu Asn Ile Ala GluThr Xaa Gly
Glu Ser Lys Glu
40 45 50
aga gag gta aca agg aaa rga tgg agaagg gag gac 247
acg gaa aag cat
Arg Glu Val Thr Arg Lys Xaa Trp ArgArg Glu Asp
Thr Glu Lys His
55 60 65
ggc tat gaa atg gca cag cat tta agatca tgt cct 295
ttg agg cag tta
Gly Tyr Glu Met Ala Gln His Leu ArgSer Cys Pro
Leu Arg Gln Leu
70 75 80
tgg gtc tac ctt cct cag tat gca cattcc ktg att 343
tct ccc gaa aag
Trp Val Tyr Leu Pro Gln Tyr Ala HisSer Xaa Ile
Ser Pro Glu Lys
85 90 95
cta aat art ttg cac tgt ttt aaa atttct ata ttt 391
ggc cat aga cag
Leu Asn Xaa Leu His Cys Phe Lys IleSer Ile Phe
Gly His Arg Gln
100 105 110 115
get ggr ttt atg gaa gga act gag tgaagaagtaagc 437
cac gac get
Ala Gly Phe Met Glu Gly Thr Glu
His Asp Ala
120 125
agccatgttggaaaagtctt catggcaagaaactatgagttccttgmcta tgaggcctct497
aargaccgcaggcagcctct agaacgaatgtggacctgcaactacaacca gcaaaaagac557
cagtcatgcaaccacaagga aataacttctaccaaagctgaatgagtttg gaagcagatt617
cttcccagccaatccttctg atgacaatgtagtctggccaacatcttcac tggamtctga 677
cggactctgtgtctgggacc cagctgataacacgtggtgatgggattgta tttgcaaytc737
tctggtcagtaagtgataaa atgccatttctatgcacccacctggcctgt gtgactggga797
gaatytctctttttattaaw tgtgcttcaagttttaaca 836
<210> 16
<211> 882
<212> DNA
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<213> Homo sapiens
219
<220>
<221>5'UTR
<222>1..46
<220>
<221>CDS
<222>47..97
<220>
<221>3'UTR
<222>98..882
<220>
<221>polyA signal
<222>858..863
<220>
<221>allele
<222>21
<223>8-135-112 polymorphicbaseC or
. T
<220>
<221>allele
<222>75
<223>8-135-166 polymorphicbaseA or
. C
<220>
<221>allele
<222>181
<223>99-16038-118. polymorphic
base
A
or
G
<220>
<221>allele
<222>240
<223>8-137-152 polymorphicbaseG or
. T
<220>
<221>allele
<222>270
<223>8-137-182 polymorphicbaseA or
. G
<220>
<221>allele
<222>384
<223>8-145-138 polymorphicbaseG or
. T
<220>
<221>allele
<222>400
<223>8-145-154 polymorphicbaseA or
. G
<220>
<221>allele
<222>443
<223>8-145-197 polymorphicbaseA or
. G
<220>
<221>allele
<222>530
<223>8-130-220 polymorphicbaseA or
. C
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
220
<220>
<221> allele
<222> 546
<223> 8-130-236 . polymorphicase A or
b G
<220>
<221> allele
<222> 718
<223> 8-131-199 . polymorphicase A or
b C
<220>
<221> allele
<222> 781
<223> 8-132-97 . polymorphicse C or
ba T
<220>
<221> allele
<222> 848
<223> 8-132-164 . polymorphicase C or
b T
<220>
<221> allele
<222> 863
<223> 8-132-179 . polymorphicase A or
b T
<400> 16
tcatctctgc ttcacaatgc ygatgatttagctgggaggacccaaa ctg gaa 55
atg
Met Leu Glu
1
aag ctg atg ggt get gat cag ctt agg gta _97
tmt ctc ttc taa
Lys Leu Met Gly Ala Asp Gln Leu Arg Val
Xaa Leu Phe
10 15
aggaatctga acacgactga tattttctttaatttttagatccagatatacattgggtaa157
aatctacttc ataggttttc aaargagcattcttctgagcaaatctgaaaactctctaaa217
ctctattgca aaggagacag aakaaggaagagagacggtaacaaggaaagaargatggaa277
gagaaggcat gaggacggct atttggaaatggcacagaggcatttacagagatcattatg337
tccttgggtc tcttaccttc ctcagccctatgcagaacattccaagktgattctaaatgg397
cartttgcac tgtcatttta aaagaatttctcagatatttgctggrcactttatggaagg457
agacactgag gcttgaagaa gtaagcagccatgttggaaaagtcttcatggcaagaaact517
atgagttcct tgmctatgag gcctctaargaccgcaggcagcctctagaacgaatgtgga577
cctgcaacta caaccagcaa aaagaccagtcatgcaaccacaaggaaataacttctacca637
aagctgaatg agtttggaag cagattcttcccagccaatccttctgatgacaatgtagtc697
tggccaacat cttcactgga mtctgacggactctgtgtctgggacccagctgataacacg757
tggtgatggg attgtatttg caaytctctggtcagtaagtgataaaatgccatttctatg817
cacccacctg gcctgtgtga ctgggagaatytctctttttattaawtgtgcttcaagttt877
taaca 882
<210> 17
<211> 955
<212> DNA
<213> Homo sapiens
<220>
<221> 5'UTR
<222> 1..46
<220>
<221> CDS
<222> 47..235
<220>
<221> 3'UTR
<222> 236..955
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
221
<220>
<221>polyA signal
<222>931..936
<220>
<221>allele
<222>21
<223>8-135-112 polymorphicbaseC or
. T
<220>
<221>allele
<222>75
<223>8-135-166 polymorphicbaseA or
. C
<220>
<221>allele
<222>135
<223>99-16038-118. polymorphic
base A
or G
<220>
<221>allele
<222>217
<223>8-137-152 polymorphicbaseG or
. T
<220>
<221>allele
<222>247
<223>8-137-182 polymorphicbaseA or
. G
<220>
<221>allele
<222>361
<223>8-145-138 polymorphicbaseG or
. T
<220>
<221>allele
<222>377
<223>8-145-154 polymorphicbaseA or
. G
<220>
<221>allele
<222>420
<223>8-145-197 polymorphicbaseA or
. G
<220>
<221>allele
<222>505
<223>8-143-232 polymorphicbaseG or
. C
<220>
<221>allele
<222>512
<223>8-143-239 polymorphicbaseA or
. G
<220>
<221>allele
<222>515
<223>8-143-242 polymorphicbaseC or
. T
<220>
<221>allele
<222>518
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
222
<223>8-143-245 . polymorphicbase A
or C
<220>
<221>allele
<222>603
<223>8-130-220 . polymorphicbase A
or C
<220>
<221>allele
<222>619
<223>8-130-236 . polymorphicbase A
or G
<220>
<221>allele
<222>791
<223>8-131-199 . polymorphicbase A
or C
<220>
<221>allele
<222>854
<223>8-132-97 . polymorphic
base C
or T
<220>
<221>allele
<222>921
<223>8-132-164 . polymorphicbase C
or T
<220>
<221>allele
<222>936
<223>8-132-179 . polymorphicbase A
or T
<400>
17
tcatctctgcttcacaatgc ygatgatttagctgggaggacccaaa ctg gaa 55
atg
Met Leu Glu
1
aag ctg ggt get gat tmt cag ctt aga tcc tat aca 103
atg ctc ttc aga
Lys Leu Gly Ala Asp Xaa Gln Leu Arg Ser Tyr Thr
Met Leu Phe Arg
10 15
ttg ggt atc tac ttc ata ttt caa agc att ctg agc 151
aaa ggt arg ctt
Leu Gly Ile Tyr Phe Ile Phe Gln Ser Ile Leu Ser
Lys Gly Xaa Leu
20 25 30 35
aaa tct aac tct cta aac att ggt cac caa cac aaa 199
gaa tct att atc
Lys Ser Asn Ser Leu Asn Ile Gly His Gln His Lys
Glu Ser Ile Ile
40 45 50
aat caa aga cag aak aag gag aga taa caaggaaaga 245
agg gaa cgg
Asn Gln Arg Gln Xaa Lys Glu Arg
Arg Glu Arg
55 60
argatggaagagaaggcatg aggacggctatttggaaatggcacagaggcatttacagag305
atcattatgtccttgggtct cttaccttcctcagccctatgcagaacattccaagktgat365
tctaaatggcartttgcact gtcattttaaaagaatttctcagatatttgctggrcactt425
tatggaaggagacactgagg ctcattttgtataaagcaggcctttatgtcagaagctgag485
acctccaacagatggaaats aaaaccrtcytgmtaccagaccttggatctggaaggcttg545
aagaagtaagcagccatgtt ggaaaagtcttcatggcaagaaactatgagttccttgmct605
atgaggcctctaargaccgc aggcagcctctagaacgaatgtggacctgcaactacaacc665
agcaaaaagaccagtcatgc aaccacaaggaaataacttctaccaaagctgaatgagttt725
ggaagcagattcttcccagc caatccttctgatgacaatgtagtctggccaacatcttca785
ctggamtctgacggactctg tgtctgggacccagctgataacacgtggtgatgggattgt845
atttgcaaytctctggtcag taagtgataaaatgccatttctatgcacccacctggcctg905
tgtgactgggagaatytctc tttttattaawtgtgcttcaagttttaaca 955
<210>
18
<211>
851
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
223
<212>DNA
<213>Homo sapiens
<220>
<221>5'UTR
<222>1..46
<220>
<221>CDS
<222>47..343
<220>
<221>3'UTR
<222>344..851
<220>
<221>polyA signal
<222>827..832
<220>
<221>allele
<222>21
<223>8-135-112 polymorphicbase C or
. T
<220>
<221>allele
<222>75
<223>8-135-166 polymorphicbase A or
. C
<220>
<221>allele
<222>135
<223>99-16038-118. polymorphic
base A
or G
<220>
<221>allele
<222>194
<223>8-137-152 polymorphicbase G or
. T
<220>
<221>allele
<222>224
<223>8-137-182 polymorphicbase A or
. G
<220>
<221>allele
<222>362
<223>8-130-83 polymorphic
. base G
or T
<220>
<221>allele
<222>380
<223>8-130-101 polymorphicbase A or
. C
<220>
<221>allele
<222>381
<223>8-130-102 polymorphicbase A or
. G
<220>
<221>allele
<222>422
<223>8-130-143 polymorphicbase C or
. T
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
224
<220>
<221>allele
<222>423
<223>8-130-144. polymorphicbase A
or G
<220>
<221>allele
<222>499
<223>8-130-220. polymorphicbase A
or C
<220>
<221>allele
<222>515
<223>8-130-236. polymorphicbase A
or G
<220>
<221>allele
<222>687
<223>8-131-199. polymorphicbase A
or C
<220>
<221>allele
<222>750
<223>8-132-97 . polymorphic
base C or
T
<220>
<221>allele
<222>817
<223>8-132-164. polymorphicbase C
or T
<220>
<221>allele
<222>832
<223>8-132-179. polymorphicbase A
or T
<400>
18
tcatctctgcttcacaatgc ygatgatttagctgggaggacccaaa ctg gaa 55
atg
Met Leu Glu
1
aag ctg ggt get gat tmt cag ctt agatcc tat aca 103
atg ctc ttc aga
Lys Leu Gly Ala Asp Xaa Gln Leu ArgSer Tyr Thr
Met Leu Phe Arg
10 15
ttg ggt atc tac ttc ata ttt caa agcatt ctg agc 151
aaa ggt arg ctt
Leu Gly Ile Tyr Phe Ile Phe Gln SerIle Leu~Ser
Lys Gly Xaa Leu
20 25 30 35
aaa tct aac tct cta aac att gca gagaca kaa gga 199
gaa tct aag gaa
Lys Ser Asn Ser Leu Asn Ile Ala GluThr Xaa Gly
Glu Ser Lys Glu
40 45 50
aga gag gta aca agg aaa rga tgg agaagg gag gac 247
acg gaa aag cat
Arg Glu Val Thr Arg Lys Xaa Trp ArgArg Glu Asp
Thr Glu Lys His
55 60 65
ggc tat gaa atg gca cag cat tta agatca tgt cct 295
ttg agg cag tta
Gly Tyr Glu Met Ala Gln His Leu ArgSer Cys Pro
Leu Arg Gln Leu
70 75 80
tgg gtc tac ctt cct cag tat gca agctgg ttc taa 343
tct ccc gag gac
Trp Val Tyr Leu Pro Gln Tyr Ala SerTrp Phe
Ser Pro Glu Asp
85 90 95
ccaatggaacatgggaaakg tgatgacacttgactcmrgtgatgaggtta cctttcacaa403
gacctggccaactgagacyr gatctccttacaggcttgaagaagtaagca gccatgttgg463
aaaagtcttcatggcaagaa actatgagttccttgmctatgaggcctcta argaccgcag523
gcagcctctagaacgaatgt ggacctgcaactacaaccagcaaaaagacc agtcatgcaa583
ccacaaggaaataacttcta ccaaagctgaatgagtttggaagcagattc ttcccagcca643
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
225
atccttctgatgacaatgtagtctggccaacatcttcact ggamtctgac ggactctgtg703
tctgggacccagctgataacacgtggtgatgggattgtat ttgcaaytct ctggtcagta763
agtgataaaatgccatttctatgcacccacctggcctgtg tgactgggag aatytctctt823
tttattaawtgtgcttcaagttttaaca 851
<210>
19
<211>
742
<212>
DNA
<213> sapiens
Homo
<220>
<221>
5'UTR
<222>
1..46
<220>
<221> CDS
<222> 47..508
<220>
<221> 3'UTR
<222> 509..742
<220>
<221> polyA signal
<222> 718..723
<220>
<221>allele
<222>21
<223>8-135-112 polymorphicbaseC or
. T
<220>
<221>allele
<222>75
<223>8-135-166 polymorphicbaseA or
. C
<220>
<221>allele
<222>135
<223>99-16038-118. polymorphic
base A
or G
<220>
<221>allele
<222>194
<223>8-137-152 polymorphicbaseG or
. T
<220>
<221>allele
<222>224
<223>8-137-182 polymorphicbaseA or
. G
<220>
<221>allele
<222>390
<223>8-130-220 polymorphicbaseA or
. C
<220>
<221>allele
<222>406
<223>8-130-236 polymorphicbaseA or
. G
<220>
<221>allele
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
226
<222>578
<223>8-131-199. polymorphic base
A or C
<220>
<221>allele
<222>641
<223>8-132-97 . polymorphic base
C or T
<220>
<221>allele
<222>708
<223>8-132-164. polymorphic base
C or T
<220>
<221>allele
<222>723
<223>8-132-179. polymorphic base
A or T
<400> 19
tcatctctgc ttcacaatgc gctgggagga cccaaa atgctg gaa
55
ygatgattta
Met Glu
Leu
1
aagctgatgggt getgat tmtctc cagcttttc agatccagatat aca 103
LysLeuMetGly AlaAsp XaaLeu GlnLeuPhe ArgSerArgTyr Thr
10 15
ttgggtaaaatc tacttc ataggt tttcaaarg agcattcttctg agc 151
LeuGlyLysIle TyrPhe IleGly PheGlnXaa SerIleLeuLeu Ser
20 25 30 35
aaatctgaaaac tctcta aactct attgcaaag gagacagaakaa gga 199
LysSerGluAsn SerLeu AsnSer IleAlaLys GluThrGluXaa Gly
40 45 50
agagagacggta acaagg aaagaa rgatggaag agaaggcatgag gac 247
ArgGluThrVal ThrArg LysGlu XaaTrpLys ArgArgHisGlu Asp
55 60 65
ggctatttggaa atggca cagagg catttacag agatcattatgt cct 295
GlyTyrLeuGlu MetAla GlnArg HisLeuGln ArgSerLeuCys Pro
70 75 80
tgggtctcttac cttcct cagccc tatgcagag cttgaagaagta agc 343
TrpValSerTyr LeuPro GlnPro TyrAlaGlu LeuGluGluVal Ser
85 90 95
agccatgttgga aaagtc ttcatg gcaagaaac tatgagttcctt gmc 391
SerHisValGly LysVal PheMet AlaArgAsn TyrGluPheLeu Xaa
100 105 110 115
tatgaggcctct aargac cgcagg cagcctcta gaacgaatgtgg acc 439
TyrGluAlaSer LysAsp ArgArg GlnProLeu GluArgMetTrp Thr
120 125 130
tgcaactacaac cagcaa aaagac cagtcatgc aaccacaaggaa ata 487
CysAsnTyrAsn GlnGln LysAsp GlnSerCys AsnHisLysGlu Ile
135 140 145
acttctaccaaa getgaa tgagtttggaagc agattcttcc agccaatc c 538
c
ThrSerThrLys AlaGlu
150
ttctgatgac aatgtagtct ttcact ggamtctgacg
gactctgtgtctg598
ggccaacatc
ggacccagct gataacacgt ttgtat ttgcaaytctc
tggtcagtaagtg658
ggtgatggga
ataaaatgcc atttctatgc cctgtg tgactgggaga aty
ttttta718
acccacctgg tctc
ttaawtgtgc ttcaagtttt 742
aaca
<210> 20
<211> 920
<212> DNA
<213> Homo sapiens
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
227
<221>5'UTR
<222>1..46
<220>
<221>CDS
<222>47..97
<220>
<221>3'UTR
<222>98..920
<220>
<221>polyA signal
<222>896..901
<220>
<221>allele
<222>21
<223>8-135-112 polymorphicbase C or
. T
<220>
<221>allele
<222>75
<223>8-135-166 polymorphicbase A or
. C
<220>
<221>allele
<222>181
<223>99-16038-118. polymorphic base A
or G
<220>
<221>allele
<222>263
<223>8-137-152 polymorphicbase G or
, T
<220>
<221>allele
<222>293
<223>8-137-182 polymorphicbase A or
. G
<220>
<221>allele
<222>431
<223>8-130-83 polymorphicbase G or
. T
<220>
<221>allele
<222>449
<223>8-130-101 polymorphicbase A or
. C
<220>
<221>allele
<222>450
<223>8-130-102 polymorphicbase A or
. G
<220>
<221>allele
<222>491
<223>8-130-143 polymorphicbase C or
. T
<220>
<221>allele
<222>492
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
228
<223> 8-130-144 . polymorphic base A or G
<220>
<221> allele
<222> 568
<223> 8-130-220 . polymorphic base A or C
<220>
<221> allele
<222> 584
<223> 8-130-236 . polymorphic base A or G
<220>
<221> allele
<222> 756
<223> 8-131-199 . polymorphic base A or C
<220>
<221> allele
<222> 819
<223> 8-132-97 . polymorphic base C or T
<220>
<221> allele
<222> 886
<223> 8-132-164 . polymorphic base C or T
<220>
<221> allele
<222> 901
<223> 8-132-179 . polymorphic base A or T
<400> 20
tcatctctgc ttcacaatgc ygatgattta gctgggagga cccaaa atg ctg gaa 55
Met Leu Glu
1
aag ctg atg ggt get gat tmt ctc cag ctt ttc agg gta taa 97
Lys Leu Met Gly Ala Asp Xaa Leu Gln Leu Phe Arg Val
10 15
aggaatctga acacgactga tattttcttt aatttttaga tccagatata cattgggtaa 157
aatctacttc ataggttttc aaargagcat tcttctgagc aaatctgaaa actctctaaa 217
ctctattggt attcaccaaa tccacaaaaa tcaaaggaga cagaakaagg aagagagacg 277
gtaacaagga aagaargatg gaagagaagg catgaggacg gctatttgga aatggcacag 337
aggcatttac agagatcatt atgtccttgg gtctcttacc ttcctcagcc ctatgcagag 397
agctgggact tctaaccaat ggaacatggg aaakgtgatg acacttgact cmrgtgatga 457
ggttaccttt cacaagacct ggccaactga gacyrgatct ccttacaggc ttgaagaagt 517
aagcagccat gttggaaaag tcttcatggc aagaaactat gagttccttg mctatgaggc 577
ctctaargac cgcaggcagc ctctagaacg aatgtggacc tgcaactaca accagcaaaa 637
agaccagtca tgcaaccaca aggaaataac ttctaccaaa gctgaatgag tttggaagca 697
gattcttccc agccaatcct tctgatgaca atgtagtctg gccaacatct tcactggamt 757
ctgacggact ctgtgtctgg gacccagctg ataacacgtg gtgatgggat tgtatttgca 817
aytctctggt cagtaagtga taaaatgcca tttctatgca cccacctggc ctgtgtgact 877
gggagaatyt ctctttttat taawtgtgct tcaagtttta aca 920
<210> 21
<211> 811
<212> DNA
<213> Homo Sapiens
<220>
<221> 5'UTR
<222> 1..46
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
229
<220>
<221>CDS
<222>47..97
<220>
<221>3'UTR
<222>98..811
<220>
<221>polyA signal
<222>787..792
<220>
<221>allele
<222>21
<223>8-135-112 polymorphicbase C or
. T
<220>
<221>allele
<222>75
<223>8-135-166 polymorphicbase A or
. C
<220>
<221>allele
<222>181
<223>99-16038-118. polymorphic base A
or G
<220>
<221>allele
<222>263
<223>8-137-152 polymorphicbase G or
. T
<220>
<221>allele
<222>293
<223>8-137-182 polymorphicbase A or
. G
<220>
<221>allele
<222>459
<223>8-130-220 polymorphicbase A or
. C
<220>
<221>allele
<222>475
<223>8-130-236 polymorphicbase A or
. G
<220>
<221>allele
<222>647
<223>8-131-199 polymorphicbase A or
. C
<220>
<221>allele
<222>710
<223>8-132-97 polymorphicbase C or
. T
<220>
<221>allele
<222>777
<223>8-132-164 polymorphicbase C or
. T
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
230
<221>
allele
<222>
792
<223> -179 .
8-132 polymorphic
base
A or
T
<400>
21
tcatctctgcttcacaatgcygatgatttagctgggaggacccaaa ctg gaa 55
atg
Met Leu Glu
1
aag ctg ggt get agg gta 97
atg gat tmt taa
ctc cag
ctt ttc
Lys Leu Gly Ala Arg Val
Met Asp Xaa
Leu Gln
Leu Phe
10 15
aggaatctgaacacgactgatattttctttaatttttagatccagatatacattgggtaa157
aatctacttcataggttttcaaargagcattcttctgagcaaatctgaaaactctctaaa217
ctctattggtattcaccaaatccacaaaaatcaaaggagacagaakaaggaagagagacg277
gtaacaaggaaagaargatggaagagaaggcatgaggacggctatttggaaatggcacag337
aggcatttacagagatcattatgtccttgggtctcttaccttcctcagccctatgcagag397
cttgaagaagtaagcagccatgttggaaaagtcttcatggcaagaaactatgagttcctt457
gmctatgaggcctctaargaccgcaggcagcctctagaacgaatgtggacctgcaactac517
aaccagcaaaaagaccagtcatgcaaccacaaggaaataacttctaccaaagctgaatga577
gtttggaagcagattcttcccagccaatccttctgatgacaatgtagtctggccaacatc637
ttcactggamtctgacggactctgtgtctgggacccagctgataacacgtggtgatggga697
ttgtatttgcaaytctctggtcagtaagtgataaaatgccatttctatgcacccacctgg757
cctgtgtgactgggagaatytctctttttattaawtgtgcttcaagttttaaca 811
<210>
22
<211>
978
<212>
DNA
<213> sapiens
Homo
<220>
<221>
5'UTR
<222>
1..46
<220>
<221> CDS
<222> 47..97
<220>
<221> 3'UTR
<222> 98..978
<220>
<221> polyA signal
<222> 954..959
<220>
<221>allele
<222>21
<223>8-135-112 polymorphic base C or
. T
<220>
<221>allele
<222>75
<223>8-135-166 polymorphic base A or
. C
<220>
<221>allele
<222>181
<223>99-16038-118. polymorphic base A
or G
<220>
<221>allele
<222>240
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
231
<223>8-137-152. polymorphicbase G
or T
<220>
<221>allele
<222>270
<223>8-137-182. polymorphicbase A
or G
<220>
<221>allele
<222>384
<223>8-145-138. polymorphicbase G
or T
<220>
<221>allele
<222>400
<223>8-145-154. polymorphicbase A
or G
<220>
<221>allele
<222>443
<223>8-145-197. polymorphicbase A
or G
<220>
<221>allele
<222>528
<223>8-143-232. polymorphicbase G
or C
<220>
<221>allele
<222>535
<223>8-143-239. polymorphicbase A
or G
<220>
<221>allele
<222>538
<223>8-143-242. polymorphicbase C
or T
<220>
<221>allele
<222>541
<223>8-143-245. polymorphicbase A
or C
<220>
<221>allele
<222>626
<223>8-130-220. polymorphicbase A
or C
<220>
<221>allele
<222>642
<223>8-130-236. polymorphicbase A
or G
<220>
<221>allele
<222>819
<223>8-131-199. polymorphicbase A
or C
<220>
<221>allele
<222>877
<223>8-132-97 polymorphic
. base C or
T
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
232
<221>
allele
<222>
944
<223> -164 .
8-132 polymorphic
base
C or
T
<220>
<221> e
allel
<222>
959
<223> -179 .
8-132 polymorphic
base
A or
T
<400>
22
tcatctctgcttcacaatgcygatgatttagctgggaggacccaaa ctg gaa 55
atg
Met Leu Glu
1
aag ctg ggt get cag ctt agg gta 97
atg gat tmt ttc taa
ctc
Lys Leu Gly Ala Gln Leu Arg Val
Met Asp Xaa Phe
Leu
10 15
aggaatctgaacacgactgatattttctttaatttttagatccagatatacattgggtaa157
aatctacttcataggttttcaaargagcattcttctgagcaaatctgaaaactctctaaa217
ctctattgcaaaggagacagaakaaggaagagagacggtaacaaggaaagaargatggaa277
gagaaggcatgaggacggctatttggaaatggcacagaggcatttacagagatcattatg337
tccttgggtctcttaccttcctcagccctatgcagaacattccaagktgattctaaatgg397
cartttgcactgtcattttaaaagaatttctcagatatttgctggrcactttatggaagg457
agacactgaggctcattttgtataaagcaggcctttatgtcagaagctgagacctccaac517
agatggaaatsaaaaccrtcytgmtaccagaccttggatctggaaggcttgaagaagtaa577
gcagccatgttggaaaagtcttcatggcaagaaactatgagttccttgmctatgaggcct637
ctaargaccgcaggcagcctctagaacgaatgtggacctgcaactacaaccagcaaaaag697
accagtcatgcaaccacaaggaaataacttctaccaaagctgaatgagtttggaagcaga757
ttcttcccagccaatccttctgatgacaatgtagtctggccaacatcttcactggamtct817
gacggactctgtgtctgggacccagctgataacacgtggtgatgggattgtatttgcaay877
tctctggtcagtaagtgataaaatgccatttctatgcacccacctggcctgtgtgactgg937
gagaatytctctttttattaawtgtgcttcaagttttaaca 978
<210>
23
<211>
993
<212>
DNA
<213> sapiens
Homo
<220>
<221>
5'UTR
<222>
1..46
<220>
<221> CDS
<222> 47..97
<220>
<221> 3'UTR
<222> 98..993
<220>
<221> polyA signal
<222> 969..974
<220>
<221> allele
<222> 21
<223> 8-135-112 . polymorphic base C or T
<220>
<221> allele
<222> 75
<223> 8-135-166 . polymorphic base A or C
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
233
<220>
<221>allele
<222>181
<223>99-16038-118. polymorphic ase A
b or G
<220>
<221>allele
<222>240
<223>8-137-152 polymorphicbase G or
. T
<220>
<221>allele
<222>270
<223>8-137-182 polymorphicbase A or
. G
<220>
<221>allele
<222>434
<223>8-143-232 polymorphicbase G or
. C
<220>
<221>allele
<222>441
<223>8-143-239 polymorphicbase A or
. G
<220>
<221>allele
<222>444
<223>8-143-242 polymorphicbase C or
. T
<220>
<221>allele
<222>447
<223>8-143-245 polymorphicbase A or
. C
<220>
<221>allele
<222>504
<223>8-130-83 polymorphicbase G or
. T
<220>
<221>allele
<222>522
<223>8-130-101 polymorphicbase A or
. C
<220>
<221>allele
<222>523
<223>8-130-102 polymorphicbase A or
. G
<220>
<221>allele
<222>564
<223>8-130-143 polymorphicbase C or
. T
<220>
<221>allele
<222>565
<223>8-130-144 polymorphicbase A or
. G
<220>
<221>allele
<222>691
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
234
<223> 8-130-220 . polymorphic base A or C
<220>
<221> allele
<222> 657
<223> 8-130-236
. polymorphic
base A or G
<220>
<221> allele
<222> 829
<223> 8-131-199
. polymorphic
base A or C
<220>
<221> allele
<222> 892
<223> 8-132-97
. polymorphic
base C or T
<220>
<221> allele
<222> 959
<223> 8-132-164
. polymorphic
base C or T
<220>
<221> allele
<222> 974
<223> 8-132-179
. polymorphic
base A or T
<400> 23
tcatctctgc ttcacaatgcygatgatttagctgggaggacccaaa atg ctg gaa 55
Met Leu Glu
1
aag ctg atg ggt cag ctt agg gta taa 97
get gat tmt ctc ttc
Lys Leu Met Gly Gln Leu Arg Val
Ala Asp Xaa Leu Phe
10 15
aggaatctga acacgactgatattttctttaatttttagatccagatata cattgggtaa157
aatctacttc ataggttttcaaargagcattcttctgagcaaatctgaaa actctctaaa217
ctctattgca aaggagacagaakaaggaagagagacggtaacaaggaaag aargatggaa277
gagaaggcat gaggacggctatttggaaatggcacagaggcatttacaga gatcattatg337
tccttgggtc tcttaccttcctcagccctatgcagagctcattttgtata aagcaggcct397
ttatgtcaga agctgagacctccaacagatggaaatsaaaaccrtcytgm taccagacct457
tggatctgga aggagctgggacttctaaccaatggaacatgggaaakgtg atgacacttg517
actcmrgtga tgaggttacctttcacaagacctggccaactgagacyrga tctccttaca577
ggcttgaaga agtaagcagccatgttggaaaagtcttcatggcaagaaac tatgagttcc637
ttgmctatga ggcctctaargaccgcaggcagcctctagaacgaatgtgg acctgcaact697
acaaccagca aaaagaccagtcatgcaaccacaaggaaataacttctacc aaagctgaat757
gagtttggaa gcagattcttcccagccaatccttctgatgacaatgtagt ctggccaaca817
tcttcactgg amtctgacggactctgtgtctgggacccagctgataacac gtggtgatgg877
gattgtattt gcaaytctctggtcagtaagtgataaaatgccatttctat gcacccacct937
ggcctgtgtg actgggagaatytctctttttattaawtgtgcttcaagtt ttaaca 993
<210> 24
<211> 822
<212> DNA
<213> Homo sapiens
<220>
<221> 5'UTR
<222> 1..46
<220>
<221> CDS
<222> 47..97
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
235
<220>
<221>3'UTR
<222>98..822
<220>
<221>polyA signal
<222>798..803
<220>
<221>allele
<222>21
<223>8-135-112 polymorphicbaseC or T
.
<220>
<221>allele
<222>75
<223>8-135-166 polymorphicbaseA or C
.
<220>
<221>allele
<222>181
<223>99-16038-118. polymorphic ase A
b or G
<220>
<221>allele
<222>240
<223>8-137-152 polymorphicbaseG or T
.
<220>
<221>allele
<222>270
<223>8-137-182 polymorphicbaseA or G
.
<220>
<221>allele
<222>436
<223>8-130-220 polymorphicbaseA or C
.
<220>
<221>allele
<222>452
<223>8-130-236 polymorphicbaseA or G
.
<220>
<221>allele
<222>624
<223>8-131-199 polymorphicbaseA or C
.
<220>
<221>allele
<222>721
<223>8-132-97 polymorphic C or T
. base
<220>
<221>allele
<222>788
<223>8-132-164 polymorphicbaseC or T
.
<220>
<221>allele
<222>803
<223>8-132-179 polymorphicbaseA or T
.
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
236
<400>
24
tcatctctgcttcacaatgcygatgatttagctgggaggacccaaa ctg gaa 55
atg
Met Leu Glu
1
aag ctg ggt get agg gta 97
atg gat tmt taa
ctc cag
ctt ttc
Lys Leu Gly Ala Arg Val
Met Asp Xaa
Leu Gln
Leu Phe
10 15
aggaatctgaacacgactgatattttctttaatttttagatccagatatacattgggtaa157
aatctacttcataggttttcaaargagcattcttctgagcaaatctgaaaactctctaaa217
ctctattgcaaaggagacagaakaaggaagagagacggtaacaaggaaagaargatggaa277
gagaaggcatgaggacggctatttggaaatggcacagaggcatttacagagatcattatg337
tccttgggtctcttaccttcctcagccctatgcagagcttgaagaagtaagcagccatgt397
tggaaaagtcttcatggcaagaaactatgagttccttgmctatgaggcctctaargaccg457
caggcagcctctagaacgaatgtggacctgcaactacaaccagcaaaaagaccagtcatg517
caaccacaaggaaataacttctaccaaagctgaatgagtttggaagcagattcttcccag577
ccaatccttctgatgacaatgtagtctggccaacatcttcactggamtctgacggactct637
gtgtctgggacccagctgataacacgtgttttcttattattgttttgtttccttgttttt697
aggtgatgggattgtatttgcaaytctctggtcagtaagtgataaaatgccatttctatg757
cacccacctggcctgtgtgactgggagaatytctctttttattaawtgtgcttcaagttt817
taaca 822
<210> 25
<211> 776
<212> DNA
<213> Homo sapiens
<220>
<221> 5'UTR
<222> 1..46
<220>
<221> CDS
<222> 47..508
<220>
<221> 3'UTR
<222> 509..776
<220>
<221> polyA signal
<222> 752..757
<220>
<221>allele
<222>21
<223>8-135-112 polymorphic base C
. or T
<220>
<221>allele
<222>75
<223>8-135-166 polymorphic base A
. or C
<220>
<221>allele
<222>135
<223>99-16038-118. polymorphic base
A or G
<220>
<221>allele
<222>194
<223>8-137-152 polymorphic base G
. or T
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
237
<221>allele
<222>224
<223>8-137-182. polymorphicbase A
or G
<220>
<221>allele
<222>390
<223>8-130-220. polymorphicbase A
or C
<220>
<221>allele
<222>406
<223>8-130-236. polymorphicbase A
or G
<220>
<221>allele
<222>578
<223>8-131-199. polymorphicbase A
or C
<220>
<221>allele
<222>675
<223>8-132-97 polymorphic
. base C or
T
<220>
<221>allele
<222>742
<223>8-132-164. polymorphicbase C
or T
<220>
<221>allele
<222>757
<223>8-132-179. polymorphicbase A
or T
<400> 25
tcatctctgc ttcacaatgc gctgggagga cccaaa atgctg gaa
55
ygatgattta
Met Leu Glu
1
aagctgatgggt getgat tmtctc cagcttttcaga tccagatat aca 103
LysLeuMetGly AlaAsp XaaLeu GlnLeuPheArg SerArgTyr Thr
10 15
ttgggtaaaatc tacttc ataggt tttcaaargagc attcttctg agc 151
LeuGlyLysIle TyrPhe IleGly PheGlnXaaSer IleLeuLeu Ser
20 25 30 35
aaatctgaaaac tctcta aactct attgcaaaggag acagaakaa gga 199
LysSerGluAsn SerLeu AsnSer IleAlaLysGlu ThrGluXaa Gly
40 45 50
agagagacggta acaagg aaagaa rgatggaagaga aggcatgag gac 247
ArgGluThrVal ThrArg LysGlu XaaTrpLysArg ArgHisGlu Asp
55 60 65
ggctatttggaa atggca cagagg catttacagaga tcattatgt cct 295
GlyTyrLeuGlu MetAla GlnArg HisLeuGlnArg SerLeuCys Pro
70 75 80
tgggtctcttac cttcct cagccc tatgcagagctt gaagaagta agc 343
TrpValSerTyr LeuPro GlnPro TyrAlaGluLeu GluGluVal Ser
85 90 95
agccatgttgga aaagtc ttcatg gcaagaaactat gagttcctt gmc 391
SerHisValGly LysVal PheMet AlaArgAsnTyr GluPheLeu Xaa
100 105 110 115
tatgaggcctct aargac cgcagg cagcctctagaa cgaatgtgg acc 439
TyrGluAlaSer LysAsp ArgArg GlnProLeuGlu ArgMetTrp Thr
120 125 130
tgcaactacaac cagcaa aaagac cagtcatgcaac cacaaggaa ata 487
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
238
Cys Asn Asn Gln Gln Lys Asp Gln Asn His Glu Ile
Tyr Ser Cys Lys
135 140 145
act tct aaa get gaa tga gtttggaagc aatcc 538
acc agattcttcc cagcc
Thr Ser Lys Ala Glu
Thr
150
ttctgatgacaatgtagtct ggccaacatc ttcactggamtctgacggactctgtgtctg598
ggacccagctgataacacgt gttttcttat tattgttttgtttccttgtttttaggtgat658
gggattgtatttgcaaytct ctggtcagta agtgataaaatgccatttctatgcacccac718
ctggcctgtgtgactgggag aatytctctt tttattaawtgtgcttcaagttttaaca 776
<210>
26
<211>
947
<212>
DNA
<213> Sapiens
Homo
<220>
<221>
5'UTR
<222>
1..46
<220>
<221> CDS
<222> 47..367
<220>
<221> 3'UTR
<222> 368..947
<220>
<221> polyA signal
<222> 923..928
<220>
<221>allele
<222>21
<223>8-135-112 polymorphicbase C T
. or
<220>
<221>allele
<222>75
<223>8-135-166 polymorphicbase A C
. or
<220>
<221>allele
<222>135
<223>99-16038-118. polymorphic or
base A G
<220>
<221>allele
<222>194
<223>8-137-152 polymorphicbase G T
. or
<220>
<221>allele
<222>224
<223>8-137-182 polymorphicbase A G
. or
<220>
<221>allele
<222>388
<223>8-143-232 polymorphicbase G C
. or
<220>
<221>allele
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
239
<222>395
<223>8-143-239. polymorphicbase A
or G
<220>
<221>allele
<222>398
<223>8-143-242. polymorphicbase C
or T
<220>
<221>allele
<222>401
<223>8-143-245. polymorphicbase A
or C
<220>
<221>allele
<222>458
<223>8-130-83 polymorphic
. base G or
T
<220>
<221>allele
<222>476
<223>8-130-101. polymorphicbase A
or C
<220>
<221>allele
<222>477
<223>8-130-102. polymorphicbase A
or G
<220>
<221>allele
<222>518
<223>8-130-143. polymorphicbase C
or T
<220>
<221>allele
<222>519
<223>8-130-194. polymorphicbase A
or G
<220>
<221>allele
<222>595
<223>8-130-220. polymorphicbase A
or C
<220>
<221>allele
<222>611
<223>8-130-236. polymorphicbase A
or G
<220>
<221>allele
<222>783
<223>8-131-199. polymorphicbase A
or C
<220>
<221>allele
<222>846
<223>8-132-97 polymorphic
. base C or
T
<220>
<221>allele
<222>913
<223>8-132-164. polymorphicbase C
or T
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
240
<220>
<221> allele
<222> 928
<223> 8-132-179 . polymorphic base A or T
<400>
26
tcatctctgcttcacaatgc ygatgatttagctgggaggacccaaa ctg gaa 55
atg
Met Leu Glu
1
aag ctg ggt get gat tmt cag ctt aga tcc tat aca 103
atg ctc ttc aga
Lys Leu Gly Ala Asp Xaa Gln Leu Arg Ser Tyr Thr
Met Leu Phe Arg
10 15
ttg ggt atc tac ttc ata ttt caa agc att ctg agc 151
aaa ggt arg ctt
Leu Gly Ile Tyr Phe Ile Phe Gln Ser Ile Leu Ser
Lys Gly Xaa Leu
20 25 30 35
aaa tct aac tct cta aac att gca gag aca kaa gga 199
gaa tct aag gaa
Lys Ser Asn Ser Leu Asn Ile Ala Glu Thr Xaa Gly
Glu Ser Lys Glu
40 45 50
aga gag gta aca agg aaa rga tgg aga agg gag gac 247
acg gaa aag cat
Arg Glu Val Thr Arg Lys Xaa Trp Arg Arg Glu Asp
Thr Glu Lys His
55 60 65
ggc tat gaa atg gca cag cat tta aga tca tgt cct 295
ttg agg cag tta
Gly Tyr Glu Met Ala Gln His Leu Arg Ser Cys Pro
Leu Arg Gln Leu
70 75 80
tgg gtc tac ctt cct cag tat gca ctc att tat aaa 343
tct ccc gag ttg
Trp Val Tyr Leu Pro Gln Tyr Ala Leu Ile Tyr Lys
Ser Pro Glu Leu
85 90 95
gca ggc tat gtc aga agc gacctccaacagatggaaataaaaccrtc 397
ctt tga s
Ala Gly Tyr Val Arg Ser
Leu
100 105
ytgmtaccagaccttggatc tggaaggagctgggacttctaaccaatggaacatggg.aaa457
kgtgatgacacttgactcmr gtgatgaggttacctttcacaagacctggccaactgagac517
yrgatctccttacaggcttg aagaagtaagcagccatgttggaaaagtcttcatggcaag577
aaactatgagttccttgmct atgaggcctctaargaccgcaggcagcctctagaacgaat637
gtggacctgcaactacaacc agcaaaaagaccagtcatgcaaccacaaggaaataacttc697
taccaaagctgaatgagttt ggaagcagattcttcccagccaatccttctgatgacaatg757
tagtctggccaacatcttca ctggamtctgacggactctgtgtctgggacccagctgata817
acacgtggtgatgggattgt atttgcaaytctctggtcagtaagtgataaaatgccattt877
ctatgcacccacctggcctg tgtgactgggagaatytctctttttattaawtgtgcttca937
agttttaaca 947
<210> 27
<211> 16
<212> PRT
<213> Homo sapiens
<220>
<221> VARIANT
<222> 10
<223> Xaa=Ser or Tyr
<400> 27
Met Leu Glu Lys Leu Met Gly Ala Asp Xaa Leu Gln Leu Phe Arg Val
1 5 10 15
<210> 28
<211> 110
<212> PRT
<213> Homo sapiens
<220>
<221> VARIANT
<222> 47
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> Xaa=Pro or Thr
241
<220>
<221> VARIANT
<222> 80
<223> Xaa=Gly or Ser
<400> 28
Met Glu Val Gly Pro Ala Gln Arg Ile Ile Arg Ala Leu Tyr Cys Gly
1 5 10 15
Leu Glu Pro Thr Ala Lys Glu Cys Leu Gly Thr His Ser Val Arg Val
20 25 30
Leu Pro Ser Gly Gln Ile Arg Leu Glu Pro Ala Glu Lys Ser Xaa Arg
35 40 45
Tyr Val Ser Asn Cys Ser Phe Gly Cys Tyr Lys Leu Glu Val Val Lys
50 55 60
Asn Ile Lys Thr Tyr Ile Ile Gln Ser Leu Leu Ala Lys Tyr Val Xaa
65 70 75 80
Leu Ile Ile Pro Glu Phe Ser Leu Val His Thr Asp Ile Gln Ile Tyr
85 90 95
Ile Leu Lys Ile Gly Ile Gly Arg Arg Val Lys Leu Ser Phe
100 105 110
<210> 29
<211> 102
<212> PRT
<213> Homo Sapiens
<220>
<221> VARIANT
<222> 9
<223> Xaa=Ser or Tyr
<220>
<221> VARIANT
<222> 29
<223> Xaa=Lys or Arg
<220>
<221> VARIANT
<222> 49
<223> Xaa=Glu or Stop
<220>
<221> VARIANT
<222> 59
<223> Xaa=Gly or Arg
<220>
<221> VARIANT
<222> 96
<223> Xaa=Lys or Asn
<220>
<221> SITE
<222> 62..63
<223> basic protease cleavage site
<220>
<221> PEPTIDE
<222> 1..63
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<221> PEPTIDE
<222> 64..102
242
<400> 29
Leu Glu Lys Leu Met Gly Ala Asp Xaa Leu Gln Leu Phe Arg Ser Arg
1 5 10 15
Tyr Thr Leu Gly Lys Ile Tyr Phe Ile Gly Phe Gln Xaa Ser Ile Leu
20 25 30
Leu Ser Lys Ser Glu Asn Ser Leu Asn Ser Ile Ala Lys Glu Thr Glu
35 40 45
Xaa Gly Arg Glu Thr Val Thr Arg Lys Glu Xaa Trp Lys Arg Arg His
50 55 60
Glu Asp Gly Tyr Leu Glu Met Ala Gln Arg His Leu Gln Arg Ser Leu
65 70 75 80
Cys Pro Trp Val Ser Tyr Leu Pro Gln Pro Tyr Ala Glu His Ser Xaa
85 90 95
Thr Leu Ser Glu Thr Phe
100
<210>30
<211>118
<212>PRT
<213>Homo
sapiens
<220>
<221>VARIANT
<222>9
<223>Xaa=Seror Tyr
<220>
<221>VARIANT
<222>29
<223>Xaa=Lysor Arg
<220>
<221>VARIANT
<222>49
<223>Xaa=Gluor Stop
<220>
<221>VARIANT
<222>59
<223>Xaa=Glyor Arg
<220>
<221>VARIANT
<222>106
<223>Xaa=Thror Ala
<220>
<221> SITE
<222> 63..64
<223> basic protease cleavage site
<220>
<221> SITE
<222> 110..111
<223> basic protease cleavage site
<220>
<221> DISULFID
<222> 82..104
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<220>
<221> PEPTIDE
<222> 1..64
<220>
<221> PEPTIDE
<222> 65..111
<220>
<221> PEPTIDE
<222> 112..119
243
<400> 30
Leu Glu Lys Leu Met Gly Ala Asp Xaa Leu Gln Leu Phe Arg Ser Arg
1 5 10 15
Tyr Thr Leu Gly Lys Ile Tyr Phe Ile Gly Phe Gln Xaa Ser Ile Leu
20 25 30
Leu Ser Lys Ser Glu Asn Ser Leu Asn Ser Ile Ala Lys Glu Thr Glu
35 40 45
Xaa Gly Arg Glu Thr Val Thr Arg Lys Glu Xaa Trp Lys Arg Arg His
50 55 60
Glu Asp Gly Tyr Leu Glu Met Ala Gln Arg His Leu Gln Arg Ser Leu
65 70 75 80
Cys Pro Trp Val Ser Tyr Leu Pro Gln Pro Tyr Ala Glu Leu Phe Gln
85 90 95
Arg His Phe Asn Ser Arg Cys Gly Lys Xaa Asn Glu Arg Arg Lys Lys
100 105 110
Lys Phe Ser Ser Glu Thr
115
<210> 31
<211> 98
<212> PRT
<213> Homo sapiens
<220>
<221> VARIANT
<222> 10
<223> Xaa=Ser or Tyr
<220>
<221> VARIANT
<222> 30
<223> Xaa=Lys or Arg
<220>
<221> VARIANT
<222> 50
<223> Xaa=Glu or Stop
<220>
<221> VARIANT
<222> 60
<223> Xaa=Gly or Arg
<400> 31
Met Leu Glu Lys Leu Met Gly Ala Asp Xaa Leu Gln Leu Phe Arg Ser
1 5 10 15
Arg Tyr Thr Leu Gly Lys Ile Tyr Phe Ile Gly Phe Gln Xaa Ser Ile
20 25 30
Leu Leu Ser Lys Ser Glu Asn Ser Leu Asn Ser Ile Ala Lys Glu Thr
35 40 45
Glu Xaa Gly Arg Glu Thr Val Thr Arg Lys Glu Xaa Trp Lys Arg Arg
CA 02361408 2001-08-08
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50 55 60
His Glu Asp Gly Tyr Leu Glu Met Ala Gln Arg His Leu Gln Arg Ser
65 70 75 80
Leu Cys Pro Trp Val Ser Tyr Leu Pro Gln Pro Tyr Ala Glu Ser Trp
85 90 95
Asp Phe
<210> 32
<211> 126
<212> PRT
<213> Homo sapiens
<220>
<221> VARIANT
<222> 10
<223> Xaa=Ser or Tyr
<220>
<221> VARIANT
<222> 30
<223> Xaa=Lys or Arg
<220>
<221> VARIANT
<222> 50
<223> Xaa=Glu or Stop
<220>
<221> VARIANT
<222> 60
<223> Xaa=Gly or Arg
<220>
<221> VARIANT
<222> 98
<223> Xaa=Val or Leu
<220>
<221> VARIANT
<222> 103
<223> Xaa=Asn or Ser
<220>
<221> SITE
<222> 63..64
<223> basic protease cleavage site
<220>
<221> DISULFID
<222> 82..106
<220>
<221> PEPTIDE
<222> 1..64
<220>
<221> PEPTIDE
<222> 65..126
<400> 32
Met Leu Glu Lys Leu Met Gly Ala Asp Xaa Leu Gln Leu Phe Arg Ser
1 5 10 15
Arg Tyr Thr Leu Gly Lys Ile Tyr Phe Ile Gly Phe Gln Xaa Ser Ile
CA 02361408 2001-08-08
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245
20 25 30
Leu Leu Ser Lys Ser Glu Asn Ser Leu Asn Ser Ile Ala Lys Glu Thr
35 40 45
Glu Xaa Gly Arg Glu Thr Val Thr Arg Lys Glu Xaa Trp Lys Arg Arg
50 55 60
His Glu Asp Gly Tyr Leu Glu Met Ala Gln Arg His Leu Gln Arg Ser
65 70 75 80
Leu Cys Pro Trp Val Ser Tyr Leu Pro Gln Pro Tyr Ala Glu His Ser
85 90 95
Lys Xaa Ile Leu Asn Gly Xaa Leu His Cys His Phe Lys Arg Ile Ser
100 105 110
Gln Ile Phe Ala Gly His Phe Met Glu Gly Asp Thr Glu Ala
115 120 125
<210> 33
<211> 62
<212> PRT
<213> Homo sapiens
<220>
<221> VARIANT
<222> 10
<223> Xaa=Ser or Tyr
<220>
<221> VARIANT
<222> 30
<223> Xaa=Lys or Arg
<220>
<221> VARIANT
<222> 57
<223> Xaa=Lys or Asn
<220>
<221> SITE
<222> 54..55
<223> basic protease cleavage site
<220>
<221> SITE
<222> 57..58
<223> basic protease cleavage site
<220>
<221> PEPTIDE
<222> 1..53
<220>
<221> PEPTIDE
<222> 58..61
<400> 33
Met Leu Glu Lys Leu Met Gly Ala Asp Xaa Leu Gln Leu Phe Arg Ser
1 5 10 15
Arg Tyr Thr Leu Gly Lys Ile Tyr Phe Ile Gly Phe Gln Xaa Ser Ile
20 25 30
Leu Leu Ser Lys Ser Glu Asn Ser Leu Asn Ser Ile Gly Ile His Gln
35 40 45
Ile His Lys Asn Gln Arg Arg Gln Xaa Lys Glu Glu Arg Arg
50 55 60
<210> 34
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<211> 153
<212> PRT
<213> Homo Sapiens
<220>
<221> VARIANT
<222> 10
<223> Xaa=Ser or Tyr
<220>
<221> VARIANT
<222> 30
<223> Xaa=Lys or Arg
<220>
<221> VARIANT
<222> 50
<223> Xaa=Glu or Stop
<220>
<221> VARIANT
<222> 60
<223> Xaa=Gly or Arg
<220>
<221> VARIANT
<222> 115
<223> Xaa=Ala or Asp
<220>
<221> SITE
<222> 63..64
<223> basic protease cleavage site
<220>
<221> SITE
<222> 122..123
<223> basic protease cleavage site
<220>
<221> DISULFID
<222> 132..142
<220>
<221> PEPTIDE
<222> 1..64
<220>
<221> PEPTIDE
<222> 65..123
<220>
<221> PEPTIDE
<222> 124..153
246
<400> 34
Met Leu Glu Lys Leu Met Gly Ala Asp Xaa Leu Gln Leu Phe Arg Ser
1 5 10 15
Arg Tyr Thr Leu Gly Lys Ile Tyr Phe Ile Gly Phe Gln Xaa Ser Ile
20 25 30
Leu Leu Ser Lys Ser Glu Asn Ser Leu Asn Ser Ile Ala Lys Glu Thr
35 40 45
Glu Xaa Gly Arg Glu Thr Val Thr Arg Lys Glu Xaa Trp Lys Arg Arg
CA 02361408 2001-08-08
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50 55 60
His Glu Asp Gly Tyr Leu Glu Met Ala Gln Arg His Leu Gln Arg Ser
65 70 75 80
Leu Cys Pro Trp Val Ser Tyr Leu Pro Gln Pro Tyr Ala Glu Leu Glu
85 90 95
Glu Val Ser Ser His Val Gly Lys Val Phe Met Ala Arg Asn Tyr Glu
100 105 110
Phe Leu Xaa Tyr Glu Ala Ser Lys Asp Arg Arg Gln Pro Leu Glu Arg
115 120 125
Met Trp Thr Cys Asn Tyr Asn Gln Gln Lys Asp Gln Ser Cys Asn His
130 135 140
Lys Glu Ile Thr Ser Thr Lys Ala Glu
145 150
<210> 35
<211> 106
<212> PRT
<213> Homo Sapiens
<220>
<221> VARIANT
<222> 10
<223> Xaa=Ser or Tyr
<220>
<221> VARIANT
<222> 30
<223> Xaa=Lys or Arg
<220>
<221> VARIANT
<222> 50
<223> Xaa=Glu or Stop
<220>
<221> VARIANT
<222> 60
<223> Xaa=Gly or Arg
<220>
<221> SITE
<222> 62..63
<223> basic protease cleavage site
<220>
<221> SITE
<222> 63..64
<223> basic protease cleavage site
<220>
<221> PEPTIDE
<222> 1..61
<220>
<221> PEPTIDE
<222> 65..106
<400> 35
Met Leu Glu Lys Leu Met Gly Ala Asp Xaa Leu Gln Leu Phe Arg Ser
1 5 10 15
Arg Tyr Thr Leu Gly Lys Ile Tyr Phe Ile Gly Phe Gln Xaa Ser Ile
20 25 30
Leu Leu Ser Lys Ser Glu Asn Ser Leu Asn Ser Ile Ala Lys Glu Thr
CA 02361408 2001-08-08
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248
35 40 45
Glu Xaa Gly Arg Glu Thr Val Thr Arg Lys Glu Xaa Trp Lys Arg Arg
50 55 60
His Glu Asp Gly Tyr Leu Glu Met Ala Gln Arg His Leu Gln Arg Ser
65 70 75 80
Leu Cys Pro Trp Val Ser Tyr Leu Pro Gln Pro Tyr Ala Glu Leu Ile
85 90 95
Leu Tyr Lys Ala Gly Leu Tyr Val Arg Ser
100 105
<210> 36
<211> 1301
<212> DNA
<213> Homo sapiens
<220>
<221> 5'UTR
<222> 1..899
<220>
<221> CDS
<222> 900..1265
<220>
<221> 3'UTR
<222> 1266..1301
<220>
<221> polyA signal
<222> 1277. 1282
<220>
<221> allele
<222> 191
<223> 8-121-187 . polymorphic base A or C
<220>
<221> allele
<222> 313
<223> 8-122-271 . deletion of CAAA
<220>
<221>allele
<222>314
<223>8-122-272. polymorphic base
A or G
<220>
<221>allele
<222>368
<223>8-122-326. polymorphic base
A or C
<220>
<221>allele
<222>390
<223>8-123-55 polymorphic base A
. or T
<220>
<221>allele
<222>806
<223>8-127-28 polymorphic base A
. or G
<220>
<221>allele
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
249
<222>897
<223>8-127-119. polymorphicbase A
or G
<220>
<221>allele
<222>937
<223>8-127-159. polymorphicbase A
or C
<220>
<221>allele
<222>961
<223>8-128-61 . polymorphicbase G
or C
<220>
<221>allele
<222>968
<223>8-128-68 . polymorphicbase C
or T
<220>
<221>allele
<222>969
<223>8-128-69 . polymorphicbase A
or G
<220>
<221>allele
<222>985
<223>8-128-85 . polymorphicbase A
or C
<220>
<221>allele
<222>1044
<223>8-129-50 . polymorphicbase C
or T
<220>
<221>allele
<222>1055
<223>8-129-60 . deletion A
of
<400>
36
gtcattattacaatgaagggaagaaaggaagacatgaaggggaaatgggactatttacca60
agtgtatctgcatagactaaaggagacaagaggaagtactgagcaccttgattcctgcag120
ataattatttaagaaccataagaattctttcctagcttctcataagcctgctccttcaaa180
gggttaactgmagtgaatcaaactattggattataattccatgaagtaagtttattgaag240
acaaacaggccttgggccgctgcctctgtctctcctgccttccccactgaatctccagcc300
cacattcacaaacraagacaaacctgtgtaaactgaagcaccacaaaactacttttatga360
aagcagamtggaagcagatttcacctgcawttcctacattcaactgaatcctttaaattg420
actgaggcacatcctgtaccaaggagagacctttgttactgcctttgatcctgagacctt480
ctgagccaggaaccctgcttttaagaggaaggtcttggccaggctcagtggctcacacct540
gtaatcccagcactttgggaggccgaggcgggcagatcacctgaggtcaggagttcaaga600
ccagcctgaccaatatggtgaaaccccatctctactaaaaatacaaaaattagccaggca660
tggtggcaggtgcctgtagtcccagctactcgggaggctgagacaggagaattgcttgaa720
cctgggaggcggaggttgcagtgagccaagatcacaccactgcactccagcctgggcaac780
agagtgagactccatctcaaattaaraaaaaaaataagatacagaatataaagagacagc840
ataaatgatagaaaacaaaataagcatgttcatgagccagaaatcaagaagaaaagrca 899
atg ata agg get ggc atc ggc cmt tct gga 947
aaa gaa gcc cca ggg
gga
Met Ile Arg Ala Gly Ile Gly Xaa
Lys Glu Ala Pro Gly Ser
Gly Gly
1 5 10 15
agc agc gga gsc cct tgg ttg gmt tct cca 995
tct tgc tgy ctc gcc
rtt
Ser Ser Gly Xaa Pro Trp Leu Xaa Ser Pro
Ser Cys Cys Leu Ala
Xaa
20 25 30
tct tca tgc atc tgc get tcc atc ttg get 1043
aag act gca tca acg
gcc
Ser Ser Cys Ile Cys Ala Ser Ile Leu Ala
Lys Thr Ala Ser Thr
Ala
35 40 45
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
250
ytgtcgctc acatttcta cttctctct tgcaag gacccttgg gattct 1091
LeuSerLeu ThrPheLeu LeuLeuSer CysLys AspProTrp AspSer
50 55 60
attggactc acctggata atccaagat aatctt catcttaaa atcctt 1139
IleGlyLeu ThrTrpIle IleGlnAsp AsnLeu HisLeuLys IleLeu
65 70 75 80
aatttagtc acacacaga aaatcacct ctgtta tgtaaagta acatat 1187
AsnLeuVal ThrHisArg LysSerPro LeuLeu CysLysVal ThrTyr
85 90 95
ttccatatc ctggaggaa gggggcatt gatgtg tctaccaca gcatcc 1235
PheHisIle LeuGluGlu GlyGlyIle AspVal SerThrThr AlaSer
100 105 110
acaaaggga acaaaaaat attgtccaa taaatgcatatag 1285
aaataaattt
ThrLysGly ThrLysAsn IleValGln
115 120
gtggattcag 1301
gaaaaa
<210> 37
<211> 1154
<212> DNA
<213> Homo Sapiens
<220>
<221> 5'UTR
<222> 1..719
<220>
<221> CDS
<222> 720..1118
<220>
<221> 3'UTR
<222> 1119..1154
<220>
<221> polyA signal
<222> 1131. 1136
<220>
<221>allele
<222>191
<223>8-121-187. polymorphicbase A
or C
<220>
<221>allele
<222>313
<223>8-122-271. deletion CAAA
of
<220>
<221>allele
<222>314
<223>8-122-272. polymorphicbase A
or G
<220>
<221>allele
<222>368
<223>8-122-326. polymorphicbase A
or C
<220>
<221>allele
<222>390
<223>8-123-55 polymorphic
. base A
or T
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
251
<220>
<221>allele
<222>814
<223>8-128-61 . polymorphicbaseG
or
C
<220>
<221>allele
<222>821
<223>8-128-68 . polymorphicbaseC
or
T
<220>
<221>allele
<222>822
<223>8-128-69 . polymorphicbaseA
or
G
<220>
<221>allele
<222>838
<223>8-128-85 . polymorphicbaseA
or
C
<220>
<221>allele
<222>897
<223>8-129-50 . polymorphicbaseC
or
T
<220>
<221>allele
<222>908
<223>8-129-60 . deletion A
of
<400>
37
gtcattattacaatgaaggg aagaaaggaagacatgaaggggaaatgggactatttacca60
agtgtatctgcatagactaa aggagacaagaggaagtactgagcaccttgattcctgcag120
ataattatttaagaaccata agaattctttcctagcttctcataagcctgctccttcaaa180
gggttaactgmagtgaatca aactattggattataattccatgaagtaagtttattgaag240
acaaacaggccttgggccgc tgcctctgtctctcctgccttccccactgaatctccagcc300
cacattcacaaacraagaca aacctgtgtaaactgaagcaccacaaaactacttttatga360
aagcagamtggaagcagatt tcacctgcawttcctacattcaactgaatcctttaaattg420
actgaggcacatcctgtacc aaggagagacctttgttactgcctttgatcctgagacctt480
ctgagccaggaaccctgctt ttaagaggaaggtcttggccaggctcagtggctcacacct540
gtaatcccagcactttggga ggccgaggcgggcagatcacctgaggtcaggagttcaaga600
ccagcctgaccaatatggtg aaaccccatctctactaaaaatacaaaaattagccaggca660
tggtggcaggtgcctgtagt cccagctactcgggaggctgagacaggagaattgcttga 719
acc tgg gcg gag gtt gca agc caa cac acc gca ctc 767
gag gtg gat act
Thr Trp Ala Glu Val Ala Ser Gln His Thr Ala Leu
Glu Val Asp Thr
1 5 10 15
cag cct caa cag agt gag cca tct att aac gga gsc 815
ggg act caa tct
Gln Pro Gln Gln Ser Glu Pro Ser Ile Asn Gly Xaa
Gly Thr Gln Ser
20 25 30
tgc tgy cct tgg ctc ttg gcc tct tct tca tgc atc 863
rtt gmt cca aag
Cys Cys Pro Trp Leu Leu Ala Ser Ser Ser Cys Ile
Xaa Xaa Pro Lys
35 40 45
act gca tgc get tca tcc acg ttg ytg tcg aca ttt 911
gcc atc get ctc
Thr Ala Cys Ala Ser Ser Thr Leu Leu Ser Thr Phe
Ala Ile Ala Leu
50 55 60
cta ctt tct tgc aag gac tgg gat att gga acc tgg 959
ctc cct tct ctc
Leu Leu Ser Cys Lys Asp Trp Asp Ile Gly Thr Trp
Leu Pro Ser Leu
65 70 75 80
ata atc gat aat ctt cat aaa atc aat tta aca cac 1007
caa ctt ctt gtc
Ile Ile Asp Asn Leu His Lys Ile Asn Leu Thr His
Gln Leu Leu Val
85 90 95
aga aaa cct ctg tta tgt gta aca ttc cat ctg gag 1055
tca aaa tat atc
Arg Lys Pro Leu Leu Cys Val Thr Phe His Leu Glu
Ser Lys Tyr Ile
CA 02361408 2001-08-08
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100 105 110
gaa ggg ggc att gat gtg tct acc aca gca tcc aca aag gga aca aaa 1103
Glu Gly Gly Ile Asp Val Ser Thr Thr Ala Ser Thr Lys Gly Thr Lys
115 120 125
aat att gtc caa taa atgcatatag aaataaattt gtggattcag gaaaaa 1154
Asn Ile Val Gln
130
<210> 38
<211> 838
<212> DNA
<213> Homo sapiens
<220>
<221> 5'UTR
<222> 1..484
<220>
<221> CDS
<222> 485..802
<220>
<221> 3'UTR
<222> 803..838
<220>
<221> polyA signal
<222> 814..819
<220>
<221>allele
<222>191
<223>8-121-187 . polymorphicbase A or C
<220>
<221>allele
<222>313
<223>8-122-271 . deletion CAAA
of
<220>
<221>allele
<222>314
<223>8-122-272 . polymorphicbase A or G
<220>
<221>allele
<222>368
<223>8-122-326 . polymorphicbase A or C
<220>
<221>allele
<222>390
<223>8-123-55 . polymorphicbase A or T
<220>
<221>allele
<222>498
<223>8-128-61 polymorphicbase G or C
.
<220>
<221>allele
<222>505
<223>8-128-68 . polymorphicbase C or T
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
253
<220>
<221>allele
<222>506
<223>8-128-69. polymorphicbase A
or G
<220>
<221>allele
<222>522
<223>8-128-85. polymorphicbase A
or C
<220>
<221>allele
<222>581
<223>8-129-50. polymorphicbase C
or T
<220>
<221>allele
<222>592
<223>8-129-60. deletion A
of
<400>
38
gtcattattacaatgaaggg aagaaaggaagacatgaaggggaaatgggactatttacca60
agtgtatctgcatagactaa aggagacaagaggaagtactgagcaccttgattcctgcag120
ataattatttaagaaccata agaattctttcctagcttctcataagcctgctccttcaaa180
gggttaactgmagtgaatca aactattggattataattccatgaagtaagtttattgaag290
acaaacaggccttgggccgc tgcctctgtctctcctgccttccccactgaatctccagcc300
cacattcacaaacraagaca aacctgtgtaaactgaagcaccacaaaactacttttatga360
aagcagamtggaagcagatt tcacctgcawttcctacattcaactgaatcctttaaattg420
actgaggcacatcctgtacc aaggagagacctttgttactgcctttgatcctgagacctt480
ctga gcc c tct gga gsc tgc rtt cct ctc ttg t gcc tct 529
ag tgy tgg gm
Ala Se r Ser Gly Xaa Cys Xaa Pro Leu Leu a Ala Ser
Cys Trp Xa
1 5 10 15
cca tct aag tgc atc act gcc tgc tca tcc acg ttg 577
tca gca get atc
Pro Ser Lys Cys Ile Thr Ala Cys Ser Ser Thr Leu
Ser Ala Ala Ile
20 25 30
get ytg ctc aca ttt cta ctc tct aag gac tgg gat 625
tcg ctt tgc cct
Ala Leu Leu Thr Phe Leu Leu Ser Lys Asp Trp Asp
Ser Leu Cys Pro
35 40 45
tct att ctc acc tgg ata caa gat ctt cat aaa atc 673
gga atc aat ctt
Ser Ile Leu Thr Trp Ile Gln Asp Leu His Lys Ile
Gly Ile Asn Leu
50 55 60
ctt aat gtc aca cac aga tca cct tta tgt gta aca 721
tta aaa ctg aaa
Leu Asn Val Thr His Arg Ser Pro Leu Cys Val Thr
Leu Lys Leu Lys
65 70 75
tat ttc atc ctg gag gaa ggc att gtg tct aca gca 769
cat ggg gat acc
Tyr Phe Ile Leu Glu Glu Gly Ile Val Ser Thr Ala
His Gly Asp Thr
80 85 90 95
tcc aca gga aca aaa aat gtc caa atgcatatagaaataaattt822
aag att taa
Ser Thr Gly Thr Lys Asn Val Gln
Lys Ile
100 105
gtggattcaggaaaaa 838
<210> 39
<211> 985
<212> DNA
<213> Homo sapiens
<220>
<221> 5'UTR
<222> 1..583
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
254
<221>CDS
<222>584..949
<220>
<221>3'UTR
<222>950..985
<220>
<221>polyA signal
<222>961..966
<220>
<221>allele
<222>191
<223>8-121-187 polymorphicbase A
. or C
<220>
<221>allele
<222>313
<223>8-122-271 deletion CAAA
. of
<220>
<221>allele
<222>314
<223>8-122-272 polymorphicbase A
. or G
<220>
<221>allele
<222>368
<223>8-122-326 polymorphicbase A
. or C
<220>
<221>allele
<222>390
<223>8-123-55 polymorphicbase A
. or T
<220>
<221>allele
<222>490
<223>8-127-28 polymorphicbase A
. or G
<220>
<221>allele
<222>581
<223>8-127-119 polymorphicbase A
. or G
<220>
<221>allele
<222>621
<223>8-127-159 polymorphicbase A
. or C
<220>
<221>allele
<222>645
<223>8-128-61 polymorphicbase G
. or C
<220>
<221>allele
<222>652
<223>8-128-68 polymorphicbase C
. or T
<220>
<221>allele
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
255
<222>653
<223>8-128-69. polymorphicbase A
or G
<220>
<221>allele
<222>669
<223>8-128-85. polymorphicbase A
or C
<220>
<221>allele
<222>728
<223>8-129-50. polymorphicbase C
or T
<220>
<221>allele
<222>739
<223>8-129-60. deletion A
of
<400>
39
gtcattattacaatgaaggg aagaaaggaagacatgaaggggaaatgggactatttacca60
agtgtatctgcatagactaa aggagacaagaggaagtactgagcaccttgattcctgcag120
ataattatttaagaaccata agaattctttcctagcttctcataagcctgctccttcaaa180
gggttaactgmagtgaatca aactattggattataattccatgaagtaagtttattgaag240
acaaacaggccttgggccgc tgcctctgtctctcctgccttccccactgaatctccagcc300
cacattcacaaacraagaca aacctgtgtaaactgaagcaccacaaaactacttttatga360
aagcagamtggaagcagatt tcacctgcawttcctacattcaactgaatcctttaaattg420
actgaggcacatcctgtacc aaggagagacctttgttactgcctttgatcctgagacctt480
ctgagccagraaaaaaaata agatacagaatataaagagacagcataaatgatagaaaac540
aaaataagcatgttcatgag ccagaaatcaagaagaaaagrca atg aaa agg 595
ata
Met Ile Lys Arg .
1
get gaa gga ggc atc cca cmt ggg gga agc tct gga 643
gcc ggc tct agc
Ala Glu Gly Gly Ile Pro Xaa Gly Gly Ser Ser Gly
Ala Gly Ser Ser
10 15 20
gsc tgc rtt cct tgg ctc gmt gcc cca tct aag tgc 691
tgy ttg tct tca
Xaa Cys Xaa Pro Trp Leu Xaa Ala Pro Ser Lys Cys
Cys Leu Ser Ser
25 30 35
atc act gcc tgc get tca atc acg get ytg ctc aca 739
gca tcc ttg tcg
Ile Thr Ala Cys Ala Ser Ile Thr Ala Leu Leu Thr
Ala Ser Leu Ser
40 45 50
ttt cta ctc tct tgc aag cct tgg tct att ctc acc 787
ctt gac gat gga
Phe Leu Leu Ser Cys Lys Pro Trp Ser Ile Leu Thr
Leu Asp Asp Gly
55 60 65
tgg ata caa gat aat ctt ctt aaa ctt aat gtc aca 835
atc cat atc tta
Trp Ile Gln Asp Asn Leu Leu Lys Leu Asn Val Thr
Ile His Ile Leu
70 75 80
cac aga tca cct ctg tta aaa gta tat ttc atc ctg 883
aaa tgt aca cat
His Arg Ser Pro Leu Leu Lys Val Tyr Phe Ile Leu
Lys Cys Thr His
85 90 95 100
gag gaa ggc att gat gtg acc aca tcc aca gga aca 931
ggg tct gca aag
Glu Glu Gly Ile Asp Val Thr Thr Ser Thr Gly Thr
Gly Ser Ala Lys
105 110 115
aaa aat gtc caa taa atgcatatag aaataaattt g gaaaaa 985
att gtggattca
Lys Asn Val Gln
Ile
120
<210> 40
<211> 1386
<212> DNA
<213> Homo sapiens
<220>
<221> 5'UTR
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
256
<222> 1..984
<220>
<221>CDS
<222>985..1350
<220>
<221>3'UTR
<222>1351..1386
<220>
<221>polyA signal
<222>1362. 1367
<220>
<221>allele
<222>191
<223>8-121-187 polymorphic baseor
. A C
<220>
<221>allele
<222>398
<223>8-122-271 deletion of CAAA
.
<220>
<221>allele
<222>399
<223>8-122-272 polymorphic baseor
. A G
<220>
<221>allele
<222>453
<223>8-122-326 polymorphic baseor
. A C
<220>
<221>allele
<222>475
<223>8-123-55 polymorphic baseor
. A T
<220>
<221>allele
<222>891
<223>8-127-28 polymorphic baseor
. A G
<220>
<221>allele
<222>982
<223>8-127-119 polymorphic baseor
. A G
<220>
<221>allele
<222>1022
<223>8-127-159 polymorphic baseor
. A C
<220>
<221>allele
<222>1046
<223>8-128-61 polymorphic baseor
. G C
<220>
<221>allele
<222>1053
<223>8-128-68 polymorphic baseor
. C T
CA 02361408 2001-08-08
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<220>
<221>allele
<222>1054
<223>8-128-69. polymorphicbase A
or G
<220>
<221>allele
<222>1070
<223>8-128-85. polymorphicbase A
or C
<220>
<221>allele
<222>1129
<223>8-129-50. polymorphicbase C
or T
<220>
<221>allele
<222>1140
<223>8-129-60. deletion A
of
<400>
40
gtcattattacaatgaaggg aagaaaggaagacatgaaggggaaatgggactatttacca60
agtgtatctgcatagactaa aggagacaagaggaagtactgagcaccttgattcctgcag120
ataattatttaagaaccata agaattctttcctagcttctcataagcctgctccttcaaa180
gggttaactgmagtgaatca aactattggattataattccatgaagatctgccctttcat240
gtagtctgggcaccagagca ccctgagcccagtggactgcaccagtggactcttccatcc300
tcagggttttgtaagtttat tgaagacaaacaggccttgggccgctgcctctgtctctcc360
tgccttccccactgaatctc cagcccacattcacaaacraagacaaacctgtgtaaactg420
aagcaccacaaaactacttt tatgaaagcagamtggaagcagatttcacctgcawttcct480
acattcaactgaatccttta aattgactgaggcacatcctgtaccaaggagagacctttg540
ttactgcctttgatcctgag accttctgagccaggaacectgcttttaagaggaaggtct600
tggccaggctcagtggctca cacctgtaatcccagcactttgggaggccgaggcgggcag660
atcacctgaggtcaggagtt caagaccagcctgaccaatatggtgaaaccccatctctac720
taaaaatacaaaaattagcc aggcatggtggcaggtgcctgtagtcccagctactcggga780
ggctgagacaggagaattgc ttgaacctgggaggcggaggttgcagtgagccaagatcac840
accactgcactccagcctgg gcaacagagtgagactccatctcaaattaaraaaaaaaat900
aagatacagaatataaagag acagcataaatgatagaaaacaaaataagcatgttcatga960
gccagaaatcaagaagaaaa grea ta aaa get gaa gga gge 1011
atg a agg gcc
Met I le Lys Gly Gly
Arg Ala
Glu Ala
1 5
atc cca cmt ggg tct gga agc tct gsc tgc rtt cct 1059
ggc agc gga tgy
Ile Pro Xaa Gly Ser Gly Ser Ser Xaa Cys Xaa Pro
Gly Ser Gly Cys
15 20 25
tgg ctc gmt gcc tct cca tca aag atc act gcc tgc 1107
ttg tct tgc gca
Trp Leu Xaa Ala Ser Pro Ser Lys Ile Thr Ala Cys
Leu Ser Cys Ala
30 35 40
get tca atc acg ttg get tcg ctc ttt cta ctc tct 1155
tcc ytg aca ctt
Ala Ser Ile Thr Leu Ala Ser Leu Phe Leu Leu Ser
Ser Leu Thr Leu
45 50 55
tgc aag cct tgg gat tct gga ctc tgg ata caa gat 1203
gac att acc atc
Cys Lys Pro Trp Asp Ser Gly Leu Trp Ile Gln Asp
Asp Ile Thr Ile
60 65 70
aat ctt ctt aaa atc ctt tta gtc cac aga tca cct 1251
cat aat aca aaa
Asn Leu Leu Lys Ile Leu Leu Val His Arg Ser Pro
His Asn Thr Lys
75 80 85
ctg tta aaa gta aca tat cat atc gag gaa ggc att 1299
tgt ttc ctg ggg
Leu Leu Lys Val Thr Tyr His Ile Glu Glu Gly Ile
Cys Phe Leu Gly
90 95 100 105
gat gtg acc aca gca tcc aag gga aaa aat gtc caa 1347
tct aca aca att
Asp Val Thr Thr Ala Ser Lys Gly Lys Asn Val Gln
Ser Thr Thr Ile
110 115 120
taa atgcatatag aaataaattt tcag gaaaaa 1386
gtggat
CA 02361408 2001-08-08
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<210> 41
<211> 121
<212> PRT
<213> Homo sapiens
<220>
<221> SITE
<222> 86..87
<223> basic protease cleavage site
<220>
<221> PEPTIDE
<222> 1..85
<220>
<221> PEPTIDE
<222> 88..121
<400> 41
Met Ile Lys Arg Ala Glu Ala Gly Gly Ile Pro Gly Pro Gly Ser Gly
1 5 10 15
Ser Ser Ser Gly Gly Cys Cys Val Pro Trp Leu Leu Ala Ala Ser Pro
20 25 30
Ser Ser Lys Cys Ile Thr Ala Ala Cys Ala Ser Ser Ile Thr Leu Ala
35 40 45
Leu Ser Leu Thr Phe Leu Leu Leu Ser Cys Lys Asp Pro Trp Asp Ser
50 55 60
Ile Gly Leu Thr Trp Ile Ile Gln Asp Asn Leu His Leu Lys Ile Leu
65 70 75 80
Asn Leu Val Thr His Arg Lys Ser Pro Leu Leu Cys Lys Val Thr Tyr
85 90 95
Phe His Ile Leu Glu Glu Gly Gly Ile Asp Val Ser Thr Thr Ala Ser
100 105 110
Thr Lys Gly Thr Lys Asn Ile Val Gln
115 120
<210> 42
<211> 132
<212> PRT
<213> Homo Sapiens
<220>
<221> SITE
<222> 97..98
<223> basic protease cleavage site
<220>
<221> PEPTIDE
<222> 1..96
<220>
<221> PEPTIDE
<222> 99..132
<220>
<400> 42
Thr Trp Glu Ala Glu Val Ala Val Ser Gln Asp His Thr Thr Ala Leu
1 5 10 15
Gln Pro Gly Gln Gln Ser Glu Thr Pro Ser Gln Ile Asn Ser Gly Gly
20 25 30
CA 02361408 2001-08-08
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Cys Cys Val Pro Trp Leu Leu Ala Ala Ser Pro Ser Ser Lys Cys Ile
35 40 45
Thr Ala Ala Cys Ala Ser Ser Ile Thr Leu Ala Leu Ser Leu Thr Phe
50 55 60
Leu Leu Leu Ser Cys Lys Asp Pro Trp Asp Ser Ile Gly Leu Thr Trp
65 70 75 80
Ile Ile Gln Asp Asn Leu His Leu Lys Ile Leu Asn Leu Val Thr His
85 90 95
Arg Lys Ser Pro Leu Leu Cys Lys Val Thr Tyr Phe His Ile Leu Glu
100 105 110
Glu Gly Gly Ile Asp Val Ser Thr Thr Ala Ser Thr Lys Gly Thr Lys
115 120 125
Asn Ile Val Gln
130
<210> 43
<211> 105
<212> PRT
<213> Homo sapiens
<220>
<221> SITE
<222> 70..71
<223> basic protease cleavage site
<220>
<221> PEPTIDE
<222> 1..69
<220>
<221> PEPTIDE
<222> 72..105
<400> 43
Ala Ser Ser Gly Gly Cys Cys Val Pro Trp Leu Leu Ala Ala Ser Pro
1 5 10 15
Ser Ser Lys Cys Ile Thr Ala Ala Cys Ala Ser Ser Ile Thr Leu Ala
20 25 30
Leu Ser Leu Thr Phe Leu Leu Leu Ser Cys Lys Asp Pro Trp Asp Ser
35 40 45
Ile Gly Leu Thr Trp Ile Ile Gln Asp Asn Leu His Leu Lys Ile Leu
50 55 60
Asn Leu Val Thr His Arg Lys Ser Pro Leu Leu Cys Lys Val Thr Tyr
65 70 75 80
Phe His Ile Leu Glu Glu Gly Gly Ile Asp Val Ser Thr Thr Ala Ser
85 90 95
Thr Lys Gly Thr Lys Asn Ile Val Gln
100 105
<210> 44
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide g34872MbisEco
<400> 44
cccgaattcc caaacttctt tcatttaaag aacca 35
<210> 45
<211> 36
<212> DNA
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<213> Artificial Sequence
260
<220>
<223>oligonucleotideg34872LR1309nBAmH1
<400>45
atgcgggatc cccagtcaca caggcc 36
cagagattct
<210>46
<211>44
<212>DNA
<213>Artificial
Sequence
<220>
<223>oligonucleotideg34872genoLF22nEcoRI
<400>46
tactggaatt tgaagcaagt aatgtgtgtg tgag 44
ccaggtagag
<210>47
<211>35
<212>DNA
<213>Artificial
Sequence
<220>
<223>oligonucleotideg34872LR1309nBAmH1
<400>47
atgcgggatc cccagtcaca caggc 35
cagagattct
<210>48
<211>33
<212>DNA
<213>Artificial
Sequence
<220>
<223>oligonucleotideg34872MterEco
<400>48
cgagaattcg tgggaggacc caa 33
atgatttagc
<210>99
<211>26
<212>DNA
<213>Artificial
Sequence
<220>
<223>oligonucleotideg34872LR1305nBam
<400>49
tcgggatcca ccaggt 26
gtcacacagg
<210>50
<211>40
<212>DNA
<213>Artificial
Sequence
<220>
<223>oligonucleotideg34872LF1140ECOR1
<400>50
gctgggaatt gctgatgggt gctgattctc 40
cgctggaaaa
CA 02361408 2001-08-08
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261
<210> 51
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide g34872LR1309nBAmH1
<400> 51
atgcgggatc cagagattct cccagtcaca caggc 35
<210> 52
<211> 31
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide g34872LF1064Eco
<400> 52
tcagaattct catctctgct tcacaatgcc g 31
<210> 53
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> oligonucleotide g34872exRBAMl39
<400> 53
acgggatcct ttcagtactg aagttgagag ggaga 35
<210> 54
<211> 1158
<212> DNA
<213> Pan troglodytes
<900> 54
gtccacctgc tgatagtgcg ctccttaggt gcctgtctct ggctgtcctg tgccacctgc 60
acagagtcat gcatgagctc cactgtggga agtctctaga gatgagctga gcttacccta 120
caccaactga aagagtctat cttagtcctg aagatctcaa gtcatcctca tattcccatg 180
aatgtgaatg gaagttgggc ctgctcagag aatcatcagg gctctttatt gtggcctgga 240
gccaactgcc aaggaatgcc taggaacaca ctcagtaaga gtgttgccct caggccagat 300
cagacttgaa cctgcagaga aatcccctag gtatgtcagc aattgctcat ttggatgcta 360
taaacttgaa gttgtgaaaa atataaagac ttacattatc cagtctctcc tggcaaaata 420
tgtaggttta atcatacctg aattttcctt agttcacaca gatatacaga tatatatcct 480
aaaaattggc attggtaggt gtgtcaagtt atcattttga aaacatagaa acctgaacaa 540
gatgtatcac tccagtctag aatgtctata tgcagagtat ccacaaaaaa ccaaacttca 600
acattctttc atgtctatat tccttcaaca ttctttgtct tcaacattct ttcatgtcta 660
gaatgtctat atgcaaagta tccacaaaag acccaaactt ttttcattta aagaaccaaa 720
cttctttaaa taaaaatgac tcacaataat ttaatatttt accatttaca aagagattaa 780
ctacaacaat attcatcttg agttaatttc ccatgaataa ctttttcatt tcttaaaatt 840
tgctgaatgg aaagccagaa agcagagtga agcaagtaat gtgtgtgtga gtagtcattg 900
gatacacgca taacagtgag caagtttctc agctcctgca tggcagtgtt ctgattatct 960
tttgctgcaa aagagctaca ccccaaatta gtggcttaaa gtaaaagctc actagtgtat 1020
atgatgattc tgttggtcca ggatttggaa agggcatggc aggatgtctc atctctgctt 1080
cacaatgccg atgatttagc tgggaggacc caaaatgctg gaaaagctga tgggtgctga 1140
ttctctccag cttttcag 1158
<210> 55
<211> 92
<212> DNA
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<213> Pan troglodytes
262
<220>
<221> _feature
misc
<222>
71..72
<223> g, c or
n=a, t
<400>
55
atccagatatacattgggtaaaatctacttcataggttttcaaaggagca ttcttctgag60
caaatctgaannaactctctaaaactccattg 92
<210>
56
<211>
152
<212>
DNA
<213> troglodytes
Pan
<400>
56
caaaggagacagagagaagaaggaagagagacggtaacaaggaaagaagg atggaagaga60
aggcatgaggacggctatttggaaatggcacagaggcattgacagagatc attgtgtcct120
agggtctcttaccttcctcagccctgcacaga 152
<210>
57
<211>
94
<212>
DNA
<213> troglodytes
Pan
<400>
57
acattccaaggtgattctaaatggcaatttgcactgtcattttaaaagaa tttctcagat60
atttgctgggcactttatggaaggagacactgag 94
<210>
58
<211>
141
<212>
DNA
<213> troglodytes
Pan
<400>
58
gaacacagaagcttttgtagtgttggtgctaaaatggttcccttgtcaga ggagttacgt60
tttatgagatcctctaagcaaatttagaaaaggagaggaacttgaccaca gaaactgtgt120
ttgatacatttgagcagcaaa 141
<210>
59
<211>
316
<212>
DNA
<213> troglodytes
Pan
<220>
<221> _feature
misc
<222> 5
8,26
<223> g, c or
n=a, t
<400>
59
actctttncagagacattttaactcacgatttgggaaaaccaatgagaga agaaaaaaga60
aattcttatctgaaacttgaacttatcaaaactcacttgtctagaaatta gcctgggaac120
atccaggcactggaattcctcactttttttccttctccctctcaacttca gtactgaaag180
gagaaagtcatttccaaatgtctatgttttgactttttaaatagaccaaa tttagagtca240
tgtaaagatacaataattagctttncttaataattttcacccagaggtat ttttatagag300
aataaaaacaacaaca 316
<210>
60
<211>
388
<212>
DNA
<213> troglodytes
Pan
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
263
<400>
60
gagctgggacttctaaccaatggaacatgggaaaggtgatgagacgtgac tccggtgatg60
aggttaccttttacaagacttggccaactgagactggatctccttacagg ctttaagaag120
taagcagccatgttggaaaagtcttcatggcaaggaactatgagtggcct ctaaggaccg180
caggcagcctctagaacgaatgtggacctgcaactacaaccagcaaaaag accagtcatg290
caaccacaaggaaataacttccaccaaagccgaatgagtttggaagcaga ttcttcccag300
ccattccttctgatgacaatgtagtctggccaacatcttcactggactct gacggactct360
gtgtctgggaaccagctgataacacgtg 388
<210>
61
<211>
35
<212>
DNA
<213> troglodytes
Pan
<400>
61
gagctgggacttctaaccaatggaacatgggaaag 35
<210>
62
<211>
279
<212>
DNA
<213> troglodytes
Pan
<400>
62
gctttaagaagtaagcagccatgttggaaaagtcttcatggcaaggaact atgagtggcc60
tctaaggaccgcaggcagcctctagaacgaatgtggacctgcaactacaa ccagcaaaaa120
gaccagtcatgcaaccacaaggaaataacttccaccaaagccgaatgagt ttggaagcag180
attcttcccagccattccttctgatgacaatgtagtctggccaacatctt cactggactc240
tgacggactctgtgtctgggaaccagctgataacacgtg 279
<210>
63
<211>
50
<212>
DNA
<213> troglodytes
Pan
<400>
63
gtgatgggattgtatttgcaactctctggtcagtaagtgataaaatgcca 50
<210>
64
<211>
84
<212>
DNA
<213> troglodytes
Pan
<400>
64
ttttattattattgttttgtttccttgtttttaggtgatgggattgtatt tgcaactctc60
tggtcagtaagtgataaaatgcca 84
<210>
65
<211>
1152
<212>
DNA
<213> bates
Hylo sp.
<220>
<221> _feature
misc
<222>
115
<223> g, c or
n=a, t
<400>
65
gtccacctgctgacagtgcgctccttaggtgtctgtctctggctgccctg tgccatctgc60
gcagaatcatgcatgagctccactgtgggaagtctctagagatgaactga gcttnacccc120
acaccaactgaaagagtctatcttagtcctgaaggtctcaagtcatcctc atgtccccat180
gaatgtgaatggaagctgggcctgctcagagaatcatcagggctctttat tgtggcctgg240
agctaactgccaaggaatgcctaggaacacacttagtaagagtgttgccc tcaggccaga300
tcagacttgaacctgtggagaaatcccctaggtatgtctgcaattgctca tttggatgct360
CA 02361408 2001-08-08
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ataaacttgaagttatgaaaaatacaaagacttacattat ccagtctctc ctgagaaaat420
atgtaggtttaatcattcctgaattttccttagttcacac agatatatat cctaaaaatt480
tgcattggtaggtgtgtcaagttatcattttaaaaacata gaaacctgaa caagatatat540
cactccagtctagaatgtctatatgcagagtatccacaaa agaaccaaac ttcaacattc600
tttcatgtctatatgccttccacattctttgtcttcaaca ttctttcatg tctagaatgt660
ctatatgcagagtatccacaaaagacccaaacttctttca tttaaagaac caaacttctt720
taaataaagatgattagcaataatttaatattttaccatt tacaaagagt ttaactacaa780
caatatacatcttgagttaatttcccatgaataacatttt catttcttaa aatttgctga840
atggaaagccagaaagtagagtgaagcaagaaatgtgtgt gtgagtagtc attggatata900
cacataatagtaagcaagtttatcagctcctgcatggcag tgttctgatt atcttttgct960
gcataagaactacaccccaaattagtggcttaaagtaaaa gcttcctatt gtatatgatg1020
attctgttggtccaggatttggaaagggcatggcaggagg tctcatctct gcttcacaat1080
gcctatgatttagccgggaggacccaaaaggctggaaaag ctgatgggtg ctgattctct1140
ccagcttttcag 1152
<210>
66
<211>
135
<212>
DNA
<213>
Hylobates
sp.
<400>
66
ggtataaaggaatctgaacgcgactgatattttctttaat ttttagatcc agatatatat60
cgggtaaaatctacttcataggttttcaaaggaacattct tctgagcaaa tctgaaaact120
ctctaaactccattg 135
<210>
67
<211>
89
<212>
DNA
<213>
Hylobates
sp.
<400>
67
atccagatatatatcgggtaaaatctacttcataggtttt caaaggaaca ttcttctgag60
caaatctgaaaactctctaaactccattg 89
<210>
68
<211>
148
<212>
DNA
<213>
Hylobates
sp.
<400>
68
caaaggagacagaagaaggaagagagaaggtaacaaggaa agaaggatgg aagagaaggc60
atgaggacagctatttggaaatggcacagaggcatttaca gagatcatta tgtccttgcg120
tctcttaccttcctcagccctacacaga 148
<210>
69
<211>
99
<212>
DNA
<213>
Hylobates
sp.
<220>
<221> _feature
misc
<222>
54
<223> g, c or
n=a, t
<400>
69
acattccaaggtgattctaaatggcaatttgcactgtcat tttaaaagaa tttntcagat60
atttgcggggcactttatggaaggagacactgag 94
<210>
70
<211>
57
<212>
DNA
<213>
Hylobates
sp.
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
265
<400>
70
gaacacagaagcttttgtagtgttggtgctaaaatggttcccttgtcagaggagtta 57
<210>
71
<211>
313
<212>
DNA
<213>
Hylobates
sp.
<220>
<221> _feature
misc
<222>
21
<223> g, c or
n=a, t
<400>
71
actctttcagggacatttttnactcacgatttgggaaaaccaacgagagaaagaaaaaga60
aattcttatctgaaacttcaacttatcaaaactcacttgtctggaaattagcctgggaat120
atccaggcactggaatttctcactttttttccttctctctcaacttcagtactgaaagga180
gaaagtcatttccaaatgtccatgttttgactttttaaatagaccaaatttagagtcatg240
taaagatacaataattagccttcttaacaattttcactcagaggtatttttatagagaat300
aaaaacaacaaca 313
<210>
72
<211>
389
<212>
DNA
<213>
Hylobates
sp.
<220>
<221> feature
misc_
<222> 381
365,369,372,376,
<223> g, c or
n=a, t
<400>
72
gagctgggacttctaaccaatggaacttgggaaaggtgat gagacgtgac tccggtgatg60
aggttaccttacacaagacttggccaactgagaccagatc tccttacagg cttgaagaag120
taagcagccatgttggaaaagtcctcatggcaaggaagta tcagtggcct ctaaggactg180
caggcagcctctagaacgaatgtggacctgcaactacaac cagcaaaaag accagtcatg240
caaccacaaggaaataacttctaccaaagctgaatgagtt tggaagcaga ttcttcccag300
ccaatccttctgacgacaatgtagtctggccaacatcttc actggactct gacggactct360
gtgcngggnganccanctganaacacatg 389
<210>
73
<211>
35
<212>
DNA
<213>
Hylobates
sp.
<400>
73
gagctgggacttctaaccaatggaacttgggaaag 35
<210>
74
<211>
280
<212>
DNA
<213>
Hylobates
sp.
<220>
<221> feature
misc
_
<222>
256,260,263,267,272
<223> g, c or
n=a, t
<400>
74
gcttgaagaagtaagcagccatgttggaaaagtcctcatg gcaaggaagt atcagtggcc60
tctaaggactgcaggcagcctctagaacgaatgtggacct gcaactacaa ccagcaaaaa120
gaccagtcatgcaaccacaaggaaataacttctaccaaag ctgaatgagt ttggaagcag180
attcttcccagccaatccttctgacgacaatgtagtctgg ccaacatctt cactggactc240
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
266
tgacggactc tgtgcngggn ganccanctg anaacacatg 280
<210>
75
<211>
333
<212>
DNA
<213> la gorilla
Goril
<220>
<221> feature
misc_
<222>
58,95,165
<223> g, c or
n=a, t
<400>
75
gagggtttggaattttcttcaagatgcacatttttctttctttaacctttaaggaaancg60
agttgaagcgcgtcatggtatgtatttctacagcnaaccactttgcttctgcaatttcag120
acactttacactgtctttcaggaataaataccatttgagaaagantggcgggggtagcac180
atctctccagcctcaaactattccttcctcagggcagaatttccccgtgatgctctcttg240
tcatcatcaccttcttcttgtctgaactcatcaacatttcagccaaattactgtgctgct300
aagtcactgggaagatcaggaccccacaccaag 333
<210>
76
<211>
1158
<212>
DNA
<213>
Gorilla
gorilla
<220>
<221> feature
misc_
<222>
493,1055
<223> g, c or
n=a, t
<400>
76
gtccacctgctgatagtgcgctccttaggtgcctgtctctggctgtcctgtgccacctgc60
acagagttatgcatgagctccactgttggaagtctctagagatgagctgagcttacccta120
caccaactgaaagagtctatcttagtcctgaagatctcaagtcatcctcatattcccatg180
aatgtgaatggaagttgaacctgctcagagaatcagcagggctctttattgtggcctgga240
gccaactgccaaggaatgcctaggaacacactcagtaagagtgttgccctcaggccagat300
cagacttgaacctgcagagaaatcccctaggtatgtcatcaattgctcatttggatgcta360'
taaacttgaagttgtgaaaaatttaaagacttacattatccggtctctcctggcaaaata420
tgtaggtttaatcattcctgaattttccttagttcacatagatatacagatatataccct480
aaaaattggcatnggtaggtgtgtcaagttatcattttaaaaacatagaaacctgaacaa540
gatgtatcactccagtctagaatgtctatatgcagagtatccacaaaaaaacaaacttca600
acattctttcatgtctatattccttcaacattctttgtcttcaacattctttcatgtcta660
gaatgtctatatgcaacgtatccacaaaagacccaaacttctttcatttaaagaaccaaa720
cttctttaaataaaaactactcacaataatttaatattttaccatttacaaagagattaa780
ctacaacaatattcatcttgagttaatttcccatgaataactttttcatttcttcaaatt840
tgctgaatggaaagccagaaagcagagtgaagcaagtaatgtgtgtgtgagtagtcattg900
gacacatacataacagtgagcaagtttatcagctcctgcatggcagtgttctgattatct960
tttgctgcaaaagagctacaccccaaattagtggcttaaagtaaaagcttactattgtat1020
atgatgattctgttggtccaggatttggaaagggnatggcaggaggtctcatctctgctt1080
cacaatgccaatgatttagctgggagaacccaaaatgctggaaaagctgatgggtgctga1140
ttctctccagcttttcag 1158
<210>
77
<211>
135
<212>
DNA
<213>
Gorilla
gorilla
<400>
77
ggtataaaggaatctgaacacgactgatattttctttaatttttagatccagatatacat60
tgggtaaaatctacttcataggttttcaaaggagcattcttctgagcaaatctgaaaact120
ctctaaactccattg 135
<210> 78
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
267
<211>
89
<212>
DNA
<213>
Gorilla
gorilla
<400>
78
atccagatatacattgggtaaaatctacttcataggttttcaaaggagca ttcttctgag60
caaatctgaaaactctctaaactccattg 89
<210>
79
<211>
152
<212>
DNA
<213>
Gorilla
gorilla
<400>
79
caaaggagacagagagaagaaggaagagagacggtaacaaggaaagaagg atggaagaga60
aggcatgaggacggctatttggaaatggcacagaggcatttacagagatc attatgtcct120
tgggtctcttaccttcctcagccctacgcaga 152
<210>
80
<211>
94
<212>
DNA
<213>
Gorilla
gorilla
<400>
80
acattccaaggtgattctaaatggcaatttgcactgtcattttaaaagaa tttctcagat60
atttgctgggcactttatggaaggagacactgag 94
<210>
81
<211>
139
<212>
DNA
<213>
Gorilla
gorilla
<220>
<221> feature
misc_
<222>
83
<223> g, c or
n=a, t
<400>
81
gaacacagaagcttttgtagtgttggtgctaaaatggttcccttgtcaga ggagttacgt60
tttgagatcctctaagcaaattnagaaaaggagaggaacttgaccacaga aactgtgttt120
gatacatttgagcagcaaa 139
<210>
82
<211>
315
<212>
DNA
<213>
Gorilla
gorilla
<220>
<221> feature
misc_
<222>
16
<223> g, c or
n=a, t
<400>
82
actctttcagagacanttttaactcacaatttgggaaaaccaatgagaga agaaaaaaga60
aattcttatctgaaacttgaacttatcaaaactcacttgtctagaaatta gcctgggaac120
atccaggcactggaatttctcactttttttccttctccctctcaacttcg gtactgaaag180
gagaaagtcatttccaaatgtctgtgttttgactttttaaatagaccaaa tttagagtca240
tgtaaagatacaataattagctttcttaataattttcacccagaggtatt tttatagaga300
ataaaaacaacaaca 315
<210> 83
<211> 388
<212> DNA
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<213> Gorilla gorilla
268
<400>
83
gagctgggacttctaaccaatggaacatgggaaaggtgatgagacgtgac tccggtgatg60
aggttaccttttacaagacttggccgactgagactggatctccttacagg cttgaagaag120
taagcagtcatgttggaaaagtcttcatggcaaggaactatgagtggcct ctaaggaccg180
caggcagcctctagaacgaatgtggacctgcaactacaaccagcaaaaag accagtcatg240
caaccacaaggaaataacttctaccaaagccgaatgggtttggaagcaga ttcttcccag300
ccaatccttctgatgacaatgtagtctggccaacatcttcactggactct gacagactct360
atgtctgggatccagctgataacacgtg 388
<210>
84
<211>
35
<212>
DNA
<213>
Gorilla
gorilla
<400>
84
gagctgggacttctaaccaatggaacatgggaaag 35
<210>
85
<211>
279
<212>
DNA
<213>
Gorilla
gorilla
<400>
85
gcttgaagaagtaagcagtcatgttggaaaagtcttcatggcaaggaact atgagtggcc60
tctaaggaccgcaggcagcctctagaacgaatgtggacctgcaactacaa ccagcaaaaa120
gaccagtcatgcaaccacaaggaaataacttctaccaaagccgaatgggt ttggaagcag180
attcttcccagccaatccttctgatgacaatgtagtctggccaacatctt cactggactc240
tgacagactctatgtctgggatccagctgataacacgtg 279
<210>
86
<211>
104
<212>
DNA
<213>
Gorilla
gorilla
<400>
86
gtgatgggattgtatttgcaactctctggtcagtaagtgataaaatgcca tttctatgca60
cccacctggcctgtgtgactgggagaatctctggatcccgcata 104
<210>
87
<211>
126
<212>
DNA
<213>
Gorilla
gorilla
<400>
87
ttttcttattattgttttgtttccttgtttttaggtgatgggattgtatt tgcaactctc60
tggtcagtaagtgataaaatgccatttctatgcacccacctggcctgtgt gactgggaga120
atctct 126
<210> 88
<211> 1055
<212> DNA
<213> Pongo pygmaeus
<220>
<221> misc_feature
<222> 297,306,844,854,1021,1037
<223> n=a, g, c or t
<400> 88
gtccacctgc tgacagtgcg ctccttaggt gtctgtctct ggctgtcctg tgccacctgc 60
ccagagtcgt gcatgagctc cactgtggga agtctctaga catgagctga gcttacccta 120
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
269
caccaactgaaagaatctgtcttagtcctgaagatctcaagtcatcctca tattcccatg180
aatgtgaatggaagctgggcctgttcagagaatcatcagtgctctttatt gtggcctgga240
gccaactgccaaggaatgcctaggaacatactcagtaagagtgttgccct caggccnaga300
tcagancttgaacctgcagagaaataccctaggtatgtcagcaattgctc atttggatga360
tataaacttgaagttgtgaaaaatataaagacttacattatccagtctct cctggcaaaa420
tatgtaggtttaatcattcctgaactttccttagttcacacagatatata tcctaaaaat480
tggcaatggtaggtgtgtcaggttatcattttaaaaacatagaaacctga acaagatata540
tcactccagtctagaaggtctatatgcagagtatccacaaaagacccaaa cttctttcat600
ttaaagaaccaaacttctttaaataaaagtgactcacaataatttaatat tttaccattg660
acaaagagattaactacaacaatattcatcttgagttaatttcccatgaa taacattttc720
atttcttaaaatttgctgaatggaaagccagaaagtagagtgaagcaagt aatgtgtgtg780
tgagtagtcattggatacatacataacagtgaacaagtttatcagctcct gcatggcagt840
gttnctgattatcnttttgctgcaaaagaactacaccccaaattagtggc ttaaagtaaa900
agcttactattgtatatgatgattctgttggtccaggatttggaaagggc atggcaggag960
gtctcatctctgcttcacaatacctatgatttagctgggaggacccaaag ggctggaaaa1020
ngctgatgggtgctganttctctccagcttttcag 1055
<210>
89
<211>
135
<212>
DNA
<213> pygmaeus
Pongo
<220>
<221> feature
misc_
<222>
102
<223> g, c or
n=a, t
<400>
89
ggtataaaggaatctgaacatgactgatattttctttaatttttagatcc agatatatat60
tgggtaaaatctacttcataggttttcaaaggaacattcttntgggaaaa tctgaaaact120
ctctaaactccattg 135
<210>
90
<211>
89
<212>
DNA
<213> pygmaeus
Pongo
<220>
<221> feature
misc_
<222>
56
<223> g, c or
n=a, t
<400>
90
atccagatatatattgggtaaaatctacttcataggttttcaaaggaaca ttcttntggg60
aaaatctgaaaactctctaaactccattg 89
<210>
91
<211>
152
<212>
DNA
<213>
Pongo
pygmaeus
<400>
91
caaaggagacagagagaagaaggaagagagaaggtaacaaggaaagaagg atggaagaga60
aggcatgaggacggctatttggaaatggcacagaggcaattacagagatt attatgtcct120
tgggtctcttaccttcctcagccctatgcaga 152
<210>
92
<211>
94
<212>
DNA
<213>
Pongo
pygmaeus
<400>
92
acattccaaggtgatactaaatggcaatttgcactgtcattttaaaagaa tttctcagat60
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
270
atttactggg cactttatgg aaagagacac taag 94
<210>
93
<211>
141
<212>
DNA
<213> pygmaeus
Pongo
<220>
<221> feature
misc_
<222> 2
97,12
<223> g, c or
n=a, t
<400>
93
gaacacagaagcttttgtagtgttggtgctaaaatggttcccttgtcagaggagttacgt60
cttatgagatcctctaagcaaatttagaaaaggagangaacttgaccacagaaactgtgt120
tngatacatttgagcagcaaa 141
<210>
94
<211>
313
<212>
DNA
<213> pygmaeus
Pongo
<400>
94
actctttcagagacatttttactcacgatttgggaaaaccaatgagagaagaaaaaagaa60
attcttatctgaaacttcaacttatcaaaactcacttgtctagaaattagcctgggaata120
tccaggcactggaatttctcactttttttccttctccctctcaacttcagtactgaaagg180
agaaagtcatttccaaatgtctatgttttgacttttaaatagaccaaatttagagtcatg240
taaagatacaataattagctttcttaacaactttcacccagaggtatttttatagagaat300
aaaaacaacaaca 313
<210>
95
<211>
389
<212>
DNA
<213> pygmaeus
Pongo
<220>
<221> feature
misc_
<222>
376
<223> g, c or
n=a, t
<400>
95
gagctgggacttctaaccaatggaacacgggaaaggtgat gagacatgac tccggtgatg60
aggttaccttatacaagatttggccaactgagaccagatc tccttacagg cttgaagaag120
taagcagccatgttggaaaagtcctcatggcaatgaacta tgagtgacct ctaaggactg180
caggcagcctctagaacgaatgtggacctgcaactacaac cagcaaaaag accaatcatg240
caaccacaaggaaataacttctaccaaagctgaatgagtt tggaagcaga ttcttcccag300
ccaatccttctgatgacaatgtagtctggccaacatcttc actggactct gacggactct360
gtgtctgggacccagnctgatagcacatg 389
<210>
96
<211>
35
<212>
DNA
<213> pygmaeus
Pongo
<400>
96
gagctgggacttctaaccaatggaacacgggaaag 35
<210>
97
<211>
280
<212>
DNA
<213> pygmaeus
Pongo
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
271
<221> feature
misc_
<222>
267
<223> g, c or
n=a, t
<400>
97
gcttgaagaagtaagcagccatgttggaaaagtcctcatggcaatgaact atgagtgacc60
tctaaggactgcaggcagcctctagaacgaatgtggacctgcaactacaa ccagcaaaaa120
gaccaatcatgcaaccacaaggaaataacttctaccaaagctgaatgagt ttggaagcag180
attcttcccagccaatccttctgatgacaatgtagtctggccaacatctt cactggactc240
tgacggactctgtgtctgggacccagnctgatagcacatg 280
<210>
98
<211>
58
<212>
DNA
<213> pygmaeus
Pongo
<400>
98
gtgataggattgtatttgcaactatctggtcagtaagtgataaaatgcca gtctatgc 58
<210>
99
<211>
92
<212>
DNA
<213> pygmaeus
Pongo
<220>
<221> feature
misc_
<222>
18
<223> g, c or
n=a, t
<400>
99
ttttcttattattgttangtttccttgtttttaggtgataggattgtatt tgcaactatc60
tggtcagtaagtgataaaatgccagtctatgc 92
<210>
100
<211>
854
<212>
DNA
<213>
Macaca
mulatta
<220>
<221> misc_feature
<222> 248,250,257..258,260,263..266,268..271,276,278..279,283,285..286
289,292,294..295,297,299,301..303,307..309,312..313,316,318,321
323,350,358,365,368,372..373,375..377
<223> n=a, g, c or t
<400>
100
tgctcatttggatgctgtaaacttaacgttgtgaaaaatataaagacttatgttatccag60
tctctcttgggaaaatatgtaggtttaatcattcctgaattttccttagttcacacagat120
ttatgtcctaaaaattggcattgggtaggtgtgtcaagttatcattttaaaaacatagaa180
gcttgaacaagacatatcactccagtctagaatgtctatatgcagagtatccacaaaaga240
acccaacntnaaaattnncnttnnnnannnntgtcnanntatncnnttnaananncntng300
nnncttnnncannacntntcntnttcatgtctagaatatctatatgcagnagtatccnac360
aaaangancccnncnnnaaacttctttcatttaaagaaccaaacttctttaaataaaaat420
gactagcaataatgtagtattttaccatttacgaagagtttaacgataacaatattcatc480
ttgagttaatttctcatgaataacattctcatttcttaaaatttgctgagtggaaagcca540
gaaagtagagtgaagcaagtcatgtgtgtgtgagtagtcattggatacacgcgtaacagt600
gagcaggtttatcagctcctgccatggcgcagtgttctgattatcttttgctgcataaga660
actactccccaaattagtggcttcaagtaaaaacttactattgtgtaggatgattctgct720
gagccgggatttggaaagggcacgcaggaggtctcatctcttctcatctctgcttcacaa780
tgcctgtaatttagctgggaggacccaaaaggctggaaaagctgatgggtgctgtgtctc840
tccagtcttttcag 854
<210> 101
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<211> 126
<212> DNA
<213> Macaca mulatta
272
<400> 101
ataaaggaat ctgaacacga ctgatatttt ctttaatttt tagatccaga tatacattgg 60
gtaaaacttc ataggttttc aaaggaacag tcttctgagc aaatctgaaa actctcaact 120
ccattg 126
<210> 102
<211> 83
<212> DNA
<213> Macaca mulatta
<400> 102
atccagatat acattgggta aaacttcata ggttttcaaa ggaacagtct tctgagcaaa 60
tctgaaaact ctcaactcca ttg 83
<210> 103
<211> 143
<212> DNA
<213> Macaca mulatta
<220>
<221> misc_feature
<222> 6,8,12..14
<223> n=a, g, c or t
<400> 103
caaagnanac annnagaaga agagagaagg taacaaggaa agaaggatgg aagagagggc 60
atgaggacag ttatttggaa atggcacaga ggcatttaca gagatcatta tatccttgag 120
tcctttacct tcctcagccc tat 143
<210> 104
<211> 94
<212> DNA
<213> Macaca mulatta
<400> 104
acattccaag gtgattctaa atggcacttt gcactgtcat tttaaaagaa tttctcagat 60
atttgctggg cactttatgg aaggagacac tgag 94
<210> 105
<211> 137
<212> DNA
<213> Macaca mulatta
<220>
<221> misc_feature
<222> 25,31..32,111,114
<223> n=a, g, c or t
<400> 105
accacagaag cttttgcagt gttgngtgcc nnaatggttc tcttgtcaga ggagttacgt 60
cttacgagat cctctaagca catttacgaa aggagaggaa cttgaccaca naanactgtg 120
tttgatacat ttgagca 137
<210> 106
<211> 277
<212> DNA
<213> Macaca mulatta
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
273
<221> misc_feature
<222> 177,179,241
<223> n=a, g, c or t
<400> 106
gctctttcagagacatttttactcatgatttggaaaaaccaacaagagaagaaaaaagaa60
attcttatctgaaacttgaacttatcaaaactcacttgtctagaaattagcctgggaata120
tccaggcactggaatttctcactttttttccttctccctctcaacttcagtactganang180
agaaagtcatttccaaatgtctatgttttgaatttttaaatagaccaaatttagagtcat240
ntaaagatataataattagctttcttaacaattttca 277
<210> 107
<211> 389
<212> DNA
<213> Macaca mulatta
<220>
<221> misc_feature
<222> 377
<223> n=a, g, c or t
<400>
107
aagctgggacttctaaccaatggaacatgggaaaggtgatgagacgtgactccggtgatg60
aggttacattatccaagacttggccaactgagaccagatctccttacaggcttgaagcag120
tcatcagccatgttggaaaagtgctcatggcaaggaactatgagaggcatctaaggactt180
caggcagcatctagaatgaatgtggacgtactactacaaccagcaaaaagaccagtcatg240
caaccacaaggaatgaacttctaccaaagctgaatgggtttggaagcagactcttcccag300
ccaatccttctgatgaaaatatagtctggccaacatcttcactggactctgatggactct360
atgcctggaacccagcntgataagacatg 389
<210> 108
<211> 35
<212> DNA
<213> Macaca mulatta
<400> 108
aagctgggac ttctaaccaa tggaacatgg gaaag 35
<210> 109
<211> 280
<212> DNA
<213> Macaca mulatta
<220>
<221> misc_feature
<222> 268
<223> n=a, g, c or t
<400>
109
gcttgaagcagtcatcagccatgttggaaaagtgctcatggcaaggaact atgagaggca60
tctaaggacttcaggcagcatctagaatgaatgtggacgtactactacaa ccagcaaaaa120
gaccagtcatgcaaccacaaggaatgaacttctaccaaagctgaatgggt ttggaagcag180
actcttcccagccaatccttctgatgaaaatatagtctggccaacatctt cactggactc240
tgatggactctatgcctggaacccagcntgataagacatg 280
<210> 110
<211> 74
<212> DNA
<213> Macaca mulatta
<220>
<221> misc_feature
<222> 6
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
274
<223> n=a, g, c or t
<400> 110
gtgatnggat tgtatttgca actatctggt ccataagtga taaaatgcca tttccatgca 60
cccaccggcc tgtg 74
<210> 111
<211> 108
<212> DNA
<213> Macaca mulatta
<220>
<221> misc_feature
<222> 32,40
<223> n=a, g, c or t
<400> 111
ttttcttatt attgttttgt ttccttgttt tnaggtgatn ggattgtatt tgcaactatc 60
tggtccataa gtgataaaat gccatttcca tgcacccacc ggcctgtg 108
<210> 112
<211> 514
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 380
<223> 99-30329-380 : polymorphic base C or T
<220> '
<221> misc_binding
<222> 368. 392
<223> 99-30329-380. probe
<220>
<221> primer bind
<222> 361..379
<223> 99-30329-380.mis
<220>
<221> primer bind
<222> 381..399
<223> 99-30329-380.miscomplement
<220>
<221> primer bind
<222> 1..18
<223> 99-30329.pu
<220>
<221> primer bind
<222> 496..514
<223> 99-30329.rp
complement
<400> 112
gacatacccc aaacacagcagcacaaagcaactgcctgtg attgtcaatt atctgcacta60
actttgaata gacaactgagagtaaaattgaccattagct gttattaatc ttttaaatag120
cttatttatc aggacaatattttctttgaggaatggtttc acatcgttga taaacagttt180
cctattacta acattaaactaaataatatatgtcatattt cttttttacc cttagaaagt240
taatctaata atattattctgattagtggtacttttttta atttttgtaa tgttgtttat300
ggtgtttgat ttgtacttttttgtctttttcatacctttt aataacatcc gatttactac360
tggagcattt tattttcatygtctcttaaaatacttaata acttttagat ttgttgttca420
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
275
caaaactaaa taattgcttg atgtttcatt ttatccttct tattaaatag gcagctcgtg 480
tacatatgaa agtgtctttt tatacaccga aacc 514
<210> 113
<211> 617
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 330
<223> 99-16081-217 : polymorphic base C or T
<220>
<221> misc_binding
<222> 310. 329
<223> 99-16081-217.misl,
<220>
<221> misc_binding
<222> 331. 349
<223> 99-16081-217.mis2, complement
<220>
<221> primer bind
<222> 114..131
<223> upstream amplification primer
<220>
<221> primer bind
<222> 556..575
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 318..342
<223> 99-16081-217 probe
<220>
<221> misc_feature
<222> 4,607
<223> n=a, g, c or t
<400> 113
ctcngggagg ccaaaggggt cgcccctggg gcagatgtct atgggagaag cccaagggac 60
gcagaggcca ggggaggagc acacaccaca ggcagatgtg tgggggagga gcccaaagga 120
cagagaacca gcaggcaggc cctgggtcaa gccccgtgat gtcccaggag gaggggagga 180
gggcggagtc ggaagggagc gagggagcca gggaggcagg gccctctgag ggcagggagt 240
tctccatgaa gttccagaag ccaatgacca gatcggcgca tgcaaacagc ttaaaagaaa 300
acattaggca ctggtggctt cgctctaaay gaacagttct taaaactgct ttcagttcta 360
gccataataa aggcatttga attatgttgc ttttgatgaa actataaaga tattggcttt 420
tatacagtat catgccagaa acaaatttat aacattgtta tggtataaca gcaggaatac 480
ttggaataca catttttcag ctgagctcta agaattactt ttcccttgcc ccaggttggc 540
aattaagaac tataacttac ttccacccca ctccacctca ccctacccca gaaacaaaga 600
aaaacanaca cgcaaac 617
<210> 114
<211> 642
<212> DNA
<213> Homo Sapiens
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
276
<221> allele
<222> 233
<223> 99-16082-218 . polymorphic base A or G
<220>
<221> misc_binding
<222> 214. 232
<223> 99-16082-218.mis1
<220>
<221> misc_binding
<222> 234. 253
<223> 99-16082-218.mis2, complement
<220>
<221> primer bind
<222> 16..33
<223> upstream amplification primer
<220>
<221> primer bind
<222> 527..547
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 221. 245
<223> 99-16082-218 probe
<220>
<221> misc_feature
<222> 486,611,613
<223> n=a, g, c or t
<400> 114
gaagcgggaa ctgtgcaatt cagcaagagc cactttggtt aacaaacctt ctgggaatga 60
aggtgcttta caaagaagca ggctgtgata aaaacaaaca agacaacatt cataaactgt 120
gggaagcatt gttgtcattg ggtcacacct cctgcaccag gcaggtggtt gtctgctgcg 180
ttcctttaca gaacagatgc tgagcctgcc tggaggtggc aatttaccaa tcratggtct 240
taagcaattc caaaggctgg ggtaaggggt agaaaagaga agctcaaaaa tgttagggat 300
ggagaagggg ggagtgattc aggaagagga gaaacctgtt catttcctcc caaattacaa 360
ccactgtcac atccatggct agtcctgtgc aaacttccag tccccagctg atatccctgc 420
agacaagtag agagaggcta gaacaaaagc taaagtgtag atgtcccata cactaatcag 480
tgttgntttt taatcagagg ttgaaattca tactctgatg caaactgtat tagtcagttg 540
ttgctgctat gataacactg cataacaaac aaccccccaa atctcagtgg attacaagga 600
caaacatttg ngnttctctt tcatgggcct atgtgttggc tg 642
<210> 115
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-15056-99 : polymorphic base G or A
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-15056-99.misl, complement
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<221> misc_binding
<222> 1482 .1500
<223> 99-15056-99.mis2
277
<220>
<221> primer bind
<222> 1582..1599
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1098..1118
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-15056-99 probe
<400> 115
cacaccaacatggcacatgtatacatatgtaacaaacctgcacgtcgtgcacatgtaccc60
taaaacttaaagtataataataataataatagtaaagactttaataatcccaaagccaag120
tttccactctaagtggtgtaagagtttgtgctcagtagagtcatagcttttatatagttg180
atgaaagatttgggttccctaaaagatatttctagtcaacccatgtatcttaaacaccat240
gattcattttaaaatccattttactaactgtcaagccgtctcatattgatcaaaataaag300
atagtcgaagcacacacaataacaaatttctgggatataaccttccaactgtagtattcc360
aatgaggccactttaaatactaacatacatacttaaggtatagactaccgtgatttactg420
catataaatgtatagaactgaacatactggactatttaaaactgaattatatataatata480
gcagacagacaatatatattattactgtgataactattatgaccaattagtactaaggca540
aactagaagaaatttgaaaaacaaatttcacaatcaaaatgccatccaggtttcccttac600
atctctgtcctatttttacacatcgtttaatgtcacacacacacacacacacacacaccc660
ccatcattattaagagagatatatatcagaataggtatgtaatccaggtttatttacatt720
taattatctgtaaccaaaagtaatttttcagaaaaatacacattatttaaaatactgaca780
tgaaaattagcatgtttatttcatgctaacaataaaattatttttaatcacaagttttta840
tttctaagatgtttcatagaaatacttgaagaatataagcaacagtaaattatgtgctgg900
ttctataatagacaataaaaggctgatttcctaaaatatttatttataatctgaataaat960
tattaaatttatttagttgaaagtaatccagcattttaagtaaaatatccattttcagat1020
aaaataggtatttagcaataataactttaggatgtctaggcagtttataaacacatggaa1080
tgatagttatattacataaaagggagacgtattttggggaacaccaaacatatttataga1140
accaaaggtcaattatgcctatgtttacaataacttgagacattggtgtttttctattaa1200
caatcatagatcaactgttgctcactgtttcatcgaaacaaatattgtgaggagcacaaa1260
ggggttcaaaagaaggctagatcacaagcttattcctaaatgaatttatgatcatctagt1320
tttagaattaagatccaaaaataagaggcaaagaaaattaaagttacatagtgagcaatg1380
caaatcggcatttgattaagtggtaacttgtttgatataaacataagcacagagaatata1440
aaacaggagaaattattatttaggaagtctacgtggagaaattattatgggaactataaa1500
rgcactcatagccacttgtaaattgtaagagttaagaaggcctttgcctctttattcagg1560
aggtgctcgaaggaaatctggcttcttgtgagtttcctggaagttaggctttgactgtac1620
aatgggaggaagggagtacatttatcttaatttttatttatttctccttaatgcctttta1680
aatgatgttttaaaacaaaacgtacttatatttccattatacaaataaagaaaggcacat1740
tcttgtctcatgctttatagggcggcttcagagctgcagttttcagactagttgatcttt1800
atgttctaaaaaaattattgggtattccaaagaccttttgattttgtagttatattgatc1860
aatatttaccatattagaaattaaatcatccaaaaaattttaagttgtttgtttattaaa1920
atgacaacacaatgtgcattacgtgataacatattagtttcattaaaataactatatttt1980
ccacaacctaaaagcaggtgagaagaaatggcgttgcttaatatttttgcctatctcttt2040
aatgactcacctaataaaataaagctttattttcatgtcagctttttcattcaatatatc2100
acaattcattgttttgtttaaggtatatgaaaaaaatggcaagcctcacagagatatgga2160
taatggttgaaaaagcctttgcagataactatggatatcctttgttcttcatacgacccg2220
aaagctttacaaatggatttttaaagtttcttgtgatgtgtaatctgaaacgatatgaat2280
acacttttgtactcttttttaatgaaaaggcactaatctatcttgcacttcgaataaata2340
ttttactcaccaatgattttatagcatcatgcattggtcatttggagaatattgattttc2400
tgacatataaatcttccaaacattggcataatttattatctaatataagacatatcacat2460
tcaagtattcggaaactgtgaaactttgcttgatagataagttttccaaatttctactta2520
atccttgaaagcttgagtttgctactggcaatagctactgtccgttgttttcccgaagtg2580
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
278
actggctcacttcattcatttttgaggaagtctgccaaatgcccaaatgtggtgaaactt2640
catttctgtcagttgttctttcaagtagaagtggtgttccctaaaaaggaagaagctagt2700
tcagctcacagctccaacaatgcatgggtgcttctcctcaagaaaaccatcacatgctgt2760
aggggctgacattctttcagaaaaggagacatgccaataaggctcaagatttaattacat2820
gactaagttgtgtgacttcctcaggacattcattctcatgggaatctgaagttttatttt2880
ttcccaggagtgtgaagtggtgaagacacgatagatgttagcacactcagagctatggcc2940
tcggcttctactgtggtaccatcccgtaaatatccacagtgaaaaaggatgacgacgtcc3000
t 3001
<210> 116
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-15063-155 : polymorphic base A or C
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-15063-155.mis1
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-15063-155.mis2, complement
<220>
<221> primer bind
<222> 1347..1364
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1784..1804
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-15063-155 probe
<400> 116
aaaacctact gaaataaaat aataaataaa taaataaata aaaataaaag tgtgaactac 60
agactcagta tcttaatata ttgataaagc acaatgaaga attaaaggaa gattgtgcac 120
aaataaattg tgcaatcaag tcaccatcca gtagccctgt gaaggaaaca gggagacttg 180
gatcactaga ggcataggaa tgtcactcta ggatgtgaac tctgaactga aatacttaaa 240
agacgtagag ctggacaagt cagagatagt ggcatcccat ggctactgat tgaaacaaat 300
cttttctgta acagagtgtc acaacttagc atcacacaac tcctatttaa gagcaaacaa 360
tgagttttca atcaataaac acaaatatat gagagtttgg accactgaga ttgaaaatca 420
gcaatgacaa ataagtgaat atgcatacat acaagtttta atgtgcccaa agacaaaaaa 980
tattagaatt tttcaataca aagtatggaa taattatata taaatatttt atttaaaaaa 540
gacacaattt caaagactga tcagcagtaa cacattatca gggataaatg cagaaatttg 600
aaaacaaaac ttctaggctg tatgtctaaa tatatatcat ataacattaa ttatataggt 660
atatttaatt atttaaattt gaaagtcgac ataaagttta ccaatatatt aaacggagtt 720
gaaaagaaac agagaaatgg aaaatacaat ctagtaaata atataagata aagtgaaata 780
ttaagaggta cgacaaaaat atgaaataat cataaaaatg tattaaagat agaatgagaa 840
gatcacatac acaacaatta gagacagtag agaaaataag tgagagataa tatttgaaga 900
tatgatggct gaaaatattc caaatctcat taaaacataa atctatagat ataaatggta 960
ctatgtactt gggacaaata aaaataaaca tacatatctt gtaataagga ttaattggaa 1020
gctattatct ttaaaatcag gagcaacaca aagatgcttg ctttcttaga ttctcttcaa 1080
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
279
ctatgtactagatcatggaaacaatgcagggaaagaaaaaaaggaataaaaacataagaa1140
ttcggaagaagtaactataattatattatctaccttgaaattaaaaagaaatattacagg1200
cagactactcacaataatatgagagtagcatgttatacaggtataagctcactggaaaaa1260
aattggcatatttttagtatgtataccaaagccaaaattttaaaattgcgtttaaaaaca1320
catttcatcaatcacatctcaataaagcagtcagaaacaaacagcaaaaacctattatgt1380
acactatcaatataaacaacaaaccaactaaaaatacatcttacaaaatgcgtacaaaac1440
atacgtggaaaaaatgctgaaactctacattaaaaagaccgtaaacatacagagtaaata1500
mcatgctcttggttggaaagaaatagcgttccaaagatgtcaattctcccaaagttgaga1560
tatattctatgaaagtccaaataccaacagtttttttttcatggatctggtcaagctaaa1620
tctcaaatgtatataaaagaaagaccagccaagaaactaaagaagtggaggcttagatat1680
aatccataaataatcaaaatttaaaataaaacaatgaaaattaagggagaggatagaagc1740
ctcagaacatacttatggagtttcaatatatgacaaagcaggcctggtgggacctgttta1800
ataaactattaatatatttttttgatgcataaacaaaatgtttttgatgcataatatata1860
tattttgatgcataaacaaatatatatttttgatgcataaacaaacaaaaacataatata1920
tatttttgatgcataaaacctgatatcagacttctgcttcacaacacacagacacacaca1980
cacctcttttagaaaataaaacaatatttttctgaccttttaataggaaagtattttctt2040
aacagacccaatgtgctaattaaaataacagattgaaacactcaactacctttaaattta2100
gaagttctgttcaataaaggagagtttaaaaagtgaagatgaatcaaaatctagaagata2160
ttcacaacatacacaacagacaagtactgaaacacaaaatataaattatcaagtcagaga2220
cacttattcaaaagaaattttgaatagtaacttcacagaagaggacacatgtatgttcaa2280
cgtcaacaaattccaaaaacggaggttacaaccacaatgagaaatcattttacacttgtg2340
aaataagggaataaaagagcataacaatatgaactattggataagatatggatcaacagg2400
aactcgtatacatttctgcgggaagataatggtagaaccaacttggaaaacaatttggca2460
tttgtacagcatacaacccagaaattccatgcatagttatgaagtgaagaaacttgcagg2520
aaccagcagatggtaaccaaagcaatccctagcggccctcattgcttattagcataagac2580
actcccaccagcgtcatgacaatttacaagtgctatggcaatatctaggagtttgctgcc2640
cctctccatggcaaccagctggaaattgccgccctttccctacaaagttctaaataactt2700
gagcctcaatttgtattagcctgacccttaattttgcaggtaattgaaggagggtataag2760
tggaaataagtacagtggccaagagcccatcctttggggattctgggagcactgcctgtg2820
agttagacctgctccgaaaggagcatcacgactcagtgagagattgctgtctaacaacac2880
gcacttgaccttgaattctttcccaggtgaagccagga.acctccctgggcgaaaccccag2940
tttggaggctcggttgtcctgaatcagttataacttggagaaatgtctgcagatgtgctt3000
c 3001
<210> 117
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-15065-85 : polymorphic base C or G
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-15065-85.misl, complement
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-15065-85.mis2,
<220>
<221> primer bind
<222> 1568..1585
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1120..1140
<223> downstream amplification primer
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
280
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-15065-85 probe
<400> 117
ctcttcacctaaatttatcttttatttattctctcatcattatcaacaactactaggctt60
tgttgccttgactccagaggcaaaaatcttatctcccaacaatgtctcttaagttaagtg120
taattcattatttgatattcttgtttcaaaatgggtagaggaaaacttcctgcatatacc180
gtaaaataattttagggaaaatatactaatgtatgttccagagcactggaaggtccaaag240
ctacctatttgcattgtaccattactatttgatgtagccttttgctcattatgcaatgag300
ctgaaatacatttttcatcatgcctcctgagtctctaagtaagagtgattgactcattcc360
ttttctaccagtgagattgcaaagcaaaaagaaatatgtagtatttatttactcatggaa420
ttcattcttatgaaggtcagttgccaaatgatgccaaaaccttactttctagaatgctat480
tcaagttatcaggctttaacgttttcaagatgtttatgtttgacaaccatatataacata540
aaattatgtgaagtaaagtataacataactgtttcttttctatgaaacatgcctatttca600
agtacatagtacactgcactgcagataaccggctgataaccagctctcaacacatacaac660
ctaatgattgaattaaaccatagtgtatatttttctaaatgtattcttaattaatcacat720
tacaaccatcagtatttgggtgaacagcttcagcatccattagtttttgagcaaagaact780
agaattcggagcattcaaatgatactagagaaaagacatgaagactgtttatgagattgg840
tccatctctgagaaatgtcaagatttaagaagagccgcaatttcaaaaccagggctactt900
cattgtggacctgaatctatttacccagggtcaaatcaaggatttggaacagaccatggg960
aacacaccactttcaatttttgaaatatttgcaaatacatgatgagatatcttggggatg1020
gaacccaagtctaaacagaaaatcaatgtatgtttcgtatctaccttatagacatagtct1080
gaaggtaattttagataatatttttaatattttgtttgacaccaacattattcctgtctc1140
tgaatttatatgctacacataagcaatcattttattatacctattcacatgtaagtactt1200
aacagttaaaaattgacataccattcatgcaataaaaaataatatgctgaaggtaactaa1260
gcagtatagcagcagcatcacaataaacaagctgttacaaaatagcaataacaaacaaag1320
gaaggcttccagtctccacctacgagtctgtattttaatttaaaagttactgtacgctgt1380
attattattattttatttgagaagaaacatcagaagcagtcgagggattaggaagtgggt1490
cctctggggaagaggacatattcggctggatggcttctaaagtgtttcctccagtcatct1500
scctcattaacaatattttttcttacaagcctctctttgattttataaactgacatgatt1560
tcttgctctatgaatccatgctgctccagtccttcaataagctgattaaacattttcatt1620
atgtcttctgtaggcactttctctgcagggttaacaatgtcatcttcattgccactatta1680
tcatgatcaccttgattctgaaccattttggctatttctccatcagtcaatgagtgaaca1740
actgagccttaatatcaataacgtctataacattcttcaatgttcacttcatccagttta1800
ctgagggactctgaaggtatattttttgcatatgtaaagaggtcagacaacattttattc1860
tcacttgatacacagaatccctcaaagtcaccaccttattaatcctcatcactgagcata1920
gttgcagacccagagggtatgctagacatgcatagctatgtatttagttcctgtgttcca1980
agccttggcaaaagccaaaacagcatccttcatgctaagttcctttttagaaactttcat2040
atttataccactattcactgatgctagctagcatggtattcaagaaagtattttttatat2100
taattttcattgatctaaggatacctttgtcacacagctgaattaataaagtcacatttg2160
gggaaaacacatgaaataatcatgaatgtttaaagagaatttcagctgcaggatctgctg2220
aacagttgtcaaggaataacaaaatcttgcagtcctcatccagtccagcttccctgcagt2280
gaacatgagctgctggtacaaaatggtgatgaaaccagtcagaaaagctgcccctgatga2340
cctatcctttttcattagcatagtaacgacctagtaagaaatgtactcatggaaagcagt2400
gaggatgcaagctttgcctatcatggcgagtttacacttatgtacgcctgctgcattagc2460
acagtgcaggtgttctgttcttggcattcttaattcctgtatgagctgtctcattggctg2520
tagtcaattttggcagggaacaccaaaacagtgaagtttcattcgcattatagacttgtt2580
ttggcatcagattttcttcctttttttttttattatactttaagttttagggtatatgtg2640
cacaatgtgcaggtgagttacataggtatacatgtgccatgttggtgtgctgcacccatt2700
aactcgtcatttaacattaggtgtatctcctaatgctatccctccccctccccccagccc2760
acaacaggccctggtgtgtgatgttccccttcctgtgtccatgtgttctcattgttcaat2820
ttccacctatgagtgagaacatgcggtgtttggttttttgtccttgcgatagtttgctga2880
gaatgatggtttccagcttcatctgtgtccctacaaaggacaagaactcatcatgtttta2940
tggctgcatagtattccatggtgtatatgtgccacattttctcaatcctgtgtatcattg3000
t 3001
<210> 118
<211> 451
<212> DNA
<213> Homo Sapiens
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
281
<220>
<221> allele
<222> 404
<223> 99-15252-404 . polymorphic base C or T
<220>
<221> misc_binding
<222> 384. 403
<223> 99-15252-404.misl,
<220>
<221> misc_binding
<222> 405..423
<223> 99-15252-404.mis2, complement
<220>
<221> primer bind
<222> 1..18
<223> upstream amplification primer
<220>
<221> primer bind
<222> 434..451
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 392. 416
<223> 99-15252-404 probe
<400> 118
atgggggcat atagcaaccc tttagaaaca aaactacaaa aggtaagctt gtcttcttgc 60
atttcctttc tcttactaca tttaacatgg gaggttttct atgtctcaca ttcaaatatt 120
ctcactcggg ctgcctaatt tttccctgat tttccatcac tctttatgaa ggcttgctac 180
tttagaatac acattttctt aacagaagat aataatcaga agatgtctcc caaatataag 240
tccaaatctt tcctatcatg ctgtgttctt tggctctttt gactttattt gaagtcagcc 300
ttgaagggga tagagatagg ctgtatgaag tccacgctga gaagttttgc cctgccctac 360
ttgtcctgta atatttcatg gatagcccag tggtgattaa accygtgtgt acaggaataa 420
ccatgagaat ttgtaaaaat ataggctctg g 451
<210> 119
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-15253-382 : polymorphic base C or T
<220>
<221> misc_binding
<222> 1481..1500
<223> 99-15253-382.misl,
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-15253-382.mis2, complement
<220>
<221> primer bind
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
282
<222> 1120..1138
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1578..1596
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-15253-382 probe
<400> 119
atggagtaaagattgaaggttggaaatggaggcaacattctctgatatgcttttccctga60
tataatatttgacatacaatcaatacaaacattttgctgatacaataatagctagagata120
ttattatgtctttgtaacagagagatgtttaatatgaaataaatgatgcatagtagatag180
cttaatttgcttggtggcgaaaaacactgcctaaatcctttggggctgaaatttgctgat240
ttcaaaatgtatgccaatcacttaaaccattttaaaatttcccttttcttataataaatt300
acaattattaaaatatcacccataagaattgaaaatcaaataaatttttgaattatactt360
catgtattcttataaagaaatggaatcaggaatatgtttcaaaaagatctttgtcaatta420
taactatcattgtattactagggtttcattaaaactggattttctctactttttttgtat480
tttggttaatgagttatttgtgatttattctatcttaattaattttgccttctttttaaa540
tatatctggaaatttaagagtgtaaaaagtgacaattaaaaatctttacataaccaaaag600
tagatcaaggttacatttcgctaggttggcaataaaattatccatataattacataattc660
attcccctaaaatattattttggtaagttacttaaaaattttggcacatcttgtgttcct720
tttgaagataaatcatcctatatatttcaatatattttagatttttttctaactccatct780
ttgttttaagaaaaatcaaagtttataaactatgtctatatttacaaaatcactgtgtca840
gagcatgacttttaatcatctctgcactttaacacaggccttaggatatttacaaaaatt900
ggagaatcaaaattagagagttgcaaacacccttgaaatccatctagtccagtcatctag960
ctctccacttcttagtaccacaggctaaggagacagactgagcagtcaaggtaacaagcc1020
cctctaccctttctttgtacaaaacaatttcagtgtttttgaagtatttgtaacaatgtt1080
cttagcaacttcattataccatttaacaagaatacattgaaaatcaattccccaacactc1140
attttgtacgctaattttgtaagatcctgaaaagtttcactattttatggtttcatgtgt1200
tacagatgaaaaaaaaactagaattcaaattttctgagtttttttttacaatattttatg1260
attacaaagttagaagactaagaataaaatggcctaatttccataatgtgagtggtaaat1320
gcagagcactggcctaaagaaaatatttcaaaaaattagtcatcttttccttaatttttt1380
tccaacctatgatctgttgaatgagcattttgcatatataaataaataaattactttgta1440
aataatcttgactggtttctgttgaccacagtaacccactgcacagcacagcctgtaatt1500
yctatgaacctagggaaatgtatttaagtttattttttgattacacaggtcctcattgtg1560
taactaaacattgcatagaatatgccagtgatgatggagaaaagctgtcaaaatcaatat1620
ttaggggagaggtagctgctggcagctctgacacattgaaaaagttcagtgactcaagta1680
caaagacaggagaaaatcattcaacaaaacccctgaaatgtgtacttgtttttcctgacc1740
tacacattttaattccaaaaagagtgggaggcacataattatttttgtcaacatagattc1800
atcaaacacagggcaaatatattcagaacaatggagatatttccttcctgccaattcaag1860
aattattaatttgcctgaggaaaacgtttacatttatgatggtatatacacatgtctaca1920
cacacatatgcatatgtaaaagaaaagcgtatcaaaatctaactgtgccggaaagtagga1980
cacaagtgttagctgcattcacaatgacattgcagtgacctcatagcttgctttgccaca2040
gtttgctgcctttttcattgttgttcaaaggaagataaatttcaatatttcccttgcttg2100
cataacatggtgtcgcattccagactgttggtagtgtttccacatataaattattggtct2160
agcacttcacagaatctggtacgctgctattttcagcagtctatgcttcctcccagcctc2220
ctccttggtggtatgactgttacagaaacattagagggaacagaaatgctgccagtgcac2280
aatgtgagtggtattatgaggaatcagattgctaaaagcatgcatatttgatgaagcaag2340
ctaaacaaggttatactgtttaatagcctaaaaaggcaaataataatatatgagaaatca2400
tttctatatctgtaggtgtaagaacccaaagttagaaaaaaacatcttttgtcgggatta2460
aggaaatttattcaatgacatcatagcaaataaaatcagatttttttatgtgagtaaact2520
attaatgcatagcagaattaataatcttgtagcaatgataccaaattaattttatgtttt2580
aagcctatgatataagttagtttccaaggacaaagcagtgtgactaaagccctctgtaaa2640
atatcatttcctaaataataacaatacacctgtttgtttttacacttttaaaatttttac2700
ctctctgaataattgagaatttgaaatcatcacacaaggaaagcaatatgctttttattt2760
gcatatagcatgttcttttcattaaaaatgtaatatggtgagaggtaaacaaatctgccc2820
aaaaaaagtgtgcaaacctgccagcctaagtggtacttcttcttaaaaattgtactgatt2880
ttatttaacaaaaagttcaagtgataattctaaataaatagaattgcattgtggaacata2940
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
283
tgttatcaca ttaatcattt gctcctactg ctatttcata cttggtggtc attcttatgc 3000
c 3001
<210> 120
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-15256-392polymorphicbase C
: or T
<220>
<221> misc
binding
_
<222> 1481 .1500
<223> 99-15256-392.misl,
<220>
<221> misc
binding
_
<222> 1502 .1520
<223> 99-15256-392.mis2, complement
<220>
<221> primer bind
<222> 1110..1127
<223> upstream ication
amplif primer
<220>
<221> primer bind
<222> 1548..1565
<223> downstream ification ement
ampl primer,
compl
<220>
<221> misc
binding
_
<222> 1489 .1513
<223> 99-15256-392robe
p
<220>
<221> misc_feature
<222> 1719
<223> n=a, g, c
or t
<400> 120
aaatattaat ataagctattaaacaaagggcagaaacatctactaaaaag tttatcctac60
ataagaagtg cttagagcaaagatacaattataaataagaaggtacttaa gactgtgagt120
actttttaaa taactcaaaagctgacacagttgagcaactcatttgtata tttgagagca180
tctgataaat taaaaagtatcattatatgttaaatatgtagatggctgga aatatatatg240
tgtatatata tatataggtatataaagtatgcaaatatcagcatgatata tttcctaagc300
aaaaactaaa acttcattaagattttcaggaaaatgttactgagtatctt ccatattccc360
ttttcactaa aacataagatattttccattatataataccaagtgcatat cttaaatatt420
atacatctca actgcattaatctaatttcacatggctatacagaaataca cgagactggg480
taatttatga aagagagctttgattgactcacagttctgcagtgctggag aggcctcggg540
aaacttagaa tcataacagaagaaaagcaggagagatggagtgcaagcaa gagaaaggcc600
agatgcttat aaaactatcagatctcctgagactcactccctgtcatgag aacagcatgg660
gggaaaagtc ctccataatccaatcacctcccatcaggcttctcccttga cacatggtga720
ttacaattca aaatgagattgtgtggggacacagagccataccataccac caactcacat780
tctacagctt tcaattttctgacaattaaatatattattttagtctggga atatttgaca840
cgctttgtta ctacagagcattaagagacagagtcttcattataaatgtt agaatatagt900
tgacttgttt ccataactactgtttgaatctgactttagagacacgttct ttcaaatgca960
tgcatttgca tatactggaggatgggaagtatttggtacaagagtataag cctagaaatg1020'
aatcaaagat aggagtaaatttgggataattcaccagcacttctggtcaa tggcttctga1080
aaacaaaaag ataattatttttatatgtgcctctctatgatgcttcctat taagcaattg1140
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
284
gggaaatgtaataaacaagggttggtgagcatcttccttagtgagatgtttttggaagaa1200
ttggataattgagtgaataatagtgagaaactcctgtgtctgatgttgctccatgttgga1260
atgcttttatgttctcagagaatgagtcactgagagccaattgtgatgatacacaatggt1320
tttacccaggttggatatggtcctctgtactggtaccctttaagtcagtggcactaatca1380
gtcagtcattgtcatgctttgtgttggtccatcatatggtatgccctcttagagaacatc1440
ctgattagtccttagacatcttttcaatttgaacactggggctcctcattcgggtaaaaa1500
ytatggacagtcagtgaaactgttgcaatggcccctcatagcagattggatctcaatgca1560
ctttgtttacatttatttcctagctacaaatgtacacatgattccaagcaatttctatat1620
cattataactaaaataaacagttgataattaaaccaaaaatgccttaatagctgcttgtc1680
tatataatgtcaataacttgtttcaccacatatgctaanttttttgtgaatgtagtagca1740
tattgatatgacaacaatgtgctaaaaaatagaactttacaatagataataatgcaatat1800
tatttaataaaactacatgttagcttaagtatccagttatcacaagacacttagaccatc1860
tatatagctatcactatagaacagtttcctaacaacaaataataacccatcaagcaattt1920
tctcatgtccacaagcaattttacttatttacagcaaatggaaaaatgatggttgaagcc1980
catacaaaggttcaaatacaatagtacttgctaaactttgtggggacatggaagtattat2040
ctgtaagatgctatgttatccaaaagcgtgtgtgtatctgtgtgttgcatatacatgagt2100
atatgagtgtgcatgtgtgtttacacctgtctttcaaaacccttagaattctgatctcca2160
ttttgaaatgtgtaacttttctaaacatgtgggctaatgggttcttcctatgaaaatgtc2220
attgtcataattaattgatagctataacctgccatggagaagcatataatttgtaatggg2280
aaaatcttcgatagagaccaattagtactaaggcaaatgagaagtactttcacaatcaaa2340
atgccatcaagggttaccttatgtctctgtcctatttttatgggtcttttaatgccatat2400
acactcacacacattattattaagagagttatatttcattaagaacagtttacataattc2460
aggcttattcatatttaactatctgtaaccagtagtaatttttaagaacaatacacatga2520
ttaaaatagtgatattataattatgaacttttatgaaactacattttacttaaactttgt2580
gcaaaatacatttaagaaaaatttccatagagccaaacttgattattaagatgtcagaaa2640
atatagagaaaataatgaggggaaaaatatagtgacagatacaagaaatagaaaaaagca2700
taatgtctttactatttcatctcataaaataatctatattaactagaaaccttatgtttg2760
tttttcttttcattttatttcaccggttgaagttaagcacattcgttgtgaattatgtaa2820
tgagttacagtcaatggtttttaatagaaaaaaatcatgcagagaaatgtaaccaaaaaa2880
tgaattgagagtgacatttagtccaacataaagaaaatttttaaaggaaaaaatggttag2940
ctttaccttaatattttcataaattagtactggttaatttttcacaaatatgtacctaat3000
t 3001
<210> 121
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-15258-337 : polymorphic base G or T
<220>
<221> misc_binding
<222> 1481..1500
<223> 99-15258-337.misl,
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-15258-337.mis2, complement
<220>
<221> primer bind
<222> 1165..1183
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1685..1705
<223> downstream amplification primer, complement
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-15258-337 probe
285
<400>
121
ttataatgggattgctgggccaaatggtatttctagttctagatccttgaggaatgggag60
tttcatcttttgcattttatggccgattttgagttaattcttgtgaagcatgtaaagtct120
tgacttagattctttttatttgttttttctttgttgttgttgttgctttttgcatgtgga180
cgtacagctgctgcagatccatttgttgacatctatctttactgcatggtattgtcttta240
ttttgtcagagatgtattgactatatttttgtgtgtctgtttctggcctctctattctgt300
tccattgatctatttgtacattctttcaccaatactacactctcttgattattgtccctt360
tattataagtattgagtcttgaagttagtgtcagaactccaagtttgtttgttgtattgt420
tatgctttttatatagcatggaggaaaaaatacttaatataaaaatataaatagtgactg480
aaattcaatatgatagaaggtgagtgaagaataaaggaaaaatggaagccgtgacaggta540
gagagggaggcaaatggccaaccctcaattaggagatatttagatgtgaagatcttacag600
agggacagaaagctgaagcctagagaccaaaggaaagaaggcaatttaattatcctgctg660
aaggcaggtagttctttgttgttgctattgtttgcagacaagggagtgcaaagttaataa720
atactaagagatagaaagtagaccttaaggaaatgagagaaaaaatggtagaggaaaggc780
agagtatacaaaagaaagaaagaacctaggaagtccactgactttctccaaaagataaga840
ggcatcagctcccttcttaccattttttgcctcatgaacagttagttttgtccttattca900
gtcattttgtcaagttctggattttcttctctgcatttactgaatatggtggaaactgct960
ggtgctccatcaagccactagagggaattccttttcttctgcaagcccttcctcccctta1020
tcacaagctccagttacagaggtctcctgcattcttcaggatttgtattctggtcatgct1080
ccatgaggaagacagacaagtacaatatagctctgtgattctttccaatatcttctcatt1140
atttccagcaaccattgaggtttccagtaaagaaggacttaggaaatattttttgaatca1200
tgagctgctaatagatcagtaaataggatttattaaacacagctgtattcaggactctga1260
cctgtgtgggccttagggaaatacaaaatttacaaactgatgtgattttcttaccagtaa1320
gaaatcttatgaaagattaaattaaaaaaatataaatgggggcaactcaatcacataaaa1380
gtaatatattccatgtgactgaaatactagggaaaatttagaagtagaatttaagtgaga1440
atttcaagcagggttctgaaagattctacaggatgaaggaagaattgcccatatgccaat1500
kgcctatgtgaaatcacaaaaacagaaatcaataaggcatgtatggaagtacagagtgat1560
tgcctagttagaaaaagagcgtgaagggatcagttaacacaaacaagaagagtttaatgc1620
ttatctgcaataagttggtagagcaaaattaagcacttcccagtatactgatagacgtta1680
atttccactctaccatgtgaaattttgcaactatgagcaagctatttaatattctgtaac1740
ttggttttcttatacataaaatgcagttagtaataactaactcatgaatgattaaatggg1800
ctaatgtatttaaagaaattagaataatgcttgcagtattataaatgttcagtaaatatt1860
agcattgttgttaatcatctctaaccttcagcctgggatcttctacatacattcttactc1920
acatctaatgaatataaaatgttgcatcaaaatgactgttctaaaattaaacggttttct1980
catgtcgcaattgcacagaattcttcaatggctctctaataccatcaatcctagaatgtt2040
atccagaaatcctttccaatttggtttttgccaagttttctagtttcatcgtataatagt2100
tgtctttttattacttgcagttaagttgaactgcaggcattacaaattacttgcatatag2160
tcagccaaaacaagatccttcttctctcccttcctttgcccatcagagactgtatttata2220
attctgacttacacacatctcctcattgaggtgagcagttccccatcattttaaatttag2280
ttaaatgacatttatttagcatagcttctttcaccagaatgtagagttgaaggctttctt2340
ctctgtccactcagttcattttttagataagtatgcacctgcactgaagtcattgaaatt2400
agtgtgtgcttgattatttgtcagtccatgatccattctatgcatgacactgtggatatc2460
aaaaatttgcaaacaatatcttcttttccttatcttcaaaaggaagatgcaggttgaaac2520
atagtatgtatctaaagaagatttttgaaagactaactaaaaaaaataataacaaatgtt2580
caaagtctatctaaattggtgtttcttcacatctgactgtatatgtggaataccttcaat2640
aatgtcatgtagatataaggagaagagtatgtgtgtaaataattttactgtaaatcatat2700
taggtagtaagtgttacagtagatgcatggcaatggagtatttttcatctgaagaatctg2760
ggaagaacttgttactttgtggaataagactttttttttttaattctaatttgattagat2820
acatataacccagaagagctgtggttttatgtttaagaaagtagagaatccagaagagaa2880
atcatacagttttcagaccacaagaaagactgattgagtaacattatcaaatataccaac2940
atcagtttggaaatattccaaatcatcagattgtgggtaagctgttcagtaacatcattc3000
a 3001
<210> 122
<211> 3001
<212> DNA
<213> Homo Sapiens
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
286
<220>
<221> allele
<222> 1501
<223> 99-15261-202 : polymorphic base A or G
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-15261-202.mis1
<220>
<221> misc_binding
<222> 1502..1521
<223> 99-15261-202.mis2, complement
<220>
<221> primer bind
<222> 1302..1320
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1782..1802
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-15261-202 probe
<400>
122
tgtatgtcaagtgaaatatgggattctgcttgatttaatttttgagattcaatgcgataa60
tttgtattcattaaaataccaagaaagccttgagtatgattgcttgcaagatatgttaga120
aatcactaagcaatgtgaaaatataagcagatgaattacctattaaatctaataatttcc180
ccagaaacagattttgacagagttctgacttttaagagaaccatattattactttgccta240
gtgtaactgtcaaatgcatgtacaattatgaaataattcacaatgttctttcaaatgcag300
ctttcccattagcttatatttttaacttatataagttgggtttttttttccgtaaacgaa360
gccaaaatatttctcctgggaaatacttccattatgtaatttaattgttacatttacatt420
gtattactgtctgataaataggccttttcattgataaatcaaatttacagagacaaatgt480
atagcaatagtaataagaacattttagtgtaacatattctctgcttaaagcactcacaag540
atgatattctcaacatatattctactgcttatctcttacttccacggcatcttcatttgg600
acctactgtgtttgaaatgttccagtcattatccagaatagcattcctaaaaagaaatac660
aattatttaattggttagctatataaacggatcagtcatttcaacaatacatatatccaa720
gtcgcatttctctagtcttcatacctataaagctgcagaatgatctcccgccttggccca780
ctgaagatggtctctttcttcatgtcttcaagcagcaggtgccagtgaatggatatctgg840
tatgagtaatccagttttaaagcacattttactgaaaggtttcctatttgttttaataaa900
taatgccaaagatatggttatctactgtggtataacagaccaccccaacatttagtgact960
taaaataataattattttttgtgtccccaaatctgtactttgtgtagggcttggcaggaa1020
tggctcatctctgttccacaaggcatcgactggggtggcttggcagggaccggcattttc1080
atttccaaggcagctccccgacacggctgattagtgctggctggcagtgtgttgagatct1140
caactgcggctgtcattgggggccactctgagggaggcccctggattttttacagttaaa1200
taagttttatactacatcacttcatttctttttccagaaacactggcagctaagctgcat1260
tttatttgttggtttcttcaataataaatatttcactatttcttctaatcctttgtttcc1320
acttattttatttcattcctcattttatcccttttttctaaattccattttattatactt1380
aaggtgcttttaatatggttatcatactcctgatagtgttatttctttcttagtcttctt1440
atataagcgctatacgttcacattccatctcctttggttatctttccatttcttcaccga1500
rcctctttgctctctttttttatagctggttcactcaaaatgtcttactttgccattttt1560
gaaatttattttcattcttttatgtactgaataaaatttaaaaatactttatcatggtgg1620
gaggtacccgtgatgtccaaataagtgtttatattaattgttggggtttttttgtttgtg1680
tgttttttgaaaggttaagaaaatctcattcagaaagtaagttgtttaaaaattctggac1740
caaatttaccacacatcaagcagatacttaccaagttgtttggtagacattagcagtatt1800
tactaatgtctgcttctccttgtaagcaaatgtatatctatatttacccctgttactagg1860
aaagaaatcttgtctttggcagtggaaaacccatggagggtttaccggtttctctctgta1920
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
287
cccttgttgcaatgatatggtaagcagagttgtgataaattggtttggtcaaacaaaatt1980
agaggtatctggcttgcggagaacagctgctttgccatatggtctgagacccacagcagt2040
tctgtgtacatgggaaataaacttttattgtattatgtctatgagaatgtgggtttgttt2100
tttactgtatcatgattaatagagatgggttaataatttttatactatttctttttcctt2160
tgaccattaagaattccatgtgactatgagaatttgcaatacagtgccactctcctttgc2220
tttcattgatctacgaaaacatgaaaagctataatctttagaattagtacatccagaact2280
tttcctgtctctattcctatctctttaattgatattccaggctctcatgagtccttgcag2340
ttaatccttttcatctttgttatttatatttcttcaaactaaaggctgtattcaatggca2400
aatctatgcttggttaaagacggagaagaggaatagaggtgagtctgacttgggagatcc2460
tttccatgctccccctgattatggtaccaaagttgcagcacgtctttcaacagctccttt2520
gcattgatattttgggaaacaattatttgttctgccttcttcctgcccagtgatatattt2580
acacaggttggtgatgacttgccaatatatttctgctgtagttaaattaatttatctcta2640
actttttttaatcttagtgatttcctaaatttcctgttgttacaattttgaatatgtgat2700
ttttatgggaatagcagctttatcaactaaaatataagaaagttaaatgaagagcagcta2760
actactatcataaactaaaaatattaatataagctattaaacaaagggcagaaacatcta2820
ctaaaaagtttatcctacataagaagtgcttagagcaaagatacaattataaataagaag2880
gtacttaagactgtgagtactttttaaataactcaaaagctgacacagttgagcaactca2940
tttgtatatttgagagcatctgataaattaaaaagtatcattatatgttaaatatgtaga3000
t 3001
<210> 123
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-15280-432 : polymorphic base C or T
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-15280-432.misl,
<220>
<221> misc_binding
<222> 1502..1520
<223> 99-15280-432.mis2, complement
<220>
<221> primer bind
<222> 1070..1087
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1590..1610
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-15280-432 probe
<220>
<221> misc_feature~
<222> 170,2706..2707,2715..2716
<223> n=a, g, c or t
<400> 123
ctagatgcat gacagatatt accctttatc accttgtaaa caaatacggt tgcccttgct 60
agataacact aatatgttta agatcttcca gctaattctt ggtgcttctg ggcaccttgt 120
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
288
cttcatctccatagtgggaatagtaatatttgcattgcaggagcattttnaaggctcgag180
attatagttttcacacttatttcctcataaaagcttatcctgcactctttctcatttcag240
taaatgacaactgcattcttccatttccttggattaaaacccttagagacaactttaata300
gatctttgtcctacactgaacgactaatctattgacaaatctttttagctctaccttcat360
aaagtgtttataatatttctacttctcaccactattacagctattgtgttagtttaaggc420
catgctttgctcacccagatgacagaactaattccttgttagttttaccaactttaactc480
cttgtttctgctcttgtcaccacatcctgcccatacacaatcagttaccatcctcataga540
cacagtggtctgtaaaaatgcacatccattcttgccacttctgtgctccaaaccccccaa600
tggctaagacaaaatgttgccagtgcccccttctcttttcactccctctctcaacactcc660
ttatttcaggccctacaggtaactgctattctaaacacctgtagctcctttcctagggat720
ttcctctggctctaggaacaatactggatgagtagttaaggtagaagtacagaaatattc780
aatgccctgggagcatccatcaaccatggacagaagaaagtggtggataagtattccagt840
attcgcagccctcaggtcaagacactctgaagtatgtgatgtatcatccccaaagggtcc900
tgacagggtataattctagttgctctgggcaacctgcttatgaatgaactctgtatttgt960
tctcttcctctccctgtctcactttaccactttagtcctggtatttgctagaatattctc1020
ccaaataaactacttagcctctaatccttgtctcagacattgcttcaagatgtccatcca1080
tcttgcccagagagagtttctacaacacttcctctgcaagccctttccctacttgcctca1140
cctattgctttcctctgttacattgtattcccctcactgtttcttccaacatcttcccac1200
ctcagagcatggacacttgctgctctttctgtgtcatgatgctgctcacttgtccctttc1260
ttaatgtctcctccctgagccaatcttctccacccccacaacttacgcacacttacatgt1320
catattttccttcatagcctttaacaccatttgaaatgatatatatttgattgcttttaa1380
aatttctctgtccccccactaaatataaacttcaggatggcaagaatgtagtccattatc1440
ttatttctccagcctccatacttttaagaaaataaattttggttgtataagccatccagt1500
yagtggtacttggttatagcacccctagcaaaagaatacaaaaaaagggagaatgtttgc1560
aatcatctgtttgaggctaggaattcccagagagggaaacaaggagtaatcgtggaactc1620
aactacttaattcagattcagtgcagtgaagatgaaaaccagctttcacctaagtaagga1680
gattgacatcataatgagattgacatcataatgagattaagtcccttcactccagaaagt1740
gaggccctaatacagaattcaaaggtaaaattgctcaacacaaaacctgggtgtgttaag1800
aataggtattttatatttcccacatggaaatctagaagtaagatcacagaaactattctt1860
tttagttttatcagttttcttttttattcaaggaaaacatggtaaaaagtatactctcaa1920
ccaactatcttggcaatattacactgacttataatttaaataatatgtcagtgtgtttct1980
tttgtagtacatactttaacaaatacgttttcaaatttttctaagagtcattttgaatga2040
cctgaagtgtaggatgttgacattgttttgagtatgttgatggcatcctattgcataaaa2100
aaaaaatgtggtcttcgatgaattctaaagtgacatactgtagttaaatataaaagcaaa2160
gatataaagaaattataaaaacttaagttattaggttgatataaattgattagtaaactt2220
aaatagagactcaaattgtatgtgtgtttactctttgcatagactgaattctaatcctaa2280
tcacttgtatagatatacaaatgtatatgaggtttcataaaatcctcattctcatgacta2340
caaagactttgtagataattctggttgtttgctcagcaaagaaatgtttgattcgggaaa2400
aactttttcaaaaaatgttattcacattggctaaaatatctaagccaaagtgttctgcac2460
ttgaccttagaagctcatctttctgaaatagttctattttgtctaattacctcctgttac2520
attagataagtttcttcatgctggtctaaagagttcttctagcctgctggtatttgcaca2580
tggcatttaagtatttgcaagagtacttgcccctgttctttactcatcagtttgcaatgt2640
caatcatcacttagtctcagattctgcaaaaattatgaagcaaatactagttagtttttt2700
ggagcnntttttttnnttttttttttttttttaatatagtctccctttgtcacccaggct2760
ggagtgcagtggcacgatcttggctcatggcaacctttgcctcctgggttcaagtgttca2820
agcgattctcctgattcaacctcctgtagctgggattacaggtgtgcgctaccatgccgg2880
gctaagttttttgtggttttaatggagaccaggtgtcaccattttggccaggctggtctc2940
aaactcctgatctcaagcaatctgcctgcctcgccctcccaaagtgctaggattgaagac3000
g 3001
<210> 124
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-15355-150 : polymorphic base C or T
<220>
<221> misc_binding
<222> 1482 .1500
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> 99-15355-150.misl
289
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-15355-150.mis2, complement
<220>
<221> primer bind
<222> 1352..1369
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1822..1840
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-15355-150 probe
<400>
124
attttggtatttctcttaagtcataccactagagtctgagaagggtaaaatgaattgtaa60
aaaatgtttctaccaagattaatcaattaactggattgtcaaaatatcactgctttctct120
attttatttgaaaaaatagtgtttgatatataataactgttaattattatgcatagtaat180
tgttaaataaaagtttgccatgttatcacgttctcttaaatgactgagttttaagctatt240
attccggaaaaccaagtttgagattctaaggaaacattctgtcataggagccgtactcat300
tgccttcaagacagacctatttcaatactgtcaggatgtgcacacacatgcttgtgttct360
gtgtgtgatggacacatattattataggtgttctacaagaaaaatccttgaagggtttta420
tgggttctctaattaataaaaagaaaaaaaaaagccaaaaggatgagatggcagtaagga480
atgtagggttaaggaaaacttgaaattccacatgaagtgaatgcctatggaaaagggaca540
tttgttcactcggaatgagactgcctacttactcagtatcatagaattaaagaaaaaaaa600
tgagaataggtgtgaagactgtaattacattttcattattatgttacatgcttaggatat660
aggatggaattgccaaggtcattagaccaccttcacagccttcaaaaggaccatacatca720
tcttgttagggcagagggctgtctgccttaatcacagtttgaaaggtaagactacttcac780
ctctgccttagtaaggatatttatatctttgttgaaatagacatcttgccttaaacttat840
ctaaatctcccttgctccatttcaataggttgctaactagttctatttagtttggaatgt900
atgtgtattccatttgattgaagaaagttgaaaatgcatacgactatttatcacacacta960
agaacttcctggtatcttggatgtggaatgagaaatcaaaaatttatgaccccaactttg1020
tcatgtactcactgcataacattgaccaaattacctatcctctctaagccgtaacttcta1080
catcactagtacatttcatgaagttgtgagagtcaaatacaatgatttatatgaaggact1140
tagtaattaaacaagagacatcatatttagaagtcagtcatttttaatatagtaaacacc1200
ttcagtcaatagatgctttctaccattctttttaaataatttaaaataacattgtacagg1260
attgacttttcatgccaggctttgtttctgcaatgtggtaattcatattaatgattcatt1320
ttcctgatttcaaaatatgaaatttatcttttaacttctccgtctctccttcttagccca1380
tatgtcaataatgactgaaagtaatcatttccatctttaaactgcctattccagccccct1440
cccacctccatctctttccttctaagttttcttcatcttctactttgggcaaaaggaaat1500
ygatgtgtcagacaggcctagttttgaattctggatctgctagcacttctctgtgtgtcc1560
ttggttatatgatatagtcttaaaccttaatgttcttgcctgtaaaatggggataataaa1620
aacctcttaacagtggttgtttcatgcagctttcattacaaacttcctcattcaaaatct1680
tcaatgatttccatttttcacaaaatgaaattcaaaatttctgtagattattgagacaag1740
tcccctactcttcacctaaatttatcttttatttattctctcatcattatcaacaactac1800
taggctttgttgccttgactccagaggcaaaaatcttatctcccaacaatgtctcttaag1860
ttaagtgtaattcattatttgatattcttgtttcaaaatgggtagaggaaaacttcctgc1920
atataccgtaaaataattttagggaaaatatactaatgtatgttccagagcactggaagg1980
tccaaagctacctatttgcattgtaccattactatttgatgtagccttttgctcattatg2040
caatgagctgaaatacatttttcatcatgcctcctgagtctctaagtaagagtgattgac2100
tcattccttttctaccagtgagattgcaaagcaaaaagaaatatgtagtatttatttact2160
catggaattcattcttatgaaggtcagttgccaaatgatgccaaaaccttactttctaga2220
atgctattcaagttatcaggctttaacgttttcaagatgtttatgtttgacaaccatata2280
taacataaaattatgtgaagtaaagtataacataactgtttcttttctatgaaacatgcc2340
tatttcaagtacatagtacactgcactgcagataaccggctgataaccagctctcaacac2400
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
290
atacaacctaatgattgaattaaaccatagtgtatatttttctaaatgtattcttaatta2460
atcacattacaaccatcagtatttgggtgaacagcttcagcatccattagtttttgagca2520
aagaactagaattcggagcattcaaatgatactagagaaaagacatgaagactgtttatg2580
agattggtccatctctgagaaatgtcaagatttaagaagagccgcaatttcaaaaccagg2640
gctacttcattgtggacctgaatctatttacccagggtcaaatcaaggatttggaacaga2700
ccatgggaacacaccactttcaatttttgaaatatttgcaaatacatgatgagatatctt2760
ggggatggaacccaagtctaaacagaaaatcaatgtatgtttcgtatctaccttatagac2820
atagtctgaaggtaattttagataatatttttaatattttgtttgacaccaacattattc2880
ctgtctctgaatttatatgctacacataagcaatcattttattatacctattcacatgta2940
agtacttaacagttaaaaattgacataccattcatgcaataaaaaataatatgctgaagg3000
t 3001
<210> 125
<211> 1887
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1126
<223> 99-25224-189 : polymorphic base A or G
<220>
<221> misc_binding
<222> 1107 .1125
<223> 99-25224-189.mis1
<220>
<221> misc_binding
<222> 1127..1146
<223> 99-25224-189.mis2,
complement
<220>
<221> primer bind
<222> 937..955
<223> upstream cation
amplifi primer
<220>
<221> primer bind
<222> 1446..1466
<223> downstream
amplification
primer, complement
<220>
<221> misc
binding
_
<222> 1114 .1138
<223> 99-25224-189
probe
<220>
<221> misc_feature
<222> 1114,1877
<223> n=a, g, c
or t
<400> 125
aaattatttt gaatgcctgaatggacatgctattcaaatgttttgagcat tgtaagctct60
ataattgttt aataaaaagaagatactttaaaacagtactgagcagcttt tgtttctcag120
taaaaagaaa aacattccaaatatgatcttacaaatggtactaaaaacat aagtactttt180
ctagcttctt attacgtatagactgattagaacgttcagaaaatgcaatg agcaaaacca290
ggctatttca tttttatttatgcctattcctactcttactcaactacacg ttctcagtaa300
aagaagctac ctatcaatcactcagaacccaaagttacctcttgccattt cttgagaagg360
ttagaaaaca caacatgaactggattttactgaaacttcactttgaaaca aaatagaatg920
ttttatgctt ttatttatcaagaccactgaggaaattctgatccaagaaa actttagggc480
aaattttgaa gccagttcttcaatagacaaaaatttgtcttatttactat ggctcttaaa540
cataagcaag ccaaaactaaaatcatatactcttcttttaaaaaattaat taatattaaa600
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
291
taaatttactgctttgatttaaacagtccattcactgtttcatcacccag gctggactgc660
agtgttgtgttcacagctcacttcagcctcaacctcctgggttcacacag tcctcccact720
tcagcctctggagtagctgggactataggcgtgtgccaccatgccccaat aatcttttta780
cttttatttttgtagaaacgtggtctcactatgttgtccgggctgatctc aaactcctag840
gctcgagtgatccttccatctcagcctcccaaagcactttgattatagga atgagccatc900
acacccagccaaaaccatgttttattatgaacaaatcagataatccaagt ttaccaacct960
catcaagaatcaacacagtgttctgaataagattgtatgcaattcttttt gaacatttgg1020
aaaatgctaagtttagtgcctgttagaaatcctaagatttttagagggat atctgatagt1080
ttcaatagaaatgaacaaatgaaataaaaattcnttgacttaaggrtttt gaaacatgca1140
cagtattgaaggacttaattattctagtagaatttcaggcattgtttatg tgttctgttg1200
tttcctggttaagatctatttttttcactttacgatcccaattattatat ggtaagcttt1260
tgagtcttggggacatcatagttctatgaaaagggatataagaagatagt ttctaccttt1320
atcatgagcctaaaggtatgtatagataacccaatccctccacttacttt agacctgcca1380
aaagctcacattcatcctggttgctccatatgtgtgcccactcagacagg tacatgctca1440
cctatgggaaagttgtaaaagcacacacggtgtttgctggatcataggag ctccacatcc1500
ctccagacacttgtcggtggtagaattgtgtccccccagcaaaatatgtt gaggtcctaa1560
ctcccagaatctgttaatgtgaccttatttggaaataaggccttcacaga tgattaagat1620
gaggtcattagggtgggcgctaatccagtgtgactggtgtctgatataag gagaggagaa1680
tgccccgcgacgaggacacacaggagaatgccaagtgacaacagtggtat aaattggagt1740
catgcagctgcaaatcaagagatgtcaccgattgcctgatacctccaaag tcaggaggag1800
gcaagcgaagatgccactctacaggtttcagaggaagcatggtcctgaca ccaccttgat1860
ttcagactgttctcctncagcactgtt 1887
<210>
126
<211>
3001
<212>
DNA
<213> Sapiens
Homo
<220>
<221>
allele
<222>
1501
<223> base G
99-25950-121 or C
: polymorphic
<220>
<221> binding
misc
_
<222>
1482
.1500
<223>
99-25950-121.misl
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-25950-121.mis2, complement
<220>
<221> primer bind
<222> 1381..1399
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1859..1879
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-25950-121 probe
<400> 126
ccatcccatc ttcatttatt tcagagtaaa gttatctaaa tgaacctatt ttctaattaa 60
gaatttcttt tatggccagt aaattacttt caagatttgc cctgtaactc tgcagaatgc 120
caccagcata ctatgtcttg aggataatag agaaaatttc tatattcata aaagaatgtt 180
ttctgtccag aattgctttt gattaatatg aggctgcatt actgacactg cctttttctg 290
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
292
ggaaagaaccctgagtgtattttatctaagtgccattattgttctggaaataagatagca300
atggcattcgttagctttgactctaatggctgtaaaagctatgggaatgtaggactttgt360
gctacgtttgcatgagataatgacggctcattgcaggccagctttcatgaacttcatttg420
tgccagaacggtaatgctgggcgtgtacttagggcttttcctctcgaaggctccacatat480
cacttttgaacgtgtctgtcaaagtagctggtagaatcaatgaaaatagccttggcctcc540
agcatgaatgatctaaattgaaagaagcatattgagagggctggaacccagtcacaaatt600
cagggacaggcggccggataatgaagcaaaggcacccagtggcacagctgtgtcgcatgc660
ctctgggagctagaggggagcttcgccatcatttgtcttccatttgcacacccagagagc720
tgtgtttattgggggcttgtgatcccctcttcttttttcaaccacccaggggcatctgct780
cataaagtgtgtaattatttatttttacaattctgcattatccagataatattttgaaat840
ctggactgatttttgaaaaatcaaaaaactgctttttctgcattgttcaaaattgacttt900
gagaaatcgactagcagttgtgaattgtttcagttcatatcctacgtagctagaagttat960
aaagctattcttaaatatgatgcctagagaggggtttggtagatggggagtcaatgcaca1020
atggcattaagaaaggtggaaagaatgaaaggttgctaggaatttaataggcttaaatac1080
tttcctttcacccttctccagtatggagaggtgaggtttggactgtagacgaacaggtaa1140
gcacaaagtaatgactggaggaggtttctcagtagaagccaaggaagacctggtgccagg1200
gttcaggtaaattctaactcagaagatgtgagttttcagtcaagattgacctgttgctca1260
agatacaaattgcagtatttgaattttgtataaagataatacatagggtcttttcactga1320
agaatcgtaaagctttcaaatattaaaggactataaaattaaattatatgccattattta1380
ctaccaaatcatcaactaccaaatacctcagtgcattttctagcattaactttatttagt1440
accagaattatcacagagtctaaagttatttcacacttaattttgtagaaataaatagat1500
stgtagaaatcttccttatggattcaatattttgggaaagaagcctcagtgatggatatt1560
ttgttgtgttagaagtggctatctattgttactttgtaataaattatcttaaagggtgtt1620
tattgtaagtatcacatataatccaggatattttcctttggaagaggcaaacccagttaa1680
attgggaaaaagaatatagtctgcaaatacaaacattgaaaaatgtgacctctgcccctt1740
ttcaactcttataggacaaattcagaactcaactaaatgaaattctttatattgttaaaa1800
aatttcccctagatctcagacagatgctgagatctgttttgtagcattcacccacgtacc1860
taaatctcactctcagcaattacactacttgaagaatgtaccataagaagagcaaactta1920
atggagcttgaaggtggtgtcatattgagtgtaggcacgcaacaatataagtgatccttt1980
tcttctcttgctttttttcttagttgagtaaaaataggttagtgggcatcatctcagata2040
ttccaaatcatagctaagttatttatttgcatagcatcggatcattttttataatatctg2100
atatgaattaagcaactatattttatttaaaataataatagtaactaccatttatcaagt2160
atcaactctgaactatgaactttgcattcaaagacacagatcaggtcatggagtttttga2220
tgtagatattatcacacttttatagatgagaaaattgaggcccgaagagtctaagtaact2280
tggccaatatagcaaaggacaaatcaagaatttgaacccagtcctttagatcctggtgtc2340
catagcaatatatctcacatcttgttaattgtagtactgataagatttcagttattacag2400
catttctcagagatcaattgcacatatatttaaatattcaaaataaaaattctaaatgtc2460
tttagatgtgtttgtaaagaagatgttagtttttcttgtgggatctctacagtttcagtg2520
ctcttggacacacacttgcaaattccataaatcatcactagataataaaactagctaaag2580
tgtattaaacatctatgatatgccgggttcagagaaagttatttttatgtattgtttaat2640
tcacagaaaaaccctaccatgtaggtgaatatgttattttcagcagcagcatcttatcaa2700
tgacaaaactcaggaaaagagaatcaaaatgatttttctagagttatacagcaagatagt2760
ggctatattattcattctcatcctgctaataaagacataccatgactgggtaatttatga2820
aggaaagaggtttaatgattcacagttctgcatggctggggaggcctcaggacacttaca2880
atcatggcagaacatgtccttcttcacatggcagcagcaaggagaagtgcagagtgaagg2940
tggggaaaagccccttataaaaccatcaggtctcctgagaactcattcactatcacgaga3000
a 3001
<210> 127
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-25961-376 : polymorphic base T or G
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-25961-376.misl, complement
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
293
<220>
<221> misc_binding
<222> 1481..1500
<223> 99-25961-376.mis2,
<220>
<221> primer bind
<222> 1854..1873
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1391..1411
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-25961-376 probe
<400>
127
ctagacgatgagaatctggaatttaggatttgcaatgaaggacttgacagtgatttaatc60
attctggtcctcaagtcttcaattggaaaaccgatacagcaatgttttccttttatgaca120
gattaaatgagctaatgtttgtagtatgctaaaagtcatgcacagcacctcacgatcacc180
cccttttccttttgtcttttcacttccagtcatatgcagctcaagccacgtttttctcta240
aaagcttgacttgattgtgttttcctaatttctagttctgtggcacaaaagtggtggaca300
tttggcagacaaataaacagttgatgattggttgactattgcttgctctacagctaagtt360
gaaaataatattcagtaatgtggtttaagaaagtatgcaaaagtcattgtagaaaactga420
aaaaagggcaagtaacacatgttgatatctagagatatataaatagaggcaagtgaagct480
taagtcatattagactccaacattaggtattggtaggaatttttaaaaaagaaatctcag540
aaaatataattgcttttcatagggagaattgttatgtgagctcatgtgggctgcttgata600
tctgatacctgaaatttcctgtcttcggtacctttcctactattttcctttcttcaaaag660
aaaagccagaatcaaggttgatctcagaggccaggcagtcctcacctgagttgggcacca720
gccacatggcaactgacaagtggtgttgcaacattctatgcaatgggtgaattatgaaat780
ttattttgaacagcaaacatttatttcagtcaattgactttaattaaatttaatgtcaat840
taaatttaatgcaatttccattcaatttttctaaagtacaatacggatttttaaaatgat900
ataaaccctaaatttaattaatgtatgtatatctttacttaattaaaatatcatttttta960
agtagaaatggatgagttctgtaaaagtccgtgttgcttttggaacaagtttttggagtt1020
ttttttttcttttcttttttgaagtaaaagtagcattttggcaaaaataaaaataacccc1080
taaattcttcgaatgtttgcctgcacattttaaaaagaattccaggcatggcaaagcaca1140
ttctcccaaaagaggtggggaatgtgctggccagtttcccgttatcattactgggctgtg1200
aaacctacaactttgcctaatacttcatttatgtttccttatttatgactcataaatggt1260
ttacttcttatagttcttcccattttgtgaacgtttttaaaagttcatagcatcatctga1320
tcacactgacatttatggcaaataacgaaattccttttaaaactcattaggtgagaaaca1380
cagattttcaagccctcagtttaacagaagctaatctcacagtgacctgccatgcccctg1440
ccacattcaagggtttacaatgatcgtcttccagagtttgagatataagttgtctgtgta1500
kccccgtcccaggagccacaccaatcctattcctactgcatagtttattttctcggaaat1560
ctaagctctgggattcaagcaaagcaagagacttggggaaaggcttctcacaaattcaac1620
aaggaaaccattttcacttggggaggtggtaaggggaagaccatcaggctccaactgcat1680
atagtttcatggacaattatttgaagaaagaatggaagggaaagaaggcagaaagtgacc1740
cttccagaccttggtgaggcaggcagaaccctctgagtccaggggtgtgtctgtctttcc1800
ctccttttccaactgtggaggagaatgtagaacataatttcaaattcatacatgttccca1860
ttcacaggggagagaaaggaagacattcaactaataaaggaattatgttttcacaatgag1920
atgaattagaaagctatttttctttaacttcctcctccatagtaacttccaaaatggaat1980
catttttttttccctccagcaagagctcaacattgtattagatagaaataatgtaagtat2040
cagaaagccatctctaaaataataagaagaatctggaaaacaagctggtagagtagttat2100
ttttctttatgttctctatagtctcttcagaactgcattttttaaaaagtgcaaatctca2160
aaataaaagaaaaataaaacaacattttcattggatgattatgtattcaatcttaaaaat2220
cccagctctcaagagcctctagaaaaggtcaaggaggtctaaatgctcagtagaatggaa2280
gaaaccattgctagaagccaaacagagactctggtgacgcaagtgatcttaggagattct2340
ccaagtatttcctgaacaatttttaggggccacactcagtgctagatcctggggatgcaa2400
atactaaaagacaaggtgtcaaggagaggtcctgaaaaaatacctggtctattatgactg2460
acaaatatacaatgtaatatacgagaaacagagccataggtgagacacacatgtagagaa2520
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
294
gtcttgacttacgtgcaattctaactatagaacaaaggagccgtagtcacttttaaggat2580
tttaatgctgcgcagtccacacagacaagttgaggttttcatttagtgacacttccttta2640
tttacagaaggctcagtaacactgacccattttttttttctgcagatgattcttaatgct2700
ggttagactattaacagctgacttttacatggaatttactgttctaagcacattacttgt2760
attagctcctttactcttacaagctatatgataaattcattttattaaccattttaaaaa2820
tgagaaaactgatacacaaagaaactaaatagcgtcacataaagtgacctggccaggttt2880
ggagcacagatggacttattaactactactctatggtattttgattcctcaataacttct2940
taaaaaagctggaagttacttgagcccttcatttatgtcctacacaaaaaataaatgtgc3000
c 3001
<210> 128
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-25965-399 : polymorphic base T or C
<220>
<221> misc_binding
<222> 1502..1520
<223> 99-25965-399.misl, complement
<220>
<221> misc_binding
<222> 1481..1500
<223> 99-25965-399.mis2,
<220>
<221> primer bind
<222> 1879..1899
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1429..1449
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-25965-399 probe
<400> 128
ttatttcact tagcacagtg acctacagtt tcatccatgt tgctacaaat gacagaattt 60
tattcttttc atggctgaat aatattccat tgtgtatatg tacacatttt ctttatccat 120
tgattcattg atgaacagtt aggttgattc catatcttga caattgtgaa caatgctgca 180
agagagtaca tacatctctt caaaatacta atttcctttc ttcagaattt atacacaaca 240
gtgggattga tgaattatgt tagatttatt ttttgttttt tttgaggaac ctccatactg 300
cttttcctga tggctgcagt acttcacatt tccaccaact gtgtaaaatc ctttcttagg 360
atcctcacca gtattcattt tttgtctttt tgatactagt cattctaact ggcgtgagat 420
ggtatctcac tgtggttgtg gtttgcattt ccatgactcg gtgataatga gcaatttttc 480
atctagctgt tggccatttg tatgtcttct tttgagaaat gtctattcag gtcttttgcc 540
cactttgtaa ttagattgtt ttttgctgct gagcactttg aattccttat gcattctgct 600
tataaatccc ttgttaaata aaacagttca caaacatttt ctcccattct gtgagttgtc 660
tctttgttgt gtcctttgcc atgcagaagc tttttggatt gatgtaatcc aatttgtgta 720
ttttacaatc gttgcctgtg ctgttgatgt cttatcccag aaaatcttgc caaaaccagt 780
gtcccataac atttccccag tgttttcttc tagtagtttc gtagtttcag gtcttccatt 840
taagcctttc atctattttg aatcattttt tgtatatggt gaaagatggg aatccagttt 900
cacttttctg catatgaata tccagttttc ccagcaccat ttattacaga ctgtcctgtc 960
cccactgtat atcctcagca cctttgtcaa aaatgaatag cacgtggatt tatttctggg 1020
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
295
ctctctatgctatcccattggtctataatttaattagcctgaaaatggaaagttagggag1080
actccttcttctctttctccatgttttcttaatgagaaaatatagaaaaaaataatgcaa1140
agtaagtaccaggatgggggtgtgtagtttcattttaaaatagtaaggttgaacaaaagt1200
ttatgccaaaggtatttaaaataataacacaaataatatttaaaggcaaagatgtatatg1260
tatatatacatgaacatatttaatttatataaaggagaatgtgaatacatatgtatgaat1320
ttttttacttggtgtatacaatatgaacatatatatatatgcatatgtatttatttactt1380
gatctagaaaacttgactatgaagttctctagtataggcccttagaagttctaaaagtca1440
cagtaacccacattgtacctttggtttttaatgaggaagatgatctgctgtggtgaataa1500
ygcattttccttgtgaaagtcacgtgaccagtacgcattgacagaatcatgagacaaatt1560
aacaatgagcaaaacttattatctccttacacttcatgttaagttctttgaactttcatc1620
ttctctagtagctaaacgttacaatcgagtcagctttctctcagccaattgttttctcta1680
tttattctatcatttaaagttactgatttggatcattattttcctttcccatgacatttg1740
acctaggaagttgacaaaggtgagctggcactgaaaagcaacttgacccaggaaaggggg1800
ctctgcgcttttcttatctaagcatcctcaatcgaaacctcattctttctttccgttatc1860
ttggcctcccatttaaagctggtgtatatgtattttgagaatatatcatgtcttccatca1920
caagatatcattctttttatataagtatgtcttgtcagctctttgcttttctctgatgct1980
ggattgtggctacacagtgtgaataatgacacataagcaccctgtttatttaaaaggttt2040
cctgtggttaagtacatgtattatactagagagcaaagaatttctttctaaaattgattt2100
cagtagaccctatgagaggcatcagccagcacccgggaatgagctgccatagatatcttt2160
gtttatgctcccacttcagttcttttaagtgcattattaatagtttatgtgactccttaa2220
tgtttggtattagtgttttcatacaatgaaagatgataaagtgatgccacttttattgtg2280
tgctttaattgctaattgttaagaaatgtatattgtttccttcaagttcaattcctttgt2340
gacttaatgtcattgctggtcatctttcaactagatcaaattactctcatactgttttat2400
ctttttcctttgtctttacactttttttaagggacgtacgtttgtgtatatagataatcc2460
accgttaaccctttattttacatcattatctatggcatttatactttataattattttaa2520
aaacaatgtttataagacaaaatggtattcaatttcaggtaatttagtcttagaatactt2580
attttcttctttctcttttccttctttaaagacaggttctctctctgttgccctggctgg2640
agaacactggcgctatcatagctcactggagcctgtaaatcctaaactccagggatcctg2700
ccacctgctccctaatagctagaaatgcaggtgatcatacctagtttttcctcccccacc2760
tgccaacagacccaagctctctacaggcgtgagccactgcactcagctcagtcttagaat2820
atttcgagtcctgtcgtatgaacttaatcgagtaaggtgaaacgttaggggcagagtttt2880
aagttttcattttgaggggtcattaaggctttaagtttaactaaaaaataagtatatatt2940
attccctttgggtaatttcctagaaagcttatcaaaatatttatttggtatagatttcaa3000
a 3001
<210> 129
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-25966-241 : polymorphic base T or C
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-25966-241.misl, complement
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-25966-241.mis2,
<220>
<221> primer bind
<222> 1721..1741
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1219..1239
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> downstream amplification primer
296
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-25966-241 probe
<220>
<221> misc_feature
<222> 1659,1987
<223> n=a, g, c or t
<400> 129
tatttttgtttggaaagtacaaaattttattatttttatttttattttactttaagttct60
gggatacatgtgcaggattgttatagaggtatacatatgcatggtggtttgctttacgta120
tcaacccgtcatctatgttttaagccccgcattcattaggtatttctcctaatgctctcc180
ctcccgttgcctcccatcccctaacaggccacagtgcgtgatattcccctccctgtgtcc240
atgtgtcctcattgttctactctcacttatgagtgagagcatgcggtgtttggttttctg300
tttctgtgttagt.ttgctgaggacgatgggttccagcttcacccatgtccttgaaaggac360
atgatctcattcttttttatggttgcatagtattccatggtgcacatgttggaaagtaca420
aattttagttcatgcctgaaatattttcataaaattgggtatcttgtgcagcgaaatgtt480
tcctttttaaattattattatttcattttgaaactaaagaatcagttaagaaaatgaaag540
gcttcattcatcatgtgatttagcagctgtcaaaattgtaccctttgctgatgtcttagt600
tttatttaaatccatttactagttacggggtaattatttgcccaagagtattacgtatta660
ttactttatccaaataatcaaacttcaacctattaggaagataaaaaaactattaaaata720
atagctgtggcttttttcccttttttgtactataattaaataaaatacatttgctatttt780
taatgtataattaataacatctatatggaatattataaaaaaacacttactgtatttctt840
tgatgaccattattttataatataaattacgtcttgatgactactgaaattatgagatat900
tgagcaagaggtgttaaggagtgatctacgttggtgtcaaatatgctgggtatgtcacta960
gttccctgttaattaagtatttactggatatggcagacaaaatattgtatgttcataaaa1020
tgtttccaggttcttcctatgtccataggaatactccctttcccaggccctgtacatctc1080
caggggctgcgtggctagttgcagtcataaagcttggggagaagcgaggtcatcacttcc1140
aagcttcttcccttcatcctctttttgtttgcagctgggtaaatacagaggacctgtgag1200
aggacaccacaatgcccttgagagtcagtgaagatgatgtgcagctgatctcctgccagc1260
ctaagatacccttggagcctaagtgagaaacaaatcttcactgggtgaagccactgaaat1320
gtaagggttgatgtgttactgaagcttagcttgcctgacctgaccaatatatctacctct1380
aaataaacaaggcacatggggaatgagggagcaagagcggtaagtgtggactttaagaac1440
agttccgtgctgaagtgggatttgctatgagcttggaggaaggagtggcagtcaaccgac1500
ycttgaacattctcaatacatgcctcacactttcataccatcaagcatgactcagatttt1560
tcctgaatactgacatgacttttcctatacttaaatatgaatgcccagaagttaaataat1620
accttcttagaaagcctttcctgaactcatactcatacnttttagtctggactcctgtgt1680
caccttcatctttatgaaacttattttatgtgtttttaatggttggctgtttacactatt1740
gtctccctatctagcttttgatttccttaaggttaaagatcatatctttgtatctatgtc1800
ccacagcacttaagaaaacatttgtacatgaccatttcatcatttatttacaaacacaaa1860
tgtgtattacctatgagtcacagcccgtaatgggtctgaggatcaatacatgtgtgtcta1920
attgaattaagatttgttagggagagatagaaagccatcctgggctgatgaaagcttttt1980
gaataanggaggactttgcacaaggacatgcttttccaggaagttcaagtccacttggcg2040
ttgtagtggaaagtcaatatagagagaccaggttggtggaaagtcttgggtgccaagcta2100
agtggaaaagacttgagttcttgaagagaaatcaactaagttcaatagtctaaattttgg2160
ccacagaaaacctatagcaattaaacacataaagcaagtaatttgattctactttattgt2220
agagtacgtgaaaaatgtatggtgtcttatctcaaatcattactcaatgtcagggcagaa2280
gtacaattgatcaagcctatagtcagctgctaattcacgagtttttttgtttttgttttt2340
cctgtgacttcctagctttccagactgggcaaaatgatatctgcagacattaaagaatac2400
tggaattaaaaacacattaattttccatccattagggtgatgtgtgccccacaggtggac2460
tataaggaattccctggcttggtgcctgattgctttgcatagctggggattccacttaac2520
accctgccatgaccctctgctggtatgcttggctgccttaatcttggtatatttcatgtt2580
gaatggccgtggcagtccaagttgctccgtaggaaatataatatgtgcactgtagaaagc2640
tatgtcagttttgctggtactgagtggcttcaaattcaaacctagctgttgtaaaaacaa2700
caactaacagacaactgtgattttaattgaacatgctaatatcatggccattttgaaaca2760
atggtcaagtgtaaatattttgaagaaaagggtttcttaaggtaatgtgagtagtttcaa2820
agcataaataatatggcatgtaatttgtatgcaaatatataacagcatgtatctttacaa2880
aattaaaatatttaagaagaacctttatttatgtccataggaatttcattgagaaaatag2940
atcatgatgctttaaaataattatttatctatctatagcacaaacaaaatataaaatttc3000
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
297
a 3001
<210> 130
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99=25967-57 . polymorphic base T or C
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-25967-57.misl, complement
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-25967-57.mis2,
<220>
<221> primer bind
<222> 1537..1556
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1064..1084
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-25967-57 probe
<400>
130
tttgtagactagaatctctttgcttacatctactaaaatatgccaaaagcacacatttat60
gcactgaatatcagagagaaaaattatctgaagcaacacaccagatacattttcaggtat120
taatagaaatgttctattagtgtaccatgttcattaaagttttgcacagaacatcaaact180
atgcattttctaatgagataacatactgaatgaatcatatattacaatataaatgaccat240
tcactaagttaatttattttactctagactttatgacctccttgcaaaactttaaagagg300
gatttgtcaatattcaccatactgatattttaaatagttaaaaatggctcatgaatgaac360
atgattaaactatcagacagaaatagtaaatgatattatagcttgaatgtcaaactatag420
ctcatgatattttcagttattcactttgtgaaggataatttctattctgacctaattctt480
ttattatttaatatatagtttaatcatataaattatgtaatattaataatatgtatagcc540
tacatatgtcttttttgtcttgatttttaaaataatataaaattatattatctttaacaa600
agaataaacattttgttataattcaaaaatctggttcttgttttttaaaatatgtatttt660
cataaagttattaagtggaaaaggctggtgcaaaaatcaagattgcaaagtattttagct720
ttttgacattaaaaatgttattttattagtaaataattttcctttgcagtcattactatt780
attttgtgtatccttgatagcttccattggtttcttctctaatttgcgtggtatttcttc890
ttaaattttacgtggacatagttgtattcaaatatagatatactgttgttttaagtggta900
tatgtaaagtacaagtttatagatttcttttatttaaaaatatacttgaaatgttctaac960
attaatgctttttatttgctttaaagggcttactaactcttagataaattgttctcgttg1020
taaaaatgaattgccatatactgtatttttgatgcaaaaaatacaatcagaatgccaaaa1080
tacgcattttttgttttgtatgaaaagtaattgatatatcttttctagtataatcatttt1140
gtttaagaatggttcttgaataattatctctagcacagaactttgttcttcacttagatt1200
tatgtttccaactgactagatatctgtgcggtatggctcagcaaaatctccattcttaat1260
acaatgaaataaaacccttgaccttcctatccctcacgagcttgtccttctaggactctc1320
tgactttgtcgttggcacatttatttgcttttaatttatttttttatttttttatgtttt1380
taacttgtttttgccagaaaactgggaggagttcttgaccttctctttctcacacctcca1440
attatagtaatagcccagctgttctcttgtgcctgcttcttctcttcgtccttttcaatc1500
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
298
yaggctctgtgtaacagtccaaatagagaaaatgtacatttgtcatgtcacttgtttgtg1560
taagactcctcagtgacatctgttatacttaggataaaaatccaaggaccttactgttca1620
ggaagacactctgaactcagtcctctgctgaatggacagccccatctctccctccagcgc1680
atccctgctcacatacgatgctaaatccatattgaatttgctttagctccctaggggact1740
gaacccttttcataactgtggtcttcctaaatgcctggaatggttttcccacctccttga1800
ctggctaactttattcttgaaactaaaggttaaatttaccttcaggaaaaggcttccatt1860
agagcttaattcaaatcaggtcagactctcgtttctgtagctgcacttctcatctgcaac1920
tgcatgttaattgccgcaccacatgttgagtatctatctccgccatgagatcgagggtca1980
gtgaggacaagagacctgggctcttgattggctgttacagccctggtatgtaagatcatc2040
atatgcataggtaaaataaaaatttagtgagtgaatgtgtaaattggctttttaaacagc2100
tacatcgattagtgtcctttgaatatttgtttttctggacagtcatttctgtccattgac2160
tgctagagattggatctgaccacaaccacacggtacacatattcacacgcagctggaatt2220
aattattttctttggacttgtacttgatgccttggattttttttcttccagattcaaaac2280
aagtaaaagaataaccccttgacatcatattggatttccagtctagctaggtaaggtcac2340
tgccacagtgaaaagcagtgaggttccagaggcaaggcggtgggagcaatacaacccaga2400
gacttcagagaatttagaagcagtaattgtctgtagaaaatttcaagctagtgataaaac2460
caactaaaagttgatccgctttttattattaccattgcctggcaattttaaacagtgcca2520
atgatttaaatactcctctaggggaagggagagaacttttggtttcagttctaaacttac2580
tataatcagagttgagtttttatactacaagtgtatcctttaaattagaagaattactca2640
ttatgctttaataaaacctgtttcttacttgaaaattaatttagagaattcactattgcg2700
tagttcctgtctcgacgggactcagctatgtgcttgtgttttaggagagtagttcataat2760
agtttgaaattgggcacagttgaagtctccaaatagcactacggatttctacatttatat2820
gatatatttgaaataaacaatgctagcacaatgactataatggctaaaaaaataggactt2880
gagttgcttcagttcttctattctatgcaaccactcagtttttatatgtgtttttaaagc2940
ttatggtgaaacagaatgcataatgcaaggtactttctaaaatatttttgtttggaaagt3000
a 3001
<210> 131
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-25969-200 : polymorphic base C or A
<220>
<221> misc_binding
<222> 1502..1521
<223> 99-25969-200.misl, complement
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-25969-200.mis2
<220>
<221> primer bind
<222> 1680..1700
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1171..1191
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-25969-200 probe
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
299
<221> misc_feature
<222> 454,710,842
<223> n=a, g, c or
<400>
131
ttgcccaggctggagtgtagtggcacaatcttggactcactgcaactactccacctcccg60
ggttcaagcaactctcctgctcagcctcctgagtagctgggactacaggaatgtgccacc120
acactcagctaatttttgtatttttaatagagatgggatttcaccatgttggtcacgctg180
atcttgaattcctgaccttgtgatgcacctgcctcggcctcccaaagtgttaggattaca240
ggcgtgagccactgcgcccaaccggaaaacctattttaagacaagtctcttttccaattc300
tcttttgctagatgacactgattttttttttaagtttgaaaggagtgctatagatttatt360
gtatctcaataattcaattatttacatctgtccagtgtttcatagttttcaaaacacatt420
catatggaataaaatactctttagtcttcctaanaaccccataaatcaggttagccaggc480
atcatgagtgattctgttttctatcacagagaagtaagatcgggtagttgtttaaacttt540
gacattggataaacactaaactgtgtttgaatattggctctgaaatttactcataactaa600
cacttggtcaaataaattgcgtactgaatcatccaaaaatatttcattagcatctaccac660
atgctggcattccgctgagcactgggctggattggagggtcagatgtggncctcaatgtc720
atggtcctgcatacacatgtatttggagataggctcacattttaaacaaaaacgcaccag780
cctaaaagtgtgtatgtgtatttttctcatatcatgctaccggaaacgtctagaatagtg840
cnaatatagaagggaagaaaaagtcttttttcataatcatattttcataaacatatttcc900
ataaacataattcagggatttatattttctctcattttaattgtattcttaaatattttg960
atttaatatttaactttttaaaaattaaaatagtattcttgtaaaatacttattttctat1020
gcctagtattatatggcatctattgcctgtcaagacagtggcattaaaaatttttttaaa1080
ctcattttgaaagaactctgtaccagagcagctgtcctaaaaataaaaaaacaacactcg1140
gagagcctttggttttggtgcccttctcttgctacggtgtttgcttttctgcactcctga1200
cttcactctttgctgttggtaagcatggctccctcccctgcttccttatggcttctgaat1260
tgaactcttattttgctctgttctgtacccctcccttttctcagattttcattgacatgt1320
gaagatcattctctccttccagagtttattttacatgaggacaaaaaaaatgcttttaac1380
ttgatattgactttatgggtctaccacatataatttgttatatgttgacaggatttctag1440
gtgattcatggggcatctgtgattctccctctgtctggtttggagaatgtggtaggattt1500
mtatgctacacagtttacttgactgtgtagcatataaatgctgtacttgacttgaatatg1560
tcacagtgtacattattttaaagactgcattagaacaaaatcagctggtactccttagct1620
aaatctcctggtggcagtttaaaattttacttgataatctgctttgaaaccagaaatgtg1680
taaaagaaggagtcactaacttcctagttactcttaagtatatatagagggacattggac1740
aaagtttatattttctgcaaagcacttaaatatatatgtattagaaaggaatggttacag1800
tttaatataagggttggaaaactttttatgaaaagggcaaatagtaaataatttagaatt1860
aattggttgtacatttctgttgcaactatcccacactgtcatcatagcacaaaagaagcc1920
acaggtcctacataaacgggcatgtctatgctccagccacattgtatttacaaataggca1980
gtgggcagagcttggcccataggttctattcatagtttgtgaacacctggtttagtatat2040
tataaatacatcccaagagcatctcttatgttttttggaaccctctggatggggaaggca2100
taaacaaatttcctcagtgggggtttcatgtaagtattcacactctcccagctgctatga2160
gttgtctatttaaaacctagccatgagccttgtatgacctgtgattttacagtgattctg2220
aaccatttttcctcctccagaaggaggtatgtacaggtgctccgcagtcacattagtgtc2280
atgtctcagcggtgaggaagagacacacaggcaccaaagagtggcatgcaatcatactaa2340
agcaatctcagcaaaatggtcatttgtctatttttgttttcttttgtctcgtcttccttt2400
ttatttatttatttatttatttatttatttttgagacagggccttgctctgtcacccaag2460
ctgtagtgcagtggtgtgatcacgtctcactgcagcctcaaccacctggactccagagat2520
ccatgccaacctcctgagtagctaggactacaggtgcatgccaccatacccagctaattt2580
taaagttttttttagagacaaagtctcactatatggcctaggctggtctcaaactcctgg2640
gctcaagtgatcctctgttttgatctctcaaagtgttgggattacaggcactcagccagt2700
ccatttttaattatatatgggactacttgcttttatttatcttgtagcttgtttttcatt2760
gtatttatatgaatctaacagctacaaaactacttcaacttttattttcttttcaatacc2820
tttcatttaactaagatttaacacgaaagaaattgctcacttctatttgcttgggaccaa2880
cacatgagactcttaaacaaggggcagagccctaagttaaataatgggcatttagttttg2940
atgtgcattggttcagggtcctaagtcacctaagttttgtagatagtttctttactccac3000
c 3001
<210> 132
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
300
<221> allele
<222> 1501
<223> 99-25972-317 : polymorphic base G or A
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-25972-317.misl, complement
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-25972-317.mis2
<220>
<221> primer bind
<222> 1795..1815
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1368..1388
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-25972-317 probe
<220>
<221> misc_feature
<222> 1274
<223> n=a, g, c or t
<400>
132
ggataaagtgctatccaattttgagagctatctgcaattttgcttaatattcgctttgca60
taaagtcagaaatttttggagagaactataattgccccatatttaaaatattattgagaa120
tgcaatagactgaattcaaaatgcactttgagattcagcctactcacttaaaaaataatt180
ttttccaagttcatttgcaaagttctgttgaattctttttttagttatacttagttatat240
ttaaaaacttaataaaaaggcctgtgctataagaagttagtgttctttgccattattcct300
tttagttttaaaggtactttgcagcacatgtgttagtacaacttacaaaatctggtaaaa360
ataaaagggaattaaagatgttattgagatgctgtgagtttgcaaaacataatttaaaaa420
gttaggaattaactactgatttcttataatagtgtatttttaactcttatctaacctgga480
atcatcttgcattgtttagcaaaattcatcttgcgtttttggagtcaaatgatggcaaaa540
cagcacaagctggaaaactgatcatggattttgaaatagccaccgtcttttctgctccca600
gaattttatgaatatttttttcttatttttttccttaatcctaaggtattttatttctac660
aaaaacatttattgactcacatagtttgtcaggtatttaataaagaaaggttttacttct720
tgtgtgtttattcatttgcttaatcacaaaaaaactgtttcctccaactgtaattgatgt780
ttctttagcttctttgactcttatcaagtggtttgtgttgttatcattgactttttgaat840
tgtttagcacttttttgtcttcgtttcagtaacttcacatacagtatgtattcagaaaag900
agcctgaggtatgttaaaaggggtaatgtcagtgagccccgccacgtcacagtgacagct960
tcaggttcctgatatcttcttcgaggtgataaccattaatagctgcttgaagggctagat1020
gtattttggttgtaacaaaagggagtgtaaagtgttgccagaatcatggtgatactctac1080
tggagaaaataagaaacactaaaaaaaataaataaaaaacttacctctaagtatgataaa1140
ctccaaaggaagatgtagataaaaaaagacactaagatatttgtgtggcatgctataagc1200
aagttttgaattgtattcttcaacatttgataaaacaaaaattcaaactcttaataaaaa1260
ttaacccctctccnttttttttttttttttttttttcacttttctctgtgccaggcctgg1320
tgataaaattatcctgccaaagaccttggtctgaagccattatttgtgtagccacttctt1380
cagaaatcagaaaatcatttaagcttgggttagacagctgtgtgaagtgttatcaagtaa1440
gtgacatctgcaaattagacagaaaagtatgcagctggcaaaataatctaaaatgcaaca1500
rttttctgaaattcttgggagctaaagaagggaccaggaaaaagagaaaaagaaacaaaa1560
atgttttctaggctagattttaaagaagtcaagattatatatatatgtagcaaagaaagg1620
ccttacctatagcttaataattttaaaatgacatttctaatccaattatatgtaataatg1680
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
301
ggaataggacagacctgggctaaaaactgacaatttatgcctaagtgtgtgtgcacctgt1740
gtgtcttttttagtgtctgtctaggtaaaatgaattctctagattaagtggaatgaacca1800
atgaactcataggtcacctcctcctcctctgccaactttttcattttggtttttacttag1860
cttaattgcttttggtttgaaatttgcaatcctgctacttgaggttataaaacaatagtt1920
gacttaataagaacacaccaactaaaattatcaggagaaattaaggaatttcaggtcaat1980
aggaggatgcaagggaaacctctacattacaaacaatttatttatatgggctgcagttct2040
ctgttctagttatgtattgctgcataataagtcaccacaaaactcagtgtgaaagcaatt2100
atgattatcttgtccctgatgctgcagtacgatcaaggctccagtagatatctcagctct2160
tctccgcatgcatctgctgggccagcccaaaagtaggggttatttgacaggtgggactag2220
aattattgcagacatcacttgggttggcagtgaaggttggctgtcagctgctactttgcc2280
tgaggccatctgctagaacctttgcacatgttcttgcattgtggctagttggctttctag2340
cagcatgtctaccgggttcccaagggagtatcccaaggagacaaaatggtcaaccatggc2400
tttcctgtagccataaccaaaaaacatacctgaaactaagaagaaaaagaagtttaattg2460
gacttacagttccacatggctggggaggccttagaatcacggcaggtgatgaaaggcact2520
tcttacatggtggcgacaagagaaaaatgaggaggaagcaaaagtggaaaccactgataa2580
acccatcagatctcatgagacttattcactctcatgagaatggcacagggaagaccggcc2640
tccgtgattcaattagctccccctgggtccctcccacaacacgtgggagttctgggagac2700
acaattcaagatgggatttgggtgcagacatagccaaaccatatcaccggccttgaaggt2760
cacataacatcctttctactctattcacaaagttctacctttcaaagggagggtctgtca2820
tggaaaccacctcatgggaggaatgtcatttaacatgagcccagggaacaaaatatcttg2880
cagaggccctctttgaaaaatacagtttgccacagtctgccacctggccacaacaatcca2940
ttcccctcttccatgtaaaatgcattcaacctctccctcaaaatctaagtctcaggcctt3000
t 3001
<210> 133
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-25974-143 : polymorphic base T or C
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-25974-143.misl, complement
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-25974-143.mis2,
<220>
<221> primer bind
<222> 1623..1643
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1100..1120
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-25974-193 probe
<400> 133
ggcttttggc cgcatttatc acttgtaaaa agaattttac tgaccaggaa taaatacatt 60
tacaatgtgt ctaagtaacg cctgtgtgat tttcatttac atgacaatga ccctttccac 120
tgttttctta caactttccc ttcgactgcc tgatgtttat tggttcatta tttgtaaaag 180
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
302
agtaaaacctcatctgaaaaaaaaaaaaaaaaaagaaagtgtgttgtgtctttaatttta240
aaaaccgcccaagggccctatgggggatattaaatctgtctctttgctgtatatcttgat300
gtacattttagttgaaaccaggtgttttgtatattgaactttttaacactgcagggaggt360
aagtattcacagctggagttttatgcttcacacattttcatgtttgagaacaagaagcaa420
cccctaggaaaacctcctccggcatgaagagaggctgaacaatgcgcttctgtagctagt480
ggcaggccatggatatgatgaagtcacagatatcggaactgaatgcgagatagatgccag540
tgaaaccaagacaaaaactttcaaggaatccaagtgcacaggttctcagatcaatcacaa600
gcgatgaggttgtcactgcacagaggggctgaaaagcagcatcaaagccactaaagagag660
gggagaagcttttgttgggccggcttttgtcttcataaccagcattggaagccagctcac720
atcaactgaaaggccgagttaatctatttctagtgaacattgttcgactgtgtgtagtta780
gcccgtaatcattaaagaaaaataactaggttggcatgaccaaaaaagcattgattttcc840
tgtggagcacatttgtatgagttgaattttttgcatatgttattgtgcgcatgagagaga900
agaggtgactgacctcacaaaacaaatgcacacagcagcgctgcttcttagcctccacaa960
tgaacttggtgtttgtagagcaagacgtaagatggcctattaaaattaaaaacataacat1020
ttctaattcagccttttatggattcactttaacctttaaagactccttaaaaatacagca1080
acaaaaaaagcaccttttcacgatttggttagccttcctggagaaatttgtcatggcatt1140
gcactgagagttttgttctttgtggccagtaagaaaagattcagagagggggtaccgcta1200
gagaaggacagggtgagggagaccgatacactgcaatgtcttcatcccttcttagtatgt1260
gactttgatgtcccacatctccagaaaagagcttcatgttagctctgatcattccagatc1320
aatccagcccccatgcaaatgcagtgatcaggctatatttagtaaaatgttgttcatttt1380
aagtttttttattatttgagagcagagacttccagtaggcacagtttagaccctgttatc1440
tttgtctcacctccctctgctccaagacctcagagacccagactgttgttaggatgtcag1500
ygcttggaggcacgcagtggctgagcactgggttctgtgcagctctgacagtaggcacca1560
tgagttttcaggccaagaaaaataacttaaaaccctaagaaaataaacaaccccaaggct1620
accaaggaaggagagattatagctgaaaaatgtcagtacttgacagcacaaaacagttgc1680
ccacatatgatgggggaaggaaaatctaaaaaacaaaaagttgatgggtgttttaacatg1740
ttttttggcagaatattttcgaagtggattgaaatattttccttcccagttagacctagg1800
ctcatggtgttttgctaatgattctctgagtaagtgttttcttcaattgctttgagtgac1860
ataagttgctcagatgggtcacaccctcatgttggaacatcgagtatgaagtttcatgtg1920
gacacacagagcagaaaatctgccttttttggaatttgggggtacagattcgctctgtgt1980
ttgtgacagaatgtcatcttctgtttgtgaggaagcaggttgaggagtcaataatggatg2040
aaagtacaggagtcagagattgtggaagattctgaatgagaatgagtccaagaaggaggg2100
cttggctggcctgtaagtatcatgttctctgagctggagggtaacaagacacagtgatgc2160
aaatcactgtctctcactacaggtggcttgggagtccttatctgatgcacatgtgctttt2220
cagcctttgcacaataacatgtatcttttcatttaagcttgtggcaattatttgagactg2280
attctattaccatctgcacagaggccaacttacttaaatgagaaataaaacccactaagt2340
ttttctggctagggtaggcttatctagtttaaagccataacttctattagttctacgtaa2400
accaaaattggtaattcggagatttacaagatcttggaaaattcaactttctgttccgat2460
tcttcacctcatattcaagttaacatacattaatctagacctggaaactgaaatctgatg2520
tgcgtaggcctaaatgagaggacagaatcactccttcaacaatgtattaataaatatttc2580
aactgtattaataaacacaataaacacactgataaaatgatgactatgtgataggccctg2640
ggctaggtgtcaaatacacagtaataaataagatgagttctatatctttaaggaccatgt2700
attctaaattccatctggagtataatttttatttctcaattctattttgtctgtcatttt2760
tcctttatttttatggatttctgcattaaataacttaaaaattttaattataggccattg2820
tatatttttagtccagttgaaaaagcaccttttactaactacagactgtggacagtgatt2880
atgtaggaattgaagaaataaaaataaaacaggagaagatctcaccttacagggagggat2940
cttccagaccaggggacaacattattaaaccatatctttctctagacatgcaaatatcat3000
t 3001
<210> 134
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-25977-311 : polymorphic base A or G
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-25977-311.mis1
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
303
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-25977-311.mis2, complement
<220>
<221> primer bind
<222> 1191..1211
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1710..1730
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-25977-311 probe
<400>
134
catgccgcaggagccttcagagcaagaacaccaaagtcaggaagcacattcctcttctcc60
agcagtatcttttcatcctcctccattggccaggcctagtatcctgggtcatgtctaaat120
gtggctctcttgtgtttttttttcttgcctgtgtcatggcttgtaatttttttgttgtag180
ttgaaagctgggcgtgttgtataggacaataggagtggaggtaataggactatagtttgg240
gggcttatgttaacctgtctagaatttgggttgtgttgaaggtttattggtactccaggg300
gtcagagtcgtcatattcctctattggccttgcctttgtctcacctgttaactccagact360
ttcctaagtggttctgctcaaagagacggtctgtatcttgtacatcttttagtgaaaatt420
cacttttggtgtagtgatagatgtggaagatggaaaatgttctggaaattcatgactcat480
cctccatctcttagtgggcttgtgttcctgagctgcaaccttcactttcacacatttttt540
ttagcttccccactcctctcaggtgaaacaggaaggctggaggggcctacactcaggtaa600
atgacctttccacaggtagatcaggctctgataaagtcttttcctgtggggttaggcctt660
tgttttagagaattttcttggtatatttcacagctgttactttcccttccttctgctaaa720
gccaaaaggggatttttcttagctctaagaactaagtttctagttagaaactagtactct780
agtctctaagaacatggtccttactagctcctcactttcaaactaacccacacccagctt840
ccagcaatttattaaaattaccatctaagtgttctaccagattatgtctctggtagcttc900
tgtccaggtatatcaactccacctgtcagctgtgcctgtctctccagattttggggtggt960
taaccccaaaaccgcagttctgtaatgggtccaagagaacatgtttaagtttgttgagct1020
ttttcttattacatgtaatagagtgatcacttccaagttatttaacttttaaataaaaac1080
ctgttgagcaattaatatatacctacttctatattactttcggaacatatgtgctctttt1140
aaacccatgtagttttcaaaatgttttaaattatgactgaccccaagtcccaattctctc1200
aaaattgtctcaaataaacaagtattgagccatcgtgatgaattatgtttgttcacaggt1260
tattccatttaattttctcttcccacctcattaagatgtaaatagtaactcagcttcata1320
gagaagactgaggctaagagaaaaggattgtccaggctgaaaggttagaaaaaggcagaa1380
gctgctcttctactcagatttctgacttcaattccacaaaggtcttaaaattaggaaagc1440
aacacttaagcactttaaatagctatgaaaaatgcaaaatggaatctattcaagcccatg1500
rttctgtgttaattgtgctctgatgattgttctctttctttgcagccccacggtaacgga1560
ggtggaagtcagttctgcttctctgttgttttgcaaggaatgttcctaggaatattctgt1620
tgcaccctgggaacattatcttcatccgtattttaagctttttatagacaagcaaaagaa1680
ccatttaaaatatatataccacagcttctgatacagtgttgaaatactacaggcatatta1740
agcagtttctcccattcacaaaggaagagtcaagtgagatttgacaacaattttatgaaa1800
ctgacaaaatgaatcacaatcaattaatatgtaatggttttatttataagaatttgatgg1860
tcaaagctgtgaaagcttatatacttctctctggaagcaggattaaaggagttccctctt1920
ggtgaactcaccaacacacaatcttgagctggagaagtcattacatcattacaaagtatg1980
taatttttgactttttatttattaatccccttagatacacaatgcattttacaataatga2040
gaagttgtttcctaaagtgacaatcatttttcttcataaacataatttgcttccttaact2100
atttaggagtatttagttcctttagagtccatatctgtttttgtctttatgggtcattcc2160
acaattatccttcacttgccataagtgagtcaatctttcagtttcattggttctggaaac2220
ctgtcttagtattttgttatattatctttctattttttacttgttatggttaagaaatac2280
aactttatcaagtaaaagtatataaaagtagatattaatttctccatttgttagactgat2340
tattcactatgggcaaatggacttaagtaggcctttcagattattctgtgttcatatgtg2400
agtagcagagttttcactttgtatcctagagggtattataaacattaattaacttctata2460
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
304
acaaccctgggaaatgtaggctgtattatgtctattttgtagataaagaacttgcaactt2520
gtaatcaagctatgctgagctaggtactgaagagtttctcacaaacaagaagatattgtc2580
acaggtttgtactgaccaaaaaagaaaaaaaaaatcaaccgtgtttggctgccattttta2640
tttgtgattttaaaaattttaaaagtaaatattaatttagttattactatgggcaaagca2700
ttaagcccacccacattctttcttgtttctcacaaaagttattccctaaacacattcttt2760
ttccttacattcacagtttctcaccacccaatttgatctgtaaccttgcttctatctgtt2820
tattatgaatttaagaacagctggtgtttgatttaccaatttcccaccatttatgctttt2880
tatgtcatctattttgactccaatttgcatgtgtctgcaagcattctgaatatgagaatt2940
ctctgctcatctttaatccaatttatttttgtttcctgaagtaccttattcccatactgt3000
t 3001
<210> 135
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-25978-166 : polymorphicbase T
or C
<220>
<221> misc
binding
_
<222> 1502 .1520
<223> 99-25978-166.misl,
complement
<220>
<221> misc
binding
_
<222> 1481..1500
<223> 99-25978-166.mis2,
<220>
<221> primer bind
<222> 1644..1663
<223> upstream amplification
primer, complement
<220>
<221> primer bind
<222> 1155..1175
<223> downstream amplification
primer
<220>
<221> misc
binding
_
<222> 1489 .1513
<223> 99-25978-166 probe
<400> 135
aaaaggcaga agctgctctt ctactcagatttctgacttcaattccacaa aggtcttaaa60
attaggaaag caacacttaa gcactttaaatagctatgaaaaatgcaaaa tggaatctat120
tcaagcccat gattctgtgt taattgtgctctgatgattgttctctttct ttgcagcccc180
acggtaacgg aggtggaagt cagttctgcttctctgttgttttgcaagga atgttcctag240
gaatattctg ttgcaccctg ggaacattatcttcatccgtattttaagct ttttatagac300
aagcaaaaga accatttaaa atatatataccacagcttctgatacagtgt tgaaatacta360
caggcatatt aagcagtttc tcccattcacaaaggaagagtcaagtgaga tttgacaaca420
attttatgaa actgacaaaa tgaatcacaatcaattaatatgtaatggtt ttatttataa480
gaatttgatg gtcaaagctg tgaaagcttatatacttctctctggaagca ggattaaagg540
agttccctct tggtgaactc accaacacacaatcttgagctggagaagtc attacatcat600
tacaaagtat gtaatttttg actttttatttattaatccccttagataca caatgcattt660
tacaataatg agaagttgtt tcctaaagtgacaatcatttttcttcataa acataatttg720
cttccttaac tatttaggag tatttagttcctttagagtccatatctgtt tttgtcttta780
tgggtcattc cacaattatc cttcacttgccataagtgagtcaatctttc agtttcattg840
gttctggaaa cctgtcttag tattttgttatattatctttctatttttta cttgttatgg900
ttaagaaata caactttatc aagtaaaagtatataaaagtagatattaat ttctccattt960
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
305
gttagactgattattcactatgggcaaatggacttaagtaggcctttcagattattctgt1020
gttcatatgtgagtagcagagttttcactttgtatcctagagggtattataaacattaat1080
taacttctataacaaccctgggaaatgtaggctgtattatgtctattttgtagataaaga1140
acttgcaacttgtaatcaagctatgctgagctaggtactgaagagtttctcacaaacaag1200
aagatattgtcacaggtttgtactgaccaaaaaagaaaaaaaaaatcaaccgtgtttggc1260
tgccatttttatttgtgattttaaaaattttaaaagtaaatattaatttagttattacta1320
tgggcaaagcattaagcccacccacattctttcttgtttctcacaaaagttattccctaa1380
acacattctttttccttacattcacagtttctcaccacccaatttgatctgtaaccttgc1440
ttctatctgtttattatgaatttaagaacagctggtgtttgatttaccaatttcccacca1500
yttatgctttttatgtcatctattttgactccaatttgcatgtgtctgcaagcattctga1560
atatgagaattctctgctcatctttaatccaatttatttttgtttcctgaagtaccttat1620
tcccatactgttgtgacctctttctaataccttctgtgtcaacttcctcgtgtgtgcttc1680
ctttctgtagttcccatttaaaaaccctttgatcctctccctttccaatgattaccgtat1740
tttcccaaatattttatagtcaaatcctttaacttccgtttttatactcactgtgctcat1800
tcccttagcacatatccttttctctaacgcttgcaaaatctttcaaatctagcatacttc1860
agatatctgaatagccagacgggctacttctttccatatcttacacctttttaatgtttt1920
ctgcaatactttaaacatttgtcctctctgcaacattactagacaggttcccttctttaa1980
gttctaatcttttgaagcttctgacttccctgggccttcttgacactgtattttcttgcg2040
ctctctgactgctccttctctgttatatttgcaactcctcttttttctctcacctctaaa2100
tgcctcatgaggaaaccaatccttccctctgctcttataaactgaacctgctctatctgt2160
gaagcttaacactgcctaggagagtagtcatggagtagaatacatagctgtacgctggat2220
gcagcagatcagaaacaatgtctaactaaagcattcaagaaaataaaaataacctttctt2280
catttctacttaaatgagctctatttgagttttgatttcttcatttctacttaaatcagc2340
tctatttgagttttgagatctcattcaaccaatgcatgtcagtgcaaggtttgaattctg2400
gtgccggtctgccatcttgaatcttccacctaagatggtatttgctgaaggattcattgt2460
gtggtgggatctttaaacagaaatccgagctggacactgatgagctcatcttacctccgg2520
tttgcctgtaggtaacggatacttttgtgtcctatctaaggctatgtagctattcaccag2580
gtttatagtcacttggatatgataccctcttagggtctgaggaggcatatttacatagat2640
ttcctaaaaactcatttccattctttagccttttaatccccttcacaccgtacccctctc2700
cccagctccctcactcaaacctctgtctggggtcagggaatgggaccatcaatttgagac2760
actgaatttacatgttttcttcatctctgtctccccgtttactctgtctagcgcaaatga2820
tcttctctccagcctttatgggaaactcaagtccccagctctcttcacagtgacatttct2880
ctcacatattgaagtccctccaataacagtttagcgtcctggagatcaaaagcaagatag2940
tccttaatttctattattttttgtcatgttggaatctaagatagactactctagccccta3000
g 3001
<210> 136
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-25979-93 : polymorphic base A or G
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-25979-93.mis1
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-25979-93.mis2, complement
<220>
<221> primer bind
<222> 1409..1427
<223> upstream amplification primer
<220>
<221> primer bind
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
306
<222> 1924..1944
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-25979-93 probe
<400>
136
tatggcttctttccgtaaacatgccttccacactaaacttaatcatttctgggtttttgt60
ttcaacataagagaaatgaagtgtgacttttactttcactcaaatacttaaagagtattt120
gatattactaatatcaaattagtaatatttgatattaatgttattatgtctaatattcat180
gttattatgtctcagggaatagtgaagttccaggaaagtaagggagacaggggaatgcac240
agctcgtggagcagtcagaatacacacaacacttattaagtctgccatcttctaaggtca300
tggttcatggtgcccttaaacaattacaatagtaacatcaaagatcactgttcacgcatc360
actataacagatataataataatgaaaaagatttaaaatattgtgagaatgaccaaaatg420
tgacacagagacaaaatgtaaagacactaatagacttgctggccgcaggctttccacaaa480
tcttcgatttgtaaaaaaacacagtatctccaaaggagaataaagcaaactacagtaaaa540
aggagtgtgcctataattgtctgtgaaggagaaatagtctcaaaagaaaatgtagcatgt600
gtttgttccgtaatttttacaaaattaaaataaaactcacaaaaggtcttaaatgcaatg660
gctttctctaaacataaaaactactgcctgttacattcaagcaggttctacagttgactt720
tcttcttttgataaaattatgtgttttctgaagtatttgtttaaagacaattgtataact780
aaagtgtacactttaataggatatttgttttttgttattgttatgtttttgtttgtttgt840
ttatgtttgcagtgcagtgacacaatctcagctcactgcaacctctgcctcctgggttca900
agtgattctcctgcctcagcctcccaagtagctgggattacaggtgcccgctaccacgcc960
catctaatgtttgtatttttaatagagacgggtttttcgcatgctggccaggctggtctc1020
aaactcctgacctcacgtgatctgcctacctcagcctcccaaagtgctgggattacaggc1080
gtgagccaccacacctggccactttaatagaatatttgattacctgggtatggcagacac1140
ttgttactttctggctgctgcaaacttatccacccttacctggtagcatctctttcttgt1200
gggggaggtccccatgttgtgcagtctccacaggaagtcaatttcctgcatcagttgccc1260
actgtggcttccactatggggccaagtgttttaactaattctggttggagagggaggaca1320
gtcacttgacctaaaccctgacattcagatgttcagtactaggagtttgcttcttaagct1380
aatgaaacaaacgccaaacatcaagagacactacagtaatcggagacaatgcagtgacag1440
gattgactacccgtggatcagcctgaagcttcaccttttttttcaaagtgcattttgaga1500
rtatttgtgctatccattagtaaaaattaccaaagaggagcataatggaagcatagagaa1560
atagtaaaaatagaaacatccagatattctatgaaccctaggaaatttacacaacagtat1620
tattattcaatatattgttgtcgtgtggcaccaacgccagagaagaattaattgctgagc1680
aacggcccagacaggagttcccaagaagtaggttcaggtccatgagttgggaacttgctg1740
agttgctgtggatctttgcttctttaaagtgttgtccatggattgcgggcatcatcagta1800
ttacctgggatcttcgtagaatcacagaatcttggtccctaacccagatctgcagaatca1860
gttactgcggcttcacatgatacccactggatgtgcatgtacattcaagtttgaaatgat1920
ggtgtgaatcaggcagcagaaatgaaatatagtctgtattatctgaactgtggtccccaa1980
ggctagcctgtgcaagaaaaggtgtaactcagtctgaagagaacactgaaattaaaaatt2040
aaatctatggagtcgttttattcttggctacataggtgtgtttcacattctttaaaatct2100
caaatccacacgttttctatgtaagaattatgcatctagaaaggataacgggggaaacat2160
agtatttttttcctacatgaggaagttgagacatttccgctacatttgatcaaacctttc2220
ttttagcacatcactattattcgcttcctactaacaagaacttcaagcagagaggctttt2280
agtgaaaatatagaggatgacttcagggaaattgtggtgctttcagaggccagatgtcca2340
tcgatcaagaatgaccccaggaaattggtgaaagtttttatcttgtggcaaagacaaaaa2400
ccatgattttaaggttttgaaaatgcatatgttctttttttgtgtgagtgcttcaatctg2460
tggggaaaaagtaatttgagaagagttggttaagacttgagctgaataaaatgtgatgat2520
ctcctgcgtttacactaaattttaaaaatccattagctaagaacttataatacaaaaagt2580
gaacttttaagagataatatgctagaaagttaagatctgcctacataaaggtaaagaaaa2640
ccccctttttttctgtttttgttttttaagagtcttgctctgttgcccaggctggagtgt2700
agtggcacaatcttggactcactgcaactactccacctcccgggttcaagcaactctcct2760
gctcagcctcctgagtagctgggactacaggaatgtgccaccacactcagctaatttttg2820
tatttttaatagagatgggatttcaccatgttggtcacgctgatcttgaattcctgacct2880
tgtgatgcacctgcctcggcctcccaaagtgttaggattacaggcgtgagccactgcgcc2990
caaccggaaaacctattttaagacaagtctcttttccaattctcttttgctagatgacac3000
t 3001
<210> 137
<211> 3001
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<212> DNA
<213> Homo Sapiens
307
<220>
<221> allele
<222> 1501
<223> 99-25980-173 : polymorphic base A or T
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-25980-173.mis1
<220>
<221> misc_binding
<222> 1502..1521
<223> 99-25980-173.mis2,
complement
<220>
<221> primer
bind
<222> 1332..1352
<223> upstream
amplification
primer
<220>
<221> primer
bind
<222> 1817..1837
<223> downstream fication ement
ampli primer,
compl
<220>
~<221> binding
misc_
<222> 1489..1513
<223> 99-25980-173
probe
<220>
<221> misc_feature
<222> 1245,1633
<223> n=a,g, c or
t
<400> 137
tgtgcatgtacattcaagtttgaaatgatggtgtgaatcaggcagcagaa atgaaatata60
gtctgtattatctgaactgtggtccccaaggctagcctgtgcaagaaaag gtgtaactca120
gtctgaagagaacactgaaattaaaaattaaatctatggagtcgttttat tcttggctac180
ataggtgtgtttcacattctttaaaatctcaaatccacacgttttctatg taagaattat240
gcatctagaaaggataacgggggaaacatagtatttttttcctacatgag gaagttgaga300
catttccgctacatttgatcaaacctttcttttagcacatcactattatt cgcttcctac360
taacaagaacttcaagcagagaggcttttagtgaaaatatagaggatgac ttcagggaaa420
ttgtggtgctttcagaggccagatgtccatcgatcaagaatgaccccagg aaattggtga480
aagtttttatcttgtggcaaagacaaaaaccatgattttaaggttttgaa aatgcatatg540
ttctttttttgtgtgagtgcttcaatctgtggggaaaaagtaatttgaga agagttggtt600
aagacttgagctgaataaaatgtgatgatctcctgcgtttacactaaatt ttaaaaatcc660
attagctaagaacttataatacaaaaagtgaacttttaagagataatatg ctagaaagtt720
aagatctgcctacataaaggtaaagaaaaccccctttttttctgtttttg ttttttaaga780
gtcttgctctgttgcccaggctggagtgtagtggcacaatcttggactca ctgcaactac840
tccacctcccgggttcaagcaactctcctgctcagcctcctgagtagctg ggactacagg900
aatgtgccaccacactcagctaatttttgtatttttaatagagatgggat ttcaccatgt960
tggtcacgctgatcttgaattcctgaccttgtgatgcacctgcctcggcc tcccaaagtg1020
ttaggattacaggcgtgagccactgcgcccaaccggaaaacctattttaa gacaagtctc1080,
ttttccaattctcttttgctagatgacactgattttttttttaagtttga aaggagtgct1140
atagatttattgtatctcaataattcaattatttacatctgtccagtgtt tcatagtttt1200
caaaacacattcatatggaataaaatactctttagtcttcctaanaaccc cataaatcag1260
gttagccaggcatcatgagtgattctgttttctatcacagagaagtaaga tcgggtagtt1320
gtttaaactttgacattggataaacactaaactgtgtttgaatattggct ctgaaattta1380
ctcataactaacacttggtcaaataaattgcgtactgaatcatccaaaaa tatttcatta1440
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
308
gcatctaccacatgctggcattccgctgagcactgggctggattggagggtcagatgtgg1500
wcctcaatgtcatggtcctgcatacacatgtatttggagataggctcacattttaaacaa1560
aaacgcaccagcctaaaagtgtgtatgtgtatttttctcatatcatgctaccggaaacgt1620
ctagaatagtgcnaatatagaagggaagaaaaagtcttttttcataatcatattttcata1680
aacatatttccataaacataattcagggatttatattttctctcattttaattgtattct1740
taaatattttgatttaatatttaactttttaaaaattaaaatagtattcttgtaaaatac1800
ttattttctatgcctagtattatatggcatctattgcctgtcaagacagtggcattaaaa1860
atttttttaaactcattttgaaagaactctgtaccagagcagctgtcctaaaaataaaaa1920
aacaacactcggagagcctttggttttggtgcccttctcttgctacggtgtttgcttttc1980
tgcactcctgacttcactctttgctgttggtaagcatggctccctcccctgcttccttat2040
ggcttctgaattgaactcttattttgctctgttctgtacccctcccttttctcagatttt2100
cattgacatgtgaagatcattctctccttccagagtttattttacatgaggacaaaaaaa2160
atgcttttaacttgatattgactttatgggtctaccacatataatttgttatatgttgac2220
aggatttctaggtgattcatggggcatctgtgattctccctctgtctggtttggagaatg2280
tggtaggatttatatgctacacagtttacttgactgtgtagcatataaatgctgtacttg2340
acttgaatatgtcacagtgtacattattttaaagactgcattagaacaaaatcagctggt2400
actccttagctaaatctcctggtggcagtttaaaattttacttgataatctgctttgaaa2460
ccagaaatgtgtaaaagaaggagtcactaacttcctagttactcttaagtatatatagag2520
ggacattggacaaagtttatattttctgcaaagcacttaaatatatatgtattagaaagg2580
aatggttacagtttaatataagggttggaaaactttttatgaaaagggcaaatagtaaat2640
aatttagaattaattggttgtacatttctgttgcaactatcccacactgtcatcatagca2700
caaaagaagccacaggtcctacataaacgggcatgtctatgctccagccacattgtattt2760
acaaataggcagtgggcagagcttggcccataggttctattcatagtttgtgaacacctg2820
gtttagtatattataaatacatcccaagagcatctcttatgttttttggaaccctctgga2880
tggggaaggcataaacaaatttcctcagtgggggtttcatgtaagtattcacactctccc2940
agctgctatgagttgtctatttaaaacctagccatgagccttgtatgacctgtgatttta3000
c 3001
<210> 138
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-25984-312 : polymorphic base G or A
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-25984-312.misl, complement
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-25984-312.mis2
<220>
<221> primer bind
<222> 1794..1812
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1293..1310
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-25984-312 probe
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<400> 138
309
agcctggtttgtgattgcagaaatgatagatgaagttgggttatccatggagagaagcta60
ggaaggacaatgagactgcataaaccatggcaaactcaaattacatttaaaaaataatac120
agatttgataatagtgcccagaatggaaaattgagtatcttatctacatttaagatgagt180
gtccctctgccaggcaactcaaataaggtccattttagccgtttactattgaacagaatt240
ggagaataaatggaaaactattgactcaagtagaaaaccattgacttcaaaaatggtgag300
ataattggtattttaaacatatatatttgactgtgcatggtcatatatgatttttcatca360
tgtcctctctttgtgttatgacttattgttttctaagcaagaataaaagatttccactta420
aaaatgtgaaggatcagtacaccaattccttaaaacacaaaacatttagaggtaattttt480
ctttaagaagcactttgcagttttaactgtatcttgattttattggttgcttaaaagttt540
atgtcttatttctcaagtgttcccaatcagatcatacacatctatgtaggtaaatttgtc600
accactaacaacaacaaaaaaatgtatcaaacattcactctttacaaagtattgggttaa660
acctaggacgataagaaagataaatgagatacggtcttaacaatgagttctacctttcaa720
aaacatggactcattttgaccagcagaaccaagaaagagagaccgacttttaccttagta780
agcataacttagtgacagcagtagaaatattgccagtgcaaggtactaaagagagaatga840
caaactccaggaaatcctagtcctaactagaagatagagaaactaagtagtttattctag900
aatgagtgtacacgttcccccaaaattcatgtattgaaacctaatctccaatgtaataat960
gtttgcaggtgaggccattgggagatgatcactcatgaggatggagccctcattaatgga1020
attagtgcccttataaaaagaggccccagagagcatccttacttcttcaccatgtaaaga1080
cccacagcagaaagaaaccgtctgtgaatcaggaagccagtcctcaccagacactgaatc1140
tgccagtgcgtaatcatgaactttcagcctgcagaactgtgaggaagaaatttgtgttgt1200
ttagaagccacgcagtctatggtattttattatagcagcctgaattaagacactattata1260
aattctaatattcctgtcacaggactataatatgtagtaccgatgttctcagctggggtg1320
atactgggtgctcctaccatctggtaggttgaagacagggatcctgctaaacatcctaca1380
atacacaagacagctcccacaacaacaacaaaaaattacctggtcccaaatgtcagtcat1440
gcagattattctacttgtgatttgataagcagtctgtgatgtagtacttattaatcaata1500
rccaagatgctagttgaattgtaaatatttaatctggtttgtgtgttcccaaaactaaat1560
tagctaaattggccctatggagttgtgggtattaataaagaaattgtattgaattatttg1620
actgcttacctagatagcattcaacaattagccattaaaaagatggaaataaacaagaaa1680
aaatactatggaaacagtttaattgacaacaacatgaattcatttcttcaaaagttatgc1740
tgtggtggtagaaacacgagctttagattccaaaggccgagaaaggcaactcggaacatt1800
gtgaacttgacagtttggtcttgtgtctgtgagtcccagttaccctcttctgtaaattgc1860
aagattttcaggccatcttgtacagctgctgtgattattggaattgagctaagcaaggca1920
gggcgtatgttagggtctgaagaagacagctattattagagctgctaccactaatgttag1980
accttttattaagataaccattaatattcacggtgtgtattcccttggtatggcttgtac2040
agaattcaatatgaatagcagaggaagaaagaatctgcgattagacttccttgcatcttg2100
tctccatattttttttagcttttagaatttaggaatttttctgagtctcacggaaaattg2160
ccagttcctcatctatagaactaactttaatatatttttcttcatgagctgcatcaatgt2220
tcagaagtgtgttggtcttttctgtacagaagtatgaagagctgctcctattttgcacgc2280
ttaccctagcaaacattgctggaagaaataaaacctacattaggaagggtagggcaatgt2340
tagggaggaatattggagaattatggcagagtcacctctgttcctagcccactacatcct2400
gtgaaaaaagtgatgtctaatgaaagtcaatccattctactttaatacagatggttaatt2460
atcattgactcatattgatattttattataatgacctcattattaaaagatggatccaat2520
taagaatatatttacataacaataatataatttgactaggaagtttctcactaa.cactca2580
agtgtctaatttcattaagctaataaatattgccagagggctatgcatgtgatagtcgtg2640
tctgaacttaccaatggctaaattccaatttccctgaaatggcccctggcattttaagtg2700
ttctccatgtcaatgaagtgcatgatttttaaatttattttatttttaattattatgggt2760
acataatagttgtatatatttatggagcacatgtaatgttttcatacaggaaaacaatct2820
gtaataattggggtatcagttcaaacaagggaaatattgtttatttctattcccaagttt2880
tatttggatcctctgttaaaatcaattccctaattatatcttctgtactagattttagtt2940
ttctaccctaaaggatacttatgttgaaaatctttattaaatatattttaaaagcaaagt3000
t 3001
<210> 139
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-25985-194 . polymorphic base C or T
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<220>
310
<221> misc_binding
<222> 1481 .1500
<223> 99-25985-194.misl,
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-25985-194.mis2, complement
<220>
<221> primer bind
<222> 1308..1328
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1756..1776
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-25985-194 probe
<400> 139
ccctggttttatcttattttatttatttatttatttatttatttatttatttatttattt60
attgtgcttcctccctgccccataatgtttttgtatttccagataaaatcaaataaaatt120
aagcctttatcagggacatactcaagccacaatttttagctggagacatttcaaggaaat180
cactttttaagagattgtctgaatgacagagaaggcaaagaggcagctcaaattacctaa240
ggccatgaggcattcaaattctatacttgggcaaacatcagctccctccctgatgtgtct300
gggagcaaggcacaatagcaggatgacggagcagtcccttgtctcctgctctgtgttcat360
tagaggggactccagcccctccactggcatgattcagtacaggcgtccatgaattgttgc420
aattgcacaatggggcaagctactggcagtatttgccacatcagcattcctggttcagaa480
aacacaggctcttccacagactaatgaattgaggtgagactggggtctaagttctgcaat540
tgaccacgatggatgattgtcattagcacttgaccaaagccagtttgctcagaggattag600
aggaggccaatcccgggaggccagcctgtggggaatcagcttaggtagttaacctttacc660
tctcattctgcaaacttgggctcacatcgtgagagatgtatgtatctcccatttccctct720
gtcctgctttgtttctctctgcttcctcacttcctgatcatcagaaactacttagaacct780
ccaaactcaccaggctgaccacccaggcttcagaattgaggactcttacttgcgcagtta840
ttgcaatggggtgtttgggagtgaaagtggggattgtaacttgcctcaaaactgatgtat900
acatcatgacatcatggtggtgattgattatttcttttttttttttcctggagaaaagca960
taagttcctttggtgcctaaatctattataaaatttggcatttgcaaatattggatgagc1020
ttccgtaatcaaagaaagtttcacttatctctcttttattgaacatctcgagcccatact1080
gagacagaatttcaattaatagtttagtaatgaaagaattgtaaattaacctttaacttg1140
ataaaaaataactagggcacaagtcaatatacattattaatagtcatcacaattttgttt1200
tgttccaaacctttaagtcacaagactttatatttttggaataatttatgcagttaaata1260
ttctaatgcaatcaaatttaagtatttctctttcattcatagccctgctttgcttacaat1320
caaatgagatacaaggtatttaaacaactaactataatgtttggacatctgtgcttttaa1380
aaatagatagactagttcaaaaaaacacaaataacaaaattcataataagtaaacacttt1490
gtcactttgttaagtgttcagtatctataacctacttaggtattatttcagcataatata1500
yattattacattaacgacaaaaaaataaataccttagatctgtacaaaagtatagactga1560
actagataagacaagagaacatttttatagatttgaactcagagagctctgcacatcact1620
ttaagacatggctgaactgtccaagaagcatctgtgattattggggtgtcctccctgtga1680
aacttaaaacatattaatctctgacaatcacttgcaatcaggtaagattttcatcctgag1740
ctaatgtatgctgtgctgaaaactttactccccatttctcacatacggagatgattctaa1800
tatgttcccaaatgctaaacttattaagatagtctgaaaataaaatttagatttgacatt1860
ttatttatagttataatatcatgtaacttctagatatatactgtgtagtataatatgtta1920
gcaataatatatgcaacattagacacatatgtatatgtgtatacagacacttgagggcca1980
catattgttaaccaccctataattggataatacagttccataagcaagtgagttctacct2040
acatttccaatcttttttttttctttttttcttttgaggcagagtctccctctgtctccc2100
agactggagtgcagtggcatgatcacagctcacggtaaccttgaactccagggctcactg2160
caatctagtagctaggactacagcacacccaggccaccatatctggctactttggtttat2220
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
311
ttcttatagagacatggtctcactgtgttgcctggctggtctcaaacttctggtctcaag2280
cagtcctcctgcctcagcctcctgaagctctgggattacaggcatgagccactgccccta2340
gccctccaatttttttccttattttcaatctgtgccataacttctaagcatatgtgagtt2400
ttccatacttacttaatatctgaaaaccaaattttttgattcactgggaatgccggaccc2460
cttagtatcattgaagttcttggaatttaagatttttatttttgaataaggcacatatca2520
cctctggtgaaatcattataactgactgtcaataatgttcaagaagacagaattttaata2580
cataccaaatggcaccccttggggagggggtgggtgtggaaaaaaagctaaccaagaact2640
tagatgtacatatattcacaatgatgattacccagcaggaatatcttagaacaaggctgc2700
ttatttatagtgaatgtaatgagctttccgtactgagctcaactctttttagaaccacaa2760
acaaagaaagtgtgtattagaagagctcttcaacttacaccatcaattggactctctgcc2820
aaactacaggagcaatctgagaccttgactagggtaagtggttcttagcagagttcatga2880
caaaatagcgaaagccaggggtgttctaccaacagcacgtgctgtatactgagttccttt2940
catacttgcaagaggccagcatttatttattttgcattgtacgcaaacatcttcagtgat3000
a 3001
<210> 190
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-25989-398 : polymorphic base T or C
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-25989-398.misl, complement
<220> '
<221> misc_binding
<222> 1481 .1500
<223> 99-25989-398.mis2,
<220>
<221> primer bind
<222> 1880..1898
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1346..1366
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-25989-398 probe
<220>
<221> misc_feature
<222> 1322
<223> n=a, g, c or t
<400> 140
aaaaaagtca gccttggtta accctttaca ttttatatcg atttcatgca atagcctttc 60
actccaaaga atttcatctt ttatgatagt gtttctgcaa gattatttag tatgttatat 120
aaaatgtctc tgaatagttc tttcaaaatt acttagggtt tatatcaaag tcaatcattt 180
aactgttgtt caaaattgat gcctttctat gaaatagaag actggaaagg aattgtgatt 240
ctcatggaaa gagcaaggca actgaacaaa tctgctcatt ttaagtatta ttttaaagtc 300
tagctaatga agatattcat ggagaaagta tgttccctgc catgtacttt ctgtacagct 360
tatcacagtc taagatgaga cttaaaccac ctccagagta tatgcattaa ctatcttttt 420
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
312
ctagttggatattaaataatttaaagataatgatgttccataagctatgtttaaaaatta480
gattttgatagctgaaaaataattggatttagaagaatccaaattttttcaataaaactt540
acctataaaagtaaattttgtatttttctatagtatcaaaatgatatgttacccatgaaa600
gttctttcctttcattcaaaaagcatattttacaagtctacttggtatacattttttagg660
tactagatactgtaatacaagaaaaaaaaaaaaaaagtcattgcctgcccttgaggaact720
tccagtccacactgtctcctccagatagtttgcatttcatttataaaatatagtaattcg780
tgattcaggacgaatgagttggattttaccaattaaaagggattggagtgacagagaatt840
gtcccaaatggaaaggccagcatatgtgaaagcctggaaggtcaagatttcttaaaataa900
ttttacgaagtattttctcaggtacctagagtatatagacttcccttgaaacctcacacc960
ttcctcagtacaaagaactccaaacaccaaagataaactctttttaatctttttcacaca1020
aaatgaagatgctaattcacaatgcctgctttgtatctacatggtcccagatataatgtt1080
ggaccatggtctttcaaaagttttcaagaaacttggaaatatggattaacagcagaaaag1140
agtgaaagcatagtactatgagttcagggtcatagcagaaaacaaatcaaagccttcgga1200
agagattcttggaatctcttctaagattcctgttcatctaggggagaataggccaagttt1260
tttctaagctttctaaagtccctcattcatcaatgagctctaatcctcatggctttaaac1320
tnagatggaaagtaatatttcgttttcacagttgttttcaaatcccaatatgaactgaaa1380
taatctgaatgaggccagggccttacctctagaaatttcattttctaaaacatttgtatc1440
ttggaaagacagtatgcttgagtatggttagcaaagtccatagtgaatactcagtaaata1500
ygtaatgattattataattatcgctgttatttgagttagtagccactgatagtagttgtg1560
atgcaaatagctctcaagaattactgtcttggaatacagaaaatcaaaactatcaccctg1620
caattaccctggaattagtttacatgtgggggtcggagagaaatgactaccaaaagtgat1680
ggtgagagattttaccttttattgttaagcatatgtacattagcactccatcaagccatt1740
ttcatgatttcagggtaaactcagtggcattgcacttcttcgttttccaaaaatgacttg1800
tgctttttaaatgtctgcattatctaagaatactaattaggtttgttttatacttactgc1860
acctatagtgtaacatggggatttgaagataagatgggagagtgaatcctagttgtgagc1920
agaatttctaatacaacatgatccatgtgctgccaaagttcagagaccacaccttgtctt1980
tgtttcacaggtatccacctagcattgttgttctcagcatgatatttgtctcctaaaata2040
atcatacatttcttaaatacaaaacactgcactacctgaaaaaaaaggactagcattgat2100
taacatagcaacactacgctccttgttgtggttattctgtattgtaactctttaaatgga2160
attgggactgatgtcatttatgaaagttagttaacggtaaaaaaagttgtcatggaattg2220
acccatcttcaaggactacctgggacattttagaatactgaaaaactaggttttaggttt2280
acattttccaaaaattctagagataaacatattcagatctgtgctagaagttttaaatat2340
gacacaacacacaagcatgaagccatgcttactttttgatctgattcacacatctttaga2400
gattacacttaacttataacatttccctttttctatatgtgcatcagacgtggtgctgac2460
tgtgacatttaaactgttatgacctagaatataaagttaaaattgctattttttttcaaa2520
atggctggcagaaatcagtttctaaaatcctccttatactgtccccgtcttcagttagtg2580
acaataagcaacgggcatgaaatttttaaaaggtttaacgatggagacagaagatgtccc2640
cttcaaattcctatcagcaaaagcaacagcagactcctgctaaggaacgttctcagatct2700
cactgtgaccctgctgtgtgtcatgtcctgcgagagattgcacaaaacaacagtgtaatg2760
aagtgtgcagacacttgctctcctctcttctcccatcatactagacccaggataagatgg2820
acaaaatgaaaaaagaaatatttaagagattaacaaacttgtgagcactttgaaagggtt2880
tgtctgaggaactatccacaatttgatcccatgcagggacaaactttccatcttacccat2940
ctgccttccccagcctccaaacaccaaatccagcccactctctttaagataaatcaattt3000
g 3001
<210> 141
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26147-396 : polymorphic base G or A
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-26147-396.misl, complement
<220>
<221> misc_binding
<222> 1482 .1500
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> 99-26147-396.mis2
313
<220>
<221> primer bind
<222> 1879..1896
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1433..1453
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26147-396 probe
<400> 141
ccactgcactccaacctgggtgacagagtaagactccatctaaaaaaaaattaaaaataa60
aaataaaattatatatatatatatttctctacctcatgtttactcctctgcaaactcata120
ttagtggtaccaccttgaataagcctttaaatactatacttgaaacactatatattaaaa180
gcctgcagcaaaacctctgtccctgtctcactccccttcagttagagaaagaactgcatt240
tgaacatctgatgtgataaaatagaattccatctaattctattccatctaattctattct300
atctaaatagaatagaattctatttagaattctaatattagcccagtaattgagttgtta360
agattggtttctagaagtactgctaattgctagactgaggcaagttattctcctttatgc420
tgggaccaatttgtcctgtttttaagattgggatattagtatcaaatttaaacattatat480
ctctcttacctaatactgatcttatgaaaatagagaatgcaaagctaaatttaagattct540
tagaaaacaaagttgttgatgataaaataacatatttaatatggtttggctgtgtcccca600
cccaaatctcaacttgaattgtatctcccagaattcccacgtgttatgggagggacccag660
ggggaggtaattaaatcatgggggccggtcttttccatgctattcttgagatagtggata720
agtctcatgagatctgctgggtttatcaggggttccaggttttgcttcctcctcattttc780
ttttgacactgccatgtaagaagtgccttttgcctcccaccatgactctgaggcctccca840
accatgtggaactgtaagtctaattaaacctctttttcatcccagtctcaggtatgtctt900
taccagcagcatggaaacagactaatacaatattttgtattaatatcttggttaacttaa960
tagaaaagtctatgcttaatacaatgctttgagcttgaaggatttcaagagggatgcatg1020
actattgacctaaaatgaagttataggagttcttggaattatctaaattttttttcttga1080
tctattaaacacttcacttttatgaagaagatgttttaaaaaagaaagcaaacataaagg1140
ctaaccaaaaacacaccagtccttcaaggacaggccaaggagcttagaattattttatga1200
ctaatgctaactctgttattatttaacaacaaaatcttgcttaaaattgcaaaaccagag1260
ttgttgcattcatgaaatgacaacattaatgctttctggatatagcatacggtgattctt1320
tattttacccaactaaaaatttgaagccaataaaatgtttctctcagactagttgcttaa1380
ctaaattattcaactttgggtcaatctaaatttcaaagatacgttaaagttcagagaatg1440
ctactattgctactaataaaattagttatttcaatttttgttttaaaaattatatctgca1500
rcaattaatttggaggtcttgggaaattcaaaaaaagaatgaactccttgatttattggt1560
tgatttctcaatcacatgttgtaatgcctactctgagaacagtattgctctaggcattgt1620
gggaaatttcgagattactatacaataagtaataataaatacatggaagatagagagata1680
tagagacatgtagtcaataggcgacttcatatccaatgtaaataaaatatataaaaaatt1740
aaacacattagtttttgtttacctgtactcaaggtagttccaaatatccaatgaccttca1800
tcttgcaattgaaggtaaaatccagacttagatgctttgttagatttgatctcattccct1860
catattttcttctccagggtagatgttaggggtagtttgcctcacgccaggtcttcctcc1920
catctggacctccttggacaagttacatacctttattatgacttaatttctgtatctata1980
aaaggaatatggaaataaccatatttttcccactatactgataatcgaattaaatatttt2040
acaatatttaagtcctaaaaacagtggttggcacttagtaagtaccttgcagggcctagg2100
catgttcccgctggcttcctctgcagtggagctcccctaaggtcttagccagcatttctt2160
gcagacaatgcctgatgtctgaggtcccccctcaatatccaaaccctgggtttgcactct2220
gagtttttcaaaccctgactgagccaggtcatgtcatcctctcccttggctggtgtgcct2280
ttgaggatgccttcaggcccttctcctgaacaaggcactgtgacattgctactgacgatt2340
ctaactccatgcccaattagggcatctctctctgactgaaatttccaggaaatcagggat2400
caggtcctttatctcctgggatttccccaaaacaactgtgaaaattccatctttttattc2460
tatctctcccaaggtttttgatcctactagaggccaaggtacaactacctttgatatggt2520
ttggctgtgtccccacccaaatctcatcttgaattgtagttcccgtaatccccaggtgta2580
atgggagggccccagtgggaagtaattgaatcatgggaatggggactattacccccatgc2640
tgttcttctcatgatagtgagttctcacgagatctgatggttttataagggacttttcct2700
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
314
tctttgcttg gcaattctcc ttgctgccac catgtgaaga aggacgtttt tgcttcccct 2760
tctgccatga ttgtaagttt cctgaggcct ccccagccat gctgaactat gagtcaatta 2820
aacctctttc ctttataaat tacccagtcc caggtatgtc tttattagta gcatgagaat 2880
ggactaatac acccttttga aaaaattttg catcagtcat taaccttctt tgtattttcc 2940
ataattctgg ctctttccct cattaaacaa tgactgtatc attcttagtg ggactgagat 3000
g 3001
<210> 142
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26150-276 : polymorphic base T or C
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-26150-276.misl, complement
<220>
<221> misc_binding
<222> 1981 .1500
<223> 99-26150-276.mis2,
<220>
<221> primer bind
<222> 1758..1776
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1323..1340
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26150-276 probe
<220>
<221> misc_feature
<222> 2165
<223> n=a, g, c or t
<400> 142
catcattgca ttgaaatcaa acctaataag gcctattgtg ttcacgcata caatgctgtg 60
cggttaagtc agttaaaact cactccagca tcgagccctc tccagtcacc agaagagcat 120
atctagcatt taattagctt taattagcag cataaaacct ccaaatacca ggtagctgaa 180
gtggcttcca gaagtaactc tttataaatc ttgaatgagt aatcacttaa cttttgtgat 240
ccactatcat agtggctgca gtcacctgac cataagctgt gttttccatc taagagagct 300
tctggaaatg aaatataatt attgaaataa taaggtacta catcttgtgc tgttttgttc 360
atgatttcaa aatcattaaa ttatcccaag agaaaatcaa tatgatgaga atgcaagtat 420
gatatatagc atttgaggtt ttcttcagcg aggcccctgt tgtaacttgt taattttaat 480
tcattaaagt tctatatagt atatgttttt actcttattc atcagtatat aatgaggctg 540
cacattggaa aaactaagtc ttttaacctt tgattaagat aatttagcct taggcctggt 600
gtagtggctc acacctgtaa gcctagcact ttcggaggcc aaggtgggtg atcacttgag 660
gttaggagtt cgagaccagc ctggccgaca tggtgaaacc tcatctctac taaaaataca 720
aaacaaaaca acaaaaaaag aaaaaatgga gtttagtctt aaattttttt ttatgttaaa 780
tatttttcag acagactatt ggaaaggagg cttgatgtct gcaaagttag tgacaagtga 840
aaaggtggca attagcaagg ctgggagtaa aaatgggcaa gacctaaatg atgttctgtg 900
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
315
atgcctccctgtctcgtttcaccttgtaggctttgttcttatttgtgggctgctgcttaa960
aatgtacctggagaagggtgttaatgcatggggaacattatccaccccacctaggacatg1020
atttaatagcaaaggacacagaaagcatttattcacactaggaccaaaaagactcaagtt1080
gaaaggtaaacaatgctaaggccttatgccagctctgtatgatcatttctgattcattgc1140
agtcaaatccttgaaatgtttctttaggtcaatttaaaaatcaggcataccaatcatgaa1200
acatgtttgaattgtctctgtatataatattcaaaacacattataattggagaaaataca1260
ctcatccgacttggctgtcattcagttcaataggtattatctactatgtgctatatgcac1320
tctgtgccaccaaaagtaccatatttctttgcatctcagatgccatgtatcatagcatat1380
gtttttaacagagaaaaacaatgtatcaaactgacatgtcatcaattagaagatgcgttc1440
aactttagaaacctcaaaatatgaaaagttagtatgctgttaaataaactgtccaaaata1500
ygctcatttatctccatctccgtggaaatgaccacagtacaaaacaccagattgtcacat1560
gaaccaaatgtctcaataggccttcctcaaactgagtcttatctcctctctgactctctc1620
cgctcgcaattcattctcctccaacaagctggtgtcttttcaaattgcaaagttgattgt1680
ggtacgaatattgcagtaactgttcttggatcccttgataaaatattaaaaaggcagaat1740
tttagagatcagattatctcatgcaactaatctttctagaacttcttgaagtacaagctt1800
tcatatcatgaaataaactctgcaaaatatatatttttgtcatgtttaaaaaacatttaa1860
gccatgagttatttgggggggaaaaaagggggggctgggcgcggtggctcatgcctgtaa1920
tcccagcactttgagaggctgaggcgggccgatcacgaggtcaggagattgagaccatcc1980
tggctaacacggtgaaaccctgtctctactaaaaatacgaaaaaattagcagggtgcggt2040
ggcgggcgcctgtagtcccagctactcgggaggctgaggcgggagaatggcgtgaaccct2100
ggaggcagagcttgcagtgagccactgtactccaacctgggcgacagagtgagactccgt2160
ctcanaaaaaaaaaaaaaaaaaaaaaagatttattggcagattgtatttctaaacatggc2220
cagagcaatactttctatcttaaaggcctttttgcctggtcatcttgaagctttctatca2280
agatgtggagtctacaataatttgtgacaaaagaaaagttatgtcacttctcaggttggc2340
tttaggagatgagaagcttctgctttccatgtatgtgggctgccatttctttggaaggca2900
ctttcaatgctgcgagaagtccacaaggccatgtggagtagaagcacagccaccgttgaa2460
agtcccaggtgaactcccagccggcagccagcagccccttccagacatggacccagatca2520
ttttaaaaatttcccattctgaccaaccaccagctaaatgcagctaagtaaacgatccca2580
gtgaaccccacttggagaagcagaactgtgccgcctaacctgagttcctagtctcagagt2640
catgaacaaattgcttttatttaagccagtaaatttgggggtactttgttacgcaggaac2700
agatagtcaaaaactattttctatttggaaatgtttcatattttgtgaagacaaattaaa2760
agaagaggtcacatttatcaccacaaatatctagagaaaaaatcattttaaaaatatgat2820
aaagagctgctagagaaaaatggtacatttaaaaaaagctaagcaagcattatcccagca2880
cattttacaataatctttcaaaaaataattctttgtatatttgtttttatgactgaaagt2940
gtatgtttaaaaaagattttcccagtgattcttattaactatcaatgatttttggtggta3000
t 3001
<210> 143
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26153-44 . polymorphic base A or C
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-26153-44.mis1
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-26153-44.mis2, complement
<220>
<221> primer bind
<222> 1458..1476
<223> upstream amplification primer
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
316
<221> primer bind
<222> 1885..1905
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26153-44 probe
<400> 143
accccatatttcccttccacactgccctggcaaaggttctccatgagggccctgtccctg60
caggaaacttctgactggacatccaggcattttcatacttcctctgtaatctaggcagag120
gttcccaaaccttaactcttcacttctgtgcactcgcaggctcaacaccatgtggaagct180
gccaaggcttggggcttccaccctctgaagccacaacctgagctgtaccttggccccttt240
tagccatggctagagtggctgggatgcagggcaccaagtccctaggctgcacatggcagg300
ggtccctaggcccagcccatgagaccatttcttcctcctaggcctctgggtctgtgatgg360
gaggcactgctgcaaacatctctgacatgtcctggagacacttttcccattgtcttgggg420
attgacattcagctcctcattacttatgcacattacttcagcgggcttgaatttctcctc480
agaaaatagattttccttttctatcacatcatcaggctgcaaattttctgaatttttatg540
ctgttttccttttaaaaccaaatgcttttagcatcacctaaatcatatcttgaatgctgt600
gctgcttagaaatttcttccgccagatatcctaaataatctctctcaagttcaaagttcc660
acaaatccctagggcaggggtgaaatgccgccagtttctttgctaaaacatagcaagagt720
cacctttactccagttcccaataagtttctcatctccatctgagaccacctcagcctgga780
tttcattgtccatatcactatcagcattttggtcaaagccattcaacaagtctctaggaa840
gttccaaactttctcacatctttctatcctcttcttagctctccaaactgtaccaacctc900
tgcctgttacccattccaaagttacttccacattttggggtatctttacagcagcaccca960
gctctccaggtaccaatttactgtattagaccattttcacattgctgataaagacatacc1020
tgaaactggggaatttatgaagaaaaagaggtttaatgaacttacatttctatgtggctg1080
gggaggcctcacaatcatggtagaaggtggaaggcatgtcttattttggcagctggcaag1140
agagagaatgagagccaagaggaagggttttctccttataaagccacccaatctcttgag1200
acttattcactaccatgagaacagtatgggggaaaccacccccatgattcaattaccttc1260
cgctgggtccctcccataacacatgggaattatggaagctacaattcaagatgagatttg1320
ggtggggacacagccaaaccatatcaacataaaatataattataatacaatgtagattat1380
atataatataatagaaatgtatacataactatgtataacatatatctgatatatacctaa1440
gtatatgggtataactaatgcttaatgcacatctacataatctatataaatcaatcaatc1500
matctatgtctacctgttcagggtataaaatctttgcatactacgttaacatagtataca1560
agttccttgtgcaacagatagtgtacagcaattaactgctgtcaagttttatctttcctg1620
taaaactcccagcacctgcactgaacttcgctggtcaataagtgcattatatacacaccc1680
atatgcacatacatatataatatttttatatgtcaattgctcctctagattgagtccaat1740
gctcagaattataacggtaatttctcaaaaacaaagaaacggaaggaaagaaggaagggg1800
gatggagagaagtcagaaacagagaatgagggaagaagaaaggaagtgctgaaaatgtat1860
ttggggtgaataaacacatgagatggtataaagaggcaggtaatgtttcacttctttaat1920
agaaatggcaacacctttcagttgaaatcaacttacactttacaatcagtgattttgtgt1980
cattaggtaaaattatttgttttctaaacctcagttttatatacacacacatacacaaat2040
atatacaatatctatattgtatatacagcatatgtatctatacataaatacatctaaaca2100
atgaacatatttatttacctaagtgattggcacataaaaatggtctaataagtgatatta2160
gcagttggtccattagaattgttggcgaagattcaaaggcagctagagattgaattgcag2220
tgaaccttgaaagtttgataaggaatctggatgacatttggtggttaatacttattgaaa2280
gttttaaagtcagggaactatctgataaaagccacagctaacataaaatatgtttgagaa2340
tgttctgaccacagaatacaaaatgttataaatagaataatttcatttacacattaatca2400
cttaaattttgttaggcattgacatttcctaataaaattaaaatctaggaaaagtcagtc2460
atggtacaaatcaaaggggtagggattatgaaatacccagtaagagaggaaactgctata2520
gcactgaatcagtgtatcaggaccaattaatttatttttgctttattttccctgatcata2580
acttttgtgtttgtttgcattgtttaatttactgaatatgtatgttagattataaaacta2640
aagatgtaagatactgtgaggtccattccctagggatagctgagtgagggtcaatagaat2700
gaaacaggaaaccagggtagcttgcaaactggagagaaaagactgatggtgatcaaatta2760
tatcaatctcattgattcttccaaagagctctgagcagggatggaatacaaccgccccgt2820
tcagtcagaaggtgttttgcagggtgttttgccaatgtcctgggagctgccaccgaacga2880
tggaggtgccaagaggttggacatgtgagtgatatcttaggcctcactcatgcttcaagc2940
agacgtttttttctattagctgctttctctatttaggcttatgtaagattttattttaaa3000
g 3001
<210> 144
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
317
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26154-107 . polymorphic base G or T
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-26154-107.misl,
<220>
<221> misc_binding
<222> 1502..1520
<223> 99-26154-107.mis2, complement
<220>
<221> primer bind
<222> 1396..1415
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1903..1920
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26154-107 probe
<400>
144
gcactgaacttcgctggtcaataagtgcattatatacacacccatatgcacatacatata60
taatatttttatatgtcaattgctcctctagattgagtccaatgctcagaattataacgg120
taatttctcaaaaacaaagaaacggaaggaaagaaggaagggggatggagagaagtcaga180
aacagagaatgagggaagaagaaaggaagtgctgaaaatgtatttggggtgaataaacac240
atgagatggtataaagaggcaggtaatgtttcacttctttaatagaaatggcaacacctt300
tcagttgaaatcaacttacactttacaatcagtgattttgtgtcattaggtaaaattatt360
tgttttctaaacctcagttttatatacacacacatacacaaatatatacaatatctatat420
tgtatatacagcatatgtatctatacataaatacatctaaacaatgaacatatttattta480
cctaagtgattggcacataaaaatggtctaataagtgatattagcagttggtccattaga540
attgttggcgaagattcaaaggcagctagagattgaattgcagtgaaccttgaaagtttg600
ataaggaatctggatgacatttggtggttaatacttattgaaagttttaaagtcagggaa660
ctatctgataaaagccacagctaacataaaatatgtttgagaatgttctgaccacagaat720
acaaaatgttataaatagaataatttcatttacacattaatcacttaaattttgttaggc780
attgacatttcctaataaaattaaaatctaggaaaagtcagtcatggtacaaatcaaagg840
ggtagggattatgaaatacccagtaagagaggaaactgctatagcactgaatcagtgtat900
caggaccaattaatttatttttgctttattttccctgatcataacttttgtgtttgtttg960
cattgtttaatttactgaatatgtatgttagattataaaactaaagatgtaagatactgt1020
gaggtccattccctagggatagctgagtgagggtcaatagaatgaaacaggaaaccaggg1080
tagcttgcaaactggagagaaaagactgatggtgatcaaattatatcaatctcattgatt1140
cttccaaagagctctgagcagggatggaatacaaccgccccgttcagtcagaaggtgttt1200
tgcagggtgttttgccaatgtcctgggagctgccaccgaacgatggaggtgccaagaggt1260
tggacatgtgagtgatatcttaggcctcactcatgcttcaagcagacgtttttttctatt1320
agctgctttctctatttaggcttatgtaagattttattttaaagcctctgctatttaaaa1380
aattagaaacccactgacagtgaaactaaatttggaggtaggcatatatcaattctagta1440
gcaactttagatccactttagaataccctgttcagaagattctaagtaccccttccagtg1500
kctgggaccatccagggccagcagtgctggcaggaatctagcctgggtctgaaagggact1560
cgcgtgggcacgggttcctgtactcttccctttggggcatgtgtggtccctcatcttatg1620
agtgggttcaaatgggtgcccagaggagccctgggactcagtctttgggttccattcaga1680
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
318
cccgtggcctcatcggtccaggatataccactggcagtcacagtatttctttccgaggat1740
ctggtcactgtcacacttgttgacacaggacaaatttagagcatagggctacctgcaatc1800
cactgtgactttctggtgtggctgcatgctgattctcacctctgggttccaaccatggaa1860
ccatgtctggtttacatcagtcaaggctggcatgggtgacagcaaccttccttaccctgt1920
gtgtccttgcccctggggtggtcacccagtctttctgctggctctgtactctatgtgagg1980
cagatctgggtggctgcacctctctgtttcaagagcttttgagatgattagtccacaatg2040
ctaatgggcctttccaattctcctgtctaacctcaaccaatggggtgatatcatgtttgc2100
tgagtggtcatctgccaggctcaatgatggattgccatactctgcataaatgggattgtt2160
ccagctccacacgcaaactccatgtttatccttcctgctggggatcaggtgtgtggccag2220
cagaggcatcgtcaacatgggaagaggaacatcctctacatacagcaattatgggttaca2280
gatttccacagagcacctgattggaaaattgttctgtgttcacactctaaaagttgaaaa2340
agttaaatgtaaacttaacataaccagacaaagaattagtgttcacattttgctatatac2400
tttggattggattgtgatcatgatcgaagagaagagtccttgaaactcagaggtcacagg2460
cagcaggatggacaatgccaagtgatgagggatgatatacccagcattgaaacaatgatg2520
tcaagaaacc.acagggaaaaggccatctatattgttcaagtacaaacacaggcctaacaa2580
ggagggtaataggagggttgctaactttttttactggtaggagatacaaaattagcccag2640
cactcaatatttgacagttaagaacacaaagagatagttcccgcatcagacaagaaagac2700
aaggtagctggacaatggacagatatgtaatccactctgctctactcattgatataaatg2760
tccagattgaatcattatatttcacaggagctccaacattttgtatttgttattgcagta2820
aattatacataacataaaatgcaccatcataaccatttttaaatgtacagtttgttggca2880
ctagggcattcacactgttgtgcagcttccaccaccttctatcaccagaaatgtcttgtc2940
ttcccagcctgaaactctggacccagtaaacactatttcctcactttcctctccactgag3000
c 3001
<210> 145
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26156-290 : polymorphic base A or C
<220>
<221> misc_binding
<222> 1482..1500
<223> 99-26156-290.mis1
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-26156-290.mis2, complement
<220>
<221> primer bind
<222> 1212..1229
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1702..1722
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26156-290 probe
<400> 145
ggaaaattgt tctgtgttca cactctaaaa gttgaaaaag ttaaatgtaa acttaacata 60
accagacaaa gaattagtgt tcacattttg ctatatactt tggattggat tgtgatcatg 120
atcgaagaga agagtccttg aaactcagag gtcacaggca gcaggatgga caatgccaag 180
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
319
tgatgagggatgatatacccagcattgaaacaatgatgtcaagaaaccacagggaaaagg240
ccatctatattgttcaagtacaaacacaggcctaacaaggagggtaataggagggttgct300
aactttttttactggtaggagatacaaaattagcccagcactcaatatttgacagttaag360
aacacaaagagatagttcccgcatcagacaagaaagacaaggtagctggacaatggacag420
atatgtaatccactctgctctactcattgatataaatgtccagattgaatcattatattt480
cacaggagctccaacattttgtatttgttattgcagtaaattatacataacataaaatgc540
accatcataaccatttttaaatgtacagtttgttggcactagggcattcacactgttgtg600
cagcttccaccaccttctatcaccagaaatgtcttgtcttcccagcctgaaactctggac660
ccagtaaacactatttcctcactttcctctccactgagcgcatgaccatctcccttctac720
tttctgtctgtatgaattagctactccaggaaattcttataaatggaaccatacaatttt780
tgtctttttgtgactgtatgagtgtattatactaatactttcaaggttcatccatgttgt840
agtatgttagaatttccttctttataaggctgaataacattccattgtgtgtatatatta900
cattttgtttatctattcatccctcaatggccacctgggtggcgtccaaattttggctat960
tgtgaatgctgctgctattaacataggtgttcaaaaacctattgtttttagttcttttgg1020
gtatgtgctcggaaatggaatggctgatgaatgaagtatttttctttttaatttctgagg1080
aactgccacactgtttcctatagcagctgcgctattttgcattccttgtagcaatgtacg1140
agggttccaatttcttcacattcttgccatacatgttatgttctgttgtattatttttta1200
atagctatcgtgatgagtgtgaggtagtgtctcattttggttttgagttttcctaatgat1260
tactgacattgaaaatctttttataatgtctatatttataaaattatatttatatagaca1320
aagacccccaaaaacatatttgtctagggccttgtagacccaaggggaagccctgatgga1380
ttcgaatcctaattccaccacctattagctgtgtagtgttgaatatatctgtaaacctac1440
ttgagtatcagaatttttatattggctgcattttaactgtagatagctgttctggagcaa1500
maatactgtaaaattagtcttttcttgaaaaacaggcagaacctagtattgacagatata1560
actattttttgcacccctcttctatatcttatgctattgtccacgagcttattatattgt1620
aacttgatattaattttaagaaagatttgaaattagccatattttagtatgtcagttttc1680
cataacaaggaaaaaaaaacacagaataaagatttaagccacaggaagggaagatatttc1740
ttttataaacacgtgattaaaaggaaaatcaattagaacttgaaagggttagcactggat1800
tactatcatttagcaaatgtattacaattgttttctccagtaaaaataaagattaaaagg1860
aaagcataactatattagagagtaaaaaatagtattttattctttcaataagtgagattc1920
taagaaatagaagatgagaagctaaatgtactgaatctgggggttccctgcctctgtgtt1980
gaccccttaatactttgtttaggttgtaaaaggttgttgcttttatgatatagacttttt2040
tggcccattatgtaagtaacctaggatgagtaatgaaatacagaatacagagtaatgtta2100
gaggaaaaaaataaaaaaaattattttcagtatgttatatattctaatctatatcttctg2160
tttttgcttttatttttaaatgcataagggacataagacaatgctatgcagattaatgga2220
gatttttctctgcaaagccccttcttttcagtacattatttgcgaatttgaaatgctttg2280
gcctctgtgcgcgcctctctgtctcatgaacccagacagcctgcttagctcaaagtgggt2340
ttaccctcctttcagtgcagtctggattttgcctcctggcaaaaaatagagacatccatt2400
catccatttatgttttttcccttaaagtttacaaccctgtgcttctgtttgtctgatatg2460
taaaaaatgttgttttttacatgtatctagttttctagatttttatcagtaagaaagcca2520
ttctcatgtaaattactgattttggggcagaagtgaacatccaggaattcgtctttgatt2580
taatactatgtatttttgtcttttaaatgcaattttaagttgcttccttaacacatttta2640
tttccttcgaaaacatctatagttcttagtttctggccctccagatattttttttttttt2700
tgctggtgtgtttctactttgtgctctttagatgcctacttcttaatagttcatagggca2760
tgccaatttttaaaacatgtctttcaaacctctggatcttataatacgtaccttttttta2820
aaaaaaaaaaagcgtctcttcttccttgagttttcagcattatctattggtcctctcatt2880
ttttttattatagactatataagttttcattgccactctcgaaaatgaatatctgttcag2940
atcttttgtttgccaacctagtatatgggtttgcttacaattctgagcctttctctcctt3000
t 3001
<210> 146
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-5873-159 : polymorphic base G or A
<220>
<221> misc_binding
<222> 1502..1520
<223> 99-5873-159.misl, complement
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
320
<220>
<221> misc_binding
<222> 1481..1500
<223> 99-5873-159.mis2,
<220>
<221> primer bind
<222> 1632..1649
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1176..1194
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-5873-159 probe
<400>
146
atttctgcatatctaatcttgactttgatttatctataattttcctttttcaggctatct60
ttgcctagttttgctattacagctatggtagccttataaaatgagtttggaagctctttc120
tcagttctctggcctcttttaagtctttgggacagtttatataattttgagattacttct180
tttagggttttatagaaatttcttaaatagattttaaactagagaaattaaactacagct240
ttaagttttacaagtagtttattgaggcttacatttcattttgaatcagttttaataatt300
tttactttttgaaaatttctattctatgtagattgtaaagctatttagacgattttgatt360
tttaagccattgaatttattgttttacattattttaatttctagtgtttgcatgtttata920
ttctttatattttcttgattcatcatggcagagttttatcaacagtatttgttttttaaa480
gaatcaggttaaaaaatattttccatagacatatcttatattgattatgttcttacacaa540
atattttttgtgcttacccttttgttatttatctaactctctgaactaaatatttatcat600
gcatttctcagcctttttgtggaaattaattttaaaatggaaaatgtccctcaaagtact660
gctacagttgcagcctccatgttttgagatatcatttgctaatattatcattaatcagta720
ttgtgtcttttgtatgttctgttatttgttttataacacatgaattatttaaatatatat780
tttttgttttccaaagtatgatgcttttggtgatttttcaaaatatgaattcagcatttt840
atggtgtgtgcatgatatgtcatctgtctttgtatttgttgagactttttttgtgtccta900
tgttggtgattggaattatctatctacacttcaaaattatattcatgtttttatatgtga960
tgtaacaatctctctttcaccttgctaattatatttttatattctttaattcttttcatg1020
tctgtgtggatcacttgttttaaaacattttgaaaaagggttattataaatagaagatgt1080
taaaattcctaattatgttgtgcattagttggttctgggggataaatttgtgaatttcat1140
ttcatatactttggtcttataacagtatgtgtcaccggtttaggatattacatcttatgt1200
atacttgttatacttttttttaaatattattattcattagctttctctattcctagttgc1260
atttatttacttcttaaagtatatttttatgatattaatattgccatggcagcatttttt1320
tctttatcatttgcaatacatctttgatggttacactaggtaatatcatcacatatatca1380
tttaattccctattcctctttttaacaatatctaatctgctgtttaagtaattcattaag1940
aattcaatttgaataactctttgttctttcaaaggatgtattttatcccttttccggtat1500
rtgttactctctttcatacctattttttttcttttttaacacttctcttcctatcatgtc1560
atctttttaagactactgatttcattagacttttttagttttcctcttatctcaagtttt1620
gtggcgactaaccctgcttattgttacgcctgctccttttctgtatggtggataatttct1680
ttttattagatatgatttcctttttcctttacttatttctattcagtatttgaagtattc1740
tccaagttggccttgagtttgtatctgttgcttatactagattgtcattgtcttggggct1800
gatttttatattcatatgggcctgatcattaaacagctcttcagtaatataaaatcaaat1860
gaatagaaagcaaggtgccagcatgagaactcaacattttttggaaaaatacccttaccc1920
tcagcccccaagtatagacataagtagcctcatcattatattatctctcaacttcatgtt1980
ttgggcagcctaagttatcttgtcactgagattttagcattgccaaaggtcagggctttc2040
atcccattcatgagtttgatttcctcccaatctttggggcagaaatgtctgatatttccc2100
aagcctctcatcactttagggctcagttgagcaattgccaacctctctgtttcctgattg2160
ttagcttcctcttaacttatagcccctgcagattttgctgccaattttagctctagcatt2220
attttaaaaagctggatttaatccagagtgtttagctatttgtaggaagattttcatggt2280
aacctacttctttattttattggaatcagaagtctccccttcttctgttattccttatcc2340
aagagaccgataaaattcagaattatttctttttaaatcagtgcgctgtatttggtctca2400
ttaaaataaacgatccactttgtttattagttgttttgtttgtttttaactccaagtaac2460
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
321
ttgtcaagctcctatttttttgtgccttttttattcacttaatcaccata gaccatcaca2520
actaccatgctcttgctgatattctcagccctgtatgcttatccaaccct tctctaccta2580
cattcatagctagaatgaaatttttttaacccatcaaattgttccttcct gcttaaaacc2640
tttgatgtctctccaatacctatagataaagatctttaacgaaagcttaa gaaatgctcg2700
atggcgtggtcttgatctccctagaaattgcaccttgagattgcttccca ttttctttcg2760
tcttttaagaatgctggcttattttcatccctcacttgatcagtgctctc tcatgtcaaa2820
aatatattatatagtaatgtttttcaaagtaggttcctagaacagcagta tcaacctcat2880
ctgggcatttattagaaaagcaacctttggggtcacatcctagacttctg aatcagaaac2940
cctgtgcgcagatcccagcagtccacactttcacaagccctccaggtgtt tctgatacat3000
g 3001
<210>
147
<211>
3001
<212>
DNA
<213> Sapiens
Homo
<220>
<221>
allele
<222>
1501
<223>
99-20977-72
: polymorphic
base
A or
C
<220>
<221> binding
misc
_
<222>
1482
.1500
<223>
99-20977-72.mis1
<220>
<221> misc
binding
_
<222> 1502 .1521
<223> 99-20977-72.mis2,
complement
<220>
<221> primer bind
<222> 1430..1447 -
<223> upstream
amplification
primer
<220>
<221> primer bind
<222> 1921..1941
<223> downstream
amplification
primer, complement
<220>
<221> misc
binding
_
<222> 1489 .1513
<223> 99-20977-72
probe
<400> 147
ggagcaggtt gtcaatgtcaaccaacctggattgtttcagaggtggttgc tttttagatt60
aaaaaaaaac aataaaaatagataaaactgtatttaataaatcgcttcct ttccctagcc120
ttctgttttc tctgaagcttcattttgtctgtatctaagcagagatttcc agacaagttc180
catttctggg ttagaggagatgtccttctccttccagaggtgatcagcag ttacatcaag240
gtgctcagta tgagacagaagtggctcgtcctccatgtccagtgtggaca gtgggttgtt300
cccatatggg cccatcataacacgtatttcctaactacaaccaaaaccat acgacctact360
taacaaatat caaacacacaaactactaacaaaagggtttgcaagaaata tgtggaaaac420
cattcaactc aatattcataacttaaatatatgctgaggagtagagctct tggtatcaaa480
gtgtatatta atgaattcatttatttgctctttcagcaaatatttattgt actccttcca540
ttgtcagcta ttgtacaacatgtgcgaagacttcaaagataagttaaaaa ttgtggttta600
aaattgaaaa agaaaaaataacaaaaacctgaaagtccaatagacaacag ttaagttaac660
cattgaagga cattttgactagatgaattctaagagttctatcttttctc agaatctgtg720
attccatgaa aatatttgtcccatttcctcaagtagtgacagctatgtag ggagttttta780
atctgtactt cttgattaattattgttaaggtgaaaccaattttcacagt acattttatt840
aatttattcc tcgagtggcttcatgttcatgaaatgtactgtgcacatca cttgtctttt900
ttccccgctg aaaaaattcagtgtcagcaaagaagatatgtcaatttctc aagttaaaat960
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
322
tgcagaaaagtacttatttacacgctgctttgctgaaagagcatgataaatccacagaca1020
cagaggcagatgttcaacggctgcattctaatatggccatatttgcattaatgaagtgag1080
tggtaatgtcgtctttaacttaagagagaatctcaggggagaaaaaataaaaccctaatt1140
tttagtaaatgttgccaccacttaaacttgaacgttttaaagcaagagcattaataatta1200
taattagaaaaagagctttgctatttctacatgttcataaaatgacacaaaatactttgg1260
ttttatattttctttcagcgtcaaagaagaaagtcataaacatcactgcagtttgcattt1320
ttatcctgatttcctctgggggttaaaaactatataaactactgtaaatagtaacaacat1380
ttatattgatcaaaatgtttcaaattttggttagctatatttgtgaatggtacatggtag1440
gtggtagatggtgaaaataatttttatatgtaaggagtttcaaagatgatctaaaacatg1500
maggcctaaaacaatagatgaaacactatttcaaaatgtattctctctttgttttcactc1560
tccatgttacaaaaatggcaacaaattacgtaaatgccaaggaagccaatatatcatatg1620
gtaaatgacaaatcaactgtaacattgaaacaacaattaatagctattatagctattaaa1680
atttgaagcaaaattgtgcatctttaaaaattatacacacatgtgagaggactcatgact1740
gaaatctcaatataccatctatccaagttgagttattttcctttttttttttttttaaga1800
taattattcttcttcctacttctgggagggacagtgtatgggaggtacctgtcaggcact1860
gtgagaaccctgggctctgaacagatatggggtatttctctcagtatcctcaatgcagct1920
ccaataactaatcccatttcttaatcactttggaattaataagaaaaataatttatttta1980
gaaattcacaaaaatatgtaaaacaacttttttctttttttccagaggaataactaaaac2040
aattcttattgaaaagccaaactatacatttttcttcacaagttgtatactaaaaattgg2100
caaaataactccctcagtgataactttcattgttttttcttttttatgttgtttgtttct2160
atggattttatatagttttaaagctataagctattgaaacaatagtgtgcatttatttga2220
ctgaaaatattggccacatttttatggtaatatgacctgtccaccagaattgatctaaca2280
cattctagagcttagagaaaaatagtgatgacaaagatagacgcagatgcagtcttgtgg2340
gacctaagagtttctacagatgtgagttccatgcgcactacattttaagtttgacttcac2400
tacattatggaaagacatattgtgctctgtgctatttagggtttcactaaatgttggttg2460
ttggtgttcagataactcatccagcctggaaggcaatttcattgaaagggtgcacaatgt2520
tcttttcagcagaaacatattagatctctgaggggttttgtccagggttagaccttggtt2580
ttaagatttgaccactccactatattaaataaagagagatgagtcacatgttaataagca2640
tgtcccagcccatacaaaagcaccataattggttgctatttgctgttctaattgaggtag2700
agactgaatgggaataacgtattttttgtgaggcttaggaataactagatttttgttctc2760
tgacaaggtggaggtattttatttgggcattcatcctggctcctatctattatttagcag2820
aaatcattatgtgggcaaaaaagaaacatcattctactttactattaagctgacactagt2880
gtctaatggtactaacccaataaattggtgaatattggtttattccatgagaaaagcatc2940
tgttgatgttatgaaataaattaactgtgtgtgcccttcatgaggaaacaatgacaaaga3000
g 3001
<210> 148
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-20978-89 : polymorphic base C or G
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-20978-89.misl, complement
<220>
<221> misc_binding
<222> 1481..1500
<223> 99-20978-89.mis2,
<220>
<221> primer bind
<222> 1571..1589
<223> upstream amplification primer, complement
<220>
<221> primer bind
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 1124..1144
<223> downstream amplification primer
323
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-20978-89 probe
<400> 148
aacacgaatgtttcagaagagaataaagaactaataattttatgagttaaaaagtatttt60
gcatttttgcatggctagctaaaatataggtgtaggactttagatatttatttttcaatt120
attcattgggaatctgtattgtaagactttgggatacatcagtatttaaaacaaaaatac180
ttgttcttgtaggccttatatttaacgtttactagaaaaatatcatgcaagccttcttat240
tctatcagtttattgaaaaaaatgagcatttttttacatattacatgtatttttacatat300
tacattaatacatgtttgtcttacacatgtaatatttccacacttttatatctgaaggta360
tgtgcatttaggatgaagtttcattttttatcctagtaactatatttcagattgtcttta420
cattttcaaactcttttggctaatttcatgttagatttcaatagatcatcatttgttttt480
gttactagtttctatacttgtttttaaccacaaaatccatgtaaaagaaaaatctcatct540
ttgttatttgttttgtgtttattttagcttattttattcgtatcacctctaatccttatt600
ctctctatgggatttttccccctaaactattctaactttaggtaaactagataatataac660
ttataaatctacttaaccaggaacacataaattgctacacattcacctatgataccataa720
aattaccataaaattgtccaaaggaagaatttgatgtcatctgaagtttcaggaaagtgc780
tcttgaggaaatggacgtgttgatagaaccagagtggggaggaggaaaaggaggcagctc840
tgcaaaggtgtgtgcatgtgggtgcatgcctacacagatgtgcaaaggggcattttaatg900
caggtggccatatttgagacagataaggttaagggaacaggatagatgtgggaaattatg960
gaatatttataggtaacccacagtgacccaggtgaggctacttgcaggggatggataagg1020
gctatagtgagcagagccatcagataagatagggccttactgcggtaaggtgcatacgta1080
actcagtggatggtgaagagtcactgcatatttccagacatgaaggatttgaaaaggaaa1140
actgcaggtgggaagaccacctaagagaggtaatgaggggctggcagtgaaaatagaaaa1200
aaagaaaaagagcgagagatgcggaagatgcatcaaaaggaattgagcaacccatttgtt1260
ttaaacttatagtactgaactagcaattttggtaaggttttaatggggcagagatgtatt1320
ggaaatgtggccaatggaaaagtgagatggatctgagaagaggtttttcaagatctttga1380
tcctttctaacctttgcgttactgctttgtaatcacaaattcagctctggctagcaggat1440
ttgggtttagacacagtggcagttaatcttcaaaatacaagttggttttggttttttaaa1500
sagatttgatttgcattttatttttagtgttgaagacattttagttcaattattccgctt1560
gtacaggctgcattaggtagcagttaagtgggcagggtccagagctgagtgatcagattc1620
cagctgttaacttactggttatgtaccctttgtcatattattactacttaattgctctgt1680
gtctcgatttcttcatcctccaagtgggcttctattaagtaaggtaatggtgaggatcca1740
agagttaataatagaatgtgcttctaataatgcctggcacctgagaagaatagaatcaat1800
ggcgttatgatttctaaaaaggaaaaacgtcaaacaatatgtaaccagatgaatcaaaat1860
caatttggttgtattttctcgaagttaaaggagaaaaacataattttacattttatttgt1920
gctccctcacccaaaatgaggcataatcccaaatctctctgtataagcatgagggcgcgt1980
gtgagtgggtgggtaggtggcttctcactgcctcgcctgatctagttaattcaactccag2040
aagacagagtagctcaaataggagactgcttaggaataagtgatgtcagaacataaaagt2100
tttacagaaaaattgtaaatcactaatattctcattttttttcttgacaagagaataata2160
aaaaattctctttttcatgtttttaactctttttgcttttattcgcttcttttccatgct2220
acatattttcagtgaagagcataaataaaatacagcaaaactaaggaagaagtctttagt2280
acttagcccagtcaggtcttccaggtgatgggcagacttaggcacaatagtatttttttt2340
ccactagtgcatatcttagaattatgtgatttgggaagttatatactacagaataaggaa2400
catatgtaacgcaatgcaataatcacttagatatttatttttaaaatcctactcttttaa2460
aagctttcatattctaatacagctagtcacactgatgttgtgatgatctgctgttcgtgc2520
attattttccaaaaggatttttccaatattataccatctatgaagcaagtctaggtacaa2580
tggagtcacgtctcaaatgatcagttttaaatgatgtgcatagaaatagatactgaaatt2640
ctttgtaatttcttcaggactaataaagagcttaaggatagctctcaaaaaaattttttt2700
gtcttcacctatttgcaagaccacaatttttctattgattataaggtactaggtttcatt2760
actcagtaacgtccgactgtttcgacagcggattgcattagcatggcccattcagctgtt2820
gtggagagatgccagttgccatggtgaagattatgatgtcccacatccaatctatccctg2880
agatggggatggcttttgcaaaaccacatgcaaatatttgttttcaaaggtacaactgac2940
tctttgtgaagcactggattactagagtggatgtcttttcaatgaatcatcaaatgagga3000
t 3001
<210> 149
<211> 3001
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
324
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-20981-300 : polymorphic base A or G
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-20981-300.misl,
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-20981-300.mis2, complement
<220>
<221> primer bind
<222> 1202..1219
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1630..1650
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-20981-300 probe
<400>
149
accacgctgtgcctattttacccttgatattcggctacagctaaaatcatatcaaaaaaa60
gtcatatcgattaccctgctatattggcaataacaagatatagtcgaccaataaaattgg120
aaaaatataagagcaagacactgcaaacggcatataaacatattcagggaaaagaaaact180
aaaacaacaataagataacttgatttttgtccttgaggtaggcaaaaattagcaattgaa240
aaaatgtgcaactgtccagtttcatcaagtttgtgagaaattggatattgaaaaagggaa300
atataaatcaatctctctctttccctctctctctctctatttcagtctctctctcacaca360
cacacccacatacacaaccttgaaaggctgtgcagaagcagcactattactttatcttca420
aaggttatttccaactccaatgtatcaatctaaagagtaaatttgaaaccttgttttgaa480
ataataagagaagttgaatgtagatttatcataaatgattttaaatgcagtgctatcctt540
tgtcatgatttacaaattctttctcttatttccagatatccataggccatcatagttaac600
ctctgtttctccctgtgaaccaacaacaaatatgttatgtctagtccatgtgtggcctgt660
aaatataagtaatatttacagaatttgctttgacttggttaagattagtaagaaacttat720
ggtaccagaacatcttaaccagaatacttaggaccctaacactgtattcctcatttataa780
ctcttgtgctggttaaatatgaactctcattcatatacatttatttgttgtttatcacca840
ttgacatctaggaggttttgagtgactaagtaccttcaccaatctgtttcccaacctttt900
tttctggattgttctgtaacggaaaggaagaattatgtcccaaatgattgtcctgttgag960
aatggagatttaaatgtattcagttctttttccaggtctccctttgaaatcctgttttag1020
aatgatactcagccttcttatttcctgttgaaaataataacacatactacctgccactta1080
gcacatataagtgggtgtttggaagaatcttttgactgaatttaatgaaactgctgaatt1140
aagtaaaagcttgtatctttttctcaggtagtgactctctgtagctatggaccaccacat1200
atttgccatccctttgctgatggtttgatttggaatgtgtcatttcgtttgtgaaatgag1260
acatagtcaaggtacccatgtgctcaagtgcttagattacaacaatgttttgatgcaaat1320
gtgcaaagtactcagagatcaacactatggtctaataacaggccatagcaaaatagagca1380
aatgaatcctgtgaaatcagagagaatgcatcaaataaagatgtactacctaaagtgcaa1440
aatctactaggagcactttgacatttcagttcaagttctacagtgtttcacattttttca1500
rtctctattgtagtctcacttggaggtgattgcttgatcactagaggaatatgatattat1560
tcgtttcagaaatgaagcagctatggtgttctcttgtgaatagcactagatatgaattag1620
gattatgatcttgtttgtgtagaatgtttcattacatttcagatatttgtgtcaggatat1680
aacaaagtgcattcatcagcttaggaggtttgctaacttcagcattcaacgtaagtttag1740
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
325
ttgccccaagtctacaattaaacagcaagacacaacgacaggctttgaattttaatggaa1800
attggcaagatgctgaatagcaatgaaaccagtggggatgaagaattacttgcaaatttg1860
aactgtgtgcaaactagccaacatcaagcaaatagtctttatgatttctatatatgtatg1920
tacatacatatatacacacatatgcatatgtatacacacacctatctgtctgtatatatg1980
tatatacacacagagcagtatttctatatagtcctttaaaaaatgtaggcatcttgtgtc2040
tttgcacaacttgaaagggattgtcttctcattgtctagttataaattaaacttgtagac2100
cttatttttttgtctgaagaacaagaaccctatttcctcaactccgtatccccaagcatt2160
gaatagtttatgcccataacaactattcagtcaacgctgttgaaaatatgtcttaactga2220
gaatccactccttttccttcacaagctcaaaagcacatacaaaagagcaatgaggctgat2280
aaatctgacttttcagaggcatttatcagacagaaacttcccattctgaaaagtatttgt2340
gtatcagaatagttcagactcatggctacactgatcctttaaaagcaaataagctcttaa2400
tgccatacctgtttagaaaggtgcagaatggggtatgcactgcatggagagaccctacct2460
cctacccaccctggcctgacatgagtgataggaaaaagtggaaaccttctcagccctggg2520
ctacccatgctagacctctgattccagggcggtgaactactgcttttcctcgtgtgtggt2580
ttctttctggtgtgatgtcaaagagatccggcaaacaaaagtaaattcatttacagacaa2640
ttgactagaatttgtgagaaaaccacagaagaatggcaaccctggtagttctttttaaac2700
atatagattccaaactctttcatgaataactcaattgcttctttttatcttaattttgtg2760
atataaactcatcccacactactcctaaaacctttctcgagaattcttatgtctttctat2820
ctcattactcttcatttaaaagttcatgtccttttcactcttcaatatcattatcatgga2880
gcagtggtcccactgccagggtacatgaaagcggggtagggagggataatttcagtctca2940
gctgctaccttcattctacttgcttttacttccactccgttcttgggttctctcaattct3000
t 3001
<210> 150
<217:> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-20983-48 : polymorphic base T or C
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-20983-48.misl, complement
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-20983-48.mis2
<220>
<221> primer bind
<222> 1530..1548
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1099..1119
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-20983-48 probe
<400> 150
atgtcggata caagccattt gattgaaggt acagtgtggg ctacaaggac gcagaataga 60
aactgtcaga gtaataattc tgccaaaaaa ttagacagtt taaaatgatg tttatgaaca 120
aaaatgtact ttaaccactt atcactattt ctagtgctga gagaagcagt caagtttttt 180
gtttgcttgt ttgttttcca agcctgtgac tttgaaagac taagaaaatc ttccgtagaa 240
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
326
agctaaggtttggaatgtaaattgtaaacaataaggaaaaactggtaatgaaaggaaaat300
gtcattcatcatcagggcagggataaaggatagttgaagtgagaatgtgtttctggcata360
agaaagatggagaagaaaaagaaggacgtaaaagagactgatgatacaatgagtaaatct420
ctgggctttattcagaacacctgggtcctggatctgacaaccaatacctgtgttaaaact480
tcctaatctctcctagtctgtcccctcatctgtcagattacatgatttctcttgaatcct540
tcaagttaattatggggtttacaattctggttttagtatgattgatttttctgaatgata600
aggtaatcttacataaaatgcatagagattccttattggtattttatcacaggctggcat660
ttatgagaatattattttcctcctggtgccatcagtgcttccatgttctaggtgcaggca720
tcttcgcggtcgtaagtgccagtgttctcctgaaattagcatctcatctgaatctgttaa780
ccagattgtataagtggagagaaatataatcctttttcatgttgattttaaaaataaacc840
aggaaaattcaaggttaccatgttttgcaaatattagggctcacgcgaatcacctggaaa900
gccaagaaaagtacagattccttggatcaccatctagatattttagttcagtgggtctaa960
tgggaggcccgagaatcaacagtttgtaagggtcaccctccctcacttctgccggttatt1020
ctaaagttactatttcaactgtggacaatcacacaacaagcattgctgcaatggtatctg1080
ggggagacggtgataacgttagaccaaggtgatggtaacagagttggtgaaaatcagtaa1140
atggactactcaggcattgaaactaaatatttggattttctaactgttctaccactaagc1200
tgaagtttacagaagtttgaaagcagaccagcatacttcttcacttaagcaacaactcag1260
aacttctggaatagggactggtcatctctgtgggctggcatcacctctcctacctatcca1320
tacaggataaatatgtatatatgaaagttctttaatcaaggaaagaaagataaatgctat1380
gtattcctcagtaagcattttcaagatcatcaaagtcttatccactctacataagatagt1440
gttctgatatcatatctttcaggagcattttcaaatgagcctcttctacaaaggtggttt1500
yacctgccctcctctgtgccagcaggcttctcttattgatgtgtcctgagttgtgtttcc1560
gtctgtccttagctttccaagagcacccaggcataaaagcatccgagcaacccacctcat1620
gcttccatgaactgttcatcttcttgcaggatctataattctagcaaaacaaggtggaac1680
aatgttattttcctcttgaaatttattcctctcttcgttgctcaagtttagggtatagaa1740
atacaactgctctgttttatcagtatggtacctatcatccttcagagtctttctaatctt1800
ccctaagagtaacacacccaaagacatacatgtccctcacctgtaagtacacactcatgg1860
agtattgcgtgaattcattgcccatccctagcacctgtcctgtctctgagtaacaccttt1920
acatgccgattctcataaaaatgttcactatttactcagacattggcagggcttcctatt1980
cctcctcccccaggttttatgtttatttgttttgttgttgtttgctaccaggcagtgcat2040
gtgcttaatcaaataaactgagctctagtggccatcactggccatcaacatccattgcag2100
gcagaccaagggccttggcagcatttgagggttgctcatcctggggaagagcctttcatt2160
ctccctgggagcactaaggcaaagctataccaagttcatctagttacacacaggtgcccc2220
tttaagaatggaaattattttattctttatcttttattcttcatctctctgaacaggttg2280
gtttctttatcataaaaagtatattaaacttgagatgattattaatgtctccaattatta2340
taacaatctatgacactatgcatgtttttctgcacaaacaatatctaacactttttgggg2400
atatatatacacatagacacacatatataattctcatatgtatgtgtatgtttcattgga2460
attatgcattctcctcaaattatatatacatttatcccacgattatgagtgtttctgttt2520
atattaataaaatgttaaataacagttttacatttgcacatactttaaagctttacttgt2580
catgctttaacaatatttctttttttaatcaagcttttctgtgacttctttcacattaga2640
gttcagttggatatatctgccaggttgaaatggctattatcctttcttggtatcttggcc2700
aagataatttatagtattaataaagcaagtatgatacttcagctaattttccccctaatg2760
ctaatttcaacatccagcattcgtgtaattcccatgacattgaatattgatgcacagaat2820
gtaattggttatgtccaagaatgccattatctacttagggtcactaactggaaaggaaaa2880
gaatttgagaaacaaatacagctagtaaactgcatttaactagttataaatcatcttttg2940
gacaacagaaattatggaatatccaatttttttatttgttaggttgaagctagataacag3000
a 3001
<210> 151
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-14021-108 : polymorphic base A or G
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-14021-108.mis1
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
327
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-14021-108.mis2, complement
<220>
<221> primer bind
<222> 1394..1411
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1853..1870
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-14021-108 probe
<220>
<221> misc_feature
<222> 267,299,336,617,679
<223> n=a, g, c or t
<400> 151
caacatggcaaaaccccgtctctactaaaagtacaaaaattagctgggtatggtggcagg60
tgcctgtaatcccagctactcaggaggctgagggcaggagaagcttgaacccaggtagca120
gaggttgcagtgagccgagatcgcaccactgtactccagcctgggcgacaaaagcgagac180
tccgtctcaaaataaataaataaataaataaataaaataataataataataataaataaa240
aggcttctatatgcacagaggatttgnttcacatattgattctcttatgtggtcttcant300
tcacaactgtatgaatctgtagcatgaaatacatanttggcaagtaaagattctataaag360
gaaagagtaggaaggtataacgaaccaattctgagatttccctaagcaatcagttcacct420
gcttgcctccatggaggccatcattgtcttctagcacaatttgtgagagacagcaaggca480
tctttttaccactattaacctaatctatggcagtgttcccagggaccaatgttgtcagtt540
gtagagtaatgccatttagaggctggatgggtttacagttgcagccaagcaagggtctgc600
attgaattgacccaaanagggaattttcaagtaatttctctatctttgtatgtgtgagtt660
ttttagtagtccattcaantttcattagcttgtcaactctaatatctgacaactgaaata720
taaagtagggaggagaaagagcagaattaagagaaggaatatatgtgccagaggagagta780
ttatcattgtcctgatgtagtcatgatgacctaagtcatcctttgatattgctttcatat840
aaaggttgtagaatatatgaaccaaatcaaaatgggacaaggagagctgcttgctcacaa900
aatgcctctgatctattgtgtgcataaagcatgactttatgacaaacacatagagactct960
agatgggggaagttacagtccttgagtgattttcgtattcaacccagtgggatcactatc1020
atttagtggtatattaaaatgctaattctcatccaaggtcaaattcaactccatacaagc1080
tgttttaaaattcagaattggttgctttatgaaaagtaaatttgagactatttggaaata1140
aagactatttgaaaattttctggcttccttaacttcagtacctcttgccattgtgtcaca1200
gcttgggtgtggtgggggaggtgcaatcttctgggtagagaccaggaatcccactaagcc1260
tatatcgtatgggatagccctatgacaaagaatgacatggcccaaaaggccaatcatgcc1320
aagcttgagaaactgctcagaataagcagggagagtgaagaaacaagctgatgctcaaac1380
tagtgaatctcattttgttgttaatcgccccttttctgcaacacttgtgggttagggaaa1440
ataattctaaagcaagagcaaagacagagttgggagatcaccagtgaggttcaattttcc1500
rtcacattcactctgctccacacctcagataatcatgtgcttaactgcgaaacttgcttg1560
acaattacagaacactttctcacccattactaccttgatcctcacaattctgtggggtag1620
taggagcagatgctgaaattgccatacgcaaatcagtgaactgaagcttagagacctcca1680
gcaggggcagagggtcagcggaaactatcccagggttcagccaacaagaaagtatattgg1740
aatcagagtattaaaataagaataataaaaccaactaaaatttaccgtgctttttatttc1800
cactcagtgccaacaattcttaacagtgtcagtgatggatccctgtgccccaggggacag1860
acttcttactagcttctgccactttggtcagctgctgttctggggaggttaactttctta1920
cttcaaattcacactagagaggaaaaggaaatgcatacatataggaccaaatttcactcc1980
tgatgtctccacacacaaagctccttcaccatgccagtctcaatctgctgctctggggag2040
gttaagttttgtttgtttgtttgtttgttttttgagacagagtttcattcttgttgccca2100
ggctggagtgcagtggtgcaatctcggctcactgcaacctccgcctcccaggttcaagcc2160
attctcctgcttcagcctcccaagtagctgggattacgggtgtgcatcaccacacctggc2220
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
328
tagtttttgtattttcactagagatggggtttcaccatgttggtcaggctggtctcaaac2280
tccttactctcaggtgatccacctgccttggcctcccaaagtgctgggattacaggcatg2340
agtcaccatgcccagccaggaagttaagtttcttacctcaaattaacgctagagaggaaa2400
aggaaatgcataaatacaggaccaaatttcactcctgatgtctccacacacaaagttcct2460
tcaccatgcctgtctcaatcttgtcattaaagtggtatttccttattaggaaaaaaagaa2520
ctaggtccttaaaatactgttcattccatcccatgggttgagtacattacatattgacag2580
tggtacattccagccacctgagacaaccaatcttatgccaatcagtgctacagagagcac2640
cccttgccttacagctggcctaaccacagctggggatgactgactggagaatgttgtgat2700
ctttgactttgtcacaggtaaaatggtgtttctaactaatcacaggtctctgtgctgtgc2760
ctttcacttcatcacactctattctctctaattccaaccctgccaaactcattaggccaa2820
atttgcttacttctgtgcattctacacacttccaacaaaccctatgtttgcctttccttg2880
tgatgataaagagaaatggcagttagtggtctgaaagatggcgtctgacctttttatgat2940
ggggctgaaggctggatgctggaggcagggtgtgtgtttggtgcagcactgatattccct3000
a 3001
<210> 152
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-14364-415 : polymorphic base G or A
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-14364-415.misl, complement
<220>
<221> misc_binding
<222> 1482..1500
<223> 99-14364-415.mis2
<220>
<221> primer bind
<222> 1798..1816
<223> upstream amplification
primer, complement
<220>
<221> primer bind
<222> 1344..1364
<223> downstream amplification
primer
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-14364-415 probe
<400> 152
aaagatgcat tactttcaaa ggaaaaagcaacaagactgataactgaattaccaaaacaa60
atggccaaac cagatgatga tgaaatggcattttaaaaattctgaaaaaaattgtcaaat120
tagaattctg tgcatagcaa aaatatcctttcatttgaaggcaaaaatcagaacttttcc180
agacaaacag atactaacag aagttgtgaccagaggagcctatcagaagaaatgttaaag240
aaaaaatttc ttcacatatt agataaaagatcaaaaagagaaagagaaacactgaagtca300
agaagcaaat aaagaaaaac aaaaagcaaatatagggtaaatctaagtgaaaaaattcca360
taaaaataag atgaagttaa actaaatctagaatgtaaatattatgatactagaatagca420
tggatacaga aataacataa agacattaggaaaaggaggttacaaatcaatctcatgaac480
tttgaaccca gaaatataca aaaaaatttatataagtagatttagtcaaggaatagaggg540
ttgctttatc attttaaaat caaaataaatagtacctttgacagaaaaaaaaattatctc600
aacatatata ctctatatta gacaatatttaaaatcattcataagaaagaaatagaaagt660
aacttcctta ttttgatgaa ggtaatctaaactaaatttatatcaaacatcatatttaga720
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
329
agtataatattgaaaggtttcatcttaaataacagaacagagagaggttctccaaagata780
gtaagtttactcaggaacacgcacagcaatgcagaacatgtcatagtaaactatggaagt840
actcagggtggcaaaagaagacaagggtttttaaaggtaaagtgaggagggttacatgag900
ttattttgaaacagctattcttagttgcaaggatcaaaaacaagtctgacattagtccaa960
ggttagacaagcagatatcctcacagaagcgtgtgcatgcacgcgagtgtgtgtatgtgt1020
gtgtgtattaggttgcaatggctttgtatatgattgtagttttgtcaaagtcttattatc1080
aggcaattgtgtatgaaaatgctttcttcatggcctttcctggcttcattatgtcagtgt1140
ctgacacaagtgacttcattttgattcagacaactttcacatttgccccttttgatcaaa1200
atacgtctctaaaaccattgctgactaatcattctgtggttagattttcatcatccatca1260
gtgccaggatgaacttgttctgggtaactctgatcccatgtcagagggaagtgattgctg1320
attaggagtcagtatgaaaccctttagccacatttgagcatcaggagttctgtggggagt1380
gttcgttgttaagtccaacttcatcagtttcatagacaagggttatcatctcaaaactct1440
gagccagcattattctctcaggagttgtacttctgctgaaatttgacaagcaataagtac1500
raagtttataaagaaaaatacaaagtaaaattaatagtaataggaaaattctagtttatg1560
taataatattgagccaagaacctaggcttgaaagcaactgactgaatcagccaaatgacc1620
atggggaattaggtaagtcctgttgtaactatgtggcctattttcttgagtatttgcatc1680
acaacttgcccaaaggggtttatccaggtacagcatgtattattggcaatagcacaaata1740
tctccttatttaaccaatagagaatctagagcaattctatcatttcgtatcttatagctg1800
ggttgaattaaaacacagaatgagcaacagttgtactagagatgctgttgaagttaccca1860
ttgggcaggctaagggcttatctgtcagggcatgtaaatatttaggatgggcatgacaga1920
tgcaacattttttacagcttcctgcagaagctattgattgtgaaattttaactataccat1980
tatcctgccaagtgaaaaaggtaggcacaagcaaggaaaaattaagaggggcaagagtct2040
cattatgataaggaatcttatttcaatgtcttgggaagaatttttcccagcatgaaattg2100
tcaacttctcaccctggtttgtggtttgaaggtctctggttacagcattcgacagtttgg2160
tgaacttgccgtgtggctcaaacatcaggcacaagtcttgtcccttgaaatttacatcaa2220
attgtctagcttcattctacgcgggtttagaaaagggtggttttgttctcactaatttca2280
tgagagaaaagtggattggaggaacctacaagtgaagtggcatcattgtctggggtaaat2340
acctggggttggtcattttgtgctgagaagattaacaacatggacacgcacacatggaat2400
gggttaaggagcggaaagtttaataagcagaagaaaggggagaggagagcagccgtctct2460
gtctgtctcttgccagagagaggtatctgaaaaggaaagacctgctggtggcagagtgca2520
ctggattctacaggcaagcttgagaaggcactgtctgatttatgtagggcccacagattg2580
attggatcaggtgtgacatttacattgtgtgtgggaaggctggtcgccccaccctaatct2640
tattatgcaaatgggctttccacttggccagaaccatcttgtctgctccttactgtacgt2700
gtggctggcaaagagagggtggagctgccattttgagcctgcctattcccaggtagtttc2760
ttcctattggcacaactgccagcaataggctgctcttcgtaagaaaagaaaatgatttgg2820
gggctgcttttcattaaaaggaaaaccttactgaggactcccatattctcactatctgcc2880
taagtaatttcttcttaactcctatatcagaagaattcaagatccagtctagactacaga2940
tagataataaaaactaagaaactatgcacagggccaacatctaacaagtatattagagtt3000
t 3001
<210> 153
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-7308-157 : polymorphic base C or T
<220>
<221> misc_binding
<222> 1482..1500
<223> 99-7308-157.mis1
<220>
<221> misc_binding
<222> 1502..1521
<223> 99-7308-157.mis2, complement
<220>
<221> primer bind
<222> 1345..1362
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> upstream amplification primer
330
<220>
<221> primer bind
<222> 1819..1834
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513 -
<223> 99-7308-157 probe
<400> 153
cctgcatgacatcatttcattttccaacaccacacattgactagaatcattacaatcatt60
ttactaaacaggaagccgagacatattgaggccaagtaactttccaatggtgaaccagct120
aggaagaaatagattcaaaatttacatccattctcattaacctcaaagtttgcacaacta180
accattaaaccacattgtatcttaatgtacatctaatgcagcaccggaaggctatatgag240
aaagtaaatttcttttgtttgaggaatcactactggtttgccagaaatttgcttgggtga300
cagtgctccgagacatctgttactccctgtcattagcccaaccatcataattacacaccc360
actgaaataatcacaagatgcttcagggctgaccttgcaatgttgttagtcactctgttg420
ctgaacttgtatcttgttaaagaaattctgagttggtggatgatgggggaaagaaaaatt480
agtatttaggatcatataatttcagagctgtaattaaagataatctaatgcaatgattca540
taatattttctagctgacatgatggggtcacgatccctttgagaatctggtgaaagacat600
ggcaatacagtgttgtgctggctgaccttcaactaatctctacttggaggtagtcccagg660
ttcagcaggaggcaggggtccctccttcaacgatattccctcttcctataccctggcagc720
tagaacaggcacacatcagacacccttggtcagggcttttattcttgagggtgaaagcaa780
aggcacaacgtctgtgggcagtgtggcaaatgcaacagcatagcaattctgggagccttg840
aagctcagcctgcagtggctgacattcagaagtgatggcagcaggaactggttcttggca900
gtgccttgcttccccaggttgctgcaggagctaattgttcaaagttgcattctgagccta960
aagccttctaataaaatattttttatcccttttaatgaagttggttttgttgtttgtaat1020
caagaaccataactggcagaacacagatctatccctggaaaaatataccaatacacattt1080
tttttggtaaaatgtcagaaggatccatgacttccttcaatttatttaatagatgaggaa1140
actcaagcatgctggggctaaatgatttgcccaaggccagctctctatctattagtagtg1200
ttggttttagaacctagattttctgaactccagtcacctttcaatgtgcataaatgctct1260
aatctttttcatgggtggatgtgcaaatgattccaataatgcaggctgtggggagaaaga1320
ggcaaactgtagtaccatcagcagtgtggtctggatatggtgaactgttccttcacacac1380
agatgtgggaagccatgatcatcagttgcattattcctgaggggcaatgcattccagtta1440
catagaaccagtttctacgtttcagggtatatgtattcatggtgacaaatttattcacat1500
yttaagtaattttaagtaattcacattttaagtaattttcctgaatgtgcctcattggct1560
tctgtgcctcttcagaaaagatgaactaaacactggcatatgtgttcagatttcaacatt1620
ccgttgttttcattgtggataatttctgtcccatatttttgtgtaaagttagacaataaa1680
gtgttaatattctggcgtcggcacattttctttcctgataaataacaattcacatatctt1740
tttaaaatatcagagaatatagtaaccaatttccaattcttttttcaccatgtatctatt1800
ggagttttaaaatgactaatactaaggcaactatgagatgaattaaccttttgcatgtaa1860
ccctaatacagtttataagatacagtggcttctgataaaaatcaaaaataacgtattagg1920
atgggcaccaaaaatagaataagacgtactgtttggtagcacaataggatgactacagtc1980
aataataacttaattgtatattttaaaataagtgaaaaagtgtaactgaattatttgtaa2040
ctcaaaaggataaattcttgagaggatgaataacccattttccatggtgtgcttatttca2100
cattgtgtcctatatcaaaacatctcatgtctcccacaaacatatacacctactatatat2160
ccacaacattttttaaaaagttaacaattaaaatataatgcattaggaaaggctaattta2220
ttgcagacagagaggtaaaaaagagtaaattcttcatgcattccatatttttttgggttt2280
ttttttagagacagagtcttgctctgtcactcaggttggagtgcagtggcatgatctcgg2340
ctcactgcaacctccgcctcctgggttcaagcaattctcctgcctcagcctcctgagcag2400
ttgggactacaggcacgtgcctggctaatttttgtaagtttattattttgctgcctcagt2460
tcacaacttctatttagccactaccacaaatcactaccaattttgtttcagtcattatca2520
tatacctatcaggtaaatttccaatcattcttcaaggtccaaggaaaacttcaccaaatc2580
tgtgacattggcatcctcctactcacacaatttcacaaatacaataaaattaactatgct2640
tcttatgtgtcctcataatttttttttttttttttttttttttttttttttttttttttt2700
tttttttaggcagagtcttgctctgtccccaggcttgagtgctggcagtgcagtgttgca2760
atcttgggtcactgcaacctctgtctcctgggttcaagcaattctcttgcctcagcctcc2820
agagtagctcggattgcaagcatgcgccaccacacccagatgattttttttttctatttt2880
tagtagagacaggattacacctgtcggccaggctggttttgaactcctggcctcaagcaa2940
tccacccgccttggcctcccaaagtgctgggatcacaggtgtgagccactatgcccggca3000
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
331
a 3001
<210> 154
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-22310-148 : polymorphic base G or A
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-22310-148.misl, complement
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-22310-148.mis2,
<220>
<221> primer bind
<222> 1630..1648
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1183..1203
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-22310-148 probe
<400>
154
aaatttttaattttagtgaagtccagtttattaattatttcttccctgaatcatgccttt60
ggtgtcatatatgaaagtcatagcacaacctaagttcatctagattttctcataggttac120
cttctaggatttttataattttgcattttacatttatttacgtgatccattttaagttaa180
tgttatgaaggacgtatgatctatgtttggatttatgttttgcatgtggacgttccagtt240
gtcccagtaccgttagttgaaaagactactttttctttattgtattgcttttgttccttt300
gtcaaaggtcagttgactgtatttatgtgggtctatttctttgctctttcctgtgctcca360
ttgatctatctgtctattccttcaccaatacttcactgtcttggttatggtaactgtata420
gtgagtcttgaggttgggtagtgctagtcctctcactctttttctccttcaatattgtgg480
tggatattcttggacctttgcctctccgtgtaaactttagtatcagtgtgtcaaaatcca540
ccaactaagtcactgggattttgattgggattgaattgaatctatagatcaagttggaaa600
taactgatattctgacaatattgagtcttcctacccatgaagatggagtatctcttcatt660
catttggttcttctttgatttttccattagagccttaccgttctcctcatatggaccttg720
aacatgttttgttagtaaatgtacttttaaacatattttcttcccactgttttatgtgga780
cattcatcaagctttttttttgcttgattcagtcttttcagagtatgattttaaggtatg840
tattatttttaaaataatagatattttatcttatgtacagttagagatttccctgttgac900
actaaaatatttacatgttgttgatttttatgttttgcttttatgttcgttttagaaaca960
ataatgcctactctaaattatgaaaacaatgaaatacaaatatgggcatcaaagaggaaa1020
atgaagaagctatttcaagctgtcaagaatatactcttagctctgtattcaaaagtactt1080
catttgtataaaaaaattaaattcaaatccacactttaaaatttttaaaaaagtaattgt1140
ttctctcaaaatacgtatggtcaaatgaccatttttttccttctgtgtagttgcttattt1200
tagagagctttgtcccaacagggtagcagagagataatgattctactattgtctttaaat1260
tcttacccgcttctctgccagtcatcgaactactccctctactccaaaacttggtctgct1320
ctgctctaaatcaatgagatattgctatctgtctgatgcaggttacattccagtatctta1380
tctttcccagtttgtattgcaataatattggggtaaaatattgcatgggtttacaaaagg1440
gattcagtaaaatacaagcacacatttagagcttgttcttggatttgatttgcattgtca1500
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
332
rtttggtgccttcaggagtcatttcacattctttgcttccacatatcagcttttagtaaa1560
gctttgctctatatcggtagctttcaacctgtgctgcacttctgaaaccctagggagctt1620
ttaaaaaaagaatgatctcgtatcacaccagaccaattaaatcagaatctctggaggctg1680
gcactctggcatcagtacttaaaacagctccccaggagattctcaaaggcagcgatggtg1740
acaaaccacagctctgtacaatagaacaggctgctcctttataattattaatcatagtgt1800
atattaattcatcatcacatacgtggctagaaaaaaatttagaacaaaaagatatgtgat1860
atgtaaaggcctacgataattcagacttctttgaggagagcttttattttattgttattc1920
ttattttatctcttgtcaatataaattgagagaataaacagacaaacattacaaattagt1980
gattaattgcatttaaagcctagttaagactatttaagactattatgcataatacaggaa2040
aactacctttattatttatagtgggtgccttctgaaggatctgaaggagaatcagttcta2100
tgcctctctcctcattcccaggaggtgcctggcattccttggcttgtagacgcatcaccc2160
taatctctacctctgccttcacatggtgtcccctgtgtgtgtgtttttgccccatgtgtc2220
tcctctttttatatggatgccagtcatgagatttaggcccaccctaaactactatgacct2280
tatttaaagtaaacttaactaattacatctgcaaagaccacacttccacataaagtcata2340
ttcagagttccaggtagacatggatttttggaggacactcttcagcccagtactgcactc2400
atattactcaacttctccactgcttttgatgctgttcaacactcttctgagaactccttc2460
ctcccatatcttctgtgtctattttgcctgttttgcccccttctgtcataatgcccctaa2520
caacatattgcaagagtctgctaaataaatatctgcttcctcttattgtctgtgcaatcc2580
tggagggcagggagttgacttattcaggtctctatgtgaacaccaaccaatttttagctc2640
atggaagcccgtagtaagaattggaaaaaaggaagagaggaagaaaaagagaaggttgtg2700
acttctgcctccatggacatcatgaggaaacacacacgtgccttgacttgatggacctat2760
acaattcattttttaaaatattggcatttcatactcacatcaaatatcttgcacctgcat2820
gatatcattccagctagtacagtttctggttataaaattgtagatcaggattaatgatta2880
ttaagcccggttttccaaattattgaggctcacaattttgagaagtgtgatttccataga2940
tttgtttaagaagtaaaaggctggccaggcacagtggctcatgcctgtaatcccagcact3000
t 3001
<210> 155
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-15232-291 : polymorphic base G or T
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-15232-291.misl,
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-15232-291.mis2, complement
<220>
<221> primer bind
<222> 1211..1228
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1677..1695
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-15232-291 probe
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
333
<221> misc_feature
<222> 2775,2807,2844
<223> n=a, g, c or t
<400>
155
gtcactgggattttgattgggattgaattgaatctatagatcaagttggaaataactgat60
attctgacaatattgagtcttcctacccatgaagatggagtatctcttcattcatttggt120
tcttctttgatttttccattagagccttaccgttctcctcatatggaccttgaacatgtt180
ttgttagtaaatgtacttttaaacatattttcttcccactgttttatgtggacattcatc240
aagctttttttttgcttgattcagtcttttcagagtatgattttaaggtatgtattattt300
ttaaaataatagatattttatcttatgtacagttagagatttccctgttgacactaaaat360
atttacatgttgttgatttttatgttttgcttttatgttcgttttagaaacaataatgcc420
tactctaaattatgaaaacaatgaaatacaaatatgggcatcaaagaggaaaatgaagaa480
gctatttcaagctgtcaagaatatactcttagctctgtattcaaaagtacttcatttgta540
taaaaaaattaaattcaaatccacactttaaaatttttaaaaaagtaattgtttctctca600
aaatacgtatggtcaaatgaccatttttttccttctgtgtagttgcttattttagagagc660
tttgtcccaacagggtagcagagagataatgattctactattgtctttaaattcttaccc720
gcttctctgccagtcatcgaactactccctctactccaaaacttggtctgctctgctcta780
aatcaatgagatattgctatctgtctgatgcaggttacattccagtatcttatctttccc840
agtttgtattgcaataatattggggtaaaatattgcatgggtttacaaaagggattcagt'900
aaaatacaagcacacatttagagcttgttcttggatttgatttgcattgtcaatttggtg960
ccttcaggagtcatttcacattctttgcttccacatatcagcttttagtaaagctttgct1020
ctatatcggtagctttcaacctgtgctgcacttctgaaaccctagggagcttttaaaaaa1080
agaatgatctcgtatcacaccagaccaattaaatcagaatctctggaggctggcactctg1140
gcatcagtacttaaaacagctccccaggagattctcaaaggcagcgatggtgacaaacca1200
cagctctgtacaatagaacaggctgctcctttataattattaatcatagtgtatattaat1260
tcatcatcacatacgtggctagaaaaaaatttagaacaaaaagatatgtgatatgtaaag1320
gcctacgataattcagacttctttgaggagagcttttattttattgttattcttatttta1380
tctcttgtcaatataaattgagagaataaacagacaaacattacaaattagtgattaatt1440
gcatttaaagcctagttaagactatttaagactattatgcataatacaggaaaactacct1500
ktattatttatagtgggtgccttctgaaggatctgaaggagaatcagttctatgcctctc1560
tcctcattcccaggaggtgcctggcattccttggcttgtagacgcatcaccctaatctct1620
acctctgccttcacatggtgtcccctgtgtgtgtgtttttgccccatgtgtctcctcttt1680
ttatatggatgccagtcatgagatttaggcccaccctaaactactatgaccttatttaaa1740
gtaaacttaactaattacatctgcaaagaccacacttccacataaagtcatattcagagt1800
tccaggtagacatggatttttggaggacactcttcagcccagtactgcactcatattact1860
caacttctccactgcttttgatgctgttcaacactcttctgagaactccttcctcccata1920
tcttctgtgtctattttgcctgttttgcccccttctgtcataatgcccctaacaacatat1980
tgcaagagtctgctaaataaatatctgcttcctcttattgtctgtgcaatcctggagggc2040
agggagttgacttattcaggtctctatgtgaacaccaaccaatttttagctcatggaagc2100
ccgtagtaagaattggaaaaaaggaagagaggaagaaaaagagaaggttgtgacttctgc2160
ctccatggacatcatgaggaaacacacacgtgccttgacttgatggacctatacaattca2220
ttttttaaaatattggcatttcatactcacatcaaatatcttgcacctgcatgatatcat2280
tccagctagtacagtttctggttataaaattgtagatcaggattaatgattattaagccc2340
ggttttccaaattattgaggctcacaattttgagaagtgtgatttccatagatttgttta2400
agaagtaaaaggctggccaggcacagtggctcatgcctgtaatcccagcactttgggagg2460
ccaaggtgggcagatcacctgaggtcaggggtttgagaccagcctggccaacatggcaaa2520
accccgtctctactaaaagtacaaaaattagctgggtatggtggcaggtgcctgtaatcc2580
cagctactcaggaggctgagggcaggagaagcttgaacccaggtagcagaggttgcagtg2640
agccgagatcgcaccactgtactccagcctgggcgacaaaagcgagactccgtctcaaaa2700
taaataaataaataaataaataaaataataataataataataaataaaaggcttctatat2760
gcacagaggatttgnttcacatattgattctcttatgtggtcttcanttcacaactgtat2820
gaatctgtagcatgaaatacatanttggcaagtaaagattctataaaggaaagagtagga2880
aggtataacgaaccaattctgagatttccctaagcaatcagttcacctgcttgcctccat2940
ggaggccatcattgtcttctagcacaatttgtgagagacagcaaggcatctttttaccac3000
t 3001
<210> 156
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
334
<221> allele
<222> 1501
<223> 99-6080-99 : polymorphic base G or A
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-6080-99.misl, complement
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-6080-99.mis2,
<220>
<221> primer bind
<222> 1572..1589
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1061..1081
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-6080-99 probe
<400> 156
gaatttaaagaaatgaattttagtaatgggtttagtatatattaaatcatgttcatataa60
cttaaaaatattaattttaagctatttactgaagaaaaacatgaccactcagtggaactt120
tatattttacgatttctaaaaatattataggttatttttctaggaactgctgttaatttt180
ggccattactgccatatactttggacatatataaagtgttttttggtaagtatctgagat240
tacatttaatatctacatgtagcacactttacacaagctaaattctatcgtatttggcat300
tttttcctcaattcagctgtattttcagagaaaacacacaagattacagagctatttcta360
tgcttaatagaatactgtctaatgatttctgcatgtagcaaaatccaactttttggatta420
acatggctacatggtaatcacccactaaatatttacaacatgaatttatctgtgactcac480
ttgatgtaccgtgattgt.gtgcgcatcctaagacgtgattcctgtactatggttgagtaa540
ttgtcatggcaggtttgcccctctagtgttggcttctcgttttgctttgtgctgcttttc600
tctgctatccaggctgccattgctatttttattttctacttctgatggttcaggaacatg660
aaggcaagataaaaagaaagtatgtgttgccttactgccactattctatgatatgagtca720
ggggtatggaaaagctgaatttttaaggagacagcaaacctcacagattcaggggattta780
atttcccctcctcatatcccagaaggtctaagttactagttacgttaaacaaaagaaata840
attaaacaatggagaagatgctatagaaaagtttcccttttcttttctttttaaatatac900
ttcttatatgcagtcctaaaaggactttctctcttcttatagcttaacaatcaaacaaca960
gcttagggcagcatttggcaaactgtaactgctggttaaatctggcctgtcccctatttc1020
tataaataaagctttattggaatgcagccacactcattcatgtgaatgcgtattgtctgt1080
gactgctttggcaaaatagtggtggagttgagtaattaatacaagcgcttttcagcctta1140
gagcctaaattatttactatctggccaactcactttttggtttaaggtaatgaaatttta1200
atttgcacacaataatgtacatgttttaatatgtgacaataaaggttttgctgcatttat1260
gcagtacatttttgaaattaaaaataaacttgtaatagaaatatagttctaaagagtttc1320
accatcttgtagatttttcaataattttttcatataaagtcaatacatctttatagaata1380
aaatattttagaatctagtttataggaaatagcataaacatctgtttcgataaacttccc1440
ctaataaagacataccttgaacacgagctattgttttgcatttgccaacttttccatttc1500
rtaattgtattaaattgctagagatggctttgtaatcaaagacattagaatattcagttg1560
aatatagcatgggtttcagggacacatttttgttgttgtagtggtttttgtttttaattc1620
tctgctgctaggtagcactaaatccccaagggactcaaagatgagaaacaggaaaaaaat1680
ttccagctgtgaactgctgctaaagcagagaagccctgtctgtgatattagttcgtttat1740
caaaatgcttgcgatttggccctagaaaaagggaccgctggcagtgttgtacataagtgg1800
tcctgcttggtttgcccatgtggtatttatctcagtcccttctgatcagggccagaaagt1860
ctacccaacaggaatattctatattgagtagcacctgactactgaccaaatcagatgttt1920
tcctttggtagatttaataaccgtagagaaagagagctgactgcaaagtgctaggaatga1980
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
335
ctagagactgagagagagcacagatgcttacagagagcctcagtagttactggcgggaaa2040
gagaaccgggggagagagacagtgagcaagaaaaggaggagagacaaagatggagaggaa2100
ataaagtaaaaacagatgaagcaaaaaaagaaattgagtcagaagaatgacagaatgaat2160
atggtcagaagccaactgcacccatttatgaggacataactgcttgaattgctgatgtga2220
cattggaagtttgtgtgtgtgtgatgcagtggcattccaattctccctgaaggtatttac2280
ctatctcccatatatttccatgtatctgcaagaagccttatcacctatgacagagctaca2340
aacatcagagtctcactaatatatatatagctaattgattattttcaaaataaaatgtga2400
agggaataaatcacacaacagccctatttatggtttagcaaatgatctcaaactcacata2460
tttagggggtcaggtgcgtcaatgagtgaatcagtttgggtgtaggaagtgatgggtcag2520
gttgagggacagaagaggctgtgcactgctggtgggactgtgaattagtgctgccattat2580
ggaaaattgtatggaggttcctcaaataactaaaaatagaattgccatatgatccagcaa2640
tcccttttctgggtatttacctaaaagattcgaaatcattatgtccaagagatgtctgca2700
ctcccatgttgattgtggcactatgtgcaatagccaacttatggaatcagtcgaagtgtc2760
catcaacacataaatagataaagacaatgtggtacatacatatacacaatgaaatactat2820
tcagccttacaaagggaagaagttctgtcatttgcaataacatgaatggaattggagaac2880
attatgctaagtgaaataagccaaacacagacaaataccacacattctcatacagaaaag2940
ttttccttttcttataacttatatgtggaatgtaaaacacttttattctcacttatatgt3000
g 3001
<210> 157
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-15229-412 : polymorphic base T or C
<220>
<221> misc_binding
<222> 1502..1520
<223> 99-15229-412.misl,
complement
<220>
<221> misc
binding
_
<222> 1481 .1500
<223> 99-15229-412.mis2,
<220>
<221> primer bind
<222> 1893..1912
<223> upstream amplification
primer, complement
<220>
<221> primer bind
<222> 1419..1437
<223> downstream amplification
primer
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-15229-412 probe
<400> 157
gttttgaatt tcagaaagtt gtgtaacgcttccatgaatttttctttatc ttggaaaaac60
attgccatgc aatgtatttt ataattactttcagaaatacagcgtttcta attgagaagt120
ttgtgaacgt ggcctgaaca ttctagctcatgtgcgtaattgatagcaat gaattatttt180
acaaggtaaa gatgtttccc ccttggctcaataactattaatatcaaatg aaagcacaca240
ctggcatcag ggggaacaca gcctcctcacccttccaatttcatttcaca ttacctgcca300
acttccagga aatcctttag gcatcattacactttttccctaggccccct atcctccctt360
aagacctcca ctctgctata ctaacctgcacagggacagggaaataactc taagtgcatc420
tcttttcttt cctaagatat gttgcttaaatgtaagggaaagctacttgg caactctaac480
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
336
acacacacacactcaccccagaaattctcggctcttcacaagagtgtgttttctccttat540
ggaagagttgatgtggttccatttataaaaatagcagctatttaaatgggaaaagctttt600
tctcatatcatctgtgggccaaatgtttttctaaaaacatacattctctttttctagcag660
agaagacaaattctaaatggattcaaggttcatcaaattgctaagttttctttgggttaa720
tgcatttgacaaccaagttcacagaagtgccaaaatgaaaataagtaaattaagaactgt780
tctatctaatttctttattagaacacacatttttgtgtgtttttcatgtgtatgcattat840
atttataaactgatgtgattaatatataaactgtgttaatctgcaattatttttatttcc900
tacatagaattttatatggtgatttttaggaagttggaacacatagtccatataaattgt960
ttcttaagctctgctttctctacttcagggaagcaaaaagagaagttcatatctcttctt1020
tccaatccttttttttttttttttttgagatggagtttcattcgtgttgcccaggctgga1080
gggcaatggcacaatctcggctcactggctaatttttgtatttttagtagagacacggtt1140
tcaccatgttggccagtctggttttgaactcctgacctcatgtgatcctcctgcctcagc1200
ctcccaaagtgctgggattacaggcatgagccaccgtgcctggccctttccaatcctttt1260
taagctcatgtattcatcaccaccttcataagttccaatttctctagcttatattcagct1320
gaatatgaccttgaaattcaaagattcactctttatccaatgcaagattctgtctatcat1380
gcatattcactgctgtttaaacatttccactagtgatgacatcagactatgcaggggatg1440
gggtggtgtaggggttgtggtaggcagggcttctaaaccagcaagactaccttcattcct1500
ytggccgtattaaatacctataagagctaacgaaagcattgagattgctatggatgaatt1560
ggttcaagattagttcattatccctgtccgcctctagcaccaaggctgctctaggcttta1620
agcctcccagtgaaagactctggatctcgactggtttccaagggtagacagaaaattaca1680
ggatacattctaattattaatattacagatgttgtccttacattgagacacatctgcctg1740
gacagtggtcaccatctgctcctctggaactacatacaaaaatgggtccaatcccttaaa1800
taaaatagttcttcaaatatttggagacagctctgttctgctaatcttagctttttcaga1860
ctgagttgtatcaaattctctaagtattattggtagcatttctcaatgacagtagcaatt1920
gcttatgttaccacagcactttggagtttccaaaacactttcacaactgtaggttcttaa1980
ttttataaatgagaaaactggggctcagagaggataagttacattaccttaataattgat2040
ttaacaagtactaatggagtgtctactgtatgcttggcgcaggcaaaatcctaggatata2100
ggagataatacatcaagaatggtgccccccttctagctcttatgatctagtatgggagga2160
atacatttttaaaaattacagatgatacccagataatagtcacacctggttgggacttta2220
gcccaagtcttctgtctctaaaccaaattaacagaccattaacttcagtacagcagacac2280
tgcacttggattcatgaaacccacttaagctagtctttctgcaactagctgtcctggtac2340
aagctcttcttaagatgtaccttcttcattccataactaaatgtgtgaggagtctgtgca2400
tgtgtggttaactcagaggagaactctacactgatttctataaaattgtattctgccatt2460
ttctttctacctctctaagttgccaaccttcttttgaactcttattttatcatttctcac2520
acattagatcttcctctcagtttctgtccatctgcaagttttatgaaattgtgttcacct2580
atatcactgacaagaaaaaaaaaatgcccacaagtgcttggtgtgaaagaaagagcacac2640
atttgtcattagtcgcagattagatttcctattagctaagtgaccttgggcagataacat2700
cctctcccagagcaactgattactcatctgtgaaatgaggaaatcaggctggagaatttc2760
tgagggatttccctgcattaaaagttttataattcaatatgttttaaaatgcgaggctga2820
gttttaaaattctttccttctgagtgtggagagaagaaaatgcagaatatgtctactgat2880
atttactgataggcatcacctcctgcttcactaaaggaaggaaatacatcagcaaacatt2940
ggtgcaaaattcatacaacaggggccacttaagcagaatagctaccacacctttccttaa3000
t 3001
<210> 158
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-6012-220 : polymorphic base G or T
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-6012-220.misl,
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-6012-220.mis2, complement
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
337
<220>
<221> primer bind
<222> 1292..1310
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1758..1776
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-6012-220 probe
<400> 158
gaatggctggtttctcagaggggagctttacttactgtaattcataaaggtcacccagga60
aagccttcattatggatctagacagttgcaattagccttgaacaaatgtcccatggccca120
gtctggttgaaatgtcaatgagagcaggatggggttgattcttatagatggtcttccaaa180
aaagtattcaaaaatagattttttcctcctaaattgaatcatgtttttaaagtgcctgct240
ctttaaaggaaatgaatagggaattgtattaaattaggttgcatttctaattaaaacaac300
tactaaattattgtgcttataattttggattttcgtttacatgattttcttggagtagga360
gcacacctgcatattgggtggctaattaaagtgctaaaaatgcatacagtcactcagtat420
atttgccttgtgagactcatcctcaggaccctctgtcataaactgggatagctcaaatta480
ctcccaaagttcatattttatgaggctctggattcaactctttttccctccacttcaccc540
atttctcctacctaactaaaaaacttcctctttggttatttaaaatatctttacttactg600
agtaaaaattttattaatgatatatttaaaataaaagaaaataaatgagatgatgaatgg660
tatccaggacagaagttctctcagtctaaacagctttccatgacagactaaaaaccctta720
catggaaaaactgcctcaacgacagcaggaaagactttacaatgaaaaagaaacaaataa780
aaaggactttcttttccttctgtttccttgggttggttgttctttccaaacatgacttcc840
atttactaaaagatggctgtattttttttgagtcaaaatcacgttgaaaaaatgtgcagt900
tgaaaagagtattttgacatatttaacaaaactgcagaattggtaagttcaaaatatatt960
gaaaaggggcaagaatcaatcattagtgcttcttttaaaacacagtgattaaaaatgagt1020
taacagcctgggtgattaaagtgatcaggaaaaaggagttgtggtcatcacagatatcat1080
gaaaggattcaggttcatgtgtctcaactatgtgatatttcatatcagggaaactggtat1140
atgcatttcagctgcaaaaatccccaaagtccaaattaaatgtttgccatttcttgacac1200
acttctcaaagtaagagtgcagtcagaattatttagattgtgacaattgtgttttttaac1260
ttcttgcgtagctatggcataattgtatttagtcttgacttgttttcctgagggtccagg1320
ttgatttgcatgctcttgaggaaatatacacgtcttctcagttttaataattgactgaca1380
gccctgtggtttctcaggacccagtgagctgctgctcccaggtcagtctgcaagggatgc1440
tggttcccttgtggtctcatcaaggtgaggaatttcctgattttagagatttctttatcc1500
kaattttgaagactttctttcacatttctaggcataaaaaaatgtacagcactctactgc1560
ttgtttaacaaatggatagtgatatatctgccaacaaagaccacatggagtatttcattg1620
actatcagagaagtttcctcgaaaggcaccatacttagtgttttatttccatgagtgaag1680
gaaaattagttatttgaagtatttggctgtctttagttgtttctaaagtagtgctgattt1740
tatatgcccataatattcatatatacacccaggatatcattttatatatgtcacaattca1800
tgaaatatcttatatttcatcttcaaacttatcctctggccctggaactattctaatcac1860
tgctcttgcttctggaatgcttagcttcatgccatagtagagcattttcagaaaactggt1920
aagctcagctaaagctaatatggcatatatggatagaacatttgatgagtaaattccagt1980
tctgaaagtctactagtcgctgaaatacttagaataaaaaatgaggattgattttgtatg2040
tgtcatgaaacagtagcatttctaggtcagcattttcccagctgtgttattctttcctgt2100
ttgtcaatgctcagtgcatcttagaggtaggaaattattctactgcttgtgaaactagaa2160
ctagatagcacatagtaataacacagtgtgaatagttattaggacctattatagcacttt2220
tcctgtagaacgctctagctgttttcttccataacatgggtcaaattgtgcctctcttaa2280
atgggaagcacacagggagagggttccatcagacagatgtaggctgcatgactatcaaga2340
ggtgagaaatggttcaactcagctggccaagacccactcacacccctgagacccagccta2400
gccagagaacagctggctgatcttggcaggagttttagggcagatagttcatcaccacag2460
caccactaatccattcattttctttctcaatataaggacccttgagaatgttcccatctc2520
ccttctgtgcatttttgctggcttccatccctggggaatcagccacattttctcatgtgt2580
cttcagggcatcttaggacataggaaggggaaagaaatgaaattttaccttcaaagatga2640
gaatggaagagagaataaaggaaactgtcctggacctcacaggcaataaacaaacagtta2700
actgaagacttcactctgattcaatccactcttctttttagtgatctgcctatctgtgat2760
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
338
gtatctccaggcaaaaactttcatatacagtagtttaaaaatgagctgtt tcttcctgca2820
ggtctgactgcacaggcatattgagcgaggcaacttgaacaccaggctga ggccgatttt2880
gtgaagcatctttcactctttctcttttctggggatgtgtgacaggttgt gggtgggtga2940
gtgtgtgtgtatgctggacttctttggaagatgtgggacccaagaagtat cactgtgaga3000
g 3001
<210>
159
<211>
3001
<212>
DNA
<213> Sapiens
Homo
<220>
<221>
allele
<222>
1501
<223> T or C
8-98-68
: polymorphic
base
<220>
<221> binding
misc
_ .1520
<222>
1502
<223>
8-98-68.misl,
complement
<220>
<221> binding
misc
_ .1500
<222>
1481
<223>
8-98-68.mis2,
<220>
<221>
primer
bind
<222> .1568
1550.
<223>
upstream
amplification
primer,
complement
<220>
<221>
primer
bind
<222> .1154
1135.
<223>
downstream
amplification
primer
<220>
<221> binding
misc
_ .1513
<222>
1489
<223>
8-98-68
probe
<400>
159
cctttagaaaaaaagtggttttttttttagctctaaataattaaaggttg cctaaactaa60
tgtgtataagtagatttacctgtaaatatgtaagggaagtcccaattatt gtacactttc120
ataattcaatgtgaatttcatacaaagcaaagtttcaccattaagaaaat aaacattttg180
ttcctatcactgagtgaatatttgtaatttctatttaagccatttctaga tttttttttt240
tttttttggtcttttgtgagcttctgagattggtgccattttatcacagt atttctcgtc300
ttgacttctttgcatgaccccaggtttccagtaagtaaggtatccttaga aaaaaaagta360
ttttaagggaaatggatgcatacttcaggcccattttatatgtaactcaa tattgtcttt420
ttaaaaggccacactaccatggaataaattaaaataaaaaatcagatttc ttgtacgcat480
aacccctgcccagttttaaaaatgtgatcccttatttctagaaacctaaa atagatatcc540
ctgaataacaattcatttttaattatcagtagatatatatactgacacag agtataaaca600
acttctgtcactatttatttaaaatgttaaattgtacatttttcataatt tctttaagag660
aatcttctttggtgagtttaaagtgagagtagacaaataacttagtggct aaatgattta720
atgtcagatgacttaatgaccagtttttgcccttgatccagccccactct gatattctac780
ctcctgtgtgcttgtcttcattgtccccatattaaaatggtgactgatac ggaattctgg840
aaaaatctgatcgattaattaatgtgaatatgcatgttttccttagattc taatatggtc900
tttcttgtgtaagaatgtggatttctaatagccatataactcaatgtttc tcagtttgag960
ccctattggcatttggggctggataattccttgtttgggggctgtcctgt acactgcggg1020
atgctcagcagcatccctggcctctacccaccaaatgtctgcagcatacc ttcctacccg1080
acccagtgtgacaatcaaaattgtctgtagatgttgccaaatgacttttg ggtggaaaaa1140
ttgctctcgttaggaaccacttatgttaattatggaagaatctttttttt ctaatgttat1200
ttgcatctaaatttgcataactcatttctaataggtactcggatttcatt cgtaattcag1260
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
339
aaatagaaaaacatacaatggtctttttaacctgtcctagtggtgaatatacatggtttc1320
cttcgcatttatatgttctaatggcccagaaaaaataagaatccagacctctctcatgta1380
attgttaaggatattctgagccaagccagatttcacatgcatttccattccatccatccc1440
agcattcacagtttccacagctacatattccattccctgcaataaaatacatataggtat1500
yatgattatgatcaaaatgtgccaaatttaaacatgctattataaatcacaagtgtccac1560
aatgaaatcatttcattcatccttggtagattttcttattgtgcaatgatgttattatta1620
catcttattaagcagctgcgagacatctaatctttcaaacaattagtggcatttatttgg1680
tgccaccctttaccgatcagatagtcaccatcctgtatcactccagctaggcttttaggt1740
gacaattttgttttcccttaaagagcaagttatatctgacttatgaataaatacagaaaa1800
acataaggctctttgacataacatgaggcaggccaagtaatccgtgaagagagtcttacg1860
tagtaaggatgggcagaaagcaaaggtctaacttaatgacgcacaaagagtcatctttta1920
ccttcagctagagctgaggagaagtacacatgtctctgtttcctcgtaacttggctaaac1980
aaatggatttataaccaattatgaggactcaataaattaggatagcagtggctatgacac2040
ggctgagccctctttatacctctcccccatacacacatccagttccctaaaagcaaccaa2100
cacatcaactagtggtacccagattctgtttaaaagaatatttcattccctataccatgt2160
tcaaagtaaaatggttgccaacaaaattcttttctgtgttcaatatacaactgcatacat2220
gtgagtttgagggtggggaggttactttgtggaaggatcccaaataatcacaaaatttag2280
cttcattctcttgtattcttctatgcctaggaataatgtgaggcttttgtgagggctttt2340
tcccaaatgcccacttcgcctttggtagatatttcatattcacggttggccctgttggtc2400
cagccacctaaagcattgcatgacgagtgtctcttggctctataacaaactgtggcatag2460
agcaattagaaaaggttaatactgcacctgtacaaatgagaccatcatgtttgtcgcagt2520
ctctgtcatcacagtcacagaactccccagaaatataccactcctcagcagaacaaatgc2580
acttcccacaatgacaagaacctgaaattacaaaggctattactcaccatcaccttataa2640
ctaaaggtttccatctcgaatagaatatcgttgacacactgacaacaggcttctaataac2700
ccatcatccaaaggtaaaagtgtattgaatggctggtttctcagaggggagctttactta2760
ctgtaattcataaaggtcacccaggaaagccttcattatggatctagacagttgcaatta2820
gccttgaacaaatgtcccatggcccagtctggttgaaatgtcaatgagagcaggatgggg2880
ttgattcttatagatggtcttccaaaaaagtattcaaaaatagattttttcctcctaaat2940
tgaatcatgtttttaaagtgcctgctctttaaaggaaatgaatagggaattgtattaaat3000
t 3001
<210> 160
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 8-97-98 . polymorphic base G or A
<220>
<221> misc_binding
<222> 1502 .1521
<223> 8-97-98.misl, complement
<220>
<221> misc_binding
<222> 1482 .1500
<223> 8-97-98.mis2
<220>
<221> primer bind
<222> 1581..1598
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1249..1268
<223> downstream amplification primer
<220>
<221> misc binding
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
340
<222> 1489..1513
<223> 8-97-98 probe
<400> 160
tcgttaggaaccacttatgttaattatggaagaatcttttttttctaatgttatttgcat60
ctaaatttgcataactcatttctaataggtactcggatttcattcgtaattcagaaatag120
aaaaacatacaatggtctttttaacctgtcctagtggtgaatatacatggtttccttcgc180
atttatatgttctaatggcccagaaaaaataagaatccagacctctctcatgtaattgtt240
aaggatattctgagccaagccagatttcacatgcatttccattccatccatcccagcatt300
cacagtttccacagctacatattccattccctgcaataaaatacatataggtatcatgat360
tatgatcaaaatgtgccaaatttaaacatgctattataaatcacaagtgtccacaatgaa420
atcatttcattcatccttggtagattttcttattgtgcaatgatgttattattacatctt480
attaagcagctgcgagacatctaatctttcaaacaattagtggcatttatttggtgccac540
cctttaccgatcagatagtcaccatcctgtatcactccagctaggcttttaggtgacaat600
tttgttttcccttaaagagcaagttatatctgacttatgaataaatacagaaaaacataa660
ggctctttgacataacatgaggcaggccaagtaatccgtgaagagagtcttacgtagtaa720
ggatgggcagaaagcaaaggtctaacttaatgacgcacaaagagtcatcttttaccttca780
gctagagctgaggagaagtacacatgtctctgtttcctcgtaacttggctaaacaaatgg840
atttataaccaattatgaggactcaataaattaggatagcagtggctatgacacggctga900
gccctctttatacctctcccccatacacacatccagttccctaaaagcaaccaacacatc960
aactagtggtacccagattctgtttaaaagaatatttcattccctataccatgttcaaag1020
taaaatggttgccaacaaaattcttttctgtgttcaatatacaactgcatacatgtgagt1080
ttgagggtggggaggttactttgtggaaggatcccaaataatcacaaaatttagcttcat1140
tctcttgtattcttctatgcctaggaataatgtgaggcttttgtgagggctttttcccaa1200
atgcccacttcgcctttggtagatatttcatattcacggttggccctgttggtccagcca1260
cctaaagcattgcatgacgagtgtctcttggctctataacaaactgtggcatagagcaat1320
tagaaaaggttaatactgcacctgtacaaatgagaccatcatgtttgtcgcagtctctgt1380
catcacagtcacagaactccccagaaatataccactcctcagcagaacaaatgcacttcc1440
cacaatgacaagaacctgaaattacaaaggctattactcaccatcaccttataactaaag1500
rtttccatctcgaatagaatatcgttgacacactgacaacaggcttctaataacccatca1560
tccaaaggtaaaagtgtattgaatggctggtttctcagaggggagctttacttactgtaa1620
ttcataaaggtcacccaggaaagccttcattatggatctagacagttgcaattagccttg1680
aacaaatgtcccatggcccagtctggttgaaatgtcaatgagagcaggatggggttgatt1740
cttatagatggtcttccaaaaaagtattcaaaaatagattttttcctcctaaattgaatc1800
atgtttttaaagtgcctgctctttaaaggaaatgaatagggaattgtattaaattaggtt1860
gcatttctaattaaaacaactactaaattattgtgcttataattttggattttcgtttac1920
atgattttcttggagtaggagcacacctgcatattgggtggctaattaaagtgctaaaaa1980
tgcatacagtcactcagtatatttgccttgtgagactcatcctcaggaccctctgtcata2040
aactgggatagctcaaattactcccaaagttcatattttatgaggctctggattcaactc2100
tttttccctccacttcacccatttctcctacctaactaaaaaacttcctctttggttatt2160
taaaatatctttacttactgagtaaaaattttattaatgatatatttaaaataaaagaaa2220
ataaatgagatgatgaatggtatccaggacagaagttctctcagtctaaacagctttcca2280
tgacagactaaaaacccttacatggaaaaactgcctcaacgacagcaggaaagactttac2340
aatgaaaaagaaacaaataaaaaggactttcttttccttctgtttccttgggttggttgt2400
tctttccaaacatgacttccatttactaaaagatggctgtattttttttgagtcaaaatc2460
acgttgaaaaaatgtgcagttgaaaagagtattttgacatatttaacaaaactgcagaat2520
tggtaagttcaaaatatattgaaaaggggcaagaatcaatcattagtgcttcttttaaaa2580
cacagtgattaaaaatgagttaacagcctgggtgattaaagtgatcaggaaaaaggagtt2640
gtggtcatcacagatatcatgaaaggattcaggttcatgtgtctcaactatgtgatattt2700
catatcagggaaactggtatatgcatttcagctgcaaaaatccccaaagtccaaattaaa2760
tgtttgccatttcttgacacacttctcaaagtaagagtgcagtcagaattatttagattg2820
tgacaattgtgttttttaacttcttgcgtagctatggcataattgtatttagtcttgact2880
tgttttcctgagggtccaggttgatttgcatgctcttgaggaaatatacacgtcttctca2940
gttttaataattgactgacagccctgtggtttctcaggacccagtgagctgctgctccca3000
g 3001
<210> 161
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
341
<222> 1501
<223> 8-95-43 : polymorphic base T or C
<220>
<221> misc_binding
<222> 1502 .1520
<223> 8-95-43.misl, complement
<220>
<221> misc_binding
<222> 1481 .1500
<223> 8-95-43.mis2,
<220>
<221> primer bind
<222> 1526..1543
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1125..1144
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 8-95-43 probe
<400>
161
gaaacaatctcttagggtggctgccatgacaatggcataagataaactgcccagcacagc60
agatgttttacgaatttatgcctggtgttccattattgggacgctaagcatgtgggagtt120
ttttatatcctactgctccaggtcatcaccaaggtctgactgcaaaaattcaaaaaagtc180
taacctcagtcataaacaggttaaaagggcttttcccctcaactcacagagaaaggaaag240
aagaaagtatttttttgtcaggtttcaaatgtcttatcgttggttagagagagaacaggc300
atatagatgattgatatagatagataatagatacacagataatagatgatagatagatag360
atagatagatagatagatagatagatagatagacagacagacagataggatggatggatg420
gtgcctcagccttccattaagacacacactctactacccattagttatttttcctgatcc480
tctccctcaacccaccctccaccctccaataagacatatgtaacaagcctacctatgcat540
ccctgaacttaaaataaaagttagaaaagacacacattctgtttctttcccccaataaag600
ggatataattattttcttgtaatgtaattccatgtccacatcacttcatttatactggaa660
acgtggaaagatctgtaattcacatgcatcagcctcagcgatatgaactttttcaagaat720
gcaatgcaagaataatgttgacccacattcccagccatggaggtgctcggatcagcactc780
tactcctgggactctcatttttgtgggttacctctgctcactaccttctatctgcctcac840
tcattctctggacagtttattaatgccagtgagctcttgtttgggtatgagaggcatcat900
agaatctgagcgtatacctcttgtgatttctaagagtaatcttactccattttttcaagt960
ttgtgggtgatattatactttctcctaccagtgtttataaataaagtaatgaaaatcatg1020
ttaaaatgctgacttgccccaaaacctttcacgatcataaagtatcttagtacttagatt1080
caatgatcttttattgatagtgtactgcgtactttcacatacctgctaaataaagagttc1190
agggaaataaaagtcattacaaacctaattgtatattgcttttaggttcaatggtatatt1200
gctttctgtttatcttatttttaacagcaattgaaaaagcaagagtcagtagaataacaa1260
aggcaggtaaagcaagttgcatgcaggtagcatacagctatgagaaaggttactacctcc1320
acagaccacaccatcgaggtcttcacagcggcgatcatcacactcacaagtcttgccata1380
cacccggcgatctcctggaggatagcaggtgcatttgccacattcacatttacctggaaa1440
gtataaagaaagtgcacacttatgaggagagtcccggaatcactaaggctttcaaggagg1500
ygagcacactattaaacccaaatctcctagaatagttccagtctgtgcctgataatagtt1560
acacaaatacacatttccaacctccctaaggtaagctgaagttcaagaagaaattccgtg1620
gtggtctggagtggaagtggcagttgctgtctcagaagtcattcacatttgctattctct1680
aatttttgtttcattcatttttgaataaatccattataaaactctctggctatttcatat1740
acaacttatcctgatgattccttgaacataacataatacattatatatactgacataatt1800
tagtatgatgtggccattttaaaatgttttaatcttgggtctatctgctccatgagaaaa1860
aaaaagtggtcataggtaatatttcaatgtgctattttagtgactatttgtagtcaattt1920
tatagttcatagaactcattttagcatagaacctatgtcaaagagcataacctaaatatc1980
tttattatcctcgtcttaaaatttaaaattataaatatttttgcaatgaatttggttcat2040
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
342
cgtttgggaaccccttaactagtcccattatgctgactttcatcatgatttattgagtgg2100
taactatgtgtcaaacactatcattccctgcatgacatcatttcattttccaacaccaca2160
cattgactagaatcattacaatcattttactaaacaggaagccgagacatattgaggcca2220
agtaactttccaatggtgaaccagctaggaagaaatagattcaaaatttacatccattct2280
cattaacctcaaagtttgcacaactaaccattaaaccacattgtatcttaatgtacatct2340
aatgcagcaccggaaggctatatgagaaagtaaatttcttttgtttgaggaatcactact2400
ggtttgccagaaatttgcttgggtgacagtgctccgagacatctgttactccctgtcatt2460
agcccaaccatcataattacacacccactgaaataatcacaagatgcttcagggctgacc2520
ttgcaatgttgttagtcactctgttgctgaacttgtatcttgttaaagaaattctgagtt2580
ggtggatgatgggggaaagaaaaattagtatttaggatcatataatttcagagctgtaat2640
taaagataatctaatgcaatgattcataatattttctagctgacatgatggggtcacgat2700
ccctttgagaatctggtgaaagacatggcaatacagtgttgtgctggctgaccttcaact2760
aatctctacttggaggtagtcccaggttcagcaggaggcaggggtccctccttcaacgat2820
attccctcttcctataccctggcagctagaacaggcacacatcagacacccttggtcagg2880
gcttttattcttgagggtgaaagcaaaggcacaacgtctgtgggcagtgtggcaaatgca2940
acagcatagcaattctgggagccttgaagctcagcctgcagtggctgacattcagaagtg3000
a 3001
<210> 162
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 8-94-252 : polymorphic base A or G
<220>
<221> misc_binding
<222> 1482..1500
<223> 8-94-252.mis1
<220>
<221> misc
binding
_
<222> 1502 .1521
<223> 8-94-252.mis2,complement
<220>
<221> primer bind
<222> 1250..1267
<223> upstream
amplification
primer
<220>
<221> primer bind
<222> 1651..1669
<223> downstream
amplification
primer, complement
<220>
<221> misc
binding
_
<222> 1489 .1513
<223> 8-94-252
probe
<400> 162
atgtccatga actcatcattttttatggctgcatagtattccatggtgta tatgtgccac60
atttgcttaa tccagtctatcattgttggacgatacaacttcactacata gaaaatcaag120
gtcaatgctt catgcttttgtctgctaatttaattagtaataggagtgag ggattggaat180
gtgctttcag gatacgcattagttccttttgctaccttagcaagtaattt aatagaaacc240
ttatgtacat ttgcactttcaagtatgtgtgctgatgaaaactcacgtga tgcattgata300
ctaaaggcca cattctacccccttgaacatagggaatgcatatggtagtt catcttaact360
aaatctaagg gctcttcgtaaaataccttaaactttcaaaaacctaaaaa gcagtttggg420
cagctctaat gcacttgtatttctgacggcagatgactttaatccctagt tttccccaac480
catcagtcac tcttatatgtcctttctcaggacttccagaaatcattttc taaaaagcca540
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
343
cgtgaactactatgattatgccaccagacactatttagataaatcctcagagtttattca600
ggtagtttcagttgctgtcttgccattctgttttctgcccctgtatcatgtcaattatta660
gatttttaataacatagcagaaaatgagttgccttctgctgcccaagggtctttttccat720
gattgtaggaaatgaacattgaaatgataatctcctgaaggctctggcttatgggaagag780
agttatttgttattattttgtgtagctttgaagttgacactagtatgactatgttgcttt840
tgaaccacatgaaagaaagtaatttaatgttctaggatgtaaataccgcagctcacaaag900
attgattgaagtgaatgagaagttcatgtgttgatattaatgtgcagtggaagggatgtc960
tgagttttctttttttgagaattaagttaaatgcctgtcattctcctatagtgtgtgtgt1020
gtgtgtgtgtgttttacatcatggacccacaaagaggccatagctcccatttaaacctgc1080
tgtcctagacaaaaatccatgcacactcatatacatattttaggtatacagaccagagaa1140
tgtgaagggagtaatgtcctctgtgggctggaaatgattgctttacaacaggaattctgt1200
ctcaatggaattgctttacttcagggaaaacagaaatgggcaaactgcagtggtctatgc1260
aggtatggatggaccattctcacacctaaccaagcaatgtttgcttttcctcctcctttc1320
ttcccatcactagttgccatgtaccgagaaccatctttgcatgatgttggggaaacggtc1380
ccgaagcctggggtgacgccaagtaaaagcacaagtgcgtctgcaataatgaatggaggc1440
aaaccagtcaacaagagtaagacaacatagccagatcctcacaggtgttgtgacttattc1500
rtcctgagcacagttgagtgatttatcctcaccagacattcctgctccgtggctgaagag1560
cagcaggaagtaagctaatgcttattctttgctgtctccgaacttctctgttgcaagtgg1620
ataaatctcaacctgttgcaccccccacaacaagaagacacctggataaccagctaaact1680
cagaccatggaatgccctaccagatatggaatgcctttttaatatcttttctgtgactgt1740
gacacttcatgtgaatgacatacttcacaagtacactcgataccttgcctgctgacagct1800
acccataatcctttttgagtcctgtttcagcgaaatctatgtgtttaagttcaattttgt1860
agcacacaaataatattgagtaatttctagttagacgctgtaaacctgtgctattacgga1920
tttctcttcttcccatttttacagggctgctcgctccactgtctgtgaccttttgcaggg1980
attttgttcctctaaatcttaaatgttgcagttggcttaggtcggagagcaatcagggaa2040
tcaggaagccttctaaacctattattacaaattgcatctataaagaaagattaagaaaga2100
ttgttgtctctggctcacactatcgattaaacacacatatacgctctgtccagtagcaga2160
tactgtgctcccaaggtcggcattgcctgggtgggaaatggctcaaacacaatccaggga2220
agctctctatgatatgtgtttgacatccccctctagtttctttgtgtgtgtgtgttttat2280
acatatcacaagcttactggtaatggtaacatttgccttgcccagcgagcaagacccact2340
ggtttttgagaaagtgggtccaaagatttctgtaggccttgtaggcctgattaaggttca2400
tttttcatctattaattctcattatttggaaaaaaaaaaaaggaaaatcagtaattataa2460
cctacaagaattgcgctacctaaatccatttcagatatactccgtcctgtttttaatgaa2520
ccaaacttaacgccatccccgtttctggctgcgttcccctcatactcagcagagcatggg2580
caagacggctgttgtgttctttcctgcagcagcaatgcaaacgttagttataaattaatt2640
agactttaatatttttggtgtttaatgacaagtttttaaactggacatattaggaaaaat2700
attttttttagctcagcatgctgagtccggtactgtgtatttcaccagtacatgcctcta2760
gctcagcatctggggctcatgttgcccagtggctgggttagaggtgccttgccatgatct2820
cagaatacagtctgttgaattatcctagatgaaaataaaggcaaaccaacacattcatcc2880
atgaggattttggtccattccatttattttcttttattttgcattcttaatttccttttt2940
agtttaacactgtttgtttgagcttagggaagacaactaccaagaaaggccaggaacagt3000
t 3001
<210> 163
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-15231-219 : polymorphic base T or G
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-15231-219.misl, complement
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-15231-219.mis2,
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
344
<220>
<221> primer bind
<222> 1701..1719
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1189..1209
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-15231-219 probe
<400> 163
gaatatggagtagggtttcaaagtgttgacagttgagtctgcaaactaaggctgagttat60
attttagttttttttttttttcctggttttcactaagtctaattccaatgtctactggca120
gagattgtgtttgcatttgaggtagtggagggcggtactttccaagtgctgttggaatcc180
agataaactcaaggagcccagaaagacaacgggtatagtggctctcctcttatgacttag240
cactttagttgacttttttgaaaaagtctctgggtggaatacctcagtgatgatttgcca300
aacaagcagcgttagtgccaacaccttctctaaacttgctgcatcccttccaattgacat360
taatcccactgcaacttcctaaaaacaggaatgagccaatgagatttgcttattttctct420
cacccattacaagtaagtttgttcttgccctgcttgttttttagagggagtttctatcat480
agagttgaaaatcacatttaagaaggaaagagtttatgtctttacatgtaactattttat540
tttttccaatctaaattcaatcacttcttaatagatatattggtgtttgcattgctggca600
tcaaaaccacacatacacacacaaacacacacatacacacaaacatagtggacagaaata660
agtaaaaatatttctgttttcaaagaaaaagcattccttggagtttaggtaccattaact720
tctactataatacagttccggtactatggtttctaactaaatgaacactagaacagagct780
gactatattttcatctttgtccaaaattttagatgaatcacattttgaactttttatggt840
atgataatttctccaatatctaaattctttttctgagaaaacaaatgccgaggacatttt900
tgacactcttcttacatgagactatgaaaaagagcagcacttttgttgtagttgttgttg960
ttaataaaaaggataataacatacagaggattataagaaaaataagacatacctgaggtt1020
ttgtgatgagctatagagaatcaagggcagttccagtggagctgaggctgacaaagtact1080
gcccagctgccagccaaatccacccttaagttgcttttgtatggcctgggagctcagaag1140
gaattttttaaattttttttacagctttaaagtattaaacagaaaccaacaaaagaatat1200
gagacagggacgtacgtggtccgtaaagtttaactttctgatccttaataggaggataag1260
cgccgtgatagagaaatccaaaggtcatttgtattacgatggctagataatgtaatgaat1320
tccaatgtctgtgcatcagcgaatacgtcatcaaaattgctacaaaacaataataatagg1380
ttgttcacagcttaaaatgtttaggtagtgaagaggaaagaatataacctacattattta1440
ttgactacttatatttccctcattttacggaagagatctatcaatttacgtactcaataa1500
kagaactacaacatggttgcactccttaatctcaggatagagataacaatttttataaat1560
ctattacattatgagaacattgttagtactataaaaatcagcatcagttaaatgttctct1620
taaaataattttcaatattaaatttttaagtaactcagtggatgcatattttccttattt1680
ttggaaatttgacttataaagtttaagccatgactagaatatttacatcattaaaataaa1740
atttccaagtaaaaattttcatcttaaagtaatacggaaatgattttgctacattattct1800
aggattttacaaagtaattcacctttagaaaaaaagtggttttttttttagctctaaata1860
attaaaggttgcctaaactaatgtgtataagtagatttacctgtaaatatgtaagggaag1920
tcccaattattgtacactttcataattcaatgtgaatttcatacaaagcaaagtttcacc1980
attaagaaaataaacattttgttcctatcactgagtgaatatttgtaatttctatttaag2090
ccatttctagatttttttttttttttttggtcttttgtgagcttctgagattggtgccat2100
tttatcacagtatttctcgtcttgacttctttgcatgaccccaggtttccagtaagtaag2160
gtatccttagaaaaaaaagtattttaagggaaatggatgcatacttcaggcccattttat2220
atgtaactcaatattgtctttttaaaaggccacactaccatggaataaattaaaataaaa2280
aatcagatttcttgtacgcataacccctgcccagttttaaaaatgtgatcccttatttct2340
agaaacctaaaatagatatccctgaataacaattcatttttaattatcagtagatatata2400
tactgacacagagtataaacaacttctgtcactatttatttaaaatgttaaattgtacat2460
ttttcataatttctttaagagaatcttctttggtgagtttaaagtgagagtagacaaata2520
acttagtggctaaatgatttaatgtcagatgacttaatgaccagtttttgcccttgatcc2580
agccccactctgatattctacctcctgtgtgcttgtcttcattgtccccatattaaaatg2640
gtgactgatacggaattctggaaaaatctgatcgattaattaatgtgaatatgcatgttt2700
tccttagattctaatatggtctttcttgtgtaagaatgtggatttctaatagccatataa2760
ctcaatgtttctcagtttgagccctattggcatttggggctggataattccttgtttggg2820
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
345
ggctgtcctg tacactgcgg gatgctcagc agcatccctg gcctctaccc accaaatgtc 2880
tgcagcatac cttcctaccc gacccagtgt gacaatcaaa attgtctgta gatgttgcca 2940
aatgactttt gggtggaaaa attgctctcg ttaggaacca cttatgttaa ttatggaaga 3000
a 3001
<210> 164
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-15239-377 : polymorphic base G or C
<220>
<221> misc_binding
<222> 1482..1500
<223> 99-15239-377.mis1
<220>
<221> binding
misc
_
<222>
1502
.1521
<223>
99-15239-377.mis2,
complement
<220>
<221>
primer
bind
<222>
1139..1156
<223>
upstream
amplification
primer
<220>
<221>
primer
bind
<222>
1579..1599
<223> ement
downstream
amplification
primer,
compl
<220>
<221> _binding
misc
<222>
1489..1513
<223>
99-15239-377
probe
<220>
<221> feature
misc
_
<222>
1878,2817
<223> g, c or
n=a, t
<400>
164
tccatttagtatctggtatattttgttgtcctaatttcttgataaaagta ttaattctat60
ttcattcagcaataactttgcatacaaggatatttttgcatgaatcctct cacacgcatt120
tcattttcttagatccaaaacttcatttggttaatcttcaagcttcaagt tggggacagc180
agaggacatagtggtttgctttcatgcaaagttcagtctgggaaagacag ttgctacatg240
ctgttctacaaatcatgtgtcagaacaggaatggagtccaggcaccagca gagatactca300
cccttccccgagcacaatatgccatctgctgattcacacagattcttgct ttgttcttcc360
gtcatgttacacttccgcggatgttggcagagctttccaaaccatcctct ctcacaaaca420
cagcgaccacaggaacatgtgccgtggcctgtgaagcaaccacaggaaag gagtgagagg480.
atgaggaaataaccagctgaagcagagagttttaagaaagaaatgtgtaa accataggat540
ctcatttcccatccaacacattcttctttatgcatagtcaatttggcatg taattgtttg600
aaagaacttacaacagagttctagcttaacataataaatttgaatgtagc ataggagatg660
acttgagagaaagaaatcttgcaataattttaaatggaattataccacct ttcttgatag720
aaaatacttcttcatttgcatttttatcagtatggagtcttagcgctatt cttcattgca780
cacaccatgccatccagaccaatttgcaaggctagtcacattaccactgg tggcagtatt840
tattgattgttctcctattgcttactaataaaacaaaagggtaactttca tacaaatggc900
atttggcactatattagtttatctgtatacctctctgcttacaaataaca acagatacaa960
gtggaagtaatggtgtctctctattattgcataaaaattaacattagctt ggattcatgt1020
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
346
ttggcacattttttttggtttggttcctgacattggttcctggtttttcagatgtttatc1080
ttttggtatatatgtaacattgtatttgtgacagctatataccaggatgtacacctgttt1140
attgcctgccaccaacacaccattagattgcatgatattccatttcaatttcttccattt1200
cagtttccgctcgaccctttattccttttcctgatatgtgcattaccttacagcagggtc1260
tctctgaatcaactatttgcctagcgaagagttactgagtatctgttatcaacagagcat1320
tttgctacaaaatcaagcaccatggacaaagtggtccctgctcttctcccagggacagat1380
acgctcatcattcacactgattagcctctctgaagctgttgacaccgttctctcctgacc1440
atttgctctggcaggaccctcaggagtgaaccttggtccatctgctccccctccattcag1500
stctccacagggaggatgagtaaccaatgcttaatggtttgcaattaattattataatta1560
ttttttcttttttttttaggagtgataggaatttctttaatttctacagaaatccctcta1620
acagtttagtggagaatgaaatagatggctgtgagaattgagagcatgaacgtgtgcaga1680
ctggtggagaagcccaagttttggcatgagaaatacagtgaaaaatgcagtagagtaaat1790
ggagtgaaggacacttgcgagaatgcggatcggtaggacgtggtaagtaactgtggtgaa1800
aaggtttttgatcactgagaggtaagcagaagtctcctggagagggtttcttggaaaact1860
atttttttttgttgttgntgtttttttttttttttttgctttttaaattaaataagagag1920
attttccctgggttataccacatccctacctcacaggccatgcaacaagtgcctcctaac1980
agccagagaaggtctgggagagcggttttttaatccagcatatgttgctcccctggagaa2040
aattgggatcctgaaagaaagacaggatactaggaatgtctgacattcttttaaaaaata2100
ttctgggaaaaacatcggatacgaatgggggactactaaatctgcaagaaaaatgtcgct2160
gccatacctttaacatgcactcaatcagcaagtgctctggcactttctaaggctaatgac2220
tgttcttgtcacacaggttagcaaaaaaggaaaaaagtaaataaataaacaaataaatga2280
ggtaattgtggtctttttcacctagcttgatttacatgcaaagtaaaaacaaacaaagaa2340
acaaacaaaaaacccaaaaactgaaaccattaaagtttaaaagtagcatgcatgtaaaca2400
tgtgaccgataattggctcagccagatcggaactgactctagttcctctgattccaatgt2460
ctacactcttcccaatgtgttgctttgcttctatatttcactttagaaagtgagacacag2520
caggatttcttaattcttgtctctttcaaccaccacatcatttgaaggtatatatttgat2580
attcacaggcactttctctccttgcaagtctcttctctattggcatgccacaaaattctc2640
ttggcctcattcaacactcctcctttgtctctatttattcttctactttttttttttttt2700
ttttttttttactgaatgaataagtgcaggtattcacccaatgtttatctttaatcatct2760
tttttaatctctccataatttctttcttgaaaaatccattaaattttgggctttcanata2820
actgccaagaccacagggctctatctccagcccctgattttctcctacattcccctttca2880
tgattccacactttgtgttctattagcatccccacttaatacctccagagctacataggc2940
agggtccgacccatagaccctggtggaacaacggatgaacaaatgcacccagacacaggt3000
a 3001
<210> 165
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26126-498 : polymorphic base A or G
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-26126-498.mis1
<220>
<221> misc_binding
<222> 1502..1521
<223> 99-26126-498.mis2, complement
<220>
<221> primer bind
<222> 1004..1022
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1525..1545
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
347
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-26126-498 probe
<400> 165
gttccatctaaggatactttgttaccctatgttgtatgaaaaagtggattttctctttag60
ttgctagtactgtattctgtgcggaaaagaccattggagtcacccctattttttgcaggc120
tcaggggttggtattagatgaagaaacacaagatttctctgtcagttgggaaatcctttt180
tcctcttaggagtttattaggttttttagctgccactaagtttagcttataagaagagag240
ggaaacagcctctgaaacttccaggctgatcctttcatttatctaaattccatttctacc300
tctgcagaaaagggctagataacaaatctgatcctcttttctctacagtaatagctccca360
cccaaagactattataaggctaaataggacaggatcttaaggactgagaagtgccataga420
gagcattgcctcctccctcttaattttacagctgagcaaactgaagcccaaaagattaag480
ttattttcccaggagtcacatcagtaagaaggtcatatgtaaaattaaaataggtgagac540
agttattcattgaatgatgtgaacctgtctttccaacctagggatcagatgttaagaatc600
gtaacaatgggtcggaagggtaatgggcactcagagaatctgtatgaatcccaggcaacc660
aagctactatgggagagaagagaaatagcccagccagatacagtctgcatgggctgcacc720
actggccccacctccgctaactgcttattgcccactgatgcattatgatctttagccatc780
ctgatcactcttggattcatcactgcattctctactccatcccaggttccctaatacatg840
tacatatatatgtgcctcaccccctcaagattcagactcccagttgagagcatctcattg900
gccacatgacatcatctacggttccctaattgctggggttagtggaaggggacagaaaag960
ttagggataggctcttacctctcacctgtcttgtgactctacccaaatcaacgtgtgttt1020
ggatgcagaattgtcaaaatgacaatactcacgataactctgtgcagtagtagctctgtt1080
ctgcacttgactcagaaagcagtcatagtcagagctctggcatgctctaaaccaagattt1140
ggttggaaatttgatctctcatggaaaaggtgcttttgttattgttgttttctcatggaa1200
gaagcaaccaaacatctgttgaatctttaagtcagattgtctcaaagcatgttggaaaca1260
acacctacatcagaatcatctagggtgcttattagagcagatacctcatccctcaaccca1320
gaactgctgatttgaaattcatggggcccagatacaaatgcacactgaattgtgaggact1380
gctgatctatactcagtcactacatatgttcctgtaggatgttacatcctttcatggact1440
ttttcgatttgttgccaaccacatagagaactagaaagttaggtcaagaaataagagaaa1500
rtattaggtttagatttctgggtgccaagcaagccctgcaattatttagttattgtgtct1560
ttatggttactgtatctttattgttactaggtccacatagttaccatgttatgctctaca1620
agggcagaagagtaaaatatattaagctactagcaagtgctcatcatactcacactgaag1680
gaatttgctagcaaaagccatatttgcattctaacttggtgcagtgatttacaaagtgtg1740
gtccctagacaaacagcatcagcatcacctgggaacttgttagaaatgcaaactcgctcc1800
tactctgtccccagacttacattttaactagctttctgggtgattctgatgcatgctaaa1860
gttagaactgctgctctcagcttccatttccttgtctgaataaaacaatgataattgatc1920
cttcatagtttttctttagattattttctgttgtcattataaaactaagataatgtacaa1980
aaaggcacttagttcaaggtaagtgttcaataaatagtaagcatattattgagcttatat2040
ttaatttacaaacactgctcttattttctaattgtttaacttcaagagaatccacaggtt2100
gcctacaatataagcagtcatgttagatgttttatatatataagttctaaatgggatgca2160
gaagttctaaaattgtgatacttaaccaggaaaatggcagatttttattcttccatttta2220
gaaattaggaccaggctacttacttttctactgtcatttaaatccactttaaggtattca2280
caatgactttaacatgacattaataagcttagtgggtctttgaatttcttaatcccagtt2340
tcctggggctaaatacaataatctgtatctcttcatctttgacacgctgataaaaatccc2400
tgaacctggatttgcatttggttttcaaaatcaatcattttgctattcaaaggcaaggca2460
attgagtgaggtttgagattgaaatacatatcaaccccactagagggtgacctttatcta2520
aatcagggtgcatataaagtaagggcatcttctgtagccatctcataaaattggattgta2580
taactgtttactcaaggtgaaggagaggctgagaagtgattcttacatgaataattaata2640
actttcaatttctaaataatctattagtcttgtgggaatatttaaaaccaagctattgca2700
aatttctcagtttgtattttaggataaaattccttattaataaattcagctctgaatttt2760
aaaattatctgcttcaattccaattcaaaatatattccccccttttctcccaaaagacac2820
acacaactaaacatatgagaaaatagaaccccaaatttgtttcataaaaacaagcaaaca2880
aaaggctataggactttgttaagttttatatggtgatttagaaataagacaaacatattc2940
tctagataccaaaggagaaaaagaaaatccaaatgttcacatagtaattagagagctcag3000
t 3001
<210> 166
<211> 3001
<212> DNA
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<213> Homo Sapiens
348
<220>
<221> allele
<222> 1501
<223> 99-26166-257 : polymorphic base G or A
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-26166-257.misl, complement
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-26166-257.mis2,
<220>
<221> primer bind
<222> 1739..1757
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1237..1257
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26166-257 probe
<400>
166
taaaagtcagcattatactctagtgtcttcctggatgtacccatagaacaggctagaatg60
tcaaccacaagattccctctgttcattcctataatttattattattattatactttaagt120
tccggggtacatgtgcagaatgtgcagttttgttacataggtatacatgtgccatggtgg180
tttgctgcactcatcaacctgtcatctacattaggtattcctcctaatgctatccctccc240
ctagctccccacctcccaacaggccccagcgtgtgatgtccccctccccatgtccatgtg300
ttctcattgtccaactcccacttatgagtgagaacacgcgatgtttggttttctattctt360
gtgttagtttgctgagaatgatggtttccagcttcatccatgtccctgcaaaggacatga420
actcatccttttttatgtctgcatagtatcccatggcgtatatgtgccacattttcttta480
tccaatctatcattgatggacatttgggtaggttccaagtctttgctgttgtgaatagtg540
ctgcaataaacatacatgtgcgtgtgtctttatagtagaataatttataatcctctgaga600
gaacatgatgcagaaactgctgggacagtaatgttacaaatgatggccaccctgcagaaa660
agagccttctccagatctgcctccactcctttctgttcaatgcatgggacaatagtttta720
aaagttatacaggacagcagagttcagacacgtctgttccatcatctcttagactttcct780
tttggagtaagccactaaagagggtgaagcaagattgaagttttcctacaagatttcaag840
tatttcatgtttgaccaacttttgttttctgcatcccaatgcctttgcattttggaaaat900
tgtaaaagttgcaaaagttgctaaagtttcaagaatatggcactcatgagcaaaggtttc960
ctgttcccatgctactgctgctgaactgacacattttttatcattagaaatgcccttagt1020
gtccaaacactcccataaatgttatcatttttactttctgcatggttgtatagtcaagtg1080
aaactgagatgcatattacactgttaagtactttttgcaactttctatactaacaaatca1190
ggctaacctaaaggtaaaggtacaatgtttgtgtctttgtgagttttgcttttgccctat1200
ggtagtagttataatgaattctccagcagaatctccccaggaacattcgtttacaagcta1260
agtctttctatttgttcactttttaaaaaaggaaacagcactttgcaatatccatttttt1320
agcaataactggtgtcatcataattgactagcctcacactgctattccttctctttttta1380
aattttctgcaacattctcattggcatctccagagataggcctgttgattttttttttct1440
taaaacctgaatataagaaaataccccaaatttcacctgcattttgtctcacacatttcc1500
rtcagtattatttaccactatccttactagagcccaaaggtccacaaaaaactgccactc1560
ttcatggtgtggtcggtgctggtaaagccctggaggtagacacactgggccttgtgctcc1620
cacaaactggctggaaaacttgggcaggtctgttaacacgcagagacctctatgcaatga1680
acccattgaacaagacaatttgatagatgcctctcagctttcagttcttcttttgcacgc1740
tgtgtagagtccctcatgaattagatcttagaacattgagacagtagtgtattcctttgc1800
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
349
cagagcaattatatgttacattagaaggccacctacattgtggttttaatttgtaggatg1860
gatacttaaggtatccatgacttcaacactatgcaatctatgcctgtaacaaaattgcac1920
ctgtactccgtacactcatacaaacaagcaaacaaacacaaaaggccctctggagaacag1980
gactgtcctctagatgctgacagtctatgttcagtgcctgtctccctgtctctgccttac2040
cccctttctttagggttggcttagactccatgcttcctgttagctgctcattaaatgcag2100
cctgaaaatagttggttaatcatctttgtatattctatagattctgtatatttgtggcac2160
acagccctccctccttccctatagtcaccctgctctatatttaggcatataaaagctaca2220
attctcctgtattcacagatttgaatatagagacaggaaaaaaaaagcctacccaagtct2280
ccactaaaagtctgtttaatgcctcccagtatttatagaactcgattcttccagacactt2340
ttatttgttttatcttaacaagtctcattattttcttctagggttcgaatctgtacagaa2400
ttatttttaaaaattacagcttgtgtacataacagcagtcacactaggtgcaaagttaaa2460
acccatttaaagagaataaagcttcaatgaggaaatatggaaataatgacaagcctagga2520
aaagaggtctaactaacatgaatgaccacacacacacacacacacacaccacaattagag2580
tctccacaactctgatctgtaacttaaatgaatgtcaaattgcctcacaggaatttcaga2640
tcttcagtctgaagttctggtagataatattgaacatattcctcagcaacagcatgcatg2700
cttctaaatagccactagaattcattggaaaagagcaatatacaaacaaacaaaaaaccc2760
cagaaaactggcaagctgatctagatggcaacattggatgaactagaaaactgagaccac2820
tggatactaaccagtttgagataacagtatcagctggctttctttggaagagagagagaa2880
gcactaaataagtgaggttctcaattttaataagttgcattattcaaacatagaactaaa2940
gctattagatttttattaaaagtgcctcctttgaaagaaggctagactaatgtgtttctg3000
a 3001
<210> 167
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26167-278 . polymorphic base T or C
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-26167-278.misl, complement
<220>
<221> misc_binding
<222> 1482..1500
<223> 99-26167-278.mis2
<220>
<221> primer bind
<222> 1759..1778
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1319..1339
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26167-278 probe
<400> 167
atatgaaata tatttacatc acattttctt tgtccattca tccattgatg gacattgacc 60
cccatattct ggcaattgtg aagagtgata caacaaacat gagagcacag actttttttt 120
catataccca gcagtgggat tgctggatca tatgatagtt ccctttttta ttttttgaga 180
aacctccata ctgttttcca tagtggctgt actaatttac tttcccacca aaaagcatat 240
gagggttccc ctttctctgc atcctccccg gcatatgtta ttttcctcat tttgattata 300
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
350
gccatgtcaactggggtgagatagtatctcattgtggctttgatttgcatttttctggtg360
attagtgatgctgaacattttaaaaatataactgttggctatttgtatgtcttctttcaa420
gaatgtctattcagatctttgtccatttttaaatggggtttgttattttgttgttgttga480
attgttcaagtttcttatatattctggttattaatcccttgttagatagatagttggcaa540
atattttctcattctgtaggttgtgtctccattctgttggtggcttcctctgctgtgcaa600
aagtttgtcagcttgatataatcccatttatctatatttgcttttcttgcttacactttt660
gaggtcttaaccccaaaattcttgctcagaccaatgtcctgagaaattctttaatgattt720
cttctggtagttttaaagtttcaggtcttacgtattacatttaaatctttaatacatttt780
cagttgattttttaatatagtgagagatggggatctatggttttgcatatggatatccag840
tcttcctagcactgcttattaaagaaagtgtccttttccccaagtgttttcttggtgcct900
ttgtcaaaaatgagtttgtgaacaaaaatgtgtggattcatttctgggctctctattctg960
ttccattggtctatgtgtctgtttttatgccagtatcatgcagtgttagttactatggct1020
ttgtagtatattttgaagtcaggcagtgtgatgcctctagcttgttcttcatagcaagca1080
tttttatagttacttctaaaggatgatcatcttccttggccagtgacatcatataaatta1140
ctataaagtgttttttgatgctgagctgttttccatataatccaacctgatggccacata1200
aagctgtaaatgttttaaggaagaaaataccttaaacttcctagtagatttggatcttaa1260
cactgtcttttcatagagctgaaattaaaggaggagtttttgtttggttttcacaaacat1320
gtcctgaagcattaacctgaaattttaaaactggtttgaaatattaggttttctatcccc1380
tgcaaagctgtactataaaattaaaggaaaccaaaaacaggcatgggaatatgatagtta1440
ggtggtgttcctgagtgtggtattttaaagttttgactttcagtttcctcatggcattca1500
yttgaaacctggttcattgagggctagctgcaaaccttccagatcttgtccttctttgca1560
gctccaggtttctctggcctatggttctccaggaccctgcagttttttttttttttttca1620
gaggcctgtgccacatcagttacacacacaaaaaaaggcttttgggtaaagggaaacttc1680
atgtactgagcaagaagcatgaatgtaaaaatatagaacccctagggataaggaattcag1740
tggctacctatgccattcgaaaggagtgtgccaaaatgtgcgctgagtagtgcctttccc1800
agcattttctttttttagaaattaaaagtatggctctgatgccaaagctacaaaccataa1860
atccaattaaagtgaaggacttaaatgtacatttgggagagtcgggggaaagtggaaaga1920
ggatctgtttctgaatcacctcgcctctttctcttcctccctcccaccctccaccctgaa1980
aacatgtccacacagtgggattgcttgttaaattaggacactatgactatgtaactatat2040
ttgtgaaatagagtcaaattaaaattgaaagaaaacaactgaaatgcaaaaaatatgaaa2100
agaaagttgaatccatgctctagtgcaaatgttcttccagctcaaactacctctaaaata2160
gccctggactgcgtgcaactccacatctcacagtttgctttatgaagtatcaaaacattc2220
tcaaacttttgactgcaataggtttccatgtttttaaacttttgctctaataagcaaggt2280
ctgtctgttttcttttaacaattttataagaaactgtttccttttctcctctccattcct2340
tcactcatgtccacccttcctcacttactaattattcatagtcaagcccctaagaagaaa2400
ggggcagcgtttgccatactttactctgtgtgtgtgtgtgtgtgtgtgtgtatgtatgtg2460
tctgtgtgtgtgtttggtcaagattaggcagggagacagggatcctaaactagtgctttt2520
taaatgataatacatttccaccgtttaaataaggtatgctttttttctcaagattttttt2580
caaagcagcaattcccttcccagttcctgtagcaaatgaccatccaactgcttgaacact2640
ttcagcgacagggaatgcattactttgtgggagagttgattcttacacaggatagctagg2700
agtattggacatttcattgtccttttggatgtatttattcatatattaatgatgtattta2760
ttgagcacctactatatgacaggctctgttctaggcacctggaatctagcagtgaccaaa2820
gggacagcaaccactgcccttatttatgttccatcttggtgtcactctacttatttgtcc2880
taattctgtcttctgaggcaaaactaaatcattccattccctgtttttgtgacagcccca2940
caaattgttgaaaatgacatgtcatcatcttcagattaaacattttcttacacggttttc3000
c 3001
<210> 168
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26169-211 : polymorphic base T or C
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-26169-211.misl, complement
<220>
ggttggaaatttgatctctcatggaaaaggtgcttttgttattgttgttttctcatggaa1200
gaagcaaccaaacatctgttgaatctttaagtcagattgtctcaaagcatgttggaaaca1260
acacctacatcagaatca
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
351
<221> misc_binding
<222> 1482 .1500
<223> 99-26169-211.mis2
<220>
<221> primer bind
<222> 1693..1711
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1262..1282
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26169-211 probe
<400> 168
gagagaaagagtaatgtacaacacagtgctcatctccatatgttttcctttcttccaaaa60
tgttggccccttaactcctggttgccttggaagctctccagtgccatcaaccaattttct120
ttcttttctcttcttgtttttaaaaatatctagctttcacatatggtaggagtgttggtc180
ttatgcttgatagttggttataactagaagtgaaaattttaagtcataattcttagagaa240
actggctattaggaaatattatttccattttgggtccctacttcttaaatatagaaagac300
tatcaaatatcttgacaaaaatagagaggatgtttttcttatataaagctcatgaccaag360
tcttcagcaccaaatttgtatgtaaattctttgaattttttggaagaaaaatattgacta420
gctttttatttgatttgatctttcagaacattacccactgagtaaatccatattccactc480
taagttttaataaaatctgtgacggagatgggtatttctgtcaatactcatttctgggga540
tatgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgttgtatgtttcatgcctttataca600
ggttgagtatctcttgtgtgaaatgcttaggaccaaaagtgtttcagatttcagattttt660
aaaatatttttgaatatttgcactattcttactgtttgaagatccctcatctaaaaatag720
aaaactcaaggtgccatggctcatgcctgtaatcccaatattttgggaggctgaggcagg780
tggatcacttgaggtcaggagttcaataccagcctggccaacatgatgaaaacttgtctc840
tactaaaaatacaaacattatctggacgtggtggcacacacctgtggtcccagctactaa900
ggaggctgagatgggaggatcacttgaacccgggaggcagagtttgcagtaagccgagac960
tgcaccactgcactccagcctgggcaacagagtaagactctgtctccaaaaaataaaaaa1020
taaaataaattaaaaatcctaaaggcttcaatgaacatttactttgagcataaccattga1080
acatcatgtcagtgttcaagaagtttcagattttggagcattttttatttcagattttta1140
aattaggaatgctcaacctatgctactaatactactagtatttttgttgtaaaaattggg1200
ttattctttcactttccaagtttatttcctggcagcaacaaagttgtagattatcaaacc1260
accttccagaatgttaaaaacctatgagcttacctgaaaaagtctctaataaagatttgt1320
gtgggatctaattatgacttagctcttaaagttcacaagagaggttggaaacagcatatc1380
tcttactccaggctgctataactctgggcaacaggtgtattcttactcataagcaccctg1440
caaagactggagtagccctgacaagaaatctgagtattcttctctgaagcctgtggttca1500
ytgtgatgctgctgccagctttggccacaccccaaatagacctctatttgcagagctctt1560
ccacattagacctgtgtgcttttgaataagtgactcggctgctctaatcttaatatcctt1620
atttctcaactaagtttataattctatctattctgcttaactcacaagtaaaacttgaat1680
gagataatgcatgtgagagcatttgtgagttgtcacactctaggcacatatggtgagcgg1740
ggcaaacccaggacctaggtaaatctttccacatgtctatggatcagaacccttttcttc1800
tcctgtacacataataatatatatcctagcataccatgtttctaatttcatttccaggaa1860
taatgatataaatcagtttggaaatgtgaattgggagaaaaagatagaagttatttgtta1920
cttacttccatctttcttatccttatttgtctctagtatattttcttatgtcttgcctag1980
aagcagtttcaatgattatcagttcagtcatcttattttatagataaagttaccccaaaa2090
catagataaggcccaaaactgtgaaatcccctattatggtctcatggtgagtcattgtca2100
gagcctgatgagaaataactctcctaattggttttattgattactgttgatgcagcattg2160
catcattgtagataaagcacacacacagatatacatgtctgcctgcgtgcatgtaggtac2220
acatatgccctccaaaaaattgcttatctgaggctgtaggaaaggatctattatattttt2280
caactcttccttcatccctaagtgacaggaaagaagggatttcctttccactcagattcc2340
ccgctgttaaaagcattaatgttttctttttggagccttttgctgcctctcattatgttt2400
ttctccattgcggagttggagtcacactatgagaaaatctgaatattagaacacaaagtc2460
tgcggatatgacccataggcttgctgaggagtgatctaatagccagggagtgatggtagg2520
tgagaggtgaaatgtacagagtggggggcatagaagagggagctatggagttcaggcaaa2580
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
352
cgcaatgcaaaagccacagcaccttagtgtgagtgccatcatctgaaactgtccttggtg2640
gtatgggaagcgttgatttggggcaagaaaaaggcaagatatttatttgatactgacttg2700
atgatatgaacacaaaatgagaaaaatattcaggcactgctattgccccaccttaatagt2760
aaaaagaaagggaagggaggtttctgctagctagcaaactttgcaaatgggtatgaatac2820
ccttggagaaccaagcagtacatgggtatgagaacccataggtatatctttgtgcagtat2880
caattttaattatggttaagtaatttaaaatacttgatatcaaaccaaacaggtatttag2940
tagattataattgttaggatattcaagtagaatacaagattccaaagaaattcctgatta3000
c 3001
<210> 169
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26171-71
: polymorphic
base A or G
<220>
<221> misc
binding
_
<222> 1481 .1500
<223> 99-26171-7l.misl,
<220>
<221> misc
binding
_
<222> 1502 .1520
<223> 99-26171-7l.mis2, t
complemen
<220>
<221> primer bind
<222> 1431..1450
<223> upstream
amplification
primer
<220>
<221> primer bind
<222> 1860..1880
<223> downstream
amplification
primer, complement
<220>
<221> misc
binding
_
<222> 1489 .1513
<223> 99-26171-71
probe
<400> 169
tagtcctttg ggtatatacccagtaatgggatggctgggtcaaatggtat ttctagttct60
agatccctga ggaatcgccacactgacttccacaatggttgaactagttt acagtcccac120
caacagtgta aaagtgttcctatttctccacatcctctctatcacctgtt gtttcctgac180
tttttaatga tcgcctttctaactggtgtgagatggtatctcattgtggt tttgatttgc240
atttctctga tggccagtgatgatgagcattttttcacgtgtcttttggc tgcataaatg300
tcttcttttg agaagtgtctgttcatatccttcacccactttatgatggg gttgtttgtt360
tttttcttgc aaatttgtctgagttcattgtagattctggatattagccc tttgtcagat420
gagtagattg caaaaattttctcccattctgtaggttgcctgttcactct gatggtggtt480
tcttttgctg tgcagaagctctttagtttaattagatcccatttgtcaat tttggctttt540
gttgccattg cttttggtgttttagacatgaagtcctcgcacatgcctat gtcctgaatg600
gtattgccta ggtttacttctagggtttttatggttttaggtctaaagtt taagtcttta660
atccatcttg aattaatttttgtgtaaggtgtaaggaagggatccagttt cagctttcta720
cttatggcta gccagttttcccagcaccctttattaaacagggaatcctt tccccatttc780
ttgtttttgt caggtttgtcaaagatcagatagttgtggatatgtggcat tatttctgag840
ggctctgttc tgttccattcatctatatctctgttttggtaccagtacca tgctgttttg900
gttactgtag ccttgtagtatagtttgaagtcaggtagcatgatgcctcc agctttgttc960
ttttgtttta ggattgacttagcaatgcgggctcttttttggttccacat gaactttaaa1020
gtagtttttt ccaattctgtgaagaaagtcattggtagcttgatggggat ggcattgaat1080
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
353
ctataaatgaccttgggcagtatggccattttcatgatattgattcttcctacccatgag1140
catggaatgttcttccatttgtttgtatcctcttttatttcattgagcagtggtttgtag1200
ttctctttgaagaggtccaataattggataattattaatgtatttaacaactacctgcat1260
gacactctgtgtctattgagtactatttaatcttcacaacaaacccatgtggtaggtaca1320
ctacattatccattcattaatacactaaattatccagtaatcgataatacactaatatta1380
tccattcattcattttacagatgaggaatcggaaacaaaaataaaaagcttgcatagctt1440
tgaagagtggggctgggattaggagaagatctgctaactgtttagcccatctgcctgcct1500
rctatttgcctgcacttacaaggctgaatttggctgaagaaaaatacgcagacacattgg1560
tcctactttaaattcacagtcaataacctcagggggccccttggtacatttcttttttaa1620
aatccattttcacttaactggatcatatttcttaccttacttcccttcaaacctcttatg1680
tctcctctcccatttctactctcagctatatccttacttctatttgtctgagaaagtaga1740
aataataagaaataaatgttcacatactccacaactgcttttataagtctatctgcagat1800
ctatccatttactcctctttttatttttttactgaacttggggataaactcctagtgctg1860
taatctaagttcaagacctcatcaaatttagcattagaccatctctcctactcagggaaa1920
tcaatccaataattttcttctcttctgcatcatcctactgtgttatcccacatcctcctg1980
tattatccttaacagtatttaaatatgctctaatatttagaacatcttaaataattaccc2040
catgttaaaaaagaatcccctcttggttatgcatttctctctagctattgaattaattgt2100
ctgttactggcaaaactctttgaaagagaaattgcaactatccttctcccattctctctt2160
ggaccctttctaaacaggtgtttgtccccagtaacaaactgttcttgtcacggtcaccca2220
tgacctgcaagtgatcaaactcaagattctgttttcagttcttatcctacccgtatagta2280
tttggcattcaaattttcataataaatttgtattttttactacaaagtggtaaagttagc2340
atcgaaatactttaaacctaccatttacccaaccagtaccctttatgcgatcatcttttt2400
atagtgacgatatatttgggtttctaattgagagtattaatacgttaactattccatgtg2460
atttgatgttcagccaaacactaatagtactcagttggtattcgggtaccattagaaggc2520
aatgcttggtgtttccttacttgggaagaatattcctttcatcacatgtatttgtgtttg2580
gacagagtggcttgtctctataaaacagaagaagatgaatggtctttctgagaattagtc2690
tttgtatttaaatataatagatttgtgattaagcaacggctgcttttcagactccttaat2700
tactatcatagcaaataatcattggcaaactaaaatattagtttgcttaatgataaatat2760
cactcaagtttaagcattatgtagaaagaaatagtcataaactttggaagggccgtttat2820
catagttcattttctctatgtggaacgttttcatggatagatttgttccttatttttaca2880
cctaagggtttcaagtattgataatatgttctacctcttctttacctacctattacacag2940
acatgattaaggtaatgtttctacatttgtgtttttagtttttctatgttaattttttgt3000
c 3001
<210> 170
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26183-156 : polymorphic base C or T
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-26183-156.mis1
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-26183-156.mis2, complement
<220>
<221> primer bind
<222> 1348..1367
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1798..1818
<223> downstream amplification primer, complement
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
354
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26183-156 probe
<400> 170
taatgctcactctacattagttaccaatgaaatctgtcagtgggtatatgttaagcaata60
taacatgctataaagagcctcttggcagaaatagtaggttaaaatgggagcggaaatttc120
tttgtcaacttcgcagctgtagcgctgggtgtggggcaggactttgtgtttctgagactg180
cttctttgtacttaggacaaggataagtctcagtcagttgccctgactgggggagttcat240
tggactaatagataattcctgagatgctatctactgctaatattttatgtctatggccta300
tacaggtggtgtttcttcaattagaagcaccagcaagctaaataaagtatcatgacaata360
atcacacaaaggtgaatttaaagctttaccttttctctcacctaaccattttcatttttc420
tatcttctcttccatatttgtatatttgtaagttattttaatcataatgtagatacaatc480
caatcttagcaggagttgttaaatctcaaatgagttaaggtatatgaaatcacctttaaa540
actctaaagggctattccaaatgcaaaagaagcctgatattattgtcactctttcttaaa600
tatctttccatatctctgcaagataaaaagtgtgaaaaaaaaaaaaagccaggaaaggtt660
gggttgagctgttgtgtttagtgaaagcactttcactaacacagaggacctgccttatga720
tgcctctgggagtcaaagaaaacacagaccctccccatgagatgctaagaatcttgtcag780
gtgtattggtttctcactgctgtaacaataagtcattacaaacttaatggcttgaaagaa840
cataaactgattatcttatagttctgtgggctaaaattctgacgtggatctcgccaggct900
aaaattgacttgtcagtagggctctgatcctttttggaagctgtagaaaagaatccattt960
ctttgccttcttccatttctagaggccatctacattccttatcacgtggcactttccttg1020
aacttcaaggtcaacaatgttgcatttttctgataattacttaatagtcacctctgcctt1080
ccactctccttttaaggaccctgttattacactggacacacccaaataatccaggataat1140
ctcaccatgccacagtccctaacttaatcttgtatgcaaaggcccttttgccatgtcatg1200
taacacagtcacacacttcaggtataagaatgtaggtgctttcagggagccattgttctc1260
tccaccacagcaaagcaatcacatggacacataatcacaatacatcatggttaatgccat1320
agcagcacttggctgcagaatattgtgatggtacaacccaggctgacttcatgcagctca1380
aggtgcaggagcaggaaaaacctgccagaggcaatcatggacagagaggtgatgacaggg1440
tgaataggaactagccatttgaaaagatgcagagactggctttcaatagcaggcagccca1500
ygcagagaacaagcctctattaaaatcctaccatcctgcctcccacattactctcacaat1560
taagtccttgtcactgtccagcctctgagaaaggatctggcatctactgcagggtcatgg1620
gtatggcatcttaactgcatgcatcatacccaacatccagtgaccagagtgatagttcac1680
ctgtctacgtatgatcttgccactgcctgctttaatctactgacctcaaatattcttagg1740
atgcaattcattttttgtataattaacagacctcccaagatttggacacttggccatctt1800
ttccatcctcattccgtggtgatgctactttcttatctaaaataacatttgagattcata1860
cagcatcctgtgctgttatttggccatatatggttatgtccacctttcagagaaattcaa1920
gaggctatgacttacattaaaccacatagctaattggcaactgaaccccactgttttccc1980
agcacactatggggagaccagcctactgtcaaatgttagattttgttcctggagatttta2040
ggatgaatatgggacaaactacctccttgttctctgcaaattcattttccctttagccat2100
ataacactgggtttggggtattttggggacgtggtagtgagtcataacaagcttaattcc2160
ttttacttcacatgttcaatggcccatgtaattacaaggcccagggatttcctctctgct2220
gttaaaagaattatcaagttaagaatgttttgatcttaattagcttttactaggcctttc2280
tgatgcccaaataatatatgtggctaaatggtaaacaataaggatgaggcctattttttt2340
gtttgtttctaaaacacttttcaaagaatgtacagtgggaacctacatggaaatcttcat2400
aacaaaaattttttaggtaatataaggcacttttccttaggggaaaattaagagtttaga2460
taagggacacatttttaaataatcaaaaaaaattgaaaagatgcttcttttgcatctttg2520
gattgtgttgtgttcaattccctattattttattttccttgctatgcaaactctagacat2580
cttgaaaattagctattggtaatcttatcagttctcctgtaagtctgccaagtaattgga2640
tagcttttcttgttttttgctatgtcacatcttcgtacctctaacatgcacactctcatt2700
ctctgtatttatttatagagctctcacctctcaacttctttctctatttctgatattctc2760
catctgaagcatgtatcagaagttctctctgtgattggtggaataaattaaaactgtgtg2820
attatttactactacattcagcagcttggatcaaaaacctagatttacaactttctaact2880
gtgtgaacattgttaaatttctgattgggttaagtttctaattttatatgtatatttata2940
tatgtgtgtgtatacatatgtatatttgtatatgtatgtatgtatatatatagaaataca3000
t 3001
<210> 171
<211> 3001
<212> DNA
<213> Homo Sapiens
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
355
<220>
<221> allele
<222> 1501
<223> 99-5912-49 : polymorphic base A or G
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-5912-49.misl,
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-5912-49.mis2, complement
<220>
<221> primer bind
<222> 1463..1483
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1946..1963
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-5912-49 probe
<400>
171
agtaaaatagagcagaataagagaatggcaagatcagtttgggaaggctctatttcagat60
gtagcactcaagggacatacaacttaactgaaatgagtgagtgagagagagagagagaca120
aagacaaagagagagcagggggagcatgctatggcaagacgcttggggagggaaagcatg180
tggggtggacagcaagtgtaagaaccgtgaggtggccatgagtagcaagcgcgaggatca240
ttaggaagatggacatgtgtggctgatgaggcacgcgcacgaaatagaggcagagttgtc300
agcagtgggaaggccatgcaggtgcatgggctgtgggaagacactggagctcttagagca360
aggagccgtctgcttcggaggaacgttagagttcctaaattcagttaatgaaatgcttgt420
taaacccctgcattgtgcttctccgtgcccctgatctccccttccccatagcctgtgtat480
cagtgctgtgtgatgagttctgttctgggtgaactgcacaaagacccttcaaagtttgaa540
gggagtgggaaaaatcagttttaaaggtttaataagggtttcttaaagaaaaataataaa600
gacatgtcaagtgcaccacccctttccccacctgacttcaaacaaagagaaaatcccacc660
atgtgtcattatacactgtcatttagacaaagacactgaccatgacaagtcaacagtgga720
gatttggacttcatgttgaagaataaaagtagcaaagactttaagttgtagattggcatc780
tttagattgacattggcatagtgacttcattttttaaatgctgccagaatttcttagaaa840
aaaaagttagagcatatggtgattcacaagtgcctggtggaaaattataaaatcagcagc900
agtatttctggctgctgagatcctgtgaaccacaactaccttcaaaagatagagggtagc960
aaaggaagcaagggtgcctttctaactccacacagtttgtagtattttacaacttgtttc1020
cctttagcaagtactggcagttctatcaatccaacaagtggggaaccttattaataatta1080
tttattttagccatatctcaactttaaatagtaaatattgtaccaccaccagtgtatcct1140
ttccagatacccaaactgatgctcagggatattaagtgaattgcccagtgccagtcagtt1200
aagaagtagctgaatcaaaatccgaatgtgcgaccatcaggtttcagagtctatgccctt1260
gatactttaccatagaaccacagagaagggaggtttttcaaggcatgatacttgctgaaa1320
ataaaaagatacaactttaaatttgtccaagaaaaaattactaaagaaacacatagccca1380
tgcagtttctctaagagattctacatgacattattgtttgctagaaagtagggtgctagt1440
tgttgcttttgtaaatataatagtcaaatcatgttaccattaggacacattaaaaatgtc1500
raattaccttgggaccttatatgaacatattaagataataatgatagtgttcagtgcaat1560
attcagatcaatagtttaaacccaaaatatttataccttcagattagatgtatgcaaatg1620
cattgattcatgtgtcttttatctgttgtttacatttggagaaatatttgagaaatattt1680
caaaatggaatttatataaatttaaacacataatggttttatgtaaaaatattgctaaat1740
tacattttccccttaattcttatttcttggaaacgtgccttagtcgctgaaatattcata1800
cattaacacaatgaaagaagtgaaccttactaggctttgactatcaggtttgctgttggt1860
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
356
ttttgactattgtgaaactatagcctgatttctaaatcaggaagaaacgtgtattgttgt1920
taatatggacacatgacatatttgtctgcctgacttttgatcccagctacaacctctggc1980
cttttcaaatgattctttaatatcacataaagggaggtgagataactaaagggggtgatt2040
ccggactaggaggcaagggagggcagataacatggtgctttgaaatcttctgtgactttt2100
cagtcacttatttcattaagtgatatatctcactagaagtgaggtagaacataacaaatc2160
catgtttgctgggcatatgttatgacaacagagaaattcacagactggtcttacccggca2220
ggggagatggcatgatcatgaaaatggtttttcccagggtgagcttacccattgcattct2280
gatgtgctgatttccgtgatttccccaaatgtgggaaactcactcggctgcataattggt2390
ggtagtgggggctgtgttatgctctctccttgatgtcagttttttttttttctaaaagca2400
aacaaaaacaattggcttcagacattttgaacaaaacaagtagaagctgttttctttaag2460
aaattacaagcagtgtctatctatagatacatacatagtcacacatgctcataaaaacac2520
acaaccacagcaaaattcatgctgtaatctataaacactttttagaaacagggagaggtt2580
gtgtgggcctaaagagccaggtggggcagaacctaaaaggaccttgagaatgacaaacat2640
ttgaccatgggaagcaggacaggagaaggatgttacagccagtgaccatagcataggtaa2700
aagcaaaacaggtaccaaggagcacactgtacagaccattcagcaaggagcccagcctga2760
ctgccaggaagaggctgcctgcaggaatggtgtggaagaccatcagctgcagactgaggc2820
aaggcgatggaggtttaggcttgcttcaataggtgagctacttatacaaggagaaccatg2880
atgaaccatgatggaagtggtgttgcaacattcacatggtgtgggttgtactgggaagag2940
atggacaatagtgtggcttagcgatggcaacgggcatctttagatgagaagaatgtacat3000
g 3001
<210>
172
<211>
3001
<212>
DNA
<213> Sapiens
Homo
<220>
<221>
allele
<222>
1501
<223> lymorphicbase A
99-7337-204 or C
. po
<220>
<221> binding
misc
_
<222>
1482
.1500
<223>
99-7337-204.mis1
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-7337-204.mis2, complement
<220>
<221> primer bind
<222> 1298..1318
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1731..1748
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-7337-204 probe
<220>
<221> misc_feature
<222> 1564
<223> n=a, g, c or t
<400> 172
atctaaaggt atgtgtaatt aagttgaaat ctattaagaa taattaaata acagccttct 60
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
357
tcatgataacaacatttgagttgcactttcaaactcaatttctcgttgtaaatataacta120
cagattacaacttaatttctagtccataaattatttttcacctctcttatttgatatttg180
aaagaaccctttgttgtttaatattatactcaaagtaagaacttggacttggagacctcc240
tcctcctttaagttcaagcctcctctgaggagagatactcctaaggagtccaggatgagg300
gtcattattgagctgttactgggaggggactgaattcgtggatgactctggaaaatagag360
gttagtaatatattagtagctattatttatcatgtatttattatgtgctatttgctactt420
gtgtctaatatcgtttctctatttcctctttttaagttattttggaattgcctagtattc480
taaaaaatgttatgattgtgttcagaatgccccttttatagttttcccttaaatggtgat540
ggtgggcaaacttgaagacattaacaaaaacataattttcatttagtcttagataacacc600
aaggtgacatagtaactaagtggagttggtgggctaattcctagtggaagcctgggctcg660
taacagaacataaaggcttttccaaggatgaaacactggtgaagctcctccttcaagttg720
tatatgtttgcatatgtgaaaatatgtgcaatccaagtttaacttgggaatgcttagctc780
cttaggaatttgctactgggttaataactcttccctcaattacttaggttggaaagtcct840
caaattttaccttagatcaggattggcaaacttttggcaaaggaccatatagtaaacatt900
ttaggttttgtgagccataaagatctttctcgaccacgcagctctgaaatttgtagtgta960
aatgcagacacagacaatatataaacaaaggaaagtgcctgttttccaatgaaaccttat1020
ttacaaaaacaggtgaaaattgtgtttggcctgagagtcagtttgctggaccactggatt1080
agattctcaaggtcactttcaattctgaggttatggttttgccagattatctgagttatt1140
cattcctgatgagttatggaaggagagctccttccaaccagaagtctctctttgtacaag1200
caaatggcccatcacggtattttcctaaacaaaggcatttccctcagaagaggaattctg1260
ctgctactgttaagataataagtacaccacagatggtgctttcatttcaaaaacaaccac1320
aacataaaaaagatataacatttctgtttaattattgcatttttctatcctatgacttga1380
tgatttagtttggcagtggtgcaaattaatattcaagcttctgctggaactcatctgttg1440
ttgattttgttgtggtgggggtgatggttctaaacatagtcaaggaggcaaggtgagaaa1500
magatacatcaaactccttatcgatctcgttttggcagattcaaagagtttatatttaag1560
cctnaaatttaaataagcattttcatattatcactgccagttttagagagtgtttcactg1620
gcacaataattgtattatccaactgtatagcaactatcaattagactaggactgccttga1680
gaagcaaagtagggctcctctttctttggttcttgctgctgtacattggaggtctcatac1740
tgaaggctcacaggcttccctgtggccccttgacccactcaaggttgaaaaacaaaaact1800
aagaaatagttgccaatgttaaaaggagattatctgtagaaacttacatttcttacttcc1860
tttgaaaaatcagatcttctaaagatctaaggtttttattttcacaggagaaccatgtga1920
gggacggctgcttttttaaaaaaatcattgcttctaccactgtcttcatctcctcaccac1980
agagcctgagtcagaggccatttatcctcattacggtgccatgatcatgccagctttcct2090
cactcctgtatctacctggtcattagaggcatttgagtttgtggcccgtgctgtgcacat2100
tatccctggagatctcatcaattacaattatttccacctactggactttaagtagttcta2160
cctattggacattttcaatgcaatctgttttcctaaagcatactgcaggattgaagcaca2220
aagtatgactgtgcaattactctcaagagcatttttgtttatgttggtcaatgtcagttt2280
tttaggtcccttataaggaaataccttttaaaaattcatgccaagaaacttttcattttc2340
aaaaaggaaaatattttctttcttgaataatttttgtaacattatagtctttctcttttt2400
gtcctggctaccagaaagttcagaagtcagtgtgtcataatcctgatattatttctcccc2460
ttactttgtgtgttctggttctctatttgtaatattaatactaactattaacgtgaacac2520
acatatactcatgtgctacaaacaactttcaggttcattttgtgagagattagggttgaa2580
aacatcagtacgacatgttcttaacttttcgaaaccatcctccacactgacaacagattt2640
gtatttataacatacgaatcaggccctattattattcccttgcatattcaggaattcaac2700
atgtcttcctctcacttataagacatctaatttgtttattagagttttcaagacccttta2760
ttatgtttctcaaacctatcttcccatctacaacattctccacttctgtcccacaaagcg2820
tgtatctcagtgatgaactatttacagttctccaaatgtaccaggccatttcccacctct2880
tgcctttcacaataccatttattctccctataatcactctagtattttataggtaagtca2940
ctcataacaaatattatattgttctgtcatttttcagtgaaatgaatgactattatttat3000
c 3001
<210> 173
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-15672-166 : polymorphic base G or A
<220>
<221> misc binding
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
358
<222> 1502..1521
<223> 99-15672-166.misl, complement
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-15672-166.mis2
<220>
<221> primer bind
<222> 1649..1666
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1120..1138
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-15672-166 probe
<400>
173
aagactttataactttttttattgattcagtgatcattttcctaatgcttattcatgaag60
ttcatcatcattttctctatgctgattacatcaagggtcatgtaatgtctacttcactaa120
atgctgcaaacgttgttgggaatcagatgtgcactatcataacagacatgaaatcaatgc180
caagcatacagtcctgcgttctttttcgttgaaactagtacaatctaccaagaaatttta240
cctctatgataagatgactggttctagccatattagccttgtataaatctttgaatgttt300
tcatttgttcttcataatattctaaaaacattaatgcaatgtgtattcaactttatgaga360
gtgcatttttaatatctttggctggagattcaatagaatctatggatataattgaacatt420
tatggatataattgagctgaaaatctcattaaaacttaaatatgtctttcatactacttg480
tatgaacctttcattctaatttttactgattaaattttataactgacaagagtataaata540
tagtctcttcttcatttcaaccacaatatgaacacatcctaagaaatttaaaagaataag600
ctttaaagagtatcaaaggcattcatttaataaatatgagctttccaattctgttttcac660
tcacaaggattttattgatagtaatttttattaataatttcagcgtcaaataattttcat720
ggttacacctcctacctcactcacaaaataatctttgactgtggcatattattaatattt780
ttacttgaactgggataatttgtaagtgttttacattgtttgcagtgaattttaacaaca840
ctttattagtcaagagggtcatacaatattggataatctatggaaatatcatttaaaacc900
aatagctatgatttagaactgtttaaattcaacttatatttggagataattattttacaa960
aaatattaacatgtttttgataattacattataaaaatttaaaaaagaacttggtaccag1020
gtaaacgaaatccttttttaaatcaaattagtttatattatagaagacaagactatccaa1080
atatgctagtaattctcagtttagctgtcattcaagtcacccttttcaaaatgtgttcta1140
ggaaattttgttttggagttatcctagaaatattgacagtctattatttactataaaaca1200
attatgcaaccatttatgtaaagtaatatgagaacttctgtacatgacaagacaacactt1260
aaattgttctcaaaacagcagtgtcacatatgtctctttcaaacacctaagaataatcct1320
ctgtttagttagactcatgtagaactaagagaatattcacaccagattttaagatgtgct1380
gctactaactgactataaggagagagcttagagtttacatgttttaaactaggtttagaa1440
ttttttcctgaggattcaggtaggttgattaaatacagctagactttacctttactcaac1500
rtgtatttgactgcacacacgtgcacatacgcacaggcacagatgtatttttcttttatt1560
ggattacttaggattaggataataataacactgataataataatcatagcaatcatttgt1620
catatataatactcttccatgtcctatagaggagttatggtattggttgatgcatgaata1680
ttattttcagtgatggcaataatctttcaagatagatagttattattagctccattttaa1740
aaatcaagaatataaagcttaaggagagtatagtatttacctgtatcaaagtactagaga1800
tcatgtctgcttagttttaaattccacattttctctattcccatagattttagagaagta1860
tgataaacatattcatagtatgagattttaactagttctcatgggcatgctttctgagtt1920
caatgaggataatttcaatcactcatgtgaatatataaaataataaattattgatcacag1980
acacaaagataaattttgtcatttttctaaaaataaagaaatcactatttacaatctatc2040
tttgtgttcaatgctattgtaaaaactaaaaacaaaagcaaaaaaccctctaagacaaaa2100
atattaagacgcatagtacttcatctcttgaaacacaattatgcacactttgaaaatgcc2160
catctaggtaaatttagggtccatggttttaaagtagaaactatactcccattaacacac2220
acacacacacacaccctatgtagagtttgatctcatatccccaaaacaaaagtttttatt2280
gactattctaagttcactaaagcatattagaatccctctgctatattattattataataa2340
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
359
attatccctcgtttgtatataaatccattatgagaaggtgttgttggtgattaggacaca2400
tttgcttttaaaaaaacaagactattagaagttctattatattctctcatgcaaataaca2460
ttcaaagtttggatgttaaatagaggcatttccaggcacagatcaactcttcgaaaatta2520
ttgtaggaggcactttaaaggaaaaaaatatgtttggcacaggaaattacatttaactaa2580
aagcattttttaaaatgggcattaacaaattagccgggaatgcatcattcccatcttacg2640
ctctcaagcacttaatgcggatagacctacaaatcacattatcatcactttccatacctt2700
catcaaatgtcatagcaacagctgccctagtagctctgagtgtgccttaggctaaaggag2760
acatctgtttgctgacaacttcagatcaaatgacaaatgggagacagaaatgtctgtgca2820
tggtaaggtcagaggccttacctatttgttagtttcagttgtaatagggattttcttctt2880
ttgataggcagggaaatgactaacatactatcagttagtgataatactaattcttcttca2940
atcaaaattaagtagggttacaaaaggaagattattattgttttgtgattgacaggtgtt3000
a 3001
<210> 174
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-15665-398 : polymorphic base T or C
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-15665-398.misl, complement
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-15665-398.mis2,
<220>
<221> primer bind
<222> 1879..1898
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1423..1441
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-15665-398 probe
<220>
<221> misc_feature
<222> 821
<223> n=a, g, c or t
<400> 174
cagaagcata caatgtggca gttatttcat atttccatga tagttcaatt tttttattga 60
ggcgattcta agaaaaatgt atgagcagtg gcaaattaag gagctggaaa gaaaataaaa 120
acgtttcttt tctgttccac aactggaatt aagtttaagc tgaattactg agtcttcaca 180
aaggcaaaat ttttgactct taattttgtt aatctatttc agcttatttc tcaggataaa 240
tatatcaact ttttgtgcta attagtactt tcatagagaa aaagtttaat gattagttat 300
tatgcttacc attattttta ttttagcaag ggtattaata ttttttatca cttacagatt 360
tttttctttt caatatgaaa gactttgcaa aattattttg acctggaagt tcagcgtatt 420
attgtttgtt cccttattat tatccatttt actttcctta ttccattgtt gttatttaat 480
ttaaaatatt tcatacggta tggcaaacca tgaacctgga aatagaaagc tgatgcattt 540
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
360
aaataaggtgcacttgatatggtagcacccaaatagcctggaggctgtataagcttttct600
ggacagtatgataatcaattcataaattatgtacacctgagcccttttcaccttaggcag660
tttcaggatgtccaaaaaaacttcaaacttagctctttcaaatcaatggtttaagccatc720
ttaataaccaattagcatcactgcagaaatagtgtaatccattatgaatatttaagtatt780
aacagtttaagaatcttacaagattttatgccaaatgtgtnaacatactctttatctttc840
tagctttaaactcttcctcctttgctgctgtctgtgtgcatttttaccaaaggtagagag900
aatttattctcttaacgaagagagaaatggaagcttgccctcataacctttgttataaca960
gaatactagaccttgaagaaaagagaaattgtaaagaaacattgaaactgaagcgttggt1020
caactgtggctcatgagaagaaaaccatgctggtcaaagattttaagaatttttgccatt1080
ttggctgtaacccccaccccaaaacacacacccaaatcaagagatttccacatgaaatgt1140
atcaccccatgcagtggcataaatgtggtgggtgagaagggaacatctctttttcttgac1200
tgtgcatgttttataataaaaatactagattgccaattaattgatcttagctgttgtaaa1260
attactaatccctaagtatcttttattggagaattaattattttctcaatattaagcaat1320
cttcttaagactcttcaagaaattgaaataaacatgaattcatatagagctaattttcaa1380
taaaaagtgaaatgattataaaagtgaatagaatctcagaagaaataagggagggtatta1440
gaataacccattgatcaaatcaatgaaatttgaaacatgaatgaaacttatacgtgaatg1500
ytctctgtgaattacattcattaccttagtaggaagcctgtttcttagtttcatagatag1560
aaagctgacaaaatattttgtttggtttttaattcattcacgattgtcaattgtgcattt1620
actctgtggtgagtctattttttaaccctgttctttgaagtgttagaacaaagatattcc1680
tttgtttccacagggaagactttaaatgtttgaaattagtcactatgttttcttctttga1740
atatggtctttcttccaagttaacaatctaatatgtccagttgttttttatataaaattc1800
tatttttatccatcaatctcctgttgacatatcaagcccagtatttcagatatttatact1860
taacattccaagaagaggctatgcttttcacatttacgtacactcaacttttattaaggc1920
aacatatgcttttctttttagcagcttcttggcactgttggtgattattgagttacagcc1980
aagtcaggtctgataaccacaaactactgtctgcagtatttactactttacatttctttt2040
tctctctctctctcttttttttaatctaaagcatgccttgagattagtttttatcagatt2100
ccatgttcttggtattcactcagcattccagtcttttgagataacctgaatctcaatttt2160
gtcatcaactattacattgtttacgccttccagtgttgtatcctctcaaatttgaaaagt2220
gacatgtgcagccttgttcataatctgcaccctgtctctccttcacaggtggaaccaatt2280
gatccatgtctgtagcatagactactgcctaattctaagagctatctttctcagatagaa2340
aatatttaagcagtttcagcttcactttcaacaaaaatatttatggtatcatgtggatat2400
gatataaaatgtagactgattgttggtattattatgtagattttaatgtgatttaatatc2460
tatagctaaattgtaaggtatgtcatttgaaatattggatgaaaaaagatatcatatatt2520
ttcatatggcattgtagatacttatgcaaatgaaaacattaatttcactacacttctaga2580
aaaaaattaatgtaaagatcaagtactgcatttaaaaaatgaagttgaaatcagaacaca2640
aagaaaccaattctactttacttgcatattatgccgtttaaattttcttacaatttcata2700
aggccgtcagaatcaaagtagctctctaatattcaagtagttaatttgttttagaatacc2760
atctttggcaagtataagtcctccctgattttcttacagaagtgaaatagtttacattaa2820
tatttgtgcaattttctagagcaaaagaaattgtgagataacctctctgattacacttaa2880
atataaggttcagtggtttcaagaaaatctaagtattttctttcttttctttttttgaga2940
cggagtcttgctgtgttgctcaggctggaatgcagtggcgcaatctcggctcaccgcaac3000
c 3001
<210> 175
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-15663-298 : polymorphic base G or A
<220>
<221> misc_binding
<222> 1502..1521
<223> 99-15663-298.misl, complement
<220>
<221> misc_binding
<222> 1482..1500
<223> 99-15663-298.mis2
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
361
<220>
<221> primer bind
<222> 1781..1798
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1349..1369
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-15663-298 probe
<400>
175
ccctgtctctccttcacaggtggaaccaattgatccatgtctgtagcatagactactgcc60
taattctaagagctatctttctcagatagaaaatatttaagcagtttcagcttcactttc120
aacaaaaatatttatggtatcatgtggatatgatataaaatgtagactgattgttggtat180
tattatgtagattttaatgtgatttaatatctatagctaaattgtaaggtatgtcatttg240
aaatattggatgaaaaaagatatcatatattttcatatggcattgtagatacttatgcaa300
atgaaaacattaatttcactacacttctagaaaaaaattaatgtaaagatcaagtactgc360
atttaaaaaatgaagttgaaatcagaacacaaagaaaccaattctactttacttgcatat420
tatgccgtttaaattttcttacaatttcataaggccgtcagaatcaaagtagctctctaa480
tattcaagtagttaatttgttttagaataccatctttggcaagtataagtcctccctgat540
tttcttacagaagtgaaatagtttacattaatatttgtgcaattttctagagcaaaagaa600
attgtgagataacctctctgattacacttaaatataaggttcagtggtttcaagaaaatc660
taagtattttctttcttttctttttttgagacggagtcttgctgtgttgctcaggctgga720
atgcagtggcgcaatctcggctcaccgcaacctccgcctcccggattcaagtaattctct780
tgcctcagccttccgagtagctgagattacaggcgtgcgcctccacgcccggctaatttt840
catatatttggtagagacggggtttctccctgttggtcaggctggtctcgaactcccaat900
ctcaggtgatccgcctgtctcggcctcccaaagtgctgtgagccacggtgcccggccagt960
catttcaatgataggttgggaaagttattttttgttgagcaagtggggatgagagtgctt1020
ctttcctttgcttttacatagagggagctcaattagagcaacatccctggcagctttctg1080
ctgtgcttcacttatttcttctcatagaggagaaacgacgtgtctcattggtgagtttgg1140
agtttgggagaggcacttggactgctcagttaagtctttctcttcttcatttcttccata1200
tctgcctagctacagatcatactcattctctctgtttttccattatgtaaatttaaagga1260
aagtatctaattcttagggtgggtattgggaaactcaccttctccaacatagactttgtg1320
agtaataaaaaagtctaacttttgtgatcatcgtcatctgtctaacttgtgatgatctct1380
aattgagaaatgaggctgtcatttattaagtgcccaaaactacaatattgtatttgtttg1440
tattatttaggtattcacttattgtttcagaatttttattttattgtggtaagaagagtt1500
rctatgagatctaacacatttttaagtggacaacatataattgttggctgtaggtacaat1560
gttacagagcagatcgctacagcttatttattttgcttgactaaaattaatgcctgttga1620
ttaataactccctatttctcccttcagtatcaaaaaataaattttagaaagaggctaaat1680
atatgataccaaaagaactatatatgtaaacaaaaaaaaacctatttctataaagtctaa1740
tttttaagtgtcctcacctatcaacgtattgaagcaacacgtttagaagaaggtgggaac1800
aagagccagacactggttgcaagtaacgtaatttgcatcttttggaaatgaacaaatatt1860
ttattcactaattatagtattttctatatatttcccttattttaaactttaacttacaca1920
tcatagatccctgcaactgagagccatggctaaaaaatcatctaattcaataccttcttg1980
tacaaagacaagtgtctaacaaagttctaaatgcaaaagttaccctactttgatatctaa2040
aacaggattatgattctatctcaaaaaattggttattttcacctaatatatactcacact2100
gttgtaaaatacataggttgtgtaagaagtattgagatggtattgcagatccctaagact2160
ggagaagctttaccaataacaaaatgaataactctgaaagttaaggatggaaattgtagg2220
caatcttctagtatcccattctagtatttaccaagtaaatgttattcctttttgtctttt2280
tgccatattcagttttaagtgtggaaaatttcatacgtatttacttatcctatctttttc2340
cagggtccttgcacaaagtaggatttatcataaaaactcagtaaaatgttcttattccag2400
tgttgttccaacttttataattttcaacacacgattctccaaaacatcagactattcttg2460
atgctgtttaatatcttcagattctttggatagcaggagttatattagatccctagaaaa2520
catttatttaatgtcgaatggaatatttttaccctaattttataataataatatttctaa2580
tagtcattcataagcacttaaagtaacatttattttcatatttcatgaagtaaggtatag2640
tgcatatcctggaagaaacagattactaaagaatcttgaggcatagtaatgtctgttaca2700
actgacattttacacgatgactatcaaaacattaaactacttaacaactgaccaccaata2760
atattaaaatacatgtttctagcacatttattaagattgttttggattgtatttgttttt2820
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
362
gaggtaccaa tactagcaag gtaatgttaa agtgtatatt ttagacatgt taaaactggt 2880
cctctgtcat caaactgctc tgtaagcaaa atgcatatat gcaggtgcgt aaaaaaactc 2940
caagacattt tttttaattt aaaaaaatca aaacattagg cagactcttt ttgaaataaa 3000
a 3001
<210> 176
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-15664-185 : polymorphic base C or A
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-15664-185.misl, complement
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-15664-185.mis2
<220>
<221>
primer
bind
<222>
1667..1685
<223>
upstream
amplification
primer,
complement
<220>
<221>
primer
bind
<222>
1184..1203
<223>
downstream
amplification
primer
<220>
<221> binding
misc
_
<222>
1489
.1513
<223>
99-15664-185
probe
<400>
176
ctaatatatactcacactgt tgtaaaatacataggttgtgtaagaagtattgagatggta60
ttgcagatccctaagactgg agaagctttaccaataacaaaatgaataactctgaaagtt120
aaggatggaaattgtaggca atcttctagtatcccattctagtatttaccaagtaaatgt180
tattcctttttgtctttttg ccatattcagttttaagtgtggaaaatttcatacgtattt240
acttatcctatctttttcca gggtccttgcacaaagtaggatttatcataaaaactcagt300
aaaatgttcttattccagtg ttgttccaacttttataattttcaacacacgattctccaa360
aacatcagactattcttgat gctgtttaatatcttcagattctttggatagcaggagtta420
tattagatccctagaaaaca tttatttaatgtcgaatggaatatttttaccctaatttta480
taataataatatttctaata gtcattcataagcacttaaagtaacatttattttcatatt540
tcatgaagtaaggtatagtg catatcctggaagaaacagattactaaagaatcttgaggc600
atagtaatgtctgttacaac tgacattttacacgatgactatcaaaacattaaactactt660
aacaactgaccaccaataat attaaaatacatgtttctagcacatttattaagattgttt720
tggattgtatttgtttttga ggtaccaatactagcaaggtaatgttaaagtgtatatttt780
agacatgttaaaactggtcc tctgtcatcaaactgctctgtaagcaaaatgcatatatgc840
aggtgcgtaaaaaaactcca agacattttttttaatttaaaaaaatcaaaacattaggca900
gactctttttgaaataaaaa ataaaacaaatatctacttctaggagctatattctgtagg960
tattctagcaaaacaaatcc tcaaatgaaaatacttcaaattaaatagctattaactaga1020
aaaatagtggggtgtacacc taacttttacctcttagaggttaatttctttatcaattgt1080
tacctctttcattttgatat aagtaaagtaaattatttataaaaagttataatgcatgaa1140
aaggaaaatattgatttcaa atgaaaaataaacagaaaaaaaatcttttacttccacgct1200
ttggatacaattttaaagca ggtaagaaatgaagagaagaaatttgggattttatttttt1260
ggtcataaacaggatagtta atgatttccaccaaggtttcgacttacttgaaaatcaaat1320
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
363
gatctgatatccaggtgatctctggaaagcatgtgaacattgtgtttctgtcttttgttt1380
gcactggaatgccaaatctgcaatacaactagttagaaggtttgaccacccgacgaccac1440
acaaagtctaagtggagagtgctgagaggtgattcaccctccttctctgcctggtcagcc1500
mgctgaaaccctccagccattaaaccgctcttaacactagggagcacactttccccagga1560
attatcctggggaagtcagagacaggaggcttcccttgtgcaagtcagcatcaggccccg1620
tgccagcccgtgctccgctgtagagaatgacaagtcacacaaatatgacagtgctaatgg1680
taaacaatgacagttctgtcaggaatctgagaggcttttcatacttctgcatgtgccgaa1740
agagaagcagagctattttatttgtggcatataaaaatgacggcatgaactcttcacccc1800
cttttttttcccctttaaacaaatcaaaattagaagagtgttagcagctttatggtttgg1860
gaacagaaagcaggaggctttagacatgtgaaaattcttctaaaaatttccctaactaaa1920
aattcgaacatatagtagttttaaaaaaattacttaaatgaccttagatttgtgatatct1980
taacataaagctttcttgcattctcaagggcatgctaatgtcatctagagggcatggaac2040
caatagccacacaccagaggctgttagacaggatacaccccatgtaaacatagatgaggc2100
atgctctgacaaggctacagtagaaggaggccacgtgatcattggatcacccgcaatgtt2160
acatccatcagattttccactgagttcgttcaaaagtgtgttatatatttacggtgtgga2220
aaacactgcctgaactatttgagacataaaaagaatgaggcaagagctttgctttaagga2280
gctctgggtaaagatgaacacctgcaatgtctgctatacgaaaacacaaagtaccgtacg2340
atcaagagatacagacaaagtacttcgtttgtttggggtgtcatgctaggtattgcgggg2400
ataagaagacaaagaagatagggacatacactgcagcgaactcagagtctaaggaaagac2460
ataagacatgtatagataaaagacacttttattaaaaagaagaaagcacaatacaatcaa2520
tgagacacgaagagaaaagaggaagcagtgatactgatatcagtaattatgaagtgctta2580
aactctgagagcaaccatgtaagctgttgacagaaatgatctcatatctcccaaacaatg2640
gactttatagataagaaagttaaagatgagagaggtggctggcaagttatagagtgaaga2700
ttcaggcacacatttaagcacaaagatgtctttgttaacgaccacataactatttgcttc2760
agtgagctccttttattttgtttgtctaaaatttctttccctttttctggcgaaagcctt2820
tgtggggtgtagctctgatggatgtcaattatggtgagacccggtccttctgtatacaag2880
ggtggaaacataactcaagcccccaagccactgtaattagactggaaataatgaagggca2940
aagccaagtcagtaaaatcccttccttgcagcgttttatagtgatgttgagagaaggatc3000
a 3001
<210> 177
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-15668-139 : polymorphic base C or T
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-15668-139.misl
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-15668-139.mis2, complement
<220>
<221> primer bind
<222> 1363..1380
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1801..1821
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> 99-15668-139 probe
364
<400> 177
ctttaatctgtcctttctcgggtacatcacctagatgcctgatttcatgatggtaatacc60
tcagtgttaagaactggttaaaatttgggtggggtggaggtggaggaaatgcagtctttc120
acatacaagacttctggacccttctactctgaaattgttctatcataaactcggcattgc180
tgctaaggatgagacatgacaattagatttgttatggttaaaaaaaaagtaaaaaatact240
gcctattgccttcatgaacaatgtatggaaacctgtagaagttccatgcaaaagattatg300
gcaacccacttttagcatctagtttagaaaagtatgtagtttataagctattgcttccat360
ttatatcctacattaaatgacccttagcacaatatatcaagatttatgcatgtacgtata420
tattgaaatgataaagttatttttgtacttttcaattaaaattccacattttaataaaat480
tgtatcataactgtggaggtgacagagggaaattctgcatacctatcaaccattagatca540
tttgccctattttcctttttaatatttttttccacaacaaacgttttagtagcaatgcct600
gtcttatttgggacaaaatgcgcaaccaataccaaagattgctgactattcctagacagt660
tttagtttatcaatatggtataattaaacctcatttccccaaatcaaatattaatattgt720
agatggtttttattcaatagcctttttttccttcttgagtgatatacttcttcgaaagta780
acctctaagtacctgtaatgagggggacatgttgagctgcaaagattatgtaactattga840
atggaagtgataatatgctcttaataatcccattaatcgaggcaaagtatactaagcctg900
aaactattcatctaaaatgctcacaggctgaggatgcaggattccttctagcctggcaga960
tgcattttctttctactagcgagcaggtaaattgagttgcacagggcgaaccatgggaag1020
tgggatctgatgcttccatttctccccagaagcctgcgtgcattatttcagaaatctgcc1080
tctggatgtcatgattgaaggagagctgctgtgcgctgtttactggggctttggactctg1140
gctaataaactcttccaaatcttcctagctgacaatgctcttctcatttgccctgtcatg1200
aggtagctacctcatgagaaaattttaaagtgcctcaagcaagcaggtagcaagtggctg1260
ctcaagattaatttccattggcaagccctctgctgcagcatgagtctgaataccaataat1320
gcaggattaaagaacaaaagcaagcaaagaaaagctcatcccagaggtgagagaaaggtg1380
aattgtgcaaatatggacatcgaagttattcagacacatatggtttccatgtcgtgagac1440
cttaaagcactctcagaaactccaagaaagctgttgattggtcagatttctcacttttgt1500
yccctcaaaacaagattgtcctgaacttataggaaatatactcaaaagtagtatgattta1560
aggaagtcttccaaatacctgcctcgtttacagataatcaatggaattccaaaagatttt1620
atgtgttttaagccctaaaaatgcaaatatccaggaaagggctagcactaaacagagctg1680
gcatgtatgcctcagtgcaggtgtatatctcagtgtctcctgaagccagggccttagagg1740
attgtggaaataggtacactgacagcagggactggaagccacagtctggagagcaaagag1800
cagaatccatacttacacctcaagatgagcagaacagaacataaccattttgctatgagc1860
tcatctccaccttcttcaccaaactgcatccctgttacttctccactaacctcaggacat1920
accaattcttctaaaatgctcagctctctcaagcttctgtgtctctccaaataatgctgt1980
ttcccttccctgcatttcttccttctccaccgtatttgacttgactaactaatatctagc2040
agagctgtcaaccagttctagtcagtttttgctgctgtaacagaataccacagactgggt2100
cattaataaagaagaagaattcatttctcatagttgtggaggctagaaagtccgagatga2160
aggcgccagcaaatttggtgtgtggtaggggttgcgctctgcttccaagatgacgctttg2220
atgctgcattttcaagatgggaagaatgctgtgtccttgcatggcagaaaagagtggaag2280
agaacaagccactccttcaagaattttttatagcagcattaatttattcatgagggtgga2340
gcccttatgatctcagctgccatgggtccccacctcccaacacttgcacttgggattaag2400
tttctaacacatgaattttagggaacacattcagactgtagcacaacccctccaggaaaa2460
cctttctgacctctgctaccactgactctagactaggcttggtatctatccttgcttccc2520
ggcatcatgtacatatcaccattatagaattgaccactatgtcagaaatgtccttcatca2580
catggctgtctctgcttagacactgcctcctcctaaagattaaacactcatgttcaaaag2640
tctttcttcatgtcagagcacagcaccacagatatagtaaacgttcagaaaacacgtagt2700
gaaaggaagaactttaacgctgaaaatgctctttcctagtaacctctaatcatgcatttg2760
aataaaatcaacatgtatatagatatatacacacatatacatatatatatatatttgttg2820
aacatttaccagtttaaacagtgtattagtttctaagcattgttcttaacaaaatggtaa2880
cacgtgttttctgtcaagtaaagactacaaatgaaatggttgatatcagaatgacgcaca2940
tatgtagagaacaaatcaacatgtgtaccccgacatccaaaacaatcacaaaatagcttt3000
t 3001
<210> 178
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
365
<223> 99-15682-318 : polymorphic base A or T
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-15682-318.misl
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-15682-318.mis2, complement
<220>
<221> primer bind
<222> 1184..1202
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1665..1683
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-15682-318 probe
<220>
<221> misc_feature
<222> 1842
<223> n=a, g, c or t
<400>
178
aacataaattctatcaaaaagtttgtacaaacccaaggaggttggtgaagaccatggttt60
tctggtgattggggcattatccagattcaatatgttctgaatttatgggatcataactac120
tttaaaaggcaccagctcttatatctaatattattccctactttagttcaaactctcatg180
atctagatggagctactaccagtgccttggctgagtgggattggagaaagctgaaactga240
catagtaagagatagtatggaaggagaactaatggggtgtgggctattgatggcttatgg300
aggtcaaaagagaagaagaagttgaggtaacttatttttgttctatactctacatgactt360
cgtagatgccaatgccttcaaaacacaggttttaaaaaatagtggtagaaaaaatgataa420
agctagtgtcagcatttgagtttgagacaatggtcaaatattctagtgaagcttttcacg480
ttttactttaaatgtggatttaaaactcaagagaataaagctatagatataataacagaa540
atgtatcatatttacaaagaaagagagaaaggaaagctgatatcacgtctttgaggaaag600
gcctgcatttctatgttaaaaggacaaagatggagtacctacagacaccaaaacaacaat660
tcaaacagatgccatatgatgaagctaataattgtcattattgatagtgctcaagtggtc720
ttgcaaggtaaagaggatgaaacagattttataatttcaagatatgtttgaatagaaaca780
atttaaataaaacaaaaagccttttgagaagaaattgataaatggaaggtggatgagatt840
gggtaacattgaaaatagcaaagtgaactacaataggaagatgtttgagggtgaaaggtc900
agtagataataatatagaaactcaaaagagtataaagttagtgggaagactttgtagaat960
gtattagtccagatggcataagttgtgcgttattttctatttaataagcacaccacagaa1020
atatagcatttgtagttttggctcttgcaaaatctgaagagagctgggtgaccccctagg1080
gcctgctccatggagtgactcagaggggcagacatcttccaatgacctccatcttgacat1140
ctttcaatgacctccatcttaaaagtggaagcagcataaagatgtttgatgagcaacaag1200
tggccacacaagtattggagaaaaaaaaaattagaatgtggggagagaggcagtagacac1260
aataaaaaattctatataacaaatgctatatctttaagaaatcgaatctttccattaaat1320
atttgtttaaagttacagactacttagatgttaaagtatcacttatcacaaagatcagta1380
acttatttcctctgtatagtagatgcctcttctgtagaattaacatttcactataatctc1440
taagatacagttcaagggcacaattttataattcaaagatatttacggcatgaaattgag1500
wtctaaaactcttgtatctttaacaaccattttgtaattaaataactgttgacatttaca1560
atcattgaagaactatttgaactctgtagagtatagatattgaagtacaaaattaattat1620
gagataatatatggagcctgtcggctttattttttaataagtatgtatgtatgccaataa1680
aggcatttttgtttccttatgtaaaatgtcctatcacccctcagctgattttgctatatc1740
cacaaacactacagttagcagttgagttttcttatttgctttttctttaaaaattattta1800
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
366
taacttttggtttctgaaaaaattggtaataaaacaggcaangtaggaaaaagaattatc1860
tggtggtagagcagacagaaaaataaacacttcagcatttatttttaatgacctagttaa1920
ccccactcactggatttatatagctgacagtttgacctcttttattgctgatatgaattg1980
aaatttattccatgaactacacgattgatcattaagaaaataaagacatgaaaagtggca2040
agacttaatctgatctctgtgtatgtgatgcttatattaaatcttccaaatatataaaat2100
aaattcaaataattcaattgttgtagacacattgattacttaattgaatttatttattta2160
tttatttaaatccagattaccaaaattattacctagaagaaaaagatattttaatcagaa2220
aaataaaatactttattattctacgtaggatgaaatttggttcagaataacaacaaccat2280
taaacgggaagaataacaacttaatttcaagtggaataaaattgagagttctttcttcct2340
tttttcttattaagaagccataagagatagtcatattactgatttatgggtaaataattt2400
tcatttcatacgctaagagattaatctggagtcagttggctttttattatttttgcgtgc2460
tttttaaatcagattttgaagaagtaaaagaaataaacatcaaaacataattaaaatttt2520
ttatttataaagtgttgttggcttctgcctattacttaatattcattcggtatttggttt2580
taaagacagattctctatgataatagatttaaggagggaagtaataagtatgtactataa2640
actttaattctggatgcataaaatatatttttcattaattttgaaacactatctcattca2700
actaaatatcagaattgtacacttattttagtttttaaatacagttttcagggtccagga2760
ccatggaatttgatataagcatttaaaaatgtgttttttctcatggtgaaagcagagaca2820
aaagataatctgtaaaggaaaataattatatatgttattggttatctttttgtttgttag2880
tgcattttgcttcattaatttgggaattatcaatataaatacagaacatagtcttcacta2940
gttcctatgggtttgcatgaattgtatgactgggaaaaatgtaaaatgcaagctgctctt3000
a 3001
<210> 179
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-20933-81 : polymorphic base T or G
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-20933-8l.misl, complement
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-20933-8l.mis2,
<220>
<221> primer bind
<222> 1563..1581
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1130..1149
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-20933-81 probe
<400> 179
ttcttaaaat gcttcaccta aaatatacat atattatttt tacctcatat atgtgtcata 60
ttgtatgtta catattatat atattatata taaaatatac tgtagccaat tatatttttg 120
cagttttaca ataagtacct ccaatgtttt aattctcttt ccctcaatct ctttattttt 180
attaatctag aaatgctcat aaattttact tgaatgtttt ctcttccgag caacttattt 240
taaaattttt attatattta agtacatgta gtatccttta ttaactattc tatgtacaaa 300
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
367
catgattgttctaagatattcaaaattccattaaactaatttaatttttaaaaaactatt360
caaaagagcattttctttttgcattttcaaggaatcaaaaaacattttttgatgttgaaa420
ttacattgcatatttcaactaaagatatttgcaaaagaaaatataatttgtactataact480
aggagataatgcatatgagaaatatgtaaacacacacagagtattgaaaaaattaactca540
cctttaaatgtatggtgcatttttagtattttattaactgtaatattacaactactagat600
tttactaatagaattgattttcaggcttagccacataatgggttccatgataatgagctt660
aagaaatttatcataaactcatattcatatttctgttaatattgctccatacactttata720
tattatatgaattggatctcttaatgcctcattgcttccttcagggtacattgtaatgat780
atgaattccttgggcctccaaagcaaagggtctatagtctgaagttcctgtccatgggaa840
tgaattctaccattataactcctatgggaatcaaaagggccacgattgagtgaatgcatg900
ttgaataaataatctccctaatgtcaagattataatgactgttgaaatccccttgtatgc960
tacttgacactatctatgacattttcttcatccatataatacttattataatcatttttg1020
ttccttgagcttctctttggcagcataaaatatgaataaataagcaattgataatccaaa1080
gtaaggtttgcaatattttttaaagaatacataaatttgctccttgattgtgtcttctac1140
aaaatgttctcccagaaatttagagaattcctgatgtatgagtaaagataagacatggga1200
tcatgttcatgttttctaggccagctttaaatcttggaagctacatgatttttacaggat1260
tttctggaagcacccgattccaggttaagtgttgcaaatgaaagaaaatgttcagatgta1320
aggaaatacgtctagcagtaacttcactattattcttattctttttatatatttactgat1380
tactcaggcccagaaagagccttgccccttgtcttgctgaaagcaatagtctggagactg1440
ttgacttggcaaatatatctcagtttttttggagtgattctgacacttgctaccccagca1500
kttactgaaaatatacaagcacacaaaatcatacaaaacataacagaaatagtaaacaca1560
tagtttctcatgtgaatggaagtgtctcccagattaaaagatggatcctgtacatttaat1620
aacacaatttccagctctgaaatccttctgctgattggcaaaatcattattctggtatta1680
tcctagaaggggttgacttttataaacattctcttttacaggcatttatctttccttttc1740
tgaaatacccattttagcactttgtccctaaacaaaccaaagacataaaaaatcaatttt1800
tgttttaaaaatataacacagccaagcaataaatcaatggtatttccaaagtcctttgca1860
taatttaagacctaagtcaataatggtggcatagcttcagttgttcatgtattattattt1920
gtcttcaaatttttgccacatgtaaggttaaaatttcacataaaatctatgatctttctt1980
atggaaaaaaagtaatacttcttgaaaagtaacaatagtgtaaattatactgaaagccat2040
tctacactaacttgagtaaacatttctgacatatgtcaagtgagcatgtattatagctat2100
agtgtctttagcataacagcagatagacttagaaaactatatgtgacacataataggtac2160
tcatttaatatttattaaatgaataaataaaatggaacattattcttctgtcagagaggg2220
ttttatctctgaaaatgcctttgaaatcttgaaatgtaaagattgttaacttgtgacttt2280
caaagcttaataggaaggtagttctggtgtttcccaagtatgaaacagaagtacattcaa2340
gaatgttaactgaaattgataacaaatatcaaagcaaaacttgaatcgttactattaact2400
gacagatctatcaatattacatgcttaaaatatgtgaacaatttattaatacattttcta2460
aaggcttatattttcaaatgttcaagaatagtttattatttaattatcttcaatgtaatt2520
aaagggttaaaatatctgctcatttacatgtgaatagttgataatgcggaaactatttta2580
atgttccaccaaaaaaaatcaaattacctgggcattgccaaaacacaatttaattttttt2640
ttgtaaacagatatttcagtaacaacaaagtttaaagtatattttccttaaaatctaaca2700
tgatattcaagcccatcttctaatttgttttggagggcaggtagtagaagccactgtaaa2760
taaagcttccattcaaccatatgcattaataatgttatttattccaactgaattccaaca2820
ggaggtagcaaggtacaaaaaacaaaaaacttgcaagaatcaggaaatctgggttcaaat2880
atccaatttgatgtctgcaagatgaataagctagaaaagattgtttatttgtcattagtt2940
ttattaagttgattaatttaaaattaggatggccaatggcagagagagctacgttaatga3000
c 3001
<210> 180
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-25029-241 : polymorphic base G or A
<220>
<221> misc_binding
<222> 1502..1521
<223> 99-25029-241.misl, complement
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<221> misc_binding
<222> 1482 .1500
<223> 99-25029-241.mis2
368
<220>
<221> primer bind
<222> 1722..1741
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1292..1307
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-25029-241 probe
<220>
<221> misc_feature
<222> 1368
<223> n=a, g, c or t
<400>
180
ctgctttcttctgaaatcatattcttctcacagacttggtacaaccacccatacaatatt60
tggatcccatatgatgaaagctctatgttttaattgctaggcctaatgatatatttagtt120
tgtatcatgaaatatcaagttaattaaagatagtgagtgattaacaaaacttgctttata180
ggtcctgttctatagatctcaatgtccaccttgtgtcctgctgttgttaactttttccca240
ttgagtgcatcgtgtgctcttaaactccacatttttcccttcaatgcatgcagtgagtgg300
gtctgaattagaagaggtctgtcttcgtatagtgaatcctccatgccttctctgagacaa360
ggaagtgattaataaacttaaaagttggtttccctttctgctagctcctgctgggcaact420
gtaaactatgacactatttatgtcaacaaagtataatcagcaaagggctaatccacatgc480
tattacccagagttaactgtaacagatcaatttctatgtatagttttgaaaacttgtcaa540
tatacagcagccacagaacccctgagcttaaccagatgtaagaatctggctggcgctgtc600
agtccctgaggaagccttggccaagcttgcaaaatctttgaccttattctcaccctccaa660
caacaggagcaataatccaaagtgttttgtctttcttgtattgtagctcatttttttttc720
ctacagaggtgaaatttccattttgtaatttttctttctgcactttttctatcaattttt780
ttttcttggaacttggtgaatagaagaaaatgctttttatttaattcttgagcaaaagta840
ggataggaagataagatgtcatcttggcaggttgaaataagtcaggaagtgtgtgttata900
ataccttacagatgtataacatttcagtttacagatctatcctgtgttcatcagctcaaa960
cctcagcaggtcccagtgggataggaggctcagaaagttgaaaagtgtgcctgatatcac1020
atgcatgtggtggttcaggaatatatacctaacacatacctagcatcacctccgacgcct1080
ttccacagctgtctccctacatgccttagtatcatgcagatcatgtggaataaggtaaaa1140
catatgcgtttatttgcttatttttaattgctgtttccatttacttgatttactgttatg1200
ttgtctatactgttgatctaaagtattatattaggtagtatttctttctcaataattttg1260
cttcacaatcatagttctaattccttcataggcaaataattaagcaactccagtaatatt1320
tccaaatcacatactgaggcttctctgcatagggtgctgagtcatcantgttaacactaa1380
taattagagttcaaggggaggggctgtccaggggtcacaccacgagaagctgttttgggg1440
taaaatgacacgatctgcaccacctgcacttagtcagaagaagggcattgaaatggtgcc1500
rtgaacagctatgatcctggaattagaaaaaatagaagaaataaatgataatttccagct1560
ttaaaatgttaagaactcaaagtgaagccacaactgatagggagagatttatatggatat1620
tggaatctatctgaggtcagtgggtccagtttgtgtcaataacccacgctgacctctgtg1680
gcaaagactcaggcaggatgacttcctggtacactcgatgaggataaatcttacacatag1740
gtatcccagaagtcccacttctcctctgatccagcaaagcatgagttgtcagaaagacac1800
tagtccagaaggcactgaagggatcatgtcggttcagaccaacagtatctaaaacatcta1860
agtcatgggtccagcataggagagactgaaagtattctagaatatgcacaactgtggagc1920
aattaggccatctttgacctaactttttcacaatactgcttggcagagagatggtgcttc1980
ctagaaagaatatataacttcagcttctcctggaataccatttagctttctcagacatca2040
actgtgtgagacacggatatctcatgaagtgtatttagatcatgacacatgttaaacatg2100
ttgggataaacatggaaatgtgtttccctcgattcattaactgattcaattccctccaca2160
tactcagttaaaatatcagtgcaagaagtgaaccgtgatgatagattaaaaacacttgtg2220
tctacttcctttatcatttattcgcctctaaaataaagaataattaattatatatttgcc2280
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
369
agactcttgtgtggacgggttgggccacatgaccttcttctgacttagcagatcgctgga2340
gtacactgcaccaccaggtacattctgggaaacatttttctctttgagaaatagatgtca2400
ctgtaacctacaaaggactgtgcaggagatgtgtatgttcttagtcatatcctaaaatgg2460
caactggatatctactgatagctttcattattcttctgaatctcaggttcacttcaaatt2520
tatggaacgttctgtttgaatacacatgtgttcctgactgtagtccttacacgtatatcc2580
taagagagcttcctctttagtattgcgaggtgaccttcttgtattcatcattaattgagg2640
tgggatacaaattccataatgtcaccgagttcttaacccacttatttcactgggttaaga2700
aataagctttgttagaaaaactaacaagacaaggggcagcagcaaaagagaaaagacaag2760
ttcctctcatcgctcattttatttctggagggggtatgcctgctgacattttatttctgg2820
agagggtaatgcccacgtcctgacagatatgccagcctctgttgcctccatactcacatg2880
ccaggcagggagcaccctgtccatcagtcttggaaggactgcttggccacttggttgtct2940
gggtttgcatggcagctgttcagttatattaactcagaaagcaggcttccaacacccagg3000
a 3001
<210> 181
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-25869-182 : polymorphic base A or C
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-25869-182.misl
<220>
<221> misc
binding
_
<222> 1502 .1521
<223> 99-25869-182.mis2,
complement
<220>
<221> primer bind
<222> 1320..1340
<223> upstream amplification
primer
<220>
<221> primer bind
<222> 1849..1868
<223> downstream amplification
primer, complement
<220>
<221> misc
binding
_
<222> 1489 .1513
<223> 99-25869-182 probe
<400> 181
cagctatcca gcagttaata cactaaacaaaaccaatttaaataatagtt atcctggcag60
aattgttgaa aattctacat tgttttgactggccctagagaaaaatctga ttcaaaaata120
accaaaaata ttcaatgaaa atatataatattctaaattgaaattgctta agttgtgtaa180
cattttctta tcatgataaa ataaaaatctagaacaaggaaatcataatt attttccttt240
gaatatgatg ttttatgtac attttatacatatatttagactgtaaaaca attagaataa300
taaaataata aaactaagct caatttttagattatgtatccactttgtct tttgttaaaa360
cagtattttt ttggtttcaa agaaaatcttttatataaaaattgaagaaa aaaatactta420
ggcaatatta taaggcactt cctggatcaggttataccaaaacacacata ccacaatgta480
tgtttctttg aaaataatat atgtttgaaaataatttatggaaattatat ctctgttttc540
agtaaataat gacaaatgag ctcataatttaataaaatgaagcaacacac ttaaagacac600
taaaaatatt tttgatagat aatatcagacacagatatcagtacactgga atgattgact660
atttgtaaca tatattacta gtagcagcagtgagaggtagagagtagata aacataatag720
aaatatcaag attcttatga cttaaaatttaataagtcaaaaagaacaaa tggaatttta780
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
370
tttgtatagtcttagaggaaagttgatcgaccagaatgaaaactattcgtacagaaatta840
agaatgtaagaaaataaattgtgccgaatattgtaatttaagagcaagtatttatactaa900
aattgattagaacattagaatttctggatcaaatgtggactgtcatatattatcagtgga960
caccagtggaacaataaccatgtgaagattttggagactcctgtctcctccaatccagat1020
aacctaaaatataacaacagggagggatgttacttacaagacgtagtaaaactcacctga1080
ctaagaagtcctgcagttctgacaatgagtttgactaatggtaagagctgtgtgaatagg1140
tagtgacaagcagctctgcaaaaccattagtttttgtttgttatatttatcaaattgaca1200
aacatttttccagcagcaagcatctccattcctttgtatttcttttacctacctagcaaa1260
atcagtttataattccaaaggcagaaactatttcattcatatcctgagctcttagcatgc1320
tttggttttgtagtgatgcggtaagggcagataatgcatctgcaaaatgaatgagctgct1380
ctaggtagaacataaaacagttctttttacatgatctacactatttaattgggtcataat1440
cattttctcttagttatattttatattaacttttattaaatcaatttagcataaatgtta1500
mattattatgtgtttaaatatcacccatcatttctgtaaaattgaaacaaagtagaaaca1560
aattaagaaagcagttgcttttcttaggaatctttatactgaaaaattccttaacttgtt1620
ccttcttcccttgctccctttcttttctccctttctttcatcttccttccttcctagctt1680
cccttcctcctctcttccttccttctggacaaatatgtagtttacttgatcttgtttgta1740
gaggttaggagaacaagacagaaatacaacactagtgctcatttagctttaatcattttg1800
gaagagatgtaagatacaaatatgaatattatgtaagataatttgagtgctatgattttc1860
cctgggtctataaagactcacacttcctgattttcctttgtttacctaaatctagtagct1920
aatgagtttcacagaagacaaaattcctacatcaaaataaaatttccctttaaattacct1980
caactagaaaatccttgtagttctcatgcaacccaatattctgagcctgttcccccattt2040
caccaatcacctttacctccttcagtccccaggctcccaggacccttttaagaaagcctg2100
tggcccttacttaaagaggaatggacaccgatacatatgtccagcagaaactggaagtga2160
tgtattacatctatgtgcctgttaataattaaataaatactttaaaaaggtattgcaact2220
gctaaaaatctaagaacgcagtttgaaattaaatactattaatatttactttgaagtcat2280
tgtttttcttcttataattcgtattatgtgggttaagctagcaattgacttttggagtat2340
tccagacatgagatcattatacctctggatttctataaaagttgttcaccactacaacct2400
acttgtctgaagcctggaacaaggggataccttcactcaacaaaagaaaataccagtatt2460
ccagagcctctttagacagaaaattctgaattgataccttgccatgaatttggttgagag2520
aaatgctatggagaggatattatctttattacatagtacacatttactcttctatgtatt2580
atgagttctatctctgagttcatctggtggtcagaaatttgaccatttcactgtattaac2640
caattcttttacagactatcctttacattttggtatttatttcacggctttttaatttta2700
atatatcttttattaaagcacatatacttacagaatactgcccatgagatgcatgtacga2760
ttagatgaaatttcatgttactgacatgaagaccaacaagaatattacagggttgcctca2820
aaataattttcgtcttcattttcttaatacagatctttagaacctatgaatttttgcctt2880
catttttcaatggtatttttcctgggttcaggatttttggttatttccgcttagaaagaa2940
gtcaatccatcgtctttttactttcgtgatttctattgagaagttggctgtcaatcttat3000
g
3001
<210> 182
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-25881-275 : polymorphic base G or T
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-25881-275.misl,
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-25881-275.mis2, complement
<220>
<221> primer bind
<222> 1227..1295
<223> upstream amplification primer
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
371
<220>
<221> primer bind
<222> 1693..1713
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-25881-275 probe
<400> 182
taatatatttaaaagtaagcatctttttgggtgttatttgctcagaaactgtaaataaac60
tactgagagatgtcctagacttatcttggtgggtaaatacatattttttgtatatacaca120
cacacacacatatgtatatatatgaaatgtatccaaaagctatataataacataagaaat180
ataataattcttatacaataaccaccacccttataagacgattcatgattttttataatt240
tgcaaagtaggtaagtttgctgtgctagatattagagaagagtcttagttatatttatag300
aagtgattttattaaaaaatcaggacattttatgcatattttattatttactttatcagt360
catttgctttgctatttttctcaaaatggcattttaaaacttcatcccataaatagtaaa420
ttctcgtctttgttaaatgatttgctagtctagtgcctggttggcaaaatcagctttgta480
aagcaggttttaagatacaggtggaaaaattaatagtaataattatttcactgtagcaaa540
agctttctcttcaaaattaaaattaaacaaagttacttgtgtagtcaggaaggatggcaa600
aggcagcaccgcctcctgaaacaatagagtcatcaggcacgttgctgcccccgtctaatt660
tgatgtgtcaggccctaatcagctctgtttcacagtgctttgctccataaaagcagattt720
gtttaaccacaacctctatttcagcatgactggagaaggaagaataacggaggagaccag780
gcatatctcacgtgttgtgttgtgggtataaagtgaatccatcatttgctggagaggcag840
aggaaaagtgacaggctcattcatgccttcgagacatttttgggtctattgaaaatttta900
atctgtgcactctggttgaacctccgcactccttaatttagtacacacagccatgcgcta960
ggtctgtctgcctcagatagggccggctggcttctgtaggacagcaacccccctgaggag1020
ttttcttctctaaattcatcctgccttgaacttta.cacacacatataagctccatttacg1080
ggaggattccagagttaattaaacgctgaatttgtttctttagaaatcgcatatgcctcg1140
gggttaaggaatagcgtttcagcaaccacgttaatttaggattaagcatactgtacattt1200
tctgaataaattttatttttataagtatacattgagagagatggggaaattttccccctc1260
tgttaccataaaaggttttaaaaatagatttaaaaaggacaccatatgccaggagatgct1320
gcaaatcagcaaattcaaaaccatcctttacgtaaaatgcattggaaacagacaaataaa1380
ctagaatgctggaaaaattgttgctttgctgataaggccatggaacgacttccaccggag1440
gctcccagctttaagtcctgttcactctggatttgctctgtgcacaccacggtaataatc1500
kcagaagcataatatttacaaatatttgggtcaaagatgacaggtcagatttttattatc1560
aaactagcaagtcaatactgacatatactagttttagttccactaaagatactacatata1620
acagcagacacgtttgttcttaattttcctaaaggtaggtgtttggcagaagataaagcc1680
tgagcaaatagagaacagaagaagccaggaaactggtattgtcctcggtggatttacttt1740
gaaacactgtactataaaaactttgcaagtaattcagtaccttgagttcattttcattga1800
tatctttgcacatcatgtacaagaaagttgtgttttggcaaaatgatcaatatcttaagt1860
cacagatttacaaaatgccagagaatattctttgcattcaaattaagagagacacagaac1920
atgaaaaaaaagtgtatttaaagatctcggacaacctcgacctttttgtttatatgttta1980
gtttaaattattaatgacatgtatgtgttcacttcaacatggaatgtttctttcctttcc2040
tgttctttttctctgtctgtaaagtttgaaataaatcagtaaagtttgaaataaaaacaa2100
ttgttacagtttctgaggtagagagacaattaggtagcatttggcattttctgtaggtca2160
gatgagcgtatggattcttggaggtaaaaagttcaattcatgaagaagaacagagacaac2220
cgaaggctacaatgactacagtaaaataaaacagccctaaagcccagccgagtaagccct2280
catccataaatcttattaatcagggctacttcgaaatacaatgagcaagggagaaaatta2340
tgccctatttcagacttgcccagtttctttatcacttagaagaaagacaaaaaaaaaaaa2400
aagaaattattaggaccatgtaagacagataatcaaatcaaggaacaatgcaactattgt2460
catatgtaggatagaaactacgcatagtattttgaagaagcataaatagcctatattgat2520
atgtcaaatttttccatttacagatgtgcggaatttctattggttgtgtgagatgatctc2580
atttttagggagacgtagctgtatgtcatttatagctgtgatttatattgcttgacctat2640
tgaggtaaaaatagtggttgttctaagagtatcccctgtctgaatgcattgtgcagagtg2700
ttcattctggaacacttgctgtttcagttctgattcattttgagaagaattccttttccg2760
gacttctataaacagacattggcaaaggaaattaaataaagcaaactaagatgatctaat2820
tgtgagtgagtcaaagcctcataaagcattataatttggatattttatcttaatgtccga2880
gaggaagctgctattaaaccactagccttaagcaaagcaacacatatgtaataatgcaaa2940
cgaagagaatcagattggcccattacttgataaaagttaattgttttaatgaatattttt3000
g 3001
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
372
<210> 183
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-25897-264 . polymorphic base A or T
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-25897-264.misl
<220>
<221> misc_binding
<222> 1502..1521
<223> 99-25897-264.mis2, complement
<220>
<221> primer bind
<222> 1242..1262
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1736..1756
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-25897-264 probe
<400>
183
aagttaaaataatcctccaaataatattgtattatatacatttatgtttcacttaggaat60
atgtttcagttttaaaacattttgtttatacaatacaattttataaaacctttccctatg120
taccaagttaatttttagatgatatacatatttatggtagatgtgagtgaaagctttgta180
tttgtatgcttcttagttattattgctagtttttgaaaaatcttgaatatatttctatta240
gtcttaatacacattaattgtattcccttggcttatttatatagtaaataacatttgcaa300
agataatttttaataaaatgttgaaacgtttccatgttctgttatttcagctaaaaaata360
actacaataaaaacagtgacccatgtgtcccaagcactcttctaagagccagaaagacag420
ctctaaaatatcacctctgctattataaagtttatagtcttactttataccatatttatt480
tctattttgatagttctgatttattcttttattctttaatatattgttatatattacttt540
tcaaaggatgagcttcagtatttataatgtctttttttctgttacctatatcattagcat600
caatatatgcattttttttcttattttcatcttattggggctacttttagtctaacttat660
tgccttgagtgcctgttttttttttttttaaatctttcaaattggtttgaccataattag720
actaaggtttattgaggtggcatctagagggtgttaaattttatgcttcctatctttttt780
tttcctatccagaccctatctatagctatagatagatagggacataggtgatggtagaga840
tatagactagataaatcagaactctgagagattagaaacttcaacatccacaagagagta900
aacaagggaagaaagaagccttattctattttgaggtctttctttgaacattacaaataa960
tttctctccttccactgcctcctttaatttatattggggtcccttagttctgggtcaatt1020
tgttaaaatgagcaggttatgagatgttgagtgaggagcccacacgactgtcctcctgag1080
gtcccgcactgccatctgagcaggagcaggcgtctgtcacgctgaagacctgcgtgctac1140
tctgtggtttcagaatcctggtagaggagagcgttactttaagaagcagacacgtgagcc1200
tccagatgcagccaagcatgaaatcagctcgggtggataaccttgaacagcgacaaaaga1260
acaatctccttccaaactgggctaggaatttgtattactgaactatgccaagttcgaagg1320
aggcaagtacggttgcttgaaagttatgggaaacaaacaaataaaaactaaagaaatcca1380
gatctttccaggtgtagacaaatgctctatttctggatgacaggtttgatttgcttaaac1440
acatttcaatgaattgaaggttggagttgagagtgtgtcgtgacacattcctgtcttacc1500
wgaataggggggaggaaattgctgatcccgggagctaaagcaccttttttcacacacgtg1560
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
373
gtcggcctttggcacttttgtcacatgcacattgcctgccagctcctccaccctccactg1620
ggtgaggagacgctgctgccttgagtcaggacctgcattaatgggggcgtaaggttttta1680
ctcagcggaggagacacccccacctagtgaagctaaaactgaaatctgatcatgagggag1740
aggttgtgttggtcttgccattactatgtgttcatatcatatgttaaattttacgtattt1800
ccttttccacttatcagatacactttatatcagtgctttcctccgatgaattaagattgt1860
atttctattttcaaattatttaaaaaattggaaatctttagagagaaatgttttgtacca1920
ctagtttgttcttactaccagatgagtttgatggtggggcggaaagtgtttctttaggtt1980
ggaagttagaatgtattctcgaaagtttagattctcatctaaactgattcatataaacca2040
atagtctaacaaagaaaatgtgaattcacttacgtgttttcatttagatgttaccaacaa2100
ttattctacaatttgtaagaatgtgtgtgtgtatgtatctcttggtgcgtgtgtgtgtgt2160
gtgtgtttggtgtattattaattctatttcttaactattttaggtgtttgtaaattaatt2220
tgacttagcaaattctggaagccatattcatagtttttatttaaatctagacacataaag2280
tcttttttattaattttctcatgtcacagttttccacactcactcattatgtctaaaacc2340
cagtagcttctagaggtaaattgctttttaggagaatattcgctaagtatctacactcta2400
ttttagttccaaaatcttttaagttggaaatgtgcatgtgcctgggaaaattgaaatcaa2460
aattaaattttctgtcaaggaaaatataaaatttgaaatcacaaatgactcattcctttc2520
taatgactattttgcatcactattattaatgacgttttagaaggtttacacacattcaaa2580
atgttagtatcttttgatattaacaaatgaagggaacactttcgacaatcaagctttggg2640
tattttttacatttattaaatatgtgattgaaatttatttaataagcattcctgaatgac2700
aaaaataatttaaatgctgctacttttagaaagattagaagacgtgcggcagagggcttg2760
gggtcatgagtctggagtattggacacatatactagttattccactaactggttatgcta2820
ccttgcaaaatccttaatagggctaagctatattagggtcagtttccacatgcataggct2880
gtggtgtttagaatgatctatttaaaatttatttcaaaaattgtattgctgtaataaatg2940
acagttgttattgcaaattcttctattattattaatattatcaacacattaatgttaaaa3000
c 3001
<210> 184
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-25906-131 : polymorphic base G or T
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-25906-131.misl,
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-25906-131.mis2, complement
<220>
<221> primer bind
<222> 1379..1392
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1888..1908
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-25906-131 probe
<400> 184
aagtaacaaa gacttgaagg ggttaagtga ctgaatataa aaccaggaaa tgggcattgg 60
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
374
tacaatgtgcacaacttattcaggttttgccaattttacatgcactctgtgtgtgtgtgt120
gtgtgtgtgtgtgtgagatcgtccatgcaattttgtcacatgtgtagatttcttgtatca180
caaccataatcaagatttaaaactgttcttcaccctaagattccctcatgccctacatca240
ccatccccaaactctgcccaccactaatctcttctccatctctataatgttatcattttg300
agattatatatatatatatattagatggagttgtgctcttgttgcccaggctggagtgta360
atggcgggacctcagctcaccgcaacctctgcctcccgggttcaagcaattctcctgcct420
cagcctccggagtacctgggattacaggcatgcgccaccacgcgggattaattatgtatt480
tttagtagagaccgggtttctcaatggaggtcaggctggtctcaaactcccgacctcagg540
tgatatgcccgccttggcctcccaaagtgctgggattataggcgtgagccaccgtgcccg600
gccgagaattttatgtaaacagaatcatacagtatgacttgtgcatgtcttttgagagtt660
agcttctagactcagcactacgtccttgagagatccctccaaattgttgtagttgtgtat720
atcaatagttcttcagcttttattgctgtatttcatggtgtgaaataccataatttctgt780
aactattctcctattgagaaaaatttggattgtcctcattcttgactattataaataaat840
ctaatatgtacaagatttggggaacgtaaatttatgtttctccgaaatatgaaaccaaaa900
gtgcatatattaggttgtgtggtaaacaatgcggttattcagacagacaaaagtagatag960
agctcagagtgacagggttgtgttgtgagtaaggatgtgttctctgagaccaaaatgtct1020
ttgttttatatacgagcttcacaacctgctactcatgggaccctcagtgataaaaatgaa1080
gatgataataacaatgatgccatttcaaatggaatcattgtgatgattgtgttagttaat1140
tcatgacaagtccttagacctgtaactaacaagcaataagttttcaataaatgttagcta1200
ttattgtaattgcataactttggacactagtcatattaaacactttcccatatatttatt1260
atcttcttgaatttattctcttgtagaaaaatgttcatgcttaaatatactgatattatc1320
taagaatttttattactgatttgaataacttttatagggttttggaagcaaatgccgtca1380
actgtttcaatcaatattaatataaacaattgtgtataaaaatcaataatgaaattttaa1440
aaaaattcctaggaatgagactttttataaaatttacttattttatgtttggaaggctag1500
kcaacacattgaaggagggtgttaatgagccagcccatatgaacagtgtggtgcccaaat1560
ttcctatgtctgtgaaatttcatggcaatctgtcaaaattagccaaacttgtttccatta1620
aatacactggtggtattcaaataatttaagttctggttccaaatcgaatataaaactgtg1680
ctgaatataaagaaaaaggaaacctcaaaaccaccttcaaaacatattgaagccttaaaa1740
tatttctggactttttaaagggtcccaagagtagagaacaaagtttggtgacagtgtttt1800
gaaatgaacagacaagggcactctctggacataatccctcaggccaaatatactgtgtaa1860
tttggctgacagcaccatttccaatttctattttgcttaactccaatgtgtttaataaaa.1920
tgcaacaaaaagtaaatacttacttcagtgagcttatttttccaaaagcagcactatgca1980
tccaccttatgtacccatagtaaaacttttgttatttttatacaattattataaattttg2040
gattttatattaattcattaatttaacacatatcgtgagggcttgctgtatacacagcac2100
taatctagccactaagatcatagggttgagcaagagagagaaagattctgctttcatgat2160
atttattctgttgggaatgttgacaaccttaatggtaaataagtgaatgaacatgagata2220
taatttcaggtcatggcatgagcattgaatgataatgaggcagggtgagggtatgaacag2280
aaacagatgtactgtcattggtgatcagagaagttctctctgaccaggatagaagcccag2340
aataaaggagaaaataaggatgcagtcatttccagaagagattttcaaccaaagaacaga2400
aaattttaacgcactgaagatgaatgggtgattgatctcagggatgaggttatacttagg2460
tcattacatgtggttttaggcctgtgtgaaaaaacatgaagttgttccaagaagagtttt2520
tgtaaggtagcctctaaacctttctaagctcccagtttaatttccaaagagcccacagtg2580
gaaaaggacaaagcattgggaattattgcaatcattttttgtatgctctccttttttagt2640
atagtgtgcattcctcaaagtagtaaataatggtgttttactcatctcatagggcaaaag2700
attctagatctctgtggggtaagtcaggcatcaagtcaatgtgtgttgaatgaaatattt2760
ttaagtccctgagattaagatcattttgttccacagaacaaaatggagccactgtttaaa2820
cctgttgttacacattttccatacccagtgtgacccttaatactgagtgtcaacttgatt2880
ggattgaaggatgcaaagtattgttcttgggtgtgtctgtgagggggttcccaaaagaga2940
ttaacatttgagtcatggactgggaaaggcagttctaccctcattctgggtgggcacaat3000
t 3001
<210> 185
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-25917-115 : polymorphic base G or A
<220>
<221> misc binding
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 1502..1520
<223> 99-25917-115.misl, complement
375
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-25917-115.mis2,
<220>
<221> primer bind
<222> 1595..1615
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1115..1135
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-25917-115 probe
<400> 185
tatttacctgtatcaaagtactagagatcatgtctgcttagttttaaattccacattttc60
tctattcccatagattttagagaagtatgataaacatattcatagtatgagattttaact120
agttctcatgggcatgctttctgagttcaatgaggataatttcaatcactcatgtgaata180
tataaaataataaattattgatcacagacacaaagataaattttgtcatttttctaaaaa240
taaagaaatcactatttacaatctatctttgtgttcaatgctattgtaaaaactaaaaac300
aaaagcaaaaaaccctctaagacaaaaatattaagacgcatagtacttcatctcttgaaa360
cacaattatgcacactttgaaaatgcccatctaggtaaatttagggtccatggttttaaa420
gtagaaactatactcccattaacacacacacacacacacaccctatgtagagtttgatct480
catatccccaaaacaaaagtttttattgactattctaagttcactaaagcatattagaat540
ccctctgctatattattattataataaattatccctcgtttgtatataaatccattatga600
gaaggtgttgttggtgattaggacacatttgcttttaaaaaaacaagactattagaagtt660
ctattatattctctcatgcaaataacattcaaagtttggatgttaaatagaggcatttcc720
aggcacagatcaactcttcgaaaattattgtaggaggcactttaaaggaaaaaaatatgt780
ttggcacaggaaattacatttaactaaaagcattttttaaaatgggcattaacaaattag840
ccgggaatgcatcattcccatcttacgctctcaagcacttaatgcggatagacctacaaa900
tcacattatcatcactttccataccttcatcaaatgtcatagcaacagctgccctagtag960
ctctgagtgtgccttaggctaaaggagacatctgtttgctgacaacttcagatcaaatga1020
caaatgggagacagaaatgtctgtgcatggtaaggtcagaggccttacctatttgttagt1080
ttcagttgtaatagggattttcttcttttgataggcagggaaatgactaacatactatca1140
gttagtgataatactaattcttcttcaatcaaaattaagtagggttacaaaaggaagatt1200
attattgttttgtgattgacaggtgttagttgacactttttttttttttggtttgtgttg1260
acattcatcatactttaaaagtaaccacagatgtttcttttagtctgatcaaaatgaaat1320
tagggactataggttccacttcttttgagctctaaagagagtggtcttttaacttaaggg1380
ttacttatttaaaatattagtttagttctttcgaactaagaaaaaagtctatttacattg1440
tttatagtcactgaatgtgaatgcccatttttaagtgaaaataactaatgtaaatagcaa1500
rtaattccatattttagtcacctttaatccttttttaaattcaggtgagagtttggtttc1560
tgtatgaaatcgccttgaagaatattgtgctattcctcctcatattgtttccacccaaaa1620
tgacagagacagatactgtgtgaaggaaaagttctcaatgctcaaagaaagatgcccgaa1680
gcctttccacagagttttgattctgttaggttttatcaagcctgcttgagatgccatcct1740
tttgtgagagagtcttggtgataaagaaagatgacatgggttcctcatacagacgtattt1800
tatctctgacaattcctgcgttatttttgtaatattttttggttagtttatgcttcattt1860
tcacatgattctatgttgtttcttttagtattattttttcttaagtctaatgtagtcaat1920
attattgaatgatttactggtcctgttaaatgattcattttgaaatctacaaattctaat1980
gtttttatgagcagattaacttgtcaattagatatacatgtaaatttagctttttacttt2040
tcttttttatttcagtgtttatctgtttatcctgttcataaaactgctaatgtacaggga2100
aaatgcctaaggcaaacaactttttaaaatgcagggaagaaaattattccctgtgtttct2160
tccttttcagctattctcttgtgaaaaattctcatttttttcactttttgctcgctttat2220
tattttaagtttgtcttgctttatattttattcaatacataacaaacttacttctcagta2280
agaaggtaatattaaattttggagtttagttcaaaatcaatctgatgcaaaaatctttga2340
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
376
tagattgacattgcttcatttattgcttcatttggcatacatttatttagtttctatatt2400
ttcttactgcaatactaggatctcaggctagaaatatgagtgggaactaagtctatcctt2460
cagaatctaaaaatctaagaattaaatatttgaacactctacatatattttgtgagagtg2520
caataatatgagaaacataaaacagtggtcaaagcaaatttactttagatggtttttaag2580
aaggagtcatttgtgctcaaccttgttaaagaattttatttttatgtttatgagtcacct2640
tactctctttcactttatatattctgttttaaaaattacattaaagtattcgaagtactt2700
ttgttttcttacctctctgtttggatgtcctacgtttctttgatcattttctcaacaaca2760
acaaattaatatagaattaggtgctatatctagacacagtcattaaaatccctcaaatgt2820
gaagcatgggataaaatataaaaggccagaggcttactgactaattgaaaatatagtaaa2880
atccttaacttcttttaattgaaaacaagactttcttaagtctacctgtaatttaccagt2940
ctattttaaaagccacattaagttatttttagttttttaatgtgtagtaaactaagacat3000
t 3001
<210> 186
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-25924-215 : polymorphic base G or C
<220>
<221> misc_binding
<222> 1482..1500
<223> 99-25924-215.mis1
<220>
<221> misc
binding
_
<222> 1502 .1521
<223> 99-25924-215.mis2,
complement
<220>
<221> primer bind
<222> 1287..1306
<223> upstream
amplification
primer
<220>
<221> primer bind
<222> 1717..1736
<223> downstream
amplification
primer, complement
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-25924-215
probe
<220>
<221> misc
feature
_
<222> 1914,2542,2811
<223> n=a, g, c
or t
<400> 186
aatttgtcaa cctcaagtgacatagtaaacatgctgagaaatagcaactt ttatgtgaaa60
agtaatcaaa tgttttgattatatgattccaaagagttttgggtttataa atttcactaa120
aaaaatttta caacacatgtactgatcgttaataaaattcaaataagata tatgttttta180
atatatggaa tgatgaattaagggagataacagcgtgttgccttgaatta aaatacgctt240
actctgtgtt cagataatcatcgaagggaaagtgcttgaaaaaataatga taatatttga300
gataaggtaa attacggctgtcacacactaattaaaacccatagatcaat tacaagatga360
gtcaacttga acactgcatttagtgggcttatctgccaatgcttcactag ctgtcctgct420
gttaaatctt ctctgaccttctttcttgtattcatgtaagcgctaaatga tttttccagt480
agagcttgca gtgggactgccttcttccctccaggtcttccacactctgt cgggaaggtg540
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
377
gtgaagagacaggactgcagccctcataaaggctctgcaggtgctcctcaatactggcct600
ttagggtgaacttgacagaggtgtaagcgtcgagaaagaaactgtgagaagttccaataa660
tcaagacagatgctcttttatgaagtgaaatttcgaccctaagacaccatctcctggggt720
cacaatcattccaacatattcttgatggaaaaggctaacatgtcttcctcaaccaccatc780
tgaatgcacttggcacatcataaaagagatgagtaggaaacacaggaacatacaagcaag840
agacagggtcaagtgggagatcctcaagaaatactcctgagcccactgtttgaaatggtc900
acacatggttttagagttagaaatgaaatagtaagaacactagcaattacagtgatcatg960
acagcaatatacaaacatgattttttttttcattgagtaattatttttttgagacagggt1020
ctttctctgtcacccagtttggagtgcagtggtgtgatctctgctcactgcagcctctgc1080
ttcccagactcaagtgattctctgcttcattctccagagtagctgggactacaggtgtgc1140
accgccatgcctgactaacttgtgtattttttgtagagacaaggtttcactatgttgccc1200
aggctggtctcgaactcctgagctcaaagagatctgcctgcctcagcctcccaaagtact1260
ggaattacaggtgtgagtcactgctcccagctcttcattgagtgactattattttacagg1320
cataattcaaagtgccttacaagtattaatgcatttaattcccaaaaaatcccatcagat1380
tttatttttcatctctgtttcatagcctatagaactaaatcacagagaggttaagtaacc1440
gcccaacattacagttagaaagaataataatcagtatacaaatgcaagcagtttctcccc1500
sgatccagcctccataaccatgccagaatgctgcctctccaatacatttgaacttttatc1560
gggcattaaaatcaaacagcatttgttgataaataacaaacttctttggtctgaaaattt1620
aacacattcaaacaatattctgaaattttcattacaaaacttccttgaaagcaaatcaac1680
ctggttattaacattagttgttggaccctggcgggtgggtgtgaagagttgaggagggga1740
tgaaaagataaagcaaaaccaaacaaacaaaatgaataaaaacactttgtgtctacagtg1800
aaagcacatgtgtggtaggtttccatttttgtgcaagagttatgtgaagggttgtcacaa1860
aattaaacgtggctctttcagaatggtacaaagtctgatggatgcttaccatanagttag1920
ctctcctgtgatttttgtttttttgcaatgactatgaggccatacaaagagctcatgtat1980
taacttgaaaactctggcttggagggtgatatagtttggctgtgtccccacccaaatttc2040
gtcttgaattgtaacacccacatttctattagtctaatatctgggtctttctgtgatagg2100
aaaataggggagttaagaagtgggtagtaagagtgaaaactgtgctccaggatatgaatg2160
ggaacaccagcaaatattggaggtcaagtcacctgtaagtttcaggattggtagaaataa2220
gaacatgagacttgtcctgagacacagaaatagtgatattgaaaacagttaaatacctct2280
atgccatgtgctccaacctatgagaaaagctccataaacaaccaacatgttcatacagtg2340
gttccttgtaaggccctctgaattatgcca.ggaaaataatagtcactcaacaaagagcca2400
ggagcagtgactcacacctgtaattccagatattagactgggttccatgagaggagccca2460
gtgggaggggattgaattatgggggcgcgtctttcctgtgctgttctcgtgatagtgaat2520
gagtctcgcgagatatggtggntttaaaactgggagtttccctgcacaagcactttcttt2580
gCCttCtgCCatCCatgtCttgCtCCtCCttgCCttCCdCCatggttgtgaggcctcccc2640
agccatgtggacctgtaagtccattaaacctcttttacttcccagtctcggttatgtctt2700
tatcagcagcaaggacacggactaatacagatggctcatccagaagttagaaaattagag2760
atgcagacctggcaaagtagatctgaaatgggactccggaactaatgacantggctttct2820
aggttggaaacacttacaaacccagacatgagactcacaccttaaatggtctgttggagc2880
ttttatcctggttttccacaaaaggactatgaagaatacaaatggctccttcagagagtg2940
gcagttagcagctctttattatgagcgctctcttcgtcctatttaggtaaactccattct3000
a 3001
<210> 187
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26138-193 : polymorphic base C or T
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-26138-193.misl,
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-26138-193.mis2, complement
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<220>
378
<221> primer bind
<222> 1309..1327
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1741..1761
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26138-193 probe
<220>
<221> misc_feature
<222> 65..66,980
<223> n=a, g, c or t
<400> 187
tcacgaggtcaggagattgagactatcctggctaacacggtgaaaccccatctctactaa60
aaatnnacaaaaaaaaaaaaaaaaaaaaaaattagccgggcgtggtggtgggcgcctgta120
gtcccagctactcgggatgctgaggcaggagaatggtgtgaacttgggaggcggagcttg180
cagtgagctgagatcacgccactacactccagcctgggcgacagagcgagactccgccta240
aaaaaaatttgtttccctctttcctttctcatttcatgaatcttttatattctaggttat300
ctgaaaataacaaatgaaagaattatataaaatcgatattttgtttccagaatttttcta360
catatttgttagttctgtctttgccttacttcacactatcagtttttctttaatatttgg420
tgatccttagtgttcgctcatagttacagaatgaagattcgatttcaatgaagattgatt480
tagatacgtagatacaaaaaaaggttttctctgaaattttgaccatgttcagcacattaa540
tttgtcaagggacttggaagaaaagactatcaataaaatatatatatatatatatatata600
tatatatatatatatatatatatataaaatttgcaaataaaaaacatatcaaacattaaa660
aatcatgccttcaaatcatatctagaaaatcaaaaaataagggaattatagatattcata720
atctattcatgattagtaataattagaagaaaatcaatgataatattaaaataactaata780
tcaattgtttgcatatgatgtgccacttattttactaaaatattttaagggttgattcat840
ttactttgcaaccaacttttgaggtaacatccttttcattctgttttcctgaggaggaga900
ttgaagaacataaaagtgatctaccctgcccaagcaacacaactactatacattgctgct960
ggattatagcccggctccgnttttttttttttttttttttttttttttttttttttttag1020
atagagtcttgctttgtccccaggctggagtgcagttgcgtgatctcggctcactacaac1080
ctctgcctcccgggttcgagcgattctcctgcctgagcctcccgagtagctgggattaca1140
ggcgtgcactaccatacccagctaatttttgcatttttagtagagacagggtttcactat1200
attggccaggacggtctcgatctcttgacctcgtgatccgcccgccttggcctccaaaag1260
tgctaggattagaggtataagccactgcgcccagccccagtcttaacagagagcccattt1320
tcttaactttgcatggcattttttgtctcagattcataaatgtgtgtgtgtgtgtgaatc1380
atatgtcaaaatgttatctttggatggtgatattatgggtgacattttattatttgttat1440
tattattttattatttgtgctttcaaactatctgcagtatatgtttagtaattttataag1500
yagaaaaatttctagtgactttacacaatctggattaaaaggcaaagtaatatgagaagg1560
ttaagaaatagggaaatgctcgaccggccaaggatgagcgcttctaagatggtcaaaagc1620
aagtcttcactgggaacactgagcaggcaagctgcaagactagaaaataatgcctcatac1680
tgagatggttatgttgatataagacttttaacaagtcccagaatatgtctgtgaatgaaa1740
gtagcagtaaagaagtggtcaaggccatttgatatgccatcaataaatgcagagtcttgt1800
tcatatgtagatattaacgtcatgaagatgatggcagggatgggcataatgtggatcggg1860
tttataaaagaggggcaccacctatgatgtgacagatgctggcacaggaagagaaattag1920
agttcggtcaaatcacttatgtaatcctaaaaagatgagaatttcattttataggagagc1980
gtggatgtataatagagtggtgggaaaacgatttggggtatttaggggatcagaaagaat2040
taaaactacaaccttgcaaatgagttaaatgaccataagagtataaattaatctcatgca2100
ctggaaaatgaaataggcactctatttgctgagggatgctaatgctaccaggactgtgta2160
aggttcaaatatcctaaatataatactggaacacagatattattcaattcaacatgtgtg2220
aactgcaacttgtaatattctacaccataattatggtgtagaataaataatgatgaaatc2280
agaatataaatctagttttccatgaattcttagtgagaatatgggattcatggaaaaaat2340
ttaatgttctttccattgtgatagattgtactgtgtactgaggaactttcaggtaaagga2400
tgaaacattatcaaagcaaaattgaaagatcagagaaacactatagtcaactgcataaat2460
taaaacttaaaaacaaaactagagtgagaagaaacttagacgctaacttgaagatctcct2520
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
379
ctgtttcagcttgttcctgaagggtctggtttcatgtgaacaaattttaagaccgatgca2580
ttatggtaaactcagttagttagaaccatgatattagagaggacagtgacaatgtcagca2640
tcccatatcagtcaacatactgaaagggggccaggtgggcatggcaacatacaaaaacac2700
aagccaaaggtgcccagcttgatctttgatttgtggttttatatgttggcatgcttcttg2760
ggtttgtgcctctcctcccgtgatgtttccttggggcaggctgtccgcatgtgcagtggc2820
ctgccagcccttgtgagggaccacatgcagtgtgttccctgaagttgttcacgtgcgcat2880
ttgagccgtttttcccttaccagttgagtggtcctagaagaaggttatatggcagttaaa2940
ctctgccattttgtctcttagtgtgcatgcttgagccccgcgcccaacttctgagatctt3000
a 3001
<210> 188
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26146-264 . polymorphic base C or A
<220>
<221> misc_binding
<222> 1502..1521
<223> 99-26146-264.misl., complement
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-26146-264.mis2 '
<220>
<221>
primer
bind
<222>
1746..1764
<223>
upstream
amplification
primer,
complement
<220>
<221>
primer
bind
<222>
1314..1334
<223>
downstream
amplification
primer
<220>
<221> _binding
misc
<222>
1489..1513
<223>
99-26146-264
probe
<400>
188
aatttcaatactatactctc aatattttaatcttccatttacctttttctttctttggaa60
accttacttttattaaagat tataataaaacaaaacacagagagtggctgattgggcatg120
gagtggccttatgttttgaa ataattacacgtggagccttctctggctttcagaatttct180
tctggttttgacagtaaagc atgtgccgatctagttaagtatatgtgatgcactcatggt240
gtgaccggcaaaggtatagc tgtacattctggaggagaaaattgttgtaggaatgattat300
ttcatgctgctcttcaccta tgttggctcagcaggtatccacacaaatgaagttaggtac360
caatgatcaagaggttctac atgagaaacgtggtatataaatgtatctatataccatttt420
gttatgaataattaatctgc tgatatcagaattggtaaagtcctcatagcatttcagttg480
tagctatttttattcatggt ttggaagactgcatatagttatatagctttatttcataca540
tcctcattagtagcatctat gcaaagaactatttttacaacattttaataaagaaaaaaa600
ggagctggatcaggaggagt gagtaaatctgggtttgaatcagaattctgctccttattg660
gacaggatatctttggcaag ccacttgaactcagtctcaggtttctcaactaaaaatggc720
tatattataaatatataggc acttaccactaatttcctaagtagttagataatggaagca780
atttgcaaccataaatgtaa gatatgaaaatactttatacttacttaacaccttactctg840
ctttagcatgttcatgtatg tgttgtcatttgattacacaaatttttagactaagcagga900
agaaacttttgctccaaagt tacttatttaaaaaaagtaagaaataagagaagttacaaa960
atagttaaaaaggtccgaag tgaataaaatattaatttgtgtgtttgttgaatgcctaaa1020
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
380
acaaatccaaatctatgggggcgttcacatgtacaaattaattttaatgaacactgtgaa1080
atcactattataggtaaaatgttagtgataaatataaatttattaatcatttcaaaattc1140
tcctttaaaatgagtgaactgagtcatagagaaatatagcaacttgttttctaatataaa1200
agtgaatgcctgtgaactaatatttactgagtttttgactattttttaagtcctacattc1260
aagcgaattctttattaatctacataattaacctcagaatatcactatattttcctattt1320
ttcatgcaagaaactacagatggtccccaacttaagatagttcaatttgggatttttttg1380
atattaaaataggtttactaaggtactaaatgcatttcaacttacaatagtttgaattta1440
tgatgtgtaattataaggaagtaatcccatcttaaggtgataagcatctgtagatgtaaa1500
mgatattaaataatgtagccaagataatgcctttataagtgaagttgatttcaaaacctg1560
ctttttggctcagatttgtttcataacacatcactgcattagttgtgtcataataaaaat1620
acacatactagtaacaaatcccaaataacaacttcggtctgaataagtcgagtattcatt1680
tcctcttaattgattcacttaaactcatttcctgggtagatattaaaatgtatgaaggat1740
ttttaggttttgatgggtgtaaaactgatgaaactcataaacacgtatattataaatact1800
ctaatatagataaacatagagtgagaaaagagaagcatatactgagtgctagtcaagaga1860
caaaatctcgattcatttataagtgaatagtgaggacttcaaggaaatatgctatataca1920
ttgcctttatattcccagcaaatggataaacatagaaagagtgatctgaaagtaatgtgt1980
attcagagacgctatggctaaccaataagtcacagataacggacgcaatgtcaagaaatg2040
agcttggaagacgcagcacactgtgaagggcattgagtgtgatgctgaagtatttaggtt2100
taattctggaatcaatgaggagttatcgaaggcatgggagagacgttcaagcaggaaaat2160
ggcatcatttcattattagaaaaaattacaaattgaattaaagctataaggaagttatat2220
caaatatggaaagtctaatagttttcaatgccaagattcattacaagactatgtaaagaa2280
aattctgtgctttttttttttttttgagacggagtctctctctgttccccaggctggagg2340
gcagtggcgccatctgggctcactgcaagctccgcctcctgggttcacgccattctcctg2400
cctcagcctcccgagtagctgggactacaggcgcccgccaccgcgcccgactaaattttt2460
ttttgtgtttttagtagagacggggtttcaccatgttaaccaggatggtctcgctctcct2520
gacctagtgatccgccggcctcggcctcccaaagtgctgggattacaggcgtgagccacc2580
acgcctggccagattctgtatttttatgttctgattaatatttacaaagtgaaaactcat2640
ttattttgtaaggtattgatgatcttctttctttatccataaattatatctttaggtatt2700
gtgagaagcaaatcaatattatccaaagcttattgtgccaacattttttagtgaagaggt2760
acagtacgtttttatttatactgaaacacattaaaatatgaaataacatctttaaacatt2820
ttttacttatatgtacatatatttatgagttatcaaattttctaagaaaaggaatttatc2880
attttgtagaaaggcttgctcatttttcaattgtgttctaggttaaaaaaaaaagaaaga2940
agagaaagtgtgtatctaaggtctatcttaatatttggtcatttttatactgtagtttct3000
t 3001
<210> 189
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26189-164 . polymorphic base C or A
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-26189-164.misl, complement
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-26189-164.mis2
<220>
<221> primer bind
<222> 1644..1664
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1215..1235
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> downstream amplification primer
381
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-26189-164 probe
<400>
189
tagcagaattaaatacaagctctcacatcaaatctctcaggatcaatataattacttgat60
ctaattgttttaagatgaagactattatattgtttgtttttctctgaatgtttttgtctt120
tcccaaaataccgattatgactttcattaatttttcttcatcatggatctgatattattt180
gaaaacaaatgtgtccaaaatcctttaaaatacagttgaagtgacattggttgcaaatgc240
atgctagtccacaaactcagttactgcaaacaaaatgcacattaatttttttttttagat300
taactaggcaccccagcacaaaaccttgtaaccatgcccttcaccttcatatcaaaggcc360
tatctcactctgacatgttctggccagtggatgcagggagatgggaagagcactgtatca920
aatggggctggcctgcacttgttccttttccttcccatgagagaaggccaggacaaagcc480
cctgaaggataaaacatatggagcagtgttaagttgcctcagttgtcacaatccatccca540
gacacaaagccagctgagtgacctcaccaaaaccagagatctacttaaccaagcccagcc600
taaatcactgatgtgtagacccgtgaaccaaataaatgaggattattaaagtcaatgtgt660
tctgtgatagcttctatacagcattataatgacactagataactaatacaaaaatacaca720
aagcatattttatgcatgtttaaagtaaaataaattttttaaaaaaactgcagtgactgt780
ggaaatcaaaacaaaaacataccttattctgtttggaaattaaccaaactttttcatcat840
tatagaaagtcacatcaacaatggcaatgttatccattattttaaagtgacagatgcaat900
ctgtctgcatcattctatattcaggatgccatatacatcattttaccggtaagcgtgcat960
gtgcaataatatatatgcagtcaatcttcattctttgcagattgcatatctgtgagtttt1020
tcttactaaagtttatttttatcccccaaatgaatactcacagtgctttcatagtcattc1080
acagatatgcttagagtgatagaaaatttgaatttttaagaagcatgtttgaatgaggct1140
gagttgaacaaggcaatgtcttctctccttgttacagctttcatgctgtaaacacttgtt1200
ctcctcatggtctagtgagtggcactttttttcagctttgtgtttttgtgagtaatttta1260
ctgtttaaagtggcccccaaatgtaacactaaagtgttgtatagtattctcaatcacaag1320
aaggctgtgatgtgccttatggggaaaaattcatatgttagagaagctttgttcacgtgt1380
gagttatagatagtgttcttggccatccgatattggatttcagggttaattataaacaat1440
ctattaatagcatatccagaaaagtagaaaagaaatgtatcaatttgcctgtgaggctgc1500
mccagaaagtgctaaagtgatccctggtgtgtgtaataatggtatggaaaaggtggacaa1560
aggaccaaatttatggattcatgagatgataactgacttttaaagatgcatttggcagca1620
tcattatgaagctggaggccaaaggagcttatggttacatgacccagcatcagaaaaatg1680
tgaaaccctgttcccagctagcactggctcacacacttcatagggtgatacagcatgaac1740
actttcagcttgcaggcaggcaaggtagtctctccagatcaggaggcagtggaagcattt1800
ttcaaatccctaataactgttatgtgaaagagcaggttttcaacactgatgagactggct1860
tgttttacaaggatgttgggaaacaaacctgtatgaaacaaatgcatttcagttaatgaa1920
aatgttgtggccagaggcttgcaggaccctaactctgtacttctcctaggagcaataatt1980
cagtattcactaattcagtattctcagaaactctatagaaaatacctaccatgaacaagg2040
aagactgcgtgtgctggggggcgggggtggcaggtgtgtttgtgtgtgggtgttaaatat2100
tgtttcacttctcatacccatcttattcattatgagcaactgtaaaactttatcaacttc2160
attacggctattagggttatcatgcctgaacattaaacatatgaatatgtatgcatatat2220
agacacttttaacatgaattactcttcttttttattttacagtaagtatacaattttact2280
aatttttagaaattacatgtgaagtagctatattaaatgtaagttttattgcagaattgt2340
aaagggaaccctatacaaaacaatttagttctcctaagattaaacaccactaaggtagat2400
cactcatgtagaaaaggaaggctagattctgtttaaatttttaaaagaatataaaattga2460
ttttactgagagaattagagaagtagagaaaaatttaaaaatcatgggtcaactgttgat2520
catttggaaattgcaagtttagatatcaaatgcatatcttacatcaaaatgaagtcctca2580
tgaaatagatacacatgtgaaatctgaaataataaaataagaagggattttaaatatgtg2640
ttttggaaagacaaaattacctgagaaactgtaaagacaaacaataattatacaaaaatt2700
gtaacactttgtgtaaaaaattacataaaactgaaagataaaatgggaagtgataggatt2760
tttgctgattaaattgataaagactaggttgagtgttgaggacaagtatcagtaactctg2820
taagagatgtgtggtcatatgatggtacatttttataacttttccgaaaaagcagttggt2880
catgtatcatacctcaaaatccctaaaattcttgacctagtgattttacatttaggcatg2940
tatcaaaagtatacaaacatatatacataagtacataaatgtatgcatatatatacacat3000
a 3001
<210> 190
<211> 2997
<212> DNA
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<213> Homo Sapiens
382
<220>
<221> allele
<222> 1501
<223> 99-26190-20 : polymorphic base C or A
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-26190-20.misl, complement
<220>
<221> misc_binding
<222> 1482..1500
<223> 99-26190-20.mis2
<220>
<221> primer bind
<222> 1502..1520
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1071..1091
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-26190-20 probe
<400>
190
gaagatacttgttacacattgggaagcagtacagtgttgcccttctgagccagggcctgt60
gataagtctgtgtttaaatgccagctttaacccttgccagctgagctccccagtgtttgt120
tacttagcatcccctgttcagaggcagccactgcatctacctaagtctgtgctgcaacaa180
gacctccaaagtccaaagtactgcagaaagcttttaatttgcgtcatttattcccaggtc240
attcgtagtggccctctatcatgcttacctagactctcaaaaacccaagtcacaaatcac300
tgtatatgtcatctgttggaaaattctgaatcccccatctccctcctccaggcaaaagtt360
attttggcttcacatctcgtctgtataacaaaagcttgtcataaaacgtatgttctactg420
cctattctaggtgacccacaaacagttatttaaaatttaattattcatcctttcccttct480
tatgtcttcaggggaatgataaaaatattcaggcaaagatctgtggataggtgaggtgtc540
acctttaaccagggtagcagaattaaatacaagctctcacatcaaatctctcaggatcaa600
tataattacttgatctaattgttttaagatgaagactattatattgtttgtttttctctg660
aatgtttttgtctttcccaaaataccgattatgactttcattaatttttcttcatcatgg720
atctgatattatttgaaaacaaatgtgtccaaaatcctttaaaatacagttgaagtgaca780
ttggttgcaaatgcatgctagtccacaaactcagttactgcaaacaaaatgcacattaat840
ttttttttttagattaactaggcaccccagcacaaaaccttgtaaccatgcccttcacct900
tcatatcaaaggcctatctcactctgacatgttctggccagtggatgcagggagatggga960
agagcactgtatcaaatggggctggcctgcacttgttccttttccttcccatgagagaag1020
gccaggacaaagcccctgaaggataaaacatatggagcagtgttaagttgcctcagttgt1080
cacaatccatcccagacacaaagccagctgagtgacctcaccaaaaccagagatctactt1140
aaccaagcccagcctaaatcactgatgtgtagacccgtgaaccaaataaatgaggattat1200
taaagtcaatgtgttctgtgatagcttctatacagcattataatgacactagataactaa1260
tacaaaaatacacaaagcatattttatgcatgtttaaagtaaaataaattttttaaaaaa1320
actgcagtgactgtggaaatcaaaacaaaaacataccttattctgtttggaaattaacca1380
aactttttcatcattatagaaagtcacatcaacaatggcaatgttatccattattttaaa1440
gtgacagatgcaatctgtctgcatcattctatattcaggatgccatatacatcattttac1500
mggtaagcgtgcatgtgcaataatatatatgcagtcaatcttcattctttgcagattgca1560
tatctgtgagtttttcttactaaagtttatttttatcccccaaatgaatactcacagtgc1620
tttcatagtcattcacagatatgcttagagtgatagaaaatttgaatttttaagaagcat1680
gtttgaatgaggctgagttgaacaaggcaatgtcttctctccttgttacagctttcatgc1740
tgtaaacacttgttctcctcatggtctagtgagtggcactttttttcagctttgtgtttt1800
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
383
tgtgagtaattttactgtttaaagtggcccccaaatgtaacactaaagtg ttgtatagta1860
ttctcaatcacaagaaggctgtgatgtgccttatggggaaaaattcatat gttagagaag1920
ctttgttcacgtgtgagttatagatagtgttcttggccatccgatattgg atttcagggt1980
taattataaacaatctattaatagcatatccagaaaagtagaaaagaaat gtatcaattt2040
gcctgtgaggctgcaccagaaagtgctaaagtgatccctggtgtgtgtaa taatggtatg2100
gaaaaggtggacaaaggaccaaatttatggattcatgagatgataactga cttttaaaga2160
tgcatttggcagcatcattatgaagctggaggccaaaggagcttatggtt acatgaccca2220
gcatcagaaaaatgtgaaaccctgttcccagctagcactggctcacacac ttcatagggt2280
gatacagcatgaacactttcagcttgcaggcaggcaaggtagtctctcca gatcaggagg2340
cagtggaagcatttttcaaatccctaataactgttatgtgaaagagcagg ttttcaacac2400
tgatgagactggcttgttttacaaggatgttgggaaacaaacctgtatga aacaaatgca2460
tttcagttaatgaaaatgttgtggccagaggcttgcaggaccctaactct gtacttctcc2520
taggagcaataattcagtattcactaattcagtattctcagaaactctat agaaaatacc2580
taccatgaacaaggaagactgcgtgtgctggggggcgggggtggcaggtg tgtttgtgtg2640
tgggtgttaaatattgtttcacttctcatacccatcttattcattatgag caactgtaaa2700
actttatcaacttcattacggctattagggttatcatgcctgaacattaa acatatgaat2760
atgtatgcatatatagacacttttaacatgaattactcttcttttttatt ttacagtaag2820
tatacaattttactaatttttagaaattacatgtgaagtagctatattaa atgtaagttt2880
tattgcagaattgtaaagggaaccctatacaaaacaatttagttctccta agattaaaca2940
ccactaaggtagatcactcatgtagaaaaggaaggctagattctgtttaa attttta 2997
<210>
191
<211>
3001
<212>
DNA
<213> Sapiens
Homo
<220>
<221>
allele
<222>
1501
<223>
99-26191-58
: polymorphic
base
G or
A
<220>
<221> binding
misc
_
<222>
1502
.1520
<223>
99-26191-58.misl,
complement
<220>
<221> binding
misc
_
<222>
1481
.1500
<223>
99-26191-58.mis2,
<220>
<221>
primer
bind
<222>
1539..1558
<223> cation
upstream primer,
amplifi complement
<220>
<221>
primer
bind
<222>
1095..1115
<223>
downstream
amplification
primer
<220>
<221> binding
misc_
<222>
1489..1513
<223>
99-26191-58
probe
<400>
191
tcagctctgtcttgcagtctgcacataggtcgcatagcctaagtgtcata actgaatgta60
tcacatttgaacagccggccattaggcagtgcattacacaaagccgttcc agtaaaagct120
ctgagaatggctcgatcttggagaggccagacctatgcaaacagagccct tgagatccat180
tttcttgaacttcctttgtttgtattctctgatgtttgcagatgctatgt gtgtcttttg240
attgattctatttggttgcttcaatgagtacacccagtgggctttgttcc ctgtgagtta300
aaatagcaaatgaccatgatgaaatatttccacctgcacataaagatctt atcatatgtt360
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
384
acagccagcttcatcacgtttaaaactggtggattttctgagagtcgttaactattaaca420
aaacgttctttaaaatcctctacaaagttcacagatataaaatatctctcatcagatagc480
tataaatatcatttgccccatcagaaaaagcaatcttccatctcttgcgttcaatcatct540
agatgcatcaaatataaatgttttcaattaacgagtttctgaataattgcctcatgtcta600
catgtattttttatgttgttgaatggtccatgtggtatatgacacatttctaaaaactga660
cctggctattgctaacttttaaattttaaatgtagacttaaacaatttgaacaacaatgg720
gtatgtgtatctgcttattccaagaggagatttctctgtgattcaaattatgctgggtaa780
gaacagagttcagagtttcatttcattgattttatttgctatgaccattctcctccaccc840
tttttgcccagttctatcaagttcttcattgcactgcttcttgatctaaaaccacttaag900
aattttagctttttttctcccattgagacattttctaaagtctgatgattaaactttcct960
ccatttggttcccaataacttccctaaatatcattataactttttttcctgtagaagttt1020
atttcataagttctctttttagtggtagttgaatgaacaggcacaatgacatccgaaatg1080
tcctaatttacaagatgtgttgtgatattggctggaaaaaaaatgccaagcatgcagcac1140
ctacacagatactacaccaaagagaaaactgagtaagttcatacgtttgtgcaaaacaaa1200
attatacggataaaatataaatgaccaaagcaactgatttgccattttgtacttgctaaa1260
ttagcaaaaatataaaatatatataggtttcaaacccaagactcccacgtactgttggtt1320
gaaattaaaatgaggagagagactttttagaaatgaatttgattaaactttcaaaaagtc1380
tcagaattgttcaaatcttttgacccacttacttcatttctgggaattatataaataatc1440
tcaagtattacaatactgataggcatgacaaccttcattgcaaagtgattgatagaagct1500
rtattagaaacaaaacttaatacaagtatccaaaatgtccataatgagaagatacttgtt1560
acacattgggaagcagtacagtgttgcccttctgagccagggcctgtgataagtctgtgt1620
ttaaatgccagctttaacccttgccagctgagctccccagtgtttgttacttagcatccc1680
ctgttcagaggcagccactgcatctacctaagtctgtgctgcaacaagacctccaaagtc1740
caaagtactgcagaaagcttttaatttgcgtcatttattcccaggtcattcgtagtggcc1800
ctctatcatgcttacctagactctcaaaaacccaagtcacaaatcactgtatatgtcatc1860
tgttggaaaattctgaatcccccatctccctcctccaggcaaaagttattttggcttcac1920
atctcgtctgtataacaaaagcttgtcataaaacgtatgttctactgcctattctaggtg1980
acccacaaacagttatttaaaatttaattattcatcctttcccttcttatgtcttcaggg2040
gaatgataaaaatattcaggcaaagatctgtggataggtgaggtgtcacctttaaccagg2100
gtagcagaattaaatacaagctctcacatcaaatctctcaggatcaatataattacttga2160
tctaattgttttaagatgaagactattatattgtttgtttttctctgaatgtttttgtct2220
ttcccaaaataccgattatgactttcattaatttttcttcatcatggatctgatattatt2280
tgaaaacaaatgtgtccaaaatcctttaaaatacagttgaagtgacattggttgcaaatg2340
catgctagtccacaaactcagttactgcaaacaaaatgcacattaatttttttttttaga2400
ttaactaggcaccccagcacaaaaccttgtaaccatgcccttcaccttcatatcaaaggc2460
ctatctcactctgacatgttctggccagtggatgcagggagatgggaagagcactgtatc2520
aaatggggctggcctgcacttgttccttttccttcccatgagagaaggccaggacaaagc2580
ccctgaaggataaaacatatggagcagtgttaagttgcctcagttgtcacaatccatccc2640
agacacaaagccagctgagtgacctcaccaaaaccagagatctacttaaccaagcccagc2700
ctaaatcactgatgtgtagacccgtgaaccaaataaatgaggattattaaagtcaatgtg2760
ttctgtgatagcttctatacagcattataatgacactagataactaatacaaaaatacac2820
aaagcatattttatgcatgtttaaagtaaaataaattttttaaaaaaactgcagtgactg2880
tggaaatcaaaacaaaaacataccttattctgtttggaaattaaccaaactttttcatca2940
ttatagaaagtcacatcaacaatggcaatgttatccattattttaaagtgacagatgcaa3000
t 3001
<210> 192
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26201-267 : polymorphic base C or G
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-26201-267.misl, complement
<220>
<221> misc binding
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 1481..1500
<223> 99-26201-267.mis2,
385
<220>
<221> primer bind
<222> 1749..1767
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1304..1324
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-26201-267 probe
<400>
192
tttcaaaattggggaggcatgtttcaaaattggggaggctgaattaaaagaactgggcta60
acatttgataggacaatcaactgtgcaattttatgaactgagaaagtgtactgacacaag120
aaaatgttatgaaaacagcagagttaggaagggcataagttctttttatactcagaatct180
atgattttatggattccaaagaggaaagctgaatgcatagtggagcagtattagggttct240
ccagagaaaaagaaccagtagcattaatggatagatagatacagtatatatataaaatat300
atatgtgtatatatattatatatacgtatacaatacatagtatatataatatatagtata360
tatagtatatacatactatatataatacactatatattactatatatagtatatattata420
tatagtatatataatatatagtgttatatatatgatatatactatatatatcatatatag480
tgcacacacacacacacaaacggagagaggttattttaaggaattggtttatgtggttgt540
gtggctggcaagtctaaaatttgcgaagtagaccagcaggatggcaatccaggggagatt600
aggtgttgctgtgtgagttcaagggcagtctggaggcagaattccctcttccttggggga660
tgtcagtctttcgccttaggacttcagctgattggatgaagcccattcatgctttggagg720
ataaactgtttatttaaagtctactgatttaagtgttaatctcggggaaaaaaaaaaggt780
ttactgcaacattcagttgtgtttatccaaatatttgtatatggtggcctagccaagttg840
acacagaaaactagccaccacgggcactgtattggaaaacttgagagaaaacagtagtca900
cagtttttgcttttaaagatgagtatgaacagtagatggaaggagaatcagccaagtaag960
ccttttgcaatagaaagatacaaactccaataaaacacctgaagtaacataaaaataagg1020
caaatgcccaaaagataaaaatggaaaagaagctacaaaaagagtatttggttggcattc1080
tctgactattctcaggatatttgaagaatcaaaggttctggaataaggaatagagaaaaa1140
aatctttaatcgaaaagggagactgaactggtcactagattttatggtgtaaaataatat1200
tctagtctctagaaggaaaatctgccaactagacagggagaaggcaagggaatttgtctg1260
ttctgctctagacagtagtgaaaatgacataaaataaagtaactctctcaaaaaatgtat1320
gaccagagacttacctttggaacagtaattcacatcatctgagtagttcaggaagtttta1380
catagagaaattagcataaaatgtataacatatgatatccctgacataaattaacacagc1440
atctctccagcgataggtcctcagtacagggtagagagaaatctcaaggataaaaactca1500
saaagcataagcctccatccaatactacaaatacatgagggggaaatacccactctcaga1560
gaaaatcagtgaaaaataaaaataaagtttggccctcattaaaattagaaaaggagggtt1620
ttttaaaatattaaatataaaagtaagtgtgcctaaaataaatcaatatataaatgttgg1680
aataaaaatatgttattaataaaaaatataagacaatgtagacaaacacttaataagata1740
atagtaaagccactaagagaaattctgggaggcaaaaaaaaaaatattctcacatattaa1800
gacaataaaacttgttaagtcagaaaatgtttgtgaaggtatattgtttaggagcaaaac1860
agaaattttaaccaccttctctaactataatgatattattacaagcagtaagatataact1920
aaatatatcttatataattgaaattttaaatacataccatgatgggtcaatgaagatatt1980
ttaatacatatttatttaaaaatattttgtattgaacaaaaattatattgaaaagtttag2040
tttagttattcatataaggtgctacagagatcaaaatttctaggaaaaatgcttataatc2100
caaaggaagaaatgaacttatgttttaggttaagaagttctcacagagaacagattcact2160
aaaaaaaggtagacagaaagaaataataaagatgtgtcaaaattaataatattaatataa2220
ataaaattgaaaaatacagacggtcccttgaccattgaagaaatgaaaacttaactgaaa2280
aaggtacacataagattcatcacactcatgtctcattttatgggctaaaagtttcttcat2340
tccaaaatctgacaaggacagaacaagaaagaaaaattatactcctatctcattaagagt2400
cactagccctatatataatattatcaagccaatcttgaattatatgttagaaaacatatg2460
attaggctgaattaaatcactggagagtgaggatggctgacccttagaaatccatgaaag2520
taacctaccacattaagtaattcacataagaaaataaaagattatctttaaaatgctgct2580
atggtctgaaagtttgtaatcccttgaaattcatattttgaaatcctaacctacaaggtg2640
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
386
atggtgtaag gaggtggaag atttgggagg tgattagttc ataaggatag agccctcatg 2700
atgggcatag tacccttata aaagaggtcc cagagatctt cctcacatct cccaccagag 2760
tgcacacagc aaaatggcac catttgtgaa ccaggaaatg ggccctcacc aggcacaatg 2820
cagcttgatc ttgaactttc caggctccaa aactgtgaga aacaaatttc tgctgttaat 2880
aagccaagca ggttatggta ttttgttata gcagcttgaa cagactaaga cagatgcaaa 2940
aaaagatctg atgaaatgtc ctcactcatt cacataaaaa aaactacttt cagaaaataa 3000
g 3001
<210> 193
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26222-149 : polymorphic base A or G
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-26222-149.misl,
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-26222-149.mis2, complement
<220>
<221> primer bind
<222> 1354..1373
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1843..1863
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26222-149 probe
<220>
<221> misc_feature
<222> 2564
<223> n=a, g, c or t
<400> 193
cttctaggct tcagactctg cccaaagtac aagtcttaga cagaccaagt taccctttag 60
catctgagtt gtcctatcag taaagtgagg acaactgtat ttctcaagaa ggatctggtt 120
tcaatggaca acaagcccaa ttcaaacttg cacaagaaca ggggaattca ttgtgtcttg 180
tgaaataatg ttcaagagaa tacctggaga aacttgaccc aggaactttc cttgtcagca 240
gggactggca tttctccatc tcagctctgt tcacatctat gtgagcccca ccttaatgta 300
gtgatattta tggagcagac ctctggatct ccaggatgac atcctcaccc tcaagcccaa 360
tagaaaagga agagacattg ttctctaagt gtatcaatac aagttttggg gtggatccca 420
ttggcgtaaa tgggattagt tacacatccc tgcaccaatc cccttggctg gtagactggg 480
gtttacagat tgacttaaac tatagccacc ttcaacaata tggttgagtt actctttatt 540
acataaagag tgaactaagg aactatctac tttaaaaaaa aaatagggca ttaccatgaa 600
acaaatgagg aacaaatact tgacaataaa gttgcaaatg tccggtatca gaaaataaaa 660
actgcctatt aagtcagaac ctcatatatt ctgtcatact ctcttggctt accctctccc 720
cacctttttt tttccctcta gccattgctg gctggggcaa ccaggatgca aaggcactgt 780
ctgacagctc ttgcctcagt tcagggactg cagtagataa gctatgtgtc attccaatcc 840
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
387
tgcttaggagaagaatcactgcccatgtgcaagagctgtagttagctggcagactccatc900
tgctaattctttccaggtccacttcagccttttggccagtcactttttaatttaatttta960
tttatttattattttttttgagatggagtcttgttctgtcacccaggctggagtgcagtg1020
gcacgatctcggctcactgcaacctccacttcccaggctcaagcaattctcctgcctcag1080
cctcccaagtagctggaactacaggcgtgcggcagcatcacgtccagttaatttttttgt1140
atttttagtagagatggggtttcaccatgttggccaggatggtctcgatctcttgaccac1200
gtgatccacccgcctcagctctcaaagtgttgggattacaggcatgagccactgcgccct1260
ggccagtcacatttttagccttgtgtcctgctcaatgattgggcaaggtagtgctgtcca1320
ggtcacttttttttgagtcgttaatagcaagatggtaacgtaacaacctagtcatttctg1380
ccctaatgagcacgctggctcagaagtccagggactcctcagtctgacagcctgtcttgg1440
ctaacttccatttcccttcttttaccccatttatgttattccttaacaaatccttcacat1500
rcacaatgccctccccgtgtctgtttcccaaacagctcaccttgaacagagattttctgc1560
tccatattggaagatatacaagagcccacccaatcatttcagtaagtgcacacccggaaa1620
tgcaagagagtcaacaatggctgtggtcagtgatggatggaagttgttaaaggcattctt1680
tcctgctttgtgtctccgatggacaacttggaggtgtattccacatgggttctcaaaggg1740
ttcacagtttgatatttagttgcacaaaaaataatcagcctactctttctggtacttcaa1800
cttctgtttccagtgaaagcatgcagatgctagtctctagctcagctcttggaggagatc1860
caaattaaaattctggctgatccagttacatagtttgtggggccaatggcaaaataaaat1920
gcaggttcccttgctcaaaaaaaattcataatttaaagacagcaacagcatgccattaaa1980
ccaaaaagcccttctagtgcccaagcacaggtcaccccctgtgaagctagccccaaacaa2040
catataaggtaatatgaatacattgaggcatatagacttttgatctgtattttctctcga2100
tgtctacataccatgtcattgctcaggaagcagtaaactggggaaatactgacctaccct2160
tataggattataagcatattataaatgtgcttcatagggaatctatcttcaaagtaaatt2220
taagctgtgaatgtgattagtttagttttattaaaatatattggaatattggactatgta2280
caatatttaccttttcactttttgtgtagtaaggtaaggggaatacttttaggacaaatg2340
cttccgctctttttgtgagcctactatgtgacacttctttgtagctgaaacactgcaaga2400
agctgaggagttctgtctagtcatgttttattttgcctttggaaattgggaggctggttg2460
gagcagggttgcgggcaatagagaaggggaggttagcagaaaggtaaactctagatggct2520
gctatgaagccgaggaaagggaacaagtcagcaatgaagctgantcctgactctgaggat2580
ccagctaggtgggagcacatgtaatttgaaacacttggcatacttaagctggatttaatg2640
cctttgcttgtgtggttgtttgcttgcttgtcattgctcaacttctatgttgataagcag2700
agaatatggatgcttccacacattcatgtatttgatctactttggaaggtacagtgaaat2760
aacacaaatttaggatgattttatgaggcatctagggtatatcaatgagatatctgccct2820
cttatgtttgttgcagcactgtttacaatagctaagatttggaagcaacctaagtgtcca2880
tcatcagataatggataaagaaaatatgattcatatacacaatggagtagtattcagcca2940
taaaaaagaatgagattcagtcatttgcaacatggttggaactggagagcattatgttaa3000
g 3001
<210> 194
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26223-225 : polymorphic base G or T
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-26223-225.misl,
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-26223-225.mis2, complement
<220>
<221> primer bind
<222> 1277..1297
<223> upstream amplification primer
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
388
<220>
<221> primer bind
<222> 1842..1862
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1989 .1513
<223> 99-26223-225 probe
<400>
194
cacatttttgtagcatcttttctgtgtgtatgtgtgtgtgtgtgtgcgcgcgtgagtgtg60
catgtgtgtgtgtgtacacgcgtgtttaatttctattcatgggaattatcaatttctttt120
actatatctctggcttggtcccacatatttcaatctttagctgttatgtaaataagatac180
tacaataagtattcaaattaaaatgtagcatatgggtaaacaggtgtaatattttaacag240
agtttgagaatttagaaaaatattttacagagccatcccctgcatattgtataatttacc300
ctgaaaaatatagaaattagtagagtggtacttgctaattttctctttgaagatgtataa360
agctggcattttccccttctgttcccagaaattattgaaaagcaacaaggagaactacaa420
ccaaaataccaggttttattttttgaatgaaactaggagaaaattagagcctccatctaa480
gaacaagtgcgtaatattccagaatgagtgaagagtccagagaaccttgtggaaggtatc540
agagatgtcttcagagaaagactcaaatagtagtcatcaaaaaagatccagtcaaataca600
aatctgaagtgcaaaatccaaaccatgtatttacaacagagagaaaggactagatgaact660
gatggcaacagccgttaaaatcctgtttagtttcagaaagagactttgcatatccaatta720
ggaattacagagaaaaattcatattcacgaatatattctatctctatggagggggagaaa780
tgttttgcattgaaaataacaacagaaattgtaaaataaaaacgattcatacagatgtca840
ctctcacttggttagaaaaaagcaaagaaatgcaaatttactcctaaactttgaaccata900
aaaacattccaggcaatcaagaacacttccctgcctctacttccagagacagaaggagag960
acagagagagagagtgagagacagaaatgtgaggagaagaaacatgtagatacacctaat1020
cctgcaaaaactcacctgcataaagttaagaaaacaaaacaaggaaattacctattaatc1080
attaatctgaacttaactgcctttggattccaagcacaatacagtagctgattggagcct1140
aatgttctactccaataagagactgggacatctgcctaaaaaaactggaaaagatagaat1200
'
agacaatgatatacagtctttgaaatgcagcaaaaaacttcatagacaagggaagtagag1260
gagctaagaatctggagaggtgaagaatgttgttaagaatctggagaggcgaagaatgtt1320
gttcaggttagtgacctgcagaacttttcccagggacggttttatcatgggagagaggat1380
gcagtggagaatcagagcttacagccatttagaaaagcaaacgaacaaacaacaacaata1440
agcaaaacaaaacaaaaaacaaacaacaacaacaaaaaacagaactttgccagagacctg1500
kgggcttccaacacctggccggtttaactctgggacactgaccaaaccccagaaggacag1560
tttggtgttgtacaccctgccctatgggcaggtactaaccaaaaaagcagaaagcttttg1620
aaacactgactggagattttctgcactctggggaggcaatggttggaagtgcctgaggta1680
agaggcctgcagaatatgtaagattctctcagataaaagtcctggagggttagggacaaa1740
ccacaggtagatagtatgagatcaacctcactccacatacccctccaaaagaaagtgaaa1800
aaaggaagttaaaagttgcataatcttggtgaaaggctttacacaactttcacacacgtc1860
gatattacaaaaaacatatacatgtggtaattgtttctctgtttctgcattaatttgatt1920
agaataatggcctctcgctgcatccatgtttcagcaaaggacatgatttcatgcttttta1980
tggcggcatagtactccatgatgtatgtgtgccactttttctttaattcactgttaatgg2040
gcacctagctctcactgagtggaagttaaacattgagtatacatgtgcatcagatagcac2100
cagcagacactatgaactactagaggagggaaggagacagggggtcatgatctgaaaaac2160
tatctattggctactatgctcactgcctggatgacaggatcatccatatgccaaacctta2220
gcatcatgcaatacatctatgtaataaacctgcaaatgtaccccctgaatctaaaataaa2280
agtagaaaatttttaacaaagttaagcattatgaatatatgtaaagacttgaggccgggc2340
atggtggctcatgcctgtaatcccagcactttgggaggctgaggcgggtggatcactcaa2400
ggacaggagttcaagaccagccttgccaaaaagacaaaatcccaactctactaaaaccta2460
catgctgtcgtcatggtgcatgcctgtaatcccatctactcaggaggctgaggcagaaga2520
atcacttgaaccgaggaagtggaggtttcagtgagccgaggtcatgccactgcactccag2580
catgggtgacagagtgagactccgtcaaaacaaaaacaaaaacaaacaaacaaacaaaag2640
actttatatatatatatatataaaatatataaggatagatagaaaaaatagaaataaaat2700
ctgtcagaaaggaaaaattttattatagacactttagtcattaaaatgataaaaaatatt2760
atgaataattttatgctaaaaagtgacaatttgaacttgaccaatttctcaaaatataac2820
tttcatttaaaatgtcacaaaaacaaacagagagtatgatgacttctaaatgtactttaa2880
aattttaaaccaaaaagccagttgcacaaaaacagaccctgtatgacttgatttatatga2940
acgatttgaaatagtgaaactcatggaaatagaatgtggaagggtagttgccagaggccg3000
t 3001
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
389
<210>
195
<211>
3001
<212>
DNA
<213> Sapiens
Homo
<220>
<221>
allele
<222>
1501
<223> base G
99-26225-148 or T
: polymorphic
<220>
<221> binding
misc
_
<222>
1981
.1500
<223>
99-26225-148.misl,
<220>
<221> binding
misc_
<222>
1502..1520
<223>
99-26225-148.mis2,
complement
<220>
<221>
primer
bind
<222>
1355..1375
<223>
upstream
amplification
primer
<220>
<221>
primer
bind
<222>
1805..1825
<223> ement
downstream
amplification
primer,
compl
<220>
<221> binding
misc_
<222>
1489..1513
<223>
99-26225-148
probe
<220>
<221> feature
misc_
<222>
37,514,2455
<223> g, c or
n=a, t
<400>
195
gagaatcaatatgagaataaacaatacctctaatccnttttgcaatcact ctatcatttt60
aggcttaaaatacagcataatttttttttctcatttattttcctccttaa taaaatcttg120
atggctcaagcaatgtgttatataaccttggaaacagattttttttaaaa aagctatcct180
cagtctaacttctatctacaggcaaaatcatcactaactcttcctacagt tttttactat240
tcttcttttttttccaataaaataaactttagaagttcttttaatgtatg cttctatttc300
agatgttctgattagttacaatggcatttgccaacataatttgccaaatt gaaaaacaga360
tacctgatcacaagtgagatatttggtaatctaaatgttgagaatgggaa aactttgtta420
ttgcaaatatttcaaatatacatcggataaggtaaaggtaattgtaaaca acttacataa480
tactaacatttctcaggagaaatgtgtgcatacncttttatcaggtatga ggtgtagagc540
aaagcattgatttatggatttaaaaagtttgtatatttcatgaattctac tttttatcaa600
attacaagtgatggagtgatggattaaaaactgtttttatttattggcag tacaggtgtt660
tatgcaacctaagtgttattttgttttattatgtgagtgtaatacacgaa aatatgggat720
aggttttcaagataattagtattattgattatttcaaaatatgtaatatg attaacaata780
tctatagtatataagcccttcctcacaaacgtaaagaataagtatataat tttatttgac840
attaaaaaaagaattttattggtttatctctgctgaaattcttggaattc ttgtaaataa900
aatgtgcattttgccaattttttaaatctcaatttttgcttttttattga ttattgattt960
tagaaaacaacatagggttgtttgtgtcatagttgttgttgggaattatt aattggattt1020
aattaatctttgcctgctctattcagatataataaattctggagaattta agttaacact1080
aattttaaaatctttatttaccaataacatcttgctatgacatgactaaa gagaaaattt1140
gttggagacacagaatctccactacagccaattattgcctctaagatttt aagtgtgagg1200
tgtgtgtatgcatgcaaatgagctcatgtgagtgtacatgtttaggggaa ggagcaagac1260
aggaagagatacattttatgaaaacaaatctataggtttagtgggtatat ggttcagcga1320
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
390
gtttctatttttactgtaaattgtggaaaggaacctctaatatcaataaagcctcaaaca1380
tgtttgctgattctaggacatattgtcaatcacgcactcacaggagaattttccatctac1440
ctgaaataatttaaatttatcttatatttctctttgatgagaatcatacaaaatggaatt1500
katctgaattcttgtgtttgcagagcacaacatatagcagaactattaaaaaaaatcaag1560
tacatttgtaatagttgaaatacaaaagaagttggccaagatatccccaaatatgctaaa1620
aagtcctctaattgtgatgctgaaagaaacttttctaaactatcaaaaatgaaatgcaaa1680
ttgtagttagtagggctaaaaaaattactaaattacctttttcttatctctacaaaaaac1740
attacaaataatattttgtcgtatgaagtgtgatcaaagtatatgtaactaaaaactaag1800
gaatcatttatagtttatcaggcagtcaattaataaaaacatgctatttttctagatttt1860
gtaatttgaagtagtttccatcattaattatttattgtgcgttttctctttctgatcatg1920
cttacccatttttattaatgaatttgtgtcaactttcttaaaaagaaccccaaaatgcat1980
aaacggcaaacatcgtatttctgatctgcacctgtatatgttctttgatattatctcttt2040
ctctgtttctcttttattttttatttttggaagcagggaagaggttattttgatgatttc2100
ttttccaaaaatagaattgtgaaattataagattcatgtaactctaaaaaatttcagctt2160
attacagtgaatctttttaaaaaataaaaaaaaaaattaaacaagcattgacatcattaa2220
agatcattaaacaaaaaacccaataatacaaagtcacattggcatgcccaaaaaagaata2280
aaatacagtttttggaaacacgataacaaagtaactgaaataaactaatttaaaacaata2340
attgattaaatatcacaaaagataagttaaacgttatttcaaattaaggttttatgaaaa2400
gaagcaatgtcagtaataggcaataaatttctttttctttttttttttttttttngagac2460
ggagtctcgctttgtcgcccaggctggagtgcactggtgtgatctcgactcactgcaacc2520
tccacttgggttcaagggattctcctgtctcagcctcccaagtagctgggactacaggca2580
agtgccaccacgcccggctaattttttgtgtttttagtaaagacagggtttcaccgtgtt2640
agtcaggatggtctcgctctcctgtccttgtgattcgcccgcgtcgaactcccaaagtcc2700
tgggattacaggcatgagccaccacgcacagcttaggtaataaatttcaagtaaaattca2760
attcatcaaaaaattgcaaatacattttaaagtacatcttatcatgtaaggataaaaaca2820
taatcctagaaaagataccaacatttttacagtaaggcatatccatgtgtgtataatagc2880
atacactatctttcgtaaaacctcacattaaatttaatataaccaaattctcatgcattt2940
tgaattttttattataaggtaaataatattcttgacttctctaatataaattcattaaat3000
t 3001
<210> 196
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26228-172 : polymorphic base G or C
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-26228-172.mis1
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-26228-172.mis2, complement
<220>
<221> primer bind
<222> 1330..1350
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1792..1812
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> 99-26228-172 probe
391
<400> 196
atcgttgttcataggcaggctcttttaagaacataaagatcaaccatcatggaaatttaa60
taactattatactcaattgctgaaacacaccttttcctcccttgatctatagttagcatt120
ccttcaataattttttttaattcatggaattcaaaaacttcaatgatttttttctactgg180
gctgtctaattttaacatggtaagtacttggtaaagttcaatacctttccccttataagt240
ttttcttctaagcaagctaa.ctgattttagaataggagatgttaacaccataaatacatt300
tgtcaggattaggttttcacattgctttggggatattggaacactttcttaatcaccctt360
taggttttgtttgaggctctatttcaggattcacagaaaggccttggtttgtggttgaat420
gacatgacgaggcatttactgtcacaaatataatagcagttataagtaaattgatatcca480
ggtaaaaaacagtgtatttttccaaatctgtcaacattatattttgttatgaagagaata540
acgaaaagaaatggaatctttgaaaaataacctttgatagataacttaatgtccttgagt600
ttaaatttactctctttttaaaaagatgggagtatatacaatattactctaacgtttctt660
tagacatcagaattggatgttggtttgagtaaagatattctatttgtgtgttttcctctc720
tccttcttttctatataataaatgcctattttgctaatgtgtttaattacataaatggtt780
tttctgattccgtttggcagaaagggttgatttcgataagtattttattattaatattat840
tcataataatcaattttagctgattactttttatgtctaaacaattgttcaagtgtcaat900
taaggatccatagagcacagaatagacataatcatcattgtgtcatttggtgtataaaca960
attagatgaatctgatctctaaattcaacaagtgggaaagtattatatcaaataaactgc1020
aaataaaaattacgtgacagatgtgatttatgcacaaaggatttgggagataacaaattt1080
ttaaaattgtctacaactgatgctatattccataaaaacatgttatttgtggtatttttt1140
aatctattatagatttttttctaacttttgttttgacattcaattttgaagctattcatt1200
tccactcaaaaatacaggccatccacctacagtgctaagttactatttagtacaatgcct1260
tataaacttgacatcttcttatactttctgaacttctatggttcagtggaaaaaagaagc1320
attgcactaggttatttcagacattgttagtctgacataatataggaagtatttttgtgc1380
tacacttttatcctggcgtaaaatgtggcataatttttaggttcaagagctgttttactc1440
ctattcaaaactttcttccagtgacctaaccaaaatagtatgtattaaaagcatgtataa1500
sctactacttttctatgaacaatagccttacaatctgtttgccttgcataaaacacatac1560
atatgtgcacacctatgcaccataagctgtggatcctttgtgtgaagaagacacctgtcc1620
accatggagaagtcccacttcccaggttttacatctccaaccccagagttcaaagccagc1680
tattcttcaatgattggaatagtttgctaaaaattaaaagtgaaatacgcaattgcaaat1740
aaatatgaaatgttttgctttctttaaatgtgcaccttttaaattttatctcttggatgt1800
attaacacactaatatgagttggcttttcaaagtatttattgtctaaaacatggtttctc1860
aaactttcatgataacaaagttttatgaaaattttttagatttttaaatgaaacgttaga1920
tatccctgcaaatgtgctaacacttgaatgaaatgaacccaggtttgcattttggttcta1980
aattttagttgcaagcaatttacttaacgtcgttaatcactagtcttttcctaaggaaag2040
gggaactgatagactttatctttttcagccgatgtagacattaaattaattaatacatgt2100
aaattgtttaacatagtttcttccacagagtaattgattagtacaataagaaattattat2160
tattaatctagcttatttttattacatttgaaacaacaatatctgaaagacttgcccata2220
tcttttcaggattcagtcattgcaatattctttctgtatttcttactcttaaatgaaata2280
cagtgttcacctctgacactaacattcaacagaacgagcccctgtcaagaaattaatcaa2340
agaaaaaatatatttgttatattttttctctctctctgtcatgattctagcaaacaaata2400
gaaacaaggctaggcacatgggtgggtggataaatatcactcttcaagtagtgagattaa2460
ttatgatatatgaatagttttgctatccatcattcacatttattgatagttgcatgaaga2520
aatatatccaacctaaactcttattcttgttggaattaaattatcacaatttccaatctt2580
atatgtgtactcacctatttactttttagccaaagaaaaatcaccccaaatttacaataa2640
tgtaacagcttagatattctaacagtaacatttatactcagtaatcacgtaagagcattc2700
taattaaaacacattagcaactaacattccttaatctgggtatgcaggttaaaagccaca2760
tagtttcattacaacatatacaataaccaactcaaaatggattaataactttaatagaat2820
acctgaagctctaaaactgctgaaagaaaactaagggaaaaactccatgacatcataaca2880
ttggtctgggtaacaactttttggttatgaatccaaaagcacaggcaacaaaatgaaaag2940
gagacaaataggattagataaaactaaaaagcttctgtagagcaaaggaaacaataaaca3000
g 3001
<210> 197
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
392
<223> 99-26233-275 : polymorphic base T or C
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-26233-275.misl, complement
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-26233-275.mis2
<220>
<221> primer bind
<222> 1755..1775
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1254..1274
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26233-275 probe
<220>
<221> misc_feature
<222> 116
<223> n=a, g, c or t
<400>
197
gcagaagactagccggaacccggaaggtggaagttgcagtgagccgagatcgtgccattg60
cattccagcctggcgacagagtgagactgtgtctcaaaaaaaaaaaaaaaaaaaanttaa120
aaaaaaaagaaatacttatcttctttttctttaatgttcaaattagctgaagcaaaaatt180
aaacagctatccagcagttaatacactaaacaaaaccaatttaaataatagttatcctgg240
cagaattgttgaaaattctacattgttttgactggccctagagaaaaatctgattcaaaa300
ataaccaaaaatattcaatgaaaatatataatattctaaattgaaattgcttaagttgtg360
taacattttcttatcatgataaaataaaaatctagaacaaggaaatcataattattttcc420
tttgaatatgatgttttatgtacattttatacatatatttagactgtaaaacaattagaa480
taataaaataataaaactaagctcaatttttagattatgtatccactttgtcttttgtta540
aaacagtatttttttggtttcaaagaaaatcttttatataaaaattgaagaaaaaaatac600
ttaggcaatattataaggcacttcctggatcaggttataccaaaacacacataccacaat660
gtatgtttctttgaaaataatatatgtttgaaaataatttatggaaattatatctctgtt720
ttcagtaaataatgacaaatgagctcataatttaataaaatgaagcaacacacttaaaga780
cactaaaaatatttttgatagataatatcagacacagatatcagtacactggaatgattg840
actatttgtaacatatattactagtagcagcagtgagaggtagagagtagataaacataa900
tagaaatatcaagattcttatgacttaaaatttaataagtcaaaaagaacaaatggaatt960
ttatttgtatagtcttagaggaaagttgatcgaccagaatgaaaactattcgtacagaaa1020
ttaagaatgtaagaaaataaattgtgccgaatattgtaatttaagagcaagtatttatac1080
taaaattgattagaacattagaatttctggatcaaatgtggactgtcatatattatcagt1140
ggacaccagtggaacaataaccatgtgaagattttggagactcctgtctcctccaatcca1200
gataacctaaaatataacaacagggagggatgttacttacaagacgtagtaaaactcacc1260
tgactaagaagtcctgcagttctgacaatgagtttgactaatggtaagagctgtgtgaat1320
aggtagtgacaagcagctctgcaaaaccattagtttttgtttgttatatttatcaaattg1380
acaaacatttttccagcagcaagcatctccattcctttgtatttcttttacctacctagc1440
aaaatcagtttataattccaaaggcagaaactatttcattcatatcctgagctcttagca1500
ygctttggttttgtagtgatgcggtaagggcagataatgcatctgcaaaatgaatgagct1560
gctctaggtagaacataaaacagttctttttacatgatctacactatttaattgggtcat1620
aatcattttctcttagttatattttatattaacttttattaaatcaatttagcataaatg1680
ttacattattatgtgtttaaatatcacccatcatttctgtaaaattgaaacaaagtagaa1740
acaaattaagaaagcagttgcttttcttaggaatctttatactgaaaaattccttaactt1800
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
393
gttccttcttcccttgctccctttcttttctccctttctttcatcttccttccttcctag1860
cttcccttcctcctctcttccttccttctggacaaatatgtagtttacttgatcttgttt1920
gtagaggttaggagaacaagacagaaatacaacactagtgctcatttagctttaatcatt1980
ttggaagagatgtaagatacaaatatgaatattatgtaagataatttgagtgctatgatt2040
ttccctgggtctataaagactcacacttcctgattttcctttgtttacctaaatctagta2100
gctaatgagtttcacagaagacaaaattcctacatcaaaataaaatttccctttaaatta2160
cctcaactagaaaatccttgtagttctcatgcaacccaatattctgagcctgttccccca2220
tttcaccaatcacctttacctccttcagtccccaggctcccaggacccttttaagaaagc2280
ctgtggcccttacttaaagaggaatggacaccgatacatatgtccagcagaaactggaag2340
tgatgtattacatctatgtgcctgttaataattaaataaatactttaaaaaggtattgca2400
actgctaaaaatctaagaacgcagtttgaaattaaatactattaatatttactttgaagt2460
cattgtttttcttcttataattcgtattatgtgggttaagctagcaattgacttttggag2520
tattccagacatgagatcattatacctctggatttctataaaagttgttcaccactacaa2580
cctacttgtctgaagcctggaacaaggggataccttcactcaacaaaagaaaataccagt2640
attccagagcctctttagacagaaaattctgaattgataccttgccatgaatttggttga2700
gagaaatgctatggagaggatattatctttattacatagtacacatttactcttctatgt2760
attatgagttctatctctgagttcatctggtggtcagaaatttgaccatttcactgtatt2820
aaccaattcttttacagactatcctttacattttggtatttatttcacggctttttaatt2880
ttaatatatcttttattaaagcacatatacttacagaatactgcccatgagatgcatgta2940
cgattagatgaaatttcatgttactgacatgaagaccaacaagaatattacagggttgcc3000
t 3001
<210> 198
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26234-336 : polymorphic base C or G
<220> .
<221> misc_binding
<222> 1502 .1520
<223> 99-26234-336.misl, complement
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-26234-336.mis2,
<220>
<221> primer bind
<222> 1813..1833
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1379..1399
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26234-336 probe
<400> 198
tttcaaatat gtcctcatat gatcaccata tggtcaccag tgaccaaatc atttcttcta 60
tactttttat atttgcttct tcatctcttt gtctactatt tattgcctcg gttctaatct 120
gtttctacta ctgatggcct atttcaggtc tgtatcaact tattctttga aaaattttga 180
aataactgtt tatactgaat aaattgccta tgaggatggt agtgcagatg aataaataag 240
aagagagttt gtaggcagaa gatgcaaaca ggacatataa tctatgctcc agaaatggtt 300
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
394
gttttatcctccatttatacttcaaatttcaagaacagctatgaatgtgttctgcaatgg360
tttaatatagaagacataaacattatatttgttaagcaacaaggtcatggaagatttacc420
tagtttgaattaaatcaatattgtttgttattctttatcctaatcccaaaagaccataca480
aaatcaataagatattgatgtaactaaatcttcttcagtaagatttatgagacactgata540
tgagaatggaggttggctaagcagtaaccagagatatgaaatcttcatttgagttttcaa600
agcagcattatttctatgtgttttctttattaaactcaaacacttgcaccaaaactatat660
agtattatttagcattatatagtaaatcataaatatctgtataaaataaaatttgcagta720
attacatgtatatcatatatttgatactataggtaacattttgtctttcacactaagcta780
aagttaattttataggtaaataaaaatgcatatatgtaagatgactgagtatacataaag840
caaaaatgtgaaattgcattattggagaatcaataaagacaataaatggactaagggaga900
catttagttgatgagtgttattaaagttttaccatcataatttatgtttggtctgtgaaa960
aagtacttctttgaactataaggtatacattcaatatgtgttttaatgaagttttatata1020
taataccataacgatttgtttagaattatgtattattttgttagctgaatttcgttttac1080
tttctttttcagtttactttaatcatttaatgaacattggagttgcagaataaaaatgga1140
aattattattcattttaaggatgtttaaagcaatgttttagtattatcttttgttaatca1200
aagtgcattttgttgttgttattattgttccaagactttaccatttgcttacaattagca1260
ggaactggccctattatttgatgtttgtttacgttagtatttatttattttgaacaagat1320
tagggagtcctataattaccatctcatcaatcatgagttgactatcctttggaaactctt1380
gtggtaaacattaggcaggagccccaaatttgatgcaggtgagtaattatactgtaatcg1440
tcactaaacacactgcaggcaaaaggctaagtgacaaagaaagacatgatcgttgcctaa1500
sagtccatgtttttgggtaattttattaaatgcaaattcagtgatttgcacacatctctt1560
ccagtagttatgccattaattagttttaagtttcagcttgagccaaaaagcactttatat1620
tttaaccataaccctgttgtattggttataagaagaatgaacacataatttaacttcaaa1680
cagggacatttgtgaaagtgaaaatagttgataatagtaaattggtggaacctgtaattc1740
taaaccaggactttcccaagctaaccagaacatacgatcattctagttataagatgtact1800
tcagaaaagaagcaaaattgttgataactctgctagtctccttcagggttctattatttt1860
tttatccacatttttctttttgtaagatgtgttacaaaatcttttttctagatttgatct1920
ccctatcagtacagaatgttttagttatccaaaaaagataaataatcacgtgctcctctg1980
gctccttttaatttctagttttgcaaaaacagctccaacatgttgcaaaatgattcaaac2040
attttggacatcttgtaagatatcttcttatctttatttggctgtagaatgcattactat2100
tttccttctttgcagaaaataataatagataataagttattatccctagatagaaatcaa2160
acatgtagagcttcaagctactttcatacttcaaagacatgattcaaggacggtttaaat2220
taaaccagtcatattctaatttatgtctactagaaactaacaatatatttagtattattt2280
aaatatataaactatgttctatattggttcaggtgaaaatttatacactaatattatgaa2340
tacttataacatcctagagtattcagtaagtaattgttgaataaataattaaataattga2400
attggcaagatatatttatataacttaaactcctaagtttaaacattatttgaatctaaa2460
agtaacactaagttattattttattattacccatgagctaaaacataatttgttgcaaca2520
ccaaaattctgagatgggttcttgctgagctacagatagatgcttgtatattaaaaagaa2580
atgctgcctttaaaaatgtcagttgtgacatttttacaaataagaatatattactcagac2640
ataatttatataataacatttatagatttgtagttatccattttcatgctgctgataaag2700
acatatctgagattgggcaatttacaaaagaaagaggtttaattggacttatagttccat2760
gtggttggggaagcctcacaatcatggtgaaaggcaaggaggagcaagtcatgtcttaca2820
tggatggcagcaggcaaaagagagagcttgtacaggaaaactcctttttattttaatcat2880
cagatctcatgagacttattcactctcatgagaataccatgagaaagacctgcccccatg2940
attcaattacctcccactgggtcccttccacaacatgtgggaattgtgagagatacaatt3000
c 3001
<210> 199
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26238-186 : polymorphic base T or A
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-26238-186.misl, complement
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
395
<221> misc_binding
<222> 1481 .1500
<223> 99-26238-186.mis2,
<220>
<221> primer bind
<222> 1668..1686
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1235..1255
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26238-186 probe
<400>
199
tttctccttaacttcttctagtggatgaagacttcctatacgttccttgtctttcatgac60
tttgatacttaggaaaagttggtgttttgagtattatgtaaaaatgccacttaatttggg120
tttggttgattttgtaatgattcaattgagattgagcatctggaaaaagaataacacaga180
agtgatatacactcttggtacatctcatcagagggtatattatttcaatgtggtttacta240
tttgcgatgttagcattgatcattggactggaataatgcctaccaggatttttccactgt300
aaaattattattgttctctttatattactaaacattttgaagagtatactgaaatcatgt360
aattatcttgtctcccctttgcatccatcagcaaatctatcctgcagcaagtattaccga420
tattttctattttcctcattctgactacgtgtattgattggaatgcctccataagaaaca480
gttaccccttttctcccacttatttcgtcagtcatttatttatactagtatggacttatg540
aatatttacataattcttgaaatttcaatccacatatgactttacgatagaaatcagaaa600
tgcatcaacttttgtaaaccctaatgagaatgtacattgggaccctcattagtacaaact660
ctgaacaatctgttgcatagcaaaaagagaattgttgacagcagatagagttcaccatgt720
gatgaagctggtagtggcactatcattcattcattaacttatttgctcttttcagatata780
tttattgagaacctactgtgtgccagaccatgttataggattggggggtacccattaaat840
aaaacagatgaattttgccacacagagaagtctagcatagagtaagcaaagaaaagaata900
ttagataaggaggttacagaagtcatcagaaacgagactattcaggacctagattttact960
ataattttgcttgtaaggcccaggcagatatttagtaagggacagttaatattttaaaat1020
acaaatatatatatatattatatatatatgagaaacatatatagtatatagatatagcat1080
atatattatatatactgtatatatagatttatagcagtacatgtatgtgtgtgtttgtgt1140
gtgtatatatatatagagagagagcagtacaaagttggaagcatggagatttgagtaatc1200
taagaaatcacgtgatttgaactaggaagctattagctaagatggtcagattcagaatat1260
cttcggaagtttaaattctcaaattatctgacagattgaatatagggtataaaagaacag1320
tcaagaaggtagacttcaaagtattgaaactgcgcaagggggtgaatgttgcatttacta1380
ttttgggagggaaaagttggaaaacagagcttattagaaatccagttagaattctaataa1440
acacctgtatacataagtctagattttagccacgatgagcctggggttgcaaactttgaa1500
wtcatttgtgtataagaagcattcagttcctctaggagagaacgttgggtggagtaaatt1560
taaaggataagcgattggaaagttaaggtattggtgcactgtaaggttgacattggggca1620
ttgagaaagggaatccagcagataaattagggtaaaatagaaaatgacatagaagtcgct1680
agatttgtgcatgcttttgtgtcaaaccagaagagattctgaaatctagagaaggctccg1740
tgtgtaattatttcaagacatgaggccgctccatgtatattcatccactctctgtgtttt1800
gctttattttaatctttgataaaagtaaggttgctaaagaaggaacaaggcaaatgaaag1860
attaaaatgttgagagtataccattgagattaactgagacgccattagacttactaacga1920
tgctgttgaagaacctttgaaacccattattagaataaagtggttacctggaatgagtct1980
attcagggcctagatgttgttatagctttgtttaaattataatacagtggcctaaaaaca2040
aggagaataacatttcaagaaaaggcagctctctcaggtgttgctaatatgtccaatgag2100
atgaaaaatgtgaatttaccattggatctggtgatgttgaattcaatgctgactttgaca2160
agagcagtttcaatgaagtaatgggaagaaaagcccttctggaatgagtttaataaataa2220
tgggaaaaggggagttaagagatagtgagggcaggtgtggtggctcacagctgtaatccc2280
agtgctttgggaggccgaagcaggaggatcacttgaatccagcagttcaaggctgcagtg2340
agctatgatcacaccactgcactctattctggggaacagaatgaggcctcatctctagaa2400
aaacataaaataaattaaaaagtaatagtgagtactgattcatatgagtgtttttgctac2460
aatggaaggtaaacaaatggagttaatgctgaatgattaggtggggtctaaagaaagtac2520
ttaatggtaaaatactatttttattaagtgaaagtgtaaatagttgaattaatgagtgaa2580
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
396
taagcacttaaaagtattttttctttattctaataatgggtgtcaaaggttcaacagcat2640
cagtaggtccaagaccaaaattcaggttctaataaattctcagttaatttcaatactata2700
ctctcaatattttaatcttccatttacctttttctttctttggaaaccttacttttatta2760
aagattataataaaacaaaacacagagagtggctgattgggcatggagtggccttatgtt2820
ttgaaataattacacgtggagccttctctggctttcagaatttcttctggttttgacagt2880
aaagcatgtgccgatctagttaagtatatgtgatgcactcatggtgtgaccggcaaaggt2940
atagctgtacattctggaggagaaaattgttgtaggaatgattatttcatgctgctcttc3000
a 3001
<210> 200
<211> 548
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 79
<223> 99-16106-48 : polymorphic base G or T
<220>
<221> misc_binding
<222> 59..78
<223> 99-16106-48.misl,
<220>
<221> misc_binding
<222> 80..99
<223> 99-16106-48.mis2, complement
<220>
<221> primer bind
<222> 32..50
<223> upstream amplification primer
<220>
<221> primer bind
<222> 518..535
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 67..91
<223> 99-16106-48 probe
<400> 200
gagagagaga gaagcatttg aaaaacatga acattaggat ttgaacagag ccttaacacc 60
taaaggtatg aatatatakt cagacaaaaa gcaattaatg ggcagctcag ctggctaaca 120
tgagagtaat gaatcatgat aagctattgg actgacatgt tcatgattaa tctgaactta 180
aaggccactg tgccctgact caggaacaca cacatacaac acacatatgc atacatagac 240
acacatatgc attattcaaa gacagacatg catacacatg gacattcaag gaaagctgta 300
tctcccagac aatcaccata agcaaatcca tcacacatga ccaggggacc tgtttaaatg 360
atgcctcagt catgtcatat ctttactccc tgtgcaacaa aaaataaaat acaagcccca 420
cagcctggaa accagaagga cccttcataa tatgttccca acaagccttc ccagccatat 480
ctcttatctc ttgattctcc cagaccagta tcaaatgctc catccaaacc acactcctca 540
acattcaa 548
<210> 201
<211> 478
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
397
<222> 125
<223> 99-25332-125 : polymorphic base A or G
<220>
<221> misc_binding
<222> 105. 124
<223> 99-25332-125.misl,
<220>
<221> misc_binding
<222> 126. 145
<223> 99-25332-125.mis2, complement
<220>
<221> primer bind
<222> 1..18
<223> upstream amplification primer
<220>
<221> primer bind
<222> 461..478
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 113..137
<223> 99-25332-125 probe
<400> 201
aacacaggca catcattgct cagctgacct gaaggcatgc ctgccaggtg cagcttacag 60
ggaagttctc aggcctgggt tgcatgtaca aggctgctca attggcctgg gggtatattt 120
gcaaraagca gcccacaggg gtgtttgtca gtcccagaat gtagtcacac acttcttagc 180
tggcctggtg tgtgtgtgtt gggggtggtt gacagggcat ttcctccagc tcaggacaca 240
ggcgcacagc tattcaacaa gcctggggac atgtctgctg gggttagcca atggaatgag 300
ccaattcctc aggtccagga catagatgca tggctccttg cctatcctgg ggatgttttt 360
gtcaagggtg gctcacactg tattttgtag gcccagaata tggacacagg gctgctcagc 420
tggcctggga acgtgtcttc tagggcatcc cacagagttg cttctcaagt ctgagaca 478
<210> 202
<211> 404
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 306
<223> 99-25516-307 : polymorphic base C or T
<220>
<221> misc_binding
<222> 286..305
<223> 99-25516-307.misl,
<220>
<221> misc_binding
<222> 307..326
<223> 99-25516-307.mis2, complement
<220>
<221> primer bind
<222> 1..18
<223> upstream amplification primer
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
398
<220>
<221> primer bind
<222> 385..404
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 294. 318
<223> 99-25516-307 probe
<400> 202
aaagtgacca actcatcctg tttggccaag gactgtcctg agaatcctct cagtcctgga 60
ccaacgaggg cagttgttcg gtccccttaa tgcaaattct ggcaacacct ctctgacatt 120
gacmckwcca ttatccccat atttcagaga gaggrctgag gctcagaatt ctaagaactt 180
gcccattatc acacaggtcc taagagctcc ctacttaggg acttaaatcc aaatcttgga 240
ctctgcgacc tccgttctca ccaccgttct gtgctattcc ctgagaggca gcgcaggtcc 300
ttgcgycgca gatggggctg cctgtctcca aggccttccc tgctcctatg acagtggagg 360
tgtgaagggg attggaagtg tcctcgagtt ctttctgaag aaac 404
<210> 203
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26173-470 : polymorphic base C or T
<220>
<221> misc_binding
<222> 1481..1500
<223> 99-26173-470.misl,
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-26173-470.mis2, complement
<220>
<221> primer bind
<222> 1033..1052
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1570..1589
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-26173-470 probe
<400> 203
tgtctcctct cccatttcta ctctcagcta tatccttact tctatttgtc tgagaaagta 60
gaaataataa gaaataaatg ttcacatact ccacaactgc ttttataagt ctatctgcag 120
atctatccat ttactcctct ttttattttt ttactgaact tggggataaa ctcctagtgc 180
tgtaatctaa gttcaagacc tcatcaaatt tagcattaga ccatctctcc tactcaggga 240
aatcaatcca ataattttct tctcttctgc atcatcctac tgtgttatcc cacatcctcc 300
tgtattatcc ttaacagtat ttaaatatgc tctaatattt agaacatctt aaataattac 360
cccatgttaa aaaagaatcc cctcttggtt atgcatttct ctctagctat tgaattaatt 420
gtctgttact ggcaaaactc tttgaaagag aaattgcaac tatccttctc ccattctctc 480
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
399
ttggaccctttctaaacaggtgtttgtccccagtaacaaactgttcttgtcacggtcacc540
catgacctgcaagtgatcaaactcaagattctgttttcagttcttatcctacccgtatag600
tatttggcattcaaattttcataataaatttgtattttttactacaaagtggtaaagtta660
gcatcgaaatactttaaacctaccatttacccaaccagtaccctttatgcgatcatcttt720
ttatagtgacgatatatttgggtttctaattgagagtattaatacgttaactattccatg780
tgatttgatgttcagccaaacactaatagtactcagttggtattcgggtaccattagaag840
gcaatgcttggtgtttccttacttgggaagaatattcctttcatcacatgtatttgtgtt900
tggacagagtggcttgtctctataaaacagaagaagatgaatggtctttctgagaattag960
tctttgtatttaaatataatagatttgtgattaagcaacggctgcttttcagactcctta1020
attactatcatagcaaataatcattggcaaactaaaatattagtttgcttaatgataaat1080
atcactcaagtttaagcattatgtagaaagaaatagtcataaactttggaagggccgttt1140
atcatagttcattttctctatgtggaacgttttcatggatagatttgttccttattttta1200
cacctaagggtttcaagtattgataatatgttctacctcttctttacctacctattacac1260
agacatgattaaggtaatgtttctacatttgtgtttttagtttttctatgttaatttttt1320
gtcaaaatgacaaacagcttttaaggtataagcaaatggcaaagagctggcaattagagt1380
agatgaacaaatttatagacatgataatattatctcttccattgagattttccggggtaa1440
catgtaactacttggctcaacaacgagacatgaatgcagtgtcttttctcaggaaactct1500
ycaatgatggatgggtatttacttgtttgttttcttcagaatccaacaattctctttctt1560
ttgaaaaagcctttaaaatagtgcgattctcattgcttaatgtctttttattacaccaca1620
tgcctcattttatctctttgaatttctgtaaataattcctgcttatccttggatacaaca1680
tgccctttaaatatttgttcatggcttttttattcctcttaccatttggccaacttacaa1740
ttgtttaaccctattaatctttctgcataagtaaatgccaccagcaccttaatcatttct1800
gtggcttagattgttcaataattacctcatccttattccagcaaatgagatgactgctgt1860
tttcatgaagagaatttcatgctgaggccaaacttggggtagagaagactgaatgcattt1920
gctgtcttgcttctctctggggtgggatctgatctgaatacagggataaggatattgtac1980
aaatctatgctaggtagaagcagtcttcttggtttcatacctgatgaattaaaggaaagt2040
gtagggaaagtaaccagacatcttcactgcatctgctcagatgagaagtgttgcatacca2100
catctcatacttctcccaacaacagggtgttgttggtattattttcatttcatggatgag2160
aggaagtgaaggaatttttccaggaactcatagtggtcaggggtagtatttgaacacaag2220
tctgacaaatatggggtacagttttagaattaactcaatgaatccttaatcataataaaa2280
gtcagcattatactctagtgtcttcctggatgtacccatagaacaggctagaatgtcaac2340
cacaagattccctctgttcattcctataatttattattattattatactttaagttccgg2400
ggtacatgtgcagaatgtgcagttttgttacataggtatacatgtgccatggtggtttgc2460
tgcactcatcaacctgtcatctacattaggtattcctcctaatgctatccctcccctagc2520
tccccacctcccaacaggccccagcgtgtgatgtccccctccccatgtccatgtgttctc2580
attgtccaactcccacttatgagtgagaacacgcgatgtttggttttctattcttgtgtt2640
agtttgctgagaatgatggtttccagcttcatccatgtccctgcaaaggacatgaactca2700
tccttttttatgtctgcatagtatcccatggcgtatatgtgccacattttctttatccaa2760
tctatcattgatggacatttgggtaggttccaagtctttgctgttgtgaatagtgctgca2820
ataaacatacatgtgcgtgtgtctttatagtagaataatttataatcctctgagagaaca2880
tgatgcagaaactgctgggacagtaatgttacaaatgatggccaccctgcagaaaagagc2940
cttctccagatctgcctccactcctttctgttcaatgcatgggacaatagttttaaaagt3000
t 3001
<210> 204
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26267-524 : polymorphic base C or T
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-26267-524.misl,
<220>
<221> misc_binding
<222> 1502..1521
<223> 99-26267-524.mis2, complement
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
400
<220>
<221> primer bind
<222> 983..1002
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1553..1573
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26267-524 probe
<400> 204
tggggttccttaaccttgtatctaaattctcacttcacttggatccttgatgataggaat60
ctgtgagataaatgtcatagtacccaccaacaccatgtgctcagcagtcaccagagaaca120
ggttcattatatcacctttgctttaagagattcagcaatttccacgaaggcccacaaaga180
ggccttgctgaaaataatttcaagtaattcatcctgcctaagtacacagactccaggtgc240
agggagattgaagttttgttcccagttttgttatgtaatagctttgtaatcttaaaacat300
ttcttaaatatcctgaacctcagtttccttatctgtaaaatgcttcatatgaagtttgta360
tctcacattgttgttttgaatataataacgaatatcaaccacgtaacactgcctggcata420
ttataaattctcaatgtctcttgtttaagagtcatttaaaatgtaattatggctgcatag480
tattccatggtgtatatgtgccacattttcttagtccagtctatcattgttggtcattga540
gaactgaacaatgagaacacatggacacaggaaggggaacatcacacaccgggccctgtt600
gtggggtggggggaggggggagggctagcattaggagatatacctaatgttaaatgaaga660
gttaatgggtgcagcacaccaacatggcacatgtatacgtatgtaacaaacctgcacatt720
gtgcacatgtaccctaaaacttaaagtataataaaataaaataaaataaaataaaataaa780
aatgtaattattatttgtagtagaaataatagtagagagaggtagtgtgatatggtagaa840
ttcgtgatctggaagaccttaatccgactcttgtttcttataatttagagaagcagggct900
ttgggtaaaccacttaacttcacttgtaaaatgaaagtattaatgaatgcatcacagggt960
ccctgtaccaatgaaatgagctcctgggtagaaaagtgcttcataaacgggtatgtgtta1020
cataaatgttaattattgaaatatggagtcattactaaccttataaaaaaacaagcaaat1080
gcattttacatgtaatttttactcaattatcctttaagtttagtcacaattagtagaaat1140
tgtccctaataataaacgtaaagaaaggaaagcacacatactgacaaggggttattgatt1200
ttagaagaaaggctttcatttttttgatattttgctaccattgacttgtgatatgggtaa1260
ttttctaaattactatacttcagtgaagttataattgtctaacttattttatgatctatg1320
agtcattataaaaaggcttatgatttttaaactcactgtgaaatattcatagaaggtgtt1380
tcttctctattctgttactgcaaaaaaatcagtgtaatgcctttgtcatattgtgataaa1440
cattaaaaaaatacaagctgatttttcccaatattatcacattacaatttctttaacttt1500
yatgggtgttctttttgtttctggcaacaagtgccacattgctgaaaagtctctaagttc1560
attttggcaaaggcttttctttttaaataaaaaaaattggggatagaaatatttcatgtt1620
tttttatccacaccaaaatatacaaattattgatatcataatgtaaataataagaccgta1680
cattgactaatttttaatgaatattttatggtcctcgaattaagaatgtacaatgttgaa1740
aagattgaaaaatggtttggggtagtggatcacatgtgggatggtgttgaatggattgct1800
gacaccacatgagttcatgcacacatactttgtgggcaactgtggtgaaatcaccataga1860
ctggccattaacttacaatatgtggatattcttagtaatttatatttgttggcagttaat1920
atctgtttcagaaagcttgaaaaggaattttgtgtgtgtgtatgcacgaaaccttttccc1980
cagatcatatttgtgtgtatatatataaaatggaatatatgtatatattatatatgtgta2040
tatatgtgtataaataatatatatacattacatataaatatgtatatttatacattatat2100
ataaataaaatattaaatatacattatataattttactatataattttatagtttaataa2160
tgtatataattttacattatacattatattcatatataaaatatataacatatataattt2220
tactatattatatattaattataattattaatttaaaagtgggaaaaacttttattatag2280
ttaatactgggtttagctctagagtttaaattttcagggatctctttgtagttatctctg2340
ataaccacaataaaaataatagtggtgacactaatgataactaatatttactgaggacat2400
tttgaagcagacctcttctaagtgacgtatattcacaacactgtttaaacttcataagta2460
gccaaatcagtaggcactgtgatttttccttttctctgggtgaagaaattgaggtgcata2520
gaagttaaataagtaatttactaatgtcttgctgtgaagtgactttgaataaaatattcc2580
cattgacaaagtgccaaatatcttaaattggaatactagctttattttttactttgaatt2640
attcttgcttttattactatcctgttaaataaaaataattttggaaaggctaatacatta2700
agtcattaactcagtgttcattagttaatgtcttagagaagcaagtccccagggaagctc2760
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
401
agaactctgggtgaccaagataggcagagaggattgtaagagtgaggaagagaggaagtg2820
ggttgcagtgagcaaatctgcctaaaggctacatgtaatcatctcatacacgtggtgtac2880
ttagaatcattttaggttatgcaaaaaaaaaaaaaaaaaaagaaaagaaaaaaactcaaa2940
ataatacagattgtaaaatcctccattctacctacaccaacagctcacacacttcttttt3000
a 3001
<210> 205
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26284-394 . polymorphic base G or A
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-26284-394.misl,
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-26284-394.mis2, complement
<220>
<221> primer bind
<222> 1874..1894
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1460..1480
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26284-399 probe
<400> 205
acagtgtcat aacttagcag gggttctggg accttttttt ccttccagag tattataatt 60
ctctgaaatc caagaagtac aaactttact ttgaagagat tgcacgtagt agattgtact 120
acttgtttcc aattacatcc atcccctttc taccccgtcc tgtgaagtaa tatgttcact 180
tctccataga ttttggggtt aggcatgctt ctagctttgg ccagtgggtt gtgaaaagat 240
aatgtgtttg ccttatatta gcagaaacct ttagaaatat tgcaagaacc ctctttcccc 300
ctcactctgc tactggagct ccttccctca acctgggaac catataaaaa gacatggagt 360
gccacactga gcggggctgg gctgattcct gtagtgccca gcagaacctg gcagaactgc 420
aacttcccag agaccccagg tgaccttcag caagaaccat gagtcagttg taagaactta 480
agatctgggg cttatttgtt gcctcagtaa aagctgaaaa atacatgcgc tctggtatga 540
agaaatactg ggatgtgcat gagataaagt tcagatggga cccacaaaac caaaaatttt 600
ccaaatcaaa gtgttaacca gctcttctga tcttccaggg tctggggagg caccagtgaa 660
gtaaactgac aatgatacca gctgtagaga agctcctatt gcagtgcaag gagacaaaaa 720
tggataagta aaacattctg tgtattatta agataaatgt tacagagaaa aatatatcag 780
gaaagggaga gaggaatata tctaaatgga gaaaggtgaa attaaacata ggatgtttga 840
gaacatcttt actgggaaag tcgcattgga ataaatatat gcaggaggca aggaagcctg 900
agttgatgtg ggtaaaggat gtttgtaaca gaggaaacca aaagtgcaaa tgtcttgcgt 960
tgagagcatg atggttttga tgaaaatatt taatgggtgt ttgatgaaaa tgaaggagaa 1020
cgatcagttt agaaaaaaat aaaaggtgag atacatatca aatcgcccag cggcttgcgg 1080
aatgcagatt tctaagctct cagagattct gattccataa acctcaggtg gggcccatga 1140
atttgcatgt ctaataagtt ctcagggaaa tactgatgca gcgcaacacc aggagcacct 1200
tgggaactac agctccaggg ctttgcaggt tgtgaggagg acttcggtgt ctcctctgag 1260
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
402
tgagatggaaaatcacaaggatgtttttagcagaggagagacattagctgaccaccagga1320
tgattgtgactgtgttgagaataagcaagaaagtgctaaaagtggaagcagagaagccaa1380
atatgaacagtactgaaacatgggacaattatactggccttatgcaaaaagaaaaatgat1440
tccttttgtttagtaagaggtaagacagttcctgatgcgggtcgggacatgttgagagat1500
rttccaaccaatgccctctgttttctctggcaaggtcatctaacttgatgagtgggaaag1560
tgaggaggggtgttggttacttttgcagggagaataaaatgatcattgcagagcgtggga1620
gagctaattgagtgaaaaaatattttattattccagaacacccttccataaacaaatgag1680
gttatgactatggatttgtagttaagagatgttaaaaggtacatcatttgttaagcttgt1740
taaactaacactaggaccactcttggcacttacatatcccaaatacaaaacccaatacat1800
cttccttgtttcaaaaacggtctcttggaggatgatgcccaagggttccttgagttttaa1860
tgaataagcatttgctgagtgaatgcaccaacactttgtgtaatactaccagtatcactt1920
tccttctgccaaatactttaaataaaaactccaccaaagatgacgtaaaatagaatcaaa1980
acctgctggtagggtgtataagcaagatagaatcagagtttactaaaatcagtatttaat2040
ggagaagatgacggcagtgatgatattagctaaccgtgctgaatattattatctgacagg2100
cactcttctaagccttgtcctgttttaactcatttcatccttttcaaaattggatgagat2160
tggtactaatattattcccatttcgcaaagatgaaaactgcagaccagcagtatacccag2220
tgttgcacagacagcataaggagcagtgaggtctgaactaaggcattctgcccagggctc2280
tgtgctttttaacaactacaccagaagcaagtgagaattacagaatgttaaatttgggct2340
cttttgtttttccttttctaaggtagactgcggggaatgacccttgtaactgaatactgc2400
accataattataatgggaagctgtttctatctcagaatctggccctgaacgatcctagga2460
tatttaggccaaaaatgcaggggagagagtcctgatggggggcgtggctgtgagtggagg2520
gggaaggaaagtgaggccaaccacacactttctgctgcagattctgcaccctcttggaaa2580
gacactgtgaaccacattgagctaactcttgatacacccgcagatacccacactcactgc2640
tcttcctaaagacaggcacttggctctttaaccttgaaatggggaatccagaaaaaaaaa2700
caaaacagttaaagatattttattcaattaataccttgcaccaagccatattaaaatgtt2760
ttctgctgtctccactcttgccctctcaatatctttcaatattttagatatatatatatc2820
taaaaatgttaaatttaactttgggaggatttaaggatacttataaaaataaccattcag2880
ttactttctaataatcatttatccaagtttaggattcttgcaaggaagaagacattaaaa2940
tggccgctctactacttttatctgctagtaaataaattcatgatgaacatttagaaggtc3000
g ~ 3001
<210> 206
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26559-315 : polymorphic base A or G
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-26559-315.misl,
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-26559-315.mis2, complement
<220>
<221> primer bind
<222> 1187..1207
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1650..1670
<223> downstream amplification primer, complement
<220>
<221> mist binding
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<222> 1489..1513
<223> 99-26559-315 probe
403
<220>
<221> misc_feature
<222> 539. 540,592,784,833,850,881,1592,1631,1682,1852,1873,1962
<223> n=a, g, c or t
<400> 206
atcacatgcagtagcttgaaatcattggtgatggatttacattttaaaaggctgaatcag60
atatagaaagcaatttatcatggtcaatacaaagtatatgtacattgtcttgtttaatat120
gaaattttaatatagtgtggtggcagaatctgtgctgttaggtgatattatttggctaac180
aagagctgagaggggaattgcagaagcataaaatgtcagctggaggagagatcataaaaa240
gctcatgaaggaatcgcctttggataaaagaaaggtccagaagtgtggagagtgtgctca300
gaatactggtctctaagacatattttctggagtttttcaacaaatacttcatgcatggct360
actcagtagcatgcacagtgccaatccattctaattctctatgaatatcaacaagagttt420
tacaagacagtgtcaaagtaggttagttgagagtcattattcattaaatagcaatgaagt480
cacctaactgaaacttaaggcagatatcagcaagagaaaacaccagaagaatacacatnn540
aaaaatacatcagatcaagggtaaaaacaaagaaatatccaagatgtaggtncaggcttt600
gccctttcaaggtaacaaactgagcacatactgcaacctcttgcccctggtaaaacagca660
taacaagtttaaatacagaaataaaaccataattgagttgtaagtgttgggaagaagaaa720
ttatcatctctgaggcagcatcagcatggatagcacattccatgctcagtagatgtgaga780
gtcntaatgactgtagcactaggtggtcttaggtattagagaggtctatgaangcataga840
gatcaagccngaaatctacctgtcattggccaatgacaatnaatatgaaaacaatgaaag900
aaaagtccaacgaaatagaagataggtccagatgttccacacctcatctaacatagtagt960
tctcaaccagaggtgatttgccactgggcatttggcagtgcctagaaacatacttcattg1020
tcacaactgaatagaatagtggaagtagctgctggcatttaacaggtaaagacaagaaat1080
gctgctaaatatcttacaatgcactgggtggccctcaatccaaataattatttgacccaa1140
aatgtcagtagtgtcaattttttttttaatgctagaaattctggaagaaaaaaaggtgca1200
atgagtggtaagtgtactatagaaaattattagataatgttatagtcaacctccaaattt1260
aagttgtgtgacaaaagagaaacatacttttactcaaataaccattcaatgcaggtgatc1320
ttgggcagtgaataagaggcttttctccctgggttgattcaggcattcagtctccttcca1380
ttttgtagctcttttttttttttttttttaatcaggaatggcccaagaatcctgtgtctg1440
tagtgtgacgaggggaaagagtaagtgaatgtggcatatcagcttcttaaatacccacac1500
rtcacttctgacaggtactgatgtggatacttctagttgcaagaggcttaggatagttag1560
tttctggataaacagctatgttgcaatgaaanctcccatactatagaaagagcatggatt1620
ttgggaacaanctagctcattcaagactccatctgcccctcttacaagaaaataactgca1680
tngagttactttttacttgtacagagaacattttccatcctttccaaggaagacaaagca1740
aagtcccatccagtgtctgtatccagatcagccttgaggaggatgagacgaatcatcagc1800
ttcctcatctgttctacatgaaagttagatgacacatcagtctccccattgnttcccacc1860
accaaaatcaaanttatagagtgatggagcctcaggtaatactgcataatacccgagagt1920
cactaggccatatgaaatgtgctatgcaggcagggggagggnccccctgcccttgcaatg1980
aaggaagttccctgacaagtctctgaatctgctctctgtaaggaagtctcattgattgaa2040
agattcttccactatacatcctgtcttctgtttccaaatgctgggaacttcctccttgtt2100
cagtttcttcctagaccacatctgaaagaatgccatcttggagaagagaatgccatcttg2160
gagaagagaatgccatcttggagaatgccatcttggagaatggcagtttcctagcctgat2220
tttgggtttttcaccatcataggattacttgggccagactcaaggtatccttgggaatat2280
aatccccacaaatgccattggccttttgagctatttccttctgttttcagtaaccccagg2340
taaagtcattgtctctgtgtaaatctcaagttggccaatttcttccgcctatgttttctc2400
tcttgtaaacctaaaggagaccactttgaaaccatttaaaacaatttggtgattaagatt2460
aagattaaaacagattaaggaaaccattaatctgatctttgccacagggcttagcttccc2520
tgtttaagtgatgattcttccccgaccttgttgttcaaagtttttactttcagccttatt2580
catttcactctggtattcagccaggttccagttttacaatgtgccacatctctgcattct2640
ctctttggcctttacttcttatctcaaacaaattgacttttgctcaattttatctcttgt2700
tgcatcaagaaactaccatcacgtgcaactaatagttatctaacctcgtatcttgaagct2760
atgggcttggccagcgtgtgttctgatttccaagttatcacagctggcagctattgtaat2820
gggtcaccacacacatattgtgaccaatctttatcttctcagactctggtatgtttcctg2880
actgttcatcacttgattattgaagcagtactgcatgttttcttttctttgtgtatttgc2940
actctgagacctatggagtattaggtaagaaataatagtcacacttagatacattacagt3000
a 3001
<210> 207
<211> 3001
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
404
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26769-256 : polymorphic base A or T
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-26769-256.misl,
<220>
<221> misc_binding
<222> 1502 .1521
<223>~99-26769-256.mis2, complement
<220>
<221> primer bind
<222> 1249..1267
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1707..1727
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26769-256 probe
<400>
207
tctgcctgcctctgtcatattcacattctattcgaccaatataatgttggggctctttca60
catcagtgagggttgtctgtctgtgtctggtacacagtaggcagatgtgatttcatactt120
cgcctgggtactatagacctaattcttactatttatggctagtccctaggaagactttat180
gttctgactccttgttgctatattctagactcactcaaaaatgtatggatggacaaagac240
agagatgtgtggatgtgtgtctctggggaagttccatgggcaaaactgtttcaaggaact300
gctgtgactctgatctgtttactacctctcttgtggcagaaatggcagacatttaaaatt360
tccacttgcacattttttcaaattaaggcttcagagaaatgtgtagttgtgtgtgtgtgt420
gtgtgtggtgttatcatggtgtgtatctccccattgtttaatagaaacactaagatacta480
agtatgcacaattttgggaaatacaaggatgtcatcagaattttgcagattactattagt540
ttctgttttcttcttgaatagtacacattatctcaggatacaatgtaaaagtttgcccta600
tgaagttccagaaaaaaatagtgaggtttatcaaatccatctgttcccatgagaaggaaa660
cattacacatggccaatattttctagctccaaagaacactttaccagttctttagctctc720
attgcagttgactttttaaaaattaatcagtcttcataagttagtgtttcccttcccttg780
attttctcatccttttagaatttatgtttcaatatgtgttatttttatatgaatttaaca840
gagaaaagaaacaacaataatgagaaagatggaagaggaacaacagcataagaaggaggg900
gaggcaggaaggagggcagagaagaaaaagaggaagaagagcaagaaaaatgaatgacga960
acgaatttacaggaagagacaacttagagagtagagacattgttgggattttcaaattaa1020
tccagaatcttaaatcaggctggaatgttaggcacagacacacagagagttgggttttta1080
gcggttccgattctttggtttctttattatatcatcatttgcagtattttctgagagcag1140
tagattttctcttccagtctcatcttattgaaaattctttgtaaatataatctattctca1200
cttgttcactttctggtgtatcttctaatttgaaatttgactttcgttctcagcgtgcta1260
ctaaaactcctttttaaaattttccctcttacttgttgaatccaacagctttttcatttg1320
ttttcagctctccaactttttttaaacttgattgtaaagcttagatcctttggtttttac1380
agtagcactctgctgactttattgccatttccttcaagctagttcccgggctcttttgcc1440
agccccttcaaggcattcacaaagttttgtcctcagtcttctactagtcccatttgtcac1500
wgcaactttaccatcccacatatttacatagttcaaaccaccacatttatgctgaagaca1560
acaagcctctgtttccaggctcaagcagctcatgtgagtttctgaatcatgcactcaact1620
gcctgctgaacacagccatttttatgttccgtgtacagctcaagtttcacaagtcaaaaa1680
acaaactcatcctctccttgagtaaacctgcacctcttttctatacctcttatatctagt1740
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
405
caagaccctggagaataatcctgcaggcatttatcttcttacctcttttaccaaatcatt1800
cttgaaactttatgttacttcccaagttttaccaaattgactcttactctctactcccat1860
ttgtgatagctgcagctcattctctgtcttatttatgtgctactgttatagagtgctgaa1920
tgacatcctgcatttgttctctaatctaccatttgcacatatactcaagatttatgtaaa1980
ctataaagctcactgcactacctacctatataaacattccacatgctctcataattaaga2040
aaaacacagtttaaacttctcaaaatggtatatggtgtctggaattgtcttcctttctag2100
caatcttacttcttgtcaatctttcctttgggattcaagctgtaacatcccagtctgttt2160
atgatgctcttgatcacaaaattctatttccacatgtagaccatctcccatgctctacct2220
tccccttgagaattccttttcctctaggattccaatttttatttttaaaataaatgacta2280
aagaaggtctctccttattgctggagaccgcggcaggggtcccgcctctgtgctgccatt2340
atgttggacccattactgctgttaaaacatcgtcatataattatgcacctgtgcctgccg2400
aaggctgagagcttgcacataaagaaagctggaaagtgttactcctacccttacaacaaa2460
aaaaacacaagacacatcttaagtcagcaactttccataaaaccatcagagaatgaagtt2520
ctaagggtaatcaactgtcccaaaatctggagacacacagactgctgcaggatctgagta2580
tttgtttacctgagatagatgcccctcaatgccatttaatctggtaagaaaattcagcta2640
gaaatttagaatgccttggtaaaggccaagtacgatccagtgagagagtatagggaagtc2700
tgcaccctttggcacgtttctatatcaggcactcaccgggaagatggggaagaatcatga2760
aaaactcaccttttattgtgctgggttggggaaatagcagtgtctgccttaatctgtcca2820
tacttattactttattggcctatgaaaaataaatcaaaacaacaatctgcagaaggacaa2880
caaaaggaaataaaaaataaaaacaacacaaaaaaacctgcaccataagagcatagattg2940
ttaaatcactcaatttattgtttaaaaattgaatgcagaaaactgtgagtatgcattcca3000
a 3001
<210> 208
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26772-268 : polymorphic base G or T
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-26772-268.misl,
<220>
<221> misc_binding
<222> 1502 .1520
<223> 99-26772-268.mis2, complement
<220>
<221> primer bind
<222> 1235..1259
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1702..1722
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-26772-268 probe
<400> 208
gcctccaaag ccatggggaa ctgtgagtca gttaaacatc ttttctttat aaattacccc 60
agtctcagtt atttcttcat agcagcatga gaacagacta atacaacagc cctcagtaaa 120
aactgtgcta gtaaatttca gtagtttctc actgaagtct ctgttgaagt cagtcttaat 180
catcaaaact gtaaaccaaa tcttccactt tcaaatgtgt tctaaagcaa aatgttcaaa 240
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
406
tttctaactatatcaaacattcaaacctgcaaaaacggcattctgcttataggaaaatgt300
tgatctcttcttacgtttgatactcttgcatgaatacaatttttttttccttattccctt360
ctcctcctcttcttccactaacttgttgtttacataataagttttatgtcatgctagtag420
agttggtatgtagttgcataaagacataacaattggaatggtgttagctagtaaaaattt480
aaaattagatcaagatcttcaagatcctcaaccacatattaaagcttcataattttgaca540
tttgggagaagacatgagagaggttctttataaaattcagtttcaagaaccaatttcaag600
gttgctatacttatgcaatttagtaaaatgcacatagtaaaagtctgaagtgttttatgg660
atttctctttttcacttactttgccaaattaagaacatggtaaaaacttgcccttatagc720
catctaagtctccgctataatttgaatatatcccacaaagttgatgtgttggaaaattaa780
ttcccaacacaaaatttgagagatgggacctttaagaggtatttaataataaattaatta840
atgttgtcattgctggagtgagtttgttattgaaagagtgagtttattataaaagtgagt900
tcaaatccctcctacctgtgtgataccttctgccttgttacgaggctgcaagaaggccct960
caccagatacagccccttaattatggacatccttgtttccacagccatgagccaaataaa1020
ttttgattcactgtgaattacacagtctgtggtattctgttacagcagcacaaaatgaac1080
taagatagaaaatgatctctaaagcgaaaaatgatttctaatgcataaaatgtaatattt1140
ttattagtaatttacagtgttttaaacgtaagacggctgaggcaatatgaaactgatgaa1200
atgaacagatataactccaggtaaagactaagaacattttctaactttgtccactgccac1260
cctcctcctcatccacacgtaaatgcacccatgtatgcgtgattttgtagaatacatata1320
tcaatgagaatatgtttattccagtggaggaggagcttaaaatctcacatgttgatatac1380
aataagcatttcatcttctcataattatccacagaagtatcacagaagccagtgacaatg1440
cttagaaatgctacagaaaatacaactaaaaataatttaattgtaaaaatccaagaattt1500
yatagttaaaattctaaaatatttcaatttaggtatattttttaccctgtgtagattact1560
tctctattaccatatttgaaaaccaacatttcaatttaatcaatccatgtgcctattcaa1620
acatataattacactaaaagacaagggtatccttagccacaactgaaggaatgatcaaat1680
tcgactccctggctttctctgcaactttctcatcctaatttctttaaaaatatatataaa1740
tcctgttcaagtaactgcaaaatcttctcagtgagtgctatggatccagacttttcttta1800
catttttgcaaaatcctgctcacttttatatatttttgtaggaagctcatgagctaactc1860
tttggaaaaagtctgcaacatcaattttactgtttttgtatttttctctttcagaaatat1920
ctgaaagttaaataagtcattatgtcttcacatcccaaatttcttcattaaaaggaagct1980
agcagaagac~aagtggaggccaggacatttttttgactatattcgatttgctcaaatgct2040
tttttcttcatctacaaagatgattatgtgttttttgtcctttattttatgaaatggttt2100
catacactgtttgatgttcacatgttaagccaacattacatttctgggataatttccact2160
tgatcatggtatatgaatttttaatatgttactgcattcagtttgttggggtaagagttt2220
gtttttaggattttcacatttgcattcagagaggatattagtctagttttttgtttgttt2280
gtttgtttgtttcttgtagtctttgccttttttttttggtatcagagtaatactggctcc2340
ttaaaataagagcgtttgcccttttcttttacttttttctttttggcagaggttggggtg2400
agtgttaatttatctttaaacatttgaaagaattcaccagtgaagccatcatctgctccc2460
ggactttcccttgtggtaatattttttattgctaaggcaatattgttgcttgttatagat2520
ctactcagattttctatttccctttgagtcaattttggtagtttatgtttttccaggatt2580
tcttaaattccatattgtttatcaaattactgattgtttgttggtgtacaattacaagaa2640
caaatataagagaatcacaatttttttataatgctttgtattttctggggtctctaataa2700
catccctacttacattttagtaatgtgaatctgttctattttttctttttcagcctaact2760
tatggtttgactttaaaaagacatttcaaagaactaatgttctttttgtgtgtgatatct2820
attgctttctcattctttatatcatttatttgtttgt.ttgtttctattaaaccttttcta2880
tttcctcccctctgcttgctttgagtttggtttgctcttcttagtctagtttatttaaat2940
gaaatattgttattgatttaagatctcttttcttttttaatatagtcatgtgcaaataca3000
a 3001
<210> 209
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26776-209 : polymorphic base G or T
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-26776-209.misl,
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
407
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-26776-209.mis2, complement
<220>
<221> primer bind
<222> 1294..1314
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1755..1775
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26776-209 probe
<400>
209
agtaataatacatagaattactgagctcttgtaattttctaagcaaaataatagaagtaa60
gaattagcatttatcacttcttatagattttcctacctaattctcatgtaataatattaa120
gttattaatattgatactattgtcaccattttacataaaaaccaagtatagcccctaaaa180
ggaaactaacttgcccagtaagtattgaaattattacccagcttgtatgtaaagagaagg240
tagcctgtggtcttcattattttgttacagcatctcccttgggcagcatctcattttggt300
ttattaatgtggtagtaacttcaaaagaaatggattctttgatctctgattatatgcaat360
ctggaagcaggtgttttatcagtcactaacaattgaagtgaatgcgttacatcagtaaag420
ctaataatgtaataacatttacatcccaatgatcttacagcaatggttctcaaagtgtgg480
ttttcagatcagaagcatcagcattgttagagaacttgttagaaatgcaagttcctagac540
ccatcacataacttttggcatttaaggattaaaatatgtatgtttactagtcctccaagt600
gattataatgcacattaaattttaagaaccacaatattcaagtataatttgatgaattta660
tacaatagatgcaaagccaactcaaacaaaaccatgtcctcttggtggcacaaagatgca720
acaatcagatgagataaaaacacatcctttagccaatctggacactatccgccatggagc780
aaagcaggcaaacagaaaagtccaggataaattcctgcaagccagggtaaatactgccag840
tcaacaaagttgactatgtcaaggaagagaaaaccacatctactattagatgaggtctta900
ccatgtattatgcactgtattatatggatataaatccatttaaattaaataacaaattta960
catggtggaatcaattattatccatattttctaaatcacaacactaggagccagtgttat1020
gcctaattcacagagttagaaataaaaaatgatggaatttcaggccggatatgtttaaat1080
ctaaggcgcatgctcatgatcattgttcactgtagcctcccagacagtacttactgcaga1140
tgccagtgggcaaaattcaaattttggcaaaataacgaggcaacatcaaaggctctagga1200
atcagggttgaaattcctatattggccccctgctatgtttaatgccatccaccataaatg1260
atgcaaaatgcagctcttttagtatcagttgtggccatccttcttgacactctccaaggc1320
atcaattgtccatattacttctttatagctcatctacagtcatcagttcatgtccttctc1380
ctacctccagacagtcagaatctttccatcatcgataacatggatgacttcatcatctga1440
cacctcactctgtattatttcttgctccagtcttgttcctagggaagtgtatattcgcat1500
kactttcactttgcttgtattacttacactgcttaagtcattcctcccttgtctggctca1560
gttaatatggtctctcttaaatgctatctctccatgaaatattcctctaccactattctc1620
ctatcttccttagaaaagttagtttcatctacctttgcaggttgtatttacaccagtgaa1680
tgattatttgccagtataaacctcctggactacaaactcaatcagggtacagatgaagac1740
ccaggctgtaatccctgcaaaaatcctggcacacagtaaatgctcaaagaaacacccctt1800
ggtagataggcaggcaatatatctatatattaatgaattaatttcttcctgatgcagaag1860
agcaatcagtctcccctctgctatggaatgtgtgaaagcagaagtgaatctcatttaatg1920
agtcacagtattcaatttcttagatttttcaatggtcttatactgatagtaaattttata1980
tttctaagagaaataatgagtacatcttaaatttcttttttgatcttgttttctgaaaga2040
taatctacatataatttttcatttttagtaagcttagaataagagaactaagtatgtttt2100
aagtatgaaagtaaatcttatcaagcttagttgactggatgattgaaaaggacgaaaagt2160
ggtgaatcacaaaaaagacataaatgcacttttaatatttcatttgaagtcaaaacatgt2220
aaacatatatgggtttgctcatcagttgatatgtgagtcagtatatggtatttaaagctt2280
gttctctggaaccagatgtcctgagttcaaatcccatgaaagatactgagcagctctata2340
acttagggaaattattcattttcttgcctctcaattttcttgcctctcaattttctcgtt2400
tgtaaaatttggaagaagaatattaaatgagttaattttataaagctcctagaaccctgt2460
gtggctcatgctatatacatttgcaaaatgtatatatggtcccagtcactgcatggctat2520
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
408
aaaaatgcatctcaagggatttttgtaatggaaatgtcctgtgtcttgactgtattggtg2580
gacccacagatacacacatatgatgaaatttcataaacctaagcgcacccgtgcacatgc2640
acacatacacacacatacacacatacacacgagtggctgggaaaccggtaaaatctgaat2700
gagatcaacagactatttcaatctcatcctcattatgatcttgtactatagttgagcaag2760
gtgataccactgggggcatatgggatctctctgtattgtttcttacaactgcacatgaat2820
atgcaataatgtcaaaacaaaaggttaaaaataaatacatgggctattgatagtggtaag2880
catgtgtagggacagaggctatacagaaaccctgtaatttccactcagtttttctgtgaa2940
cctaaaactgctataaaatataaagtctactaaaacaaccaaacagtgtttatttttgtt3000
t 3001
<210> 210
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1497
<223> 99-26779-437 : polymorphic base G or C
<220>
<221> misc_binding
<222> 1477 .1496
<223> 99-26779-437.misl,
<220>
<221> misc_binding
<222> 1498 .1517
<223> 99-26779-437.mis2, complement
<220>
<221>
primer
bind
<222>
1072..1089
<223>
upstream
amplification
primer
<220>
<221>
primer
bind
<222>
1548..1568
<223>
downstream
amplification
primer,
complement
<220>
<221> binding
misc
_
<222>
1485
.1509
<223>
99-26779-437
probe
<400>
210
atattagtggactatgtaccctaattaaaaggtagaaagtgtaagaatggattaaaaagc60
acgacccaaccatacgttacttataagcatgttttaaatgaaaagacacaaatagttgaa120
agcaaaataacaaaaatgtatatgctatggagaaactaagaagtatgttgatgtgtctgg180
attactatcagacaaagtagatttatggaagagattgttggtagataaagaaggtcattt240
attgatgataaaagtatcaatttaagaaggcaaaataataaatgtttaaatactcagtag300
caaagctctcaaatgaatgccaaaaaccccacaaaactaaaggaaactagagaaatctat360
gatcctagtgagaatctggcacagtttttccagtaaataatagaagaacttggaaaaaca420
gtattagaaaaatgcaatatttgaataatgctatcatcaacttggtctaattactatttg480
tggaacgctaccctcatttgatgcagaatatacattttaaaaaattgcccttggaacatt540
cactgagatagacaatatagttgaactatgaaagaaatcccaacaaacttaaaataatta600
aaattttacataataattctctccgatcacaatggttttaaattaaaatcactgatagta660
attttcctagaaaattccaattgtcataaattaaacaatacattaggacatatctcagtc720
aaagaagaaaccacaagaaaaattagaaaaacttttaacagatctaactctacacttctt780
agaaaaatataaatacattaaaaataacaatattgaaaacggtatatcttgctaactcta840
agcaaaagaacattagtgaagctgtatttatgttggacaaagtagagttcagagtgataa900
aaaggggataaagatggtcatttctcattgataagggagtcaatttatgaaaagagctta960
aacactcctaaaagtttatgacctaataacagaaagtcaaaatatattggagcccaaatt1020
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
409
gatggaactaaaaggtgaaatagaataacaattatatttgcagattccaggaccactctt1080
caatagtccattgagtaagtgaagagagagtcaagaaagatacagaaaactttgacccac1140
ttgacatttatagaatccaactctcaatttaggcaacatatacaaatggtcccagactta1200
acaatggttcaacttacatatttttgactttacaatgattttatcaagacgtaagcccat1260
cgtaaatcaaggagcatctatactttctttttaagggcacataaaatatatacacatata1320
agttgtgttttgagccataagacaagtgttcattaacataaatgaattcaaatccaccct1380
ttgatcaaatttaatgtaattagaaatcaataacaaaggtaaatgctgaaatcccaatat1440
ttagaaattaaattatatgcatctaaataactcatgaggcaaaaaatagagaattasata1500
gtattttgaaatgaaagaaaatagaaccacaacacatgaaaacttgtgagatgcagataa1560
agcagtattcagggagaaatttgttgcactactaccaataatacaattaaagacaggcct1620
caaatcaatgacttcagatactaccttaagaagttagaaaaataaagcaaagtaaaccta1680
aagtaagtgaagaaataatgaggattagattagttattgaaataagtaaaatggaaaaca1740
aaatcaacaaatctgattctttcagaagacccatgacttttataatcctctagccatact1800
gaccaggaaaattacaagcgacactcacaagtagtttctacagtgtagatgagttgaatc1860
attcctcaaaggacacaaattcacaaatttcaaaagcatgtgctcatcttaatggaatgg1920
agaaatgtctaatatctattacttgtgaaaactctgggtaaatgaaacaaattcagctta1980
acctgataaatgatatcttcaaaaactctacatccgaaatcatatataacaataaaagac2040
taaatgtttttcctccaaggccaggaacaatctaaaaatgtccacttcaccacatctttc2100
tagctaaataagcttatttaatgttggtgggaactattaagttagttcagtaactttgga2160
aaatgtaacatcaatatgtaagaaaaaagtatatttgtatatactagtaacaattaaata2220
tgtaaattaaaaacataacatagaatagtagtaataatatataacatttgagacaaatat2280
gatggaaaatggacaacacacttattctaaaacctatacaatatttctaatagaaattaa2340
atacatggattcatatacataaatacacatatacagaaatggattacatacatacataaa2400
tgaataaatacatcttgtttatggttgaaagattaataatgctaaatgccaattctccct2460
aaattactataggtttaatataaactcaatcaaaatcctagcagaattccttttgtcaga2520
gttggccagctcattctaaaatacatgttcaaaagcaagttacttggaatagtaaaaata2580
aatttgaatataaaaatttcagtttagtatttgcagaacttgacttctagacttattata2640
aagctacagtaatcactagaatggggtactggcatcaagagaagcaaatagacaataatt2700
gggagtccagattcaaacacatatagtcatttaatttttggcaaatatgcaagagtaatc2760
cagtcttttcaacaaatgtattggaacaattataatcttttcaacaaatgtattggaaca2820
attatatacccatatgtaagaaaataaaattccacccatttaatgtaccatacacacaca2880
cgagtttggtaagttttaaaaagctgaagacataaatggacacttctcaaaagaagacat2940
gcaagtggccaacaaacatatgaaaaaattctcaacatcactcagagaaatgcaaatcaa3000
a 3001.
<210> 211
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26781-25 : polymorphic base G or T
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-26781-25.mis1
<220>
<221> misc_binding
<222> 1502..1521
<223> 99-26781-25.mis2, complement
<220>
<221> primer bind
<222> 1477..1497
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1905..1925
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
410
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-26781-25 probe
<220>
<221> misc_feature
<222> 21,274..275
<223> n=a, g, c or t
<400>
211
atatgctcattgtgtttttgngtcgtcatagcttagctcccacttatccgtgagaacata60
caataattgattttccattcttgagttacttcacctagaacagtggtctccaacagctgg120
gcgtggtggctcacgcctgtaataccagcactttgggaggccgaggtgggcggataacga180
ggtcaggaaatcaagaccatcctggctaacaaggtgaaaccctgactctactaaaaatac240
taaaaaaaaaaaaaagaaaaagaaaaaaaaaaannttagccgggcatggtggcgggcgcc300
tgtagccccagctactcgggaggctgaggtgggagaatggcgtgaacctgggaggcggag360
cttgcagtgagtcgagatcgcgccactgcactccagcctgggcaatacagcgagactccc420
tctcaaaaaaaaaaaaaataataataatggtctccaactccatccacgttgctatgaatg480
tcattatttcattctttttcatggctaatattccacggtgtataaatactacattttctt540
catccactttttggtcaatgggcatttaggctggttccatatttttgcaattgcgaattg600
cactgctataaacatgcatgtgcaagtgtctttttcatataataacttattttcctctgg660
gtagttacccagaagcaagattgctggatcaaatggtagttctacttttggttatttaag720
gaatctccatactgtttttcacagtagttgcactaggtttcttgtttctttgtttttggt780
tttgttgtttttgttttgagcctcactctgttgcccaggctagagtgcagtagcatgatc840
ttggcttactgcaacctctgcctcctgggttcaagtgattttcctgcctcagcttcctga900
gtagctgggattacagacacccatcaccacgcctggctaatttttgtatttttggtagag960
atgaggttttgccatattggccaggctagtctcgaactcctgacctcaagtgatctgccc1020
atcttagcctcccacagtgctgggattgcaggcatgagccaccgtgcctgcctgtggttg100
tacttgtttacattcccatcagcagtgtagaagtgctccctttccacaccatccatccaa1140
catcaattttttttttgattgtggccattctcacaggagtaaagtggtatctcattgtgg1200
ttttaactttcgttttcctgataatttgtgacattgagcattttttcatgtttcttgacc1260
atttgtatatcttcttttgagagttgtctcttcatgtcctttgcccactttttgagcaaa1320
gtaagcagacaacccacagagtgagagaaaatatttgcaaactatgtatctgacaaagga1380
ctaatatccataatctacaaggaacacaaacaaatcagcaagatcattttttttccatgt1440
gtcttctttctcagctcatttcttgtaccacatgcgccatagtaaggagaaagtatcttg1500
ktatgtacaatttactgttatagtaatttggtgattaaaaagcacttaatgaaataattc1560
taaattgttatataaaaaactaaaaatcagcaggcagaggccctcctgactgccttaatt1620
caactgtacaattgtataaatcattaaattcccaggagtctcattttctcatgtataaaa1680
tggtggagatggaaaaaatgactcttaaggtcattgccagatctgatatactctgattac1740
atcccaggctgatggtaacaaaaacacatgtggaaaatatagggctgaaaggactttgcc1800
aagtagttgattactacgacatgcatcctcactgctgttactagaacaagattagtacta1860
tttgtatcttgtttcagtgtttttcaaactttgtttctcctctaggtcacttgaaatgag1920
caaaattccatcattagcaatctttttatgtgatgctagagagattattctcccgctctc1980
ccaaatatttcattgtgtctttttcccaaatctcaaaaaaaaaaaaaaaaaaaaagaatt2040
ctctcatctctcactcataacagataacttcggtttttaattcccctggaaatgcaaagg2100
aatctgataggaactccatcaatatctcatccttaaaactctgagcctttcttcttcagt2160
gcccgtattctttttctcgagttgcagtggaggccacattgcctttgggaaaataccatc2220
atcccactcacactccagatggactgcttcttatcagggttactcaagtttttgcctcat2280
tcttctactggttgttatttaaaatatttaccaaatggttatgacacaagcatagatcac2340
agaagaggaagtcagcactgaaaaccagtcctgctctttggaatcaccccttcctctctc2400
tcgctccctctcatcatatccatctgcctaacacggtgcttgacaacttcccaccttaag2460
aaaacacttccttggcaccctgggcttctttgcctgccatccagtttcagggcactaaaa2520
aatacaattgccaatatgggatgcaataaagagcaaatggcaagtgaagaagtggagata2580
ataagataccaatattcatttgagtagattttcttctaaaaggaatcgttgggtcacaca2640
ggctccatttcacactccctcttactgctcttatcaaatcatcagtgacctcatccttgc2700
ccctttcagtggatactcttctgtcattgatcctacttacttcttcatagcagtttctcc2760
tctcttgctcagcattttgttacaacatgctctatttgtgttgtcttcttcaccagctgc2820
ttccaagcttcctttcctgtctcctacaacttccaaaaaaccttaaagttttaaggtgcc2880
acaaagcttagggcacaataccttatctattgaaaaactctatgtgatctcatccttttc2940
tgcagtttaaaatggcaatcgcacactgacaattaccagatttctctctctgacatttat3000
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
411
c 3001
<210> 212
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26782-300 : polymorphic base A or G
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-26782-300.misl
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-26782-300.mis2, complement
<220>
<221> primer bind
<222> 1202..1221
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1695..1715
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26782-300 probe
<400>
212
aactaaaaatcagcaggcagaggccctcctgactgccttaattcaactgtacaattgtat60
aaatcattaaattcccaggagtctcattttctcatgtataaaatggtggagatggaaaaa120
atgactcttaaggtcattgccagatctgatatactctgattacatcccaggctgatggta180
acaaaaacacatgtggaaaatatagggctgaaaggactttgccaagtagttgattactac240
gacatgcatcctcactgctgttactagaacaagattagtactatttgtatcttgtttcag300
tgtttttcaaactttgtttctcctctaggtcacttgaaatgagcaaaattccatcattag360
caatctttttatgtgatgctagagagattattctcccgctctcccaaatatttcattgtg420
tctttttcccaaatctcaaaaaaaaaaaaaaaaaaaaagaattctctcatctctcactca480
taacagataacttcggtttttaattcccctggaaatgcaaaggaatctgataggaactcc540
atcaatatctcatccttaaaactctgagcctttcttcttcagtgcccgtattctttttct600
cgagttgcagtggaggccacattgcctttgggaaaataccatcatcccactcacactcca660
gatggactgcttcttatcagggttactcaagtttttgcctcattcttctactggttgtta720
tttaaaatatttaccaaatggttatgacacaagcatagatcacagaagaggaagtcagca780
ctgaaaaccagtcctgctctttggaatcaccccttcctctctctcgctccctctcatcat840
atccatctgcctaacacggtgcttgacaacttcccaccttaagaaaacacttccttggca900
ccctgggcttctttgcctgccatccagtttcagggcactaaaaaatacaattgccaatat960
gggatgcaataaagagcaaatggcaagtgaagaagtggagataataagataccaatattc1020
atttgagtagattttcttctaaaaggaatcgttgggtcacacaggctccatttcacactc1080
cctcttactgctcttatcaaatcatcagtgacctcatccttgcccctttcagtggatact1140
cttctgtcattgatcctacttacttcttcatagcagtttctcctctcttgctcagcattt1200
tgttacaacatgctctatttgtgttgtcttcttcaccagctgcttccaagcttcctttcc1260
tgtctcctacaacttccaaaaaaccttaaagttttaaggtgccacaaagcttagggcaca1320
ataccttatctattgaaaaactctatgtgatctcatccttttctgcagtttaaaatggca1380
atcgcacactgacaattaccagatttctctctctgacatttatccatcctctcaacgctg1440
aacacatatcccagttgacatctccactgaggagtttcacagatgggtcaaatgtaacat1500
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
412
rtccaaaacagacctcttgtcctcctctgtgtacgcccttcttactttcattttaaactc1560
agttctggataatattatttacccaaattcccaaagcaaaatatttgaatcaaacaatct1620
tgtcctcctcctccctagccaatatattagcaagtatggccaagtcttcctcacctatat1680
ttttcaaaatccatccatacctctctttcttcaatgccatatgtcctattgcatttaacc1740
ctttactggtctactgactagctatattactccattttcctactgctttgaagaaatacc1800
caagactgggtaatttataaagaaaaacaggtttaacagactcacagttccacatggctg1860
aggaggcctcacaattatgatggcagaaggcaaagggggagcaaaggcacgtcttacatg1920
gcagcaggcaagataacatgtgcaggaaacttctcctttataaaactatgagatctcatg1980
agactttttcactatcacaagaacagtgcagggtgcggggaacctgccccatggttcaat2040
tacctcctaccgggtccctcccacaacacgtggggattatgagagctacaattcgagatg2100
agatttgggtgaggacacggccaaaacatatcactagcttcttattttacagatctcatc2160
ttgagtgtcgtcttctcaggattttctttcttgagtactctactcaaggtaactccaccc2220
cagcaaacccaaagtccacacagttggcagctccctgctgtgtggttcagtgcatttcac2280
tgtacttcacaccatcaaaatgtgacatcctttgtgtgggcctgtgtattatctgctttc2340
accttctaaagtgtcagctacatgaaagcaagtatctaatcaataaaaacatccttaata2400
aataaatcagtagtaataactatcttctagctaaatctaaatgggggagaggggacctag2460
ccctctaccttcccgtcaattgcttcatactcatataatactttaaagttttaaaagtac2520
tgtattattactgttaaatctgatcataaataatccttcaaagttagtgagatccaaata2580
aatatatgctatgcacatggtcaaaaccagtatctaaagttaagtgacctttcgaatatc2640
atacaataaacattttgttttaacagtaccagaatttgagctctctaatttttcttactt2700
gggtattgtttatagaaaagtcttagtttcttgaaaaaaactaaacatgcatttgtaaat2760
tgtttaatgtatttataggtaaaattatttttcctgtgactaaacatattaaatatgatt2820
atctagtatcagtttattctgtatgactatatatatgggatatatatatcattttgttat2880
tgacactaaattggttatgtaaataatataaatgtgggataatttattcttttaaataat2940
tttatttaaaaattaatcgagtttaaaaataataagaaaatggaatttttaacattttta3000
g 3001
<210> 213
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-26783-81 : polymorphic base A or T
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-26783-8l.misl,
<220>
<221> misc_binding
<222> 1502..1521
<223> 99-26783-8l.mis2, complement
<220>
<221> primer bind
<222> 1421..1440
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1857..1877
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-26783-81 probe
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<221> misc_feature
<222> 2988 .2989
<223> n=a, g, c or t
<400> 213
413
gaaaatggaatttttaacatttttagtcttcccaaaggaaaaaaaaataacagatgtaag60
aataagagtgtcattatttaagttatatatgatgtcatgacatctaagcaaaaataaatg120
aaaactgtatagactatcaagactatcaacactaaagaaaaccttgaatttgcacgaaag180
acaagacctgaatgtaagagacaggttcagtagaaaaagaagtgtctaatatcaagtcag240
aatgacaggaggggccctatcctgtatttaaatgctgaaaggtgtaacaatgtacataat300
gatctacatgaatcacacaggtcaaaggatgcagtgccacagaaagactgctgaagaatg360
ctgatagagacgtggttagggcagggagaaagtagcaaactaagataaggcaagtgccaa420
ccctattgtgtaacacaaagcagccctttaattttaactaaaaataatttaagatttgtc480
accttaatttggatgatatatttattgtgataacaatcatcttgtcacggaatggttaaa540
tttacctagattttcaatttaaataagagttggtaggaaacatctcacattgaaaatatc600
tgtttcacagcatttggtatgaattgtgcttagaacaattagaaaagaggttgctattga660
tgcaaatatataggaatatttgtaaaaattatattacaaaagctagtcaagaaatcaaat720
tacactgcctcttccagtgccatttctgtgggaaagtgtggctatgtgtctaagcactgt780
gaaagtcatatcacattatacaatgaattaggagaccttagcattcattcatcctcaccg840
tgagctgctttgttgagcgcttttgcatctccacattaaccaattgggaaaataattgca900
ttaacatagatagttgtactggagggaaaggaaaaatattcttttcttctacacaatgtt960
attttgtaaacaaactctacagtgataaaaaggccccaggaccaaactgaagattagcta1020
gaacacattctaggagcatgattccaattattgtgatgaagctgacctatgtatcaaagt1080
gcttgatagtagaaacttcattatataagacagactaagctaatgtgcaaacaaagaaat1140
attggaaaaatgtaacaaattcaatgaaatgtcaatgcatagcacgaatctattaaaggg1200
aaatctccttttggcagaaacaaaggtaaatcactattgagaacactcagtgggagacag1260
gacaaaggggttcatgggaaatatgtaaaataggaatgagacggaagttttccattttgg1320
gaactggagtttcaatttctataggaggatgagacctgggctgtgacctgctgttggtga1380
gagtatgaaactgatcaactttcatgaacctaggagttaggcttaaaggattgctaattc1440
aaataagaattatacaaattttgcacataatctctgaaaggctttctatccacttgcata1500
wtacttcatgtctagagcctacacatgattgtttcgggactaatacaaacatattggatt1560
tagagattcttgagcatggaagatagaaataatatggtagaactagaagaagcaagtttc1620
cctaatgacctggtggagcaatctgaattgccacctatagaattctttcacttgtgaaaa1680
taaacaaagatatgtttaaagcactggattcaagtctttgctcctggaagccacaagtaa1740
ctgctaactgataaactgatctggcgccaaaaaaattgatcccaaacataattagaaaaa1800
cagatttcttcaatgggccaccccataattatttatggtctgatatgatatttgctctct1860
tttgatagttgaatgtgttaacttttttaaaagtcatgcaaaatatttcatacaatgctt1920
aataagttacattatcacaaatgttcagtataatattagatttccctttcttaacttgtg1980
aaaaagcactttagtcacagagaagctcgaaaggtagatacagatacttaaaaaagtaaa2040
attgtaaaaggagctgtaaaaattttctttaaattatgacagctaaaaaacccatctcgt2100
atcccattttagaagaagtattttaagcatcagaagcaacacacaaaatggtttgaagga2160
aatagagacaagatagacggtgtctaaaaaaagcatgaagtgattattgcagaattcacc2220
ttattgctaattatatgatgaggtgggaaatccaaatagctcctttgtgcacagactgca2280
gattttctagaacatttagtaaaatataaaaatagtttttttttttaagtttagtttccc2340
aatgctgatcagacaatgacctctattactgtttggaacaacaaaaaaaaaaagtctgac2400
agcttatgagtgaagtctacaagtcactaaaaccctaaaaagagcatctcatgagaagtc2460
tataattgcactctgggaagtttaaaaactctagtgatgtttttaagaaaatagaccttt2520
ttgtatatcttagatcttaccaacttggctactaattttggtctgcttgcacaccaagct2580
agacaagcagttaattgcacttaaattgacattttgattgattcaaatggtattcctgat2640
gaattttactatgttgtaaagaaagaagttcagaatgctcaataagaaaggcttggggaa2700
agcttttgatgtttaaattttagagttgagaaaattaagaaccaaataaattaagtgact2760
tcatactcggttaatcagtaaaacaaactagaattagacccaaggctcctaaatgctctg2820
gccagctttctcctggtggatgacacatggtaatacagatcatttgataggccaagaaaa2880
ctaccaatatactcatattgatggaatctctgtctcttgcatgcccccttctgataaagg2940
ctaatacatctataccaaaaaaaaaaaaaaaaaaaaaaaaaaaaaacnntatttaagaga3000
g 3001
<210> 214
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
414
<221> allele
<222> 1501
<223> 99-26787-96 : polymorphic base R or G
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-26787-96.mis1
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-26787-96.mis2, complement
<220>
<221> primer bind
<222> 1406..1425
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1872..1892
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-26787-96 probe
<220>
<221> misc_feature .
<222> 2873
<223> n=a, g, c or t
<400>
214
cacgacgatctctcacacacagaccaggaacaagaagtagcgaggctaacagaaaagaac60
cgcacatgaagttggatttcaagttacagttcaagatgggactaaacacagtagtgtttc120
atttgtatgatattctgaatgctgcttcttaacacacatgcaatttaattttaatgggta180
ttttactgtgattaataaatgtcaattctctgtgttatcttcgcatcataacatattcat240
agactttatctatgccaagagtacttttattgaacttcatgttctagagaattggggtgc300
tgttaacaatagtttcacagtttatgtgttttgtaaagctcaatctttaatgaaaatgct360
ttgtgaactcacagacctgtttccttgataataaaagagtaaagaaacatagaaagggca420
tggatagtgcagatgtcacatactggataaattaactttaagatttgttaatggaaatac480
aattttttaatacaatgaaggatgattcaggctggctaatttaatcagacttgttttttt540
caaattcatatcacctaaactttatccagaataacttatacagaataccattaaagccta600
ctgcttctaggaggtagatactattacttctaatgagtgtagaaaggttatttttgggca660
attaattttaaacataaacatttctcattttaacattcgcctttcattctagacttagaa720
gaagaagccattatgtaaatgctgccgtggaggacccttccctccacttattcagaacct780
caaggtccaattgatctgtgatagcgttgctgacaagttcagtcactattgagcatcact840
gctctccaatccccagagcacttctccttcatattaatagagtgcgtcttagttataaag900
ccctttcacacatgtgcacgcgttaccttcatcccaaactatagagtaggctgttttttc960
tcttcattttgtaccttttgaaactgggacttcactcacaactgtagttcagtaagtgat1020
acagttgggtaagacaaaggactactcgcacccaaccttctggcttcatgtctagcctac1080
atcacacacagtggcactcaactgtgcattattcttgtttgtgtgcacttcttgtacata1140
tatgattggaattccaaaaaaagtagacattttagggtgcagactcaaacctttctagta1200
gctcctatagcacctggtacaatctgaggcatcatggaacatagtatgaatttaaactaa1260
aattcaattcaccaacataaaccgttcattgactgcatttttaaagcagggtgcaaagaa1320
aaaagatttcaaatgtgagggacgaaaatactcaggcatgagaatagttgggagaggtag1380
tcctccattttagcgtctggtaaaggtcaggttttttgaaagcagattttaaggtggaga1440
tttgcattcgggaaatatgttgagtgctctcactcagcaggatcttctctggggtgaagg1500
rtgaagaaggcaggacagggcagagggagacgctggaccgtgagccctcagccaattgtc1560
tggagagctctggagttggatggccctctaagttctcccaacttggacaaaggacatggg1620
tatataccgcaatttcaggagtccttggagtgacactgtccagcctcctgaaagggaacc1680
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
415
ttaggtgaggctgctctcttcaaatgaagggaattctcagagaaggccga ggactgacgg1740
cttgccacccagcgccactaccagcagcttgtagaaaaaaatattttaaa tggggaatac1800
atgcagcacaacatagaattcaccactccaagaaaaaggaagaagtgagg attgtattat1860
ctctctctcaagtgaagcattgctgtagtaagtctatagaaaacatgcat acatgtgtaa1920
ctgctgtcttgagcatttctgtactgagcactttatagagattattttca ttaatcttta1980
caaaagccttagaaggcaatcactattgttattttctttttacaaatgag gaaagatgct2040
tggcgtatctgagaaggtgataaaggccggagggctgaagtgcagacagg gatggagaga2100
gtgggacggggcatggaggtgaggtagaaggaggtcctgtagtgggggcc tgatggggct2160
cagaacaggttgaaaatgttaccaataaacatgtgagccagcaaagattt acaatttctg2220
attgtgtgtgtttctacccctccctacccattgtgtttgtaatttcaatt acagacattt2280
caaagcagcctatcttcatttgaataagatgtgggtatcagcgaactttt aggcaaagag2340
ggagcaaaatcaaaaatgtcaaacttgaaataaaaataattagtaatata attttttaat2400
ttaaaaaatccatctccaatttgaaacagtcttactatgcctcgtacaag ttagtatttc2460
tgttgcaaatagattcaagaagatagaaaaagcactaaatggataaattg gagagggaaa2520
ttattttgttttcttcctattaatggataggaagtaattatacaactaag atgatacttt2580
ttcttattatccatcaaggaacttgggacccacaacccatttgttttctt taagcagaat2640
tatgaatcatagagtaaaatttttctgccaagtcttagtaggacactttt ctttccttac2700
ccataaatttaatcactcagaatgtactagtgtttataccaaatatctcc attgttaaat2760
cttggtataagtttttaccatcttcctcctacattattgcaatattcttc taattatctc2820
cttgcttctggtcttgcctccatacaatttattctattcacaggaacaaa agntttttgt2880
ttttttttttttgagtcaaactctcactctgtctcttaggttggagtaca gtggcacgat2940
ctcggtcactgcaacctctgccttccctggtcaaacaattctcttgcctc agcctcctga3000
g 3001
<210>
215
<211>
3001
<212>
DNA
<213> Sapiens
Homo
<220>
<221>
allele
<222>
1501
<223> base C T
99-26789-201 or
: polymorphic
<220>
<221> binding
misc_
<222>
1482..1500
<223>
99-26789-201.mis1
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-26789-201.mis2, complement
<220>
<221> primer bind
<222> 1301..1319
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1771..1791
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-26789-201 probe
<400> 215
taatcgccat gtgtcagaga gagatctctt gggaagtgat tggatcatgg ggacagattt 60
cttcctggct gttctcatga tagtgagggt tctcattctc acaagatcta atggtttttt 120
taaacgtgtg ttgcacttcc cccttcacct ctctctcctg acaccatgtg aagaagatcc 180
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
416
ttgcttcccctttgtctaacaccatgatggtaagcttcctgaggcctcccagtcatgctt240
cctgttaagcctgtggaactgtaagtcaattaaacctcttttcctcataaattacccagt300
ctcaggtagttccttatagcagtgtgaaaatggactaagacatgtctgatgtgtaattgt360
tgaataagaaatgggtgtgcatgcatgcacacacacacacacacacacacctgtgtcaaa420
tgaaaaaatgaaatctgtagcatgcagactgcctaaaatgcttgaaaaaatagaaagatt480
ttcccaaagccagcacaacttgaaaatttcctgaagttaacccatcaaacttaattcctt540
ctgatttcctctggaccctttcgaatgggaacttctcggttcttctaaaattatatgggc600
ccaattgctgagccgtatatttctcagggactagtatattatctaaaaattcagcagaaa660
ttatatatatatatatatatatatatatatatatatatgtgtgtgtgtgtgtgtgtgtgt720
gtgtgtgtgtgtgtgtgtttgtgtgtgtgtgtttgtgcagtatggtgtttgtatataatt780
attacttgtaaaaacaaaattaaattattacatatggtttcctccagctttggatcactt840
caaagagtattaatgaatggttaatgcattagcaaagtgattctgacttttgacaaacta900
aaaatggtattcagctaaatctttcaaaatgagtggtttaagaaaggttttcacaactaa960
aaatatttttaatgtaagacttgagtagttcttaaggaattgtttagatgagctcaaatg1020
catgccgttaaaacaatggaatgttgcaatcacaaatctaacattgtaggagagagaaaa1080
aaagccaaccaccagaaaattccaaaatatttcagttaggataattaatccaaattctgt1140
ttagacctagtgttaatctactcatgaaaacagcttattaaatggaattcaaccatcaca1200
ataaagaaatcattgtgcaattaattactcgtagattttgtggtgaaaatttcacttatg1260
aaagaaacaacatttgctataatgaagctaaaagataattaaaatcaactggcatagagg1320
gccaccgtgccatactgttttctcaaataacttgaaccataattaaatatttaggtgtga1380
tattttaattgttgacattgatttataaatagtattataatgtgtgggaaatctgtgctg1440
cttattcagctttcttcattggttgtatttttaaaagttcaactgttgtgactggctata1500
yagagcaagagttaaatgttgccccaaatgaaagtttaattagaaatattctaacctgtt1560
gataatatattctgagtcccaaatgcaagtcacttttattcagcgaaagatactttatac1620
accatgtcattccattctaagtattagaaacaagacttcttttctgtctcttagtgatgg1680
gtcaaaaaataatatgagtgttatttaatcctattttttaaaaaattaaaaaattggccc1740
ctcattgctagaagaggttgtatatatactgactaaagacattgactgtagctttacaga1800
ctaaaactttatggtatcaagctctcttgatgtgttttttcatgatgcagttaattggag1860
ggtggcagttagttttggattaagaatactttaaacctacctgacactggtttctataat1920
ttacaataatatcagttttgattctcacttccaagtttccatttttattgatgactgact1980
tgttctttgtttgataaaatgaatttgtacatttgacctaaaatagacacatttttgttc2040
tttcaaatgagagtaacgttttattttttctgcaatatttatctatggatatattgccat2100
ttattgtccttttatacttcagttacctgaagttgatatttctaaacaaatgtataagcc2160
acaacacagattatcaagtcccttcttttttgtatatgaatttgcatgttatatatatct2220
tatttattatatatgcatgattatatatatttataatgatatagtcacacttatgagaaa2280
cagaaaataaatcacctagtatagaaattacacatagctccagtattaatattgtagtat2340
ttacatatatatgtttactgttataaatttaggtatagcaaagttataagtagcaatata2400
atggatatctacattattatattaatcggtatgaacaaatcaggccatgcgtatccctcc2460
cattctattgtgctcacattttaagattattattcaaaaaaggtttattaatgtgaaaag2520
taaacatactactctcaaacctttctgaaacttctgaattaaagctatttacttgctctg2580
ggactttaagatatatattctattaaatacatgtagtttataatatccaacctcattatt2640
tttataactagagatgacctggtggacttaaaaagtgaaaaggatataataaaaaaacat2700
tagagaccaacaagccatgtttgaacttgacatttgcgtgttttctattcacagtacctg2760
gatctttgtgtgtctataacagaagaatatgactgggcttggatatatgtaggatggtta2820
acaaaaaaagaagaatgaagaacaagaaatttttagggacactcatgcggttttttagtg2880
gtgtagtctgagccctctgcctctgtatacacatcaattgagcaaaacaacctgtcttcc2940
caaaacatgttagtgaaatactgcaaaaaaaaaaaaaggccttcactaatttagcacgtt3000
g 3001
<210> 216
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-27297-280 : polymorphic base T or C
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-27297-280.misl,
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
417
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-27297-280.mis2, complement
<220>
<221> primer bind
<222> 1761..1779
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1206..1224
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-27297-280 probe
<400>
216
gaatgtatgtgtattccatttgattgaagaaagttgaaaatgcatacgactatttatcac60
acactaagaacttcctggtatcttggatgtggaatgagaaatcaaaaatttatgacccca120
actttgtcatgtactcactgcataacattgaccaaattacctatcctctctaagccgtaa180
cttctacatcactagtacatttcatgaagttgtgagagtcaaatacaatgatttatatga240
aggacttagtaattaaacaagagacatcatatttagaagtcagtcatttttaatatagta300
aacaccttcagtcaatagatgctttctaccattctttttaaataatttaaaataacattg360
tacaggattgacttttcatgccaggctttgtttctgcaatgtggtaattcatattaatga420
ttcattttcctgatttcaaaatatgaaatttatcttttaacttctccgtctctccttctt480
agcccatatgtcaataatgactgaaagtaatcatttccatctttaaactgcctattccag540
ccccctcccacctccatctctttccttctaagttttcttcatcttctactttgggcaaaa600
ggaaattgatgtgtcagacaggcctagttttgaattctggatctgctagcacttctctgt660
gtgtccttggttatatgatatagtcttaaaccttaatgttcttgcctgtaaaatggggat720
aataaaaacctcttaacagtggttgtttcatgcagctttcattacaaacttcctcattca780
aaatcttcaatgatttccatttttcacaaaatgaaattcaaaatttctgtagattattga840
gacaagtcccctactcttcacctaaatttatcttttatttattctctcatcattatcaac900
aactactaggctttgttgccttgactccagaggcaaaaatcttatctcccaacaatgtct960
cttaagttaagtgtaattcattatttgatattcttgtttcaaaatgggtagaggaaaact1020
tcctgcatataccgtaaaataattttagggaaaatatactaatgtatgttccagagcact1080
ggaaggtccaaagctacctatttgcattgtaccattactatttgatgtagccttttgctc1140
attatgcaatgagctgaaatacatttttcatcatgcctcctgagtctctaagtaagagtg1200
attgactcattccttttctaccagtgagattgcaaagcaaaaagaaatatgtagtattta1260
tttactcatggaattcattcttatgaaggtcagttgccaaatgatgccaaaaccttactt1320
tctagaatgctattcaagttatcaggctttaacgttttcaagatgtttatgtttgacaac1380
catatataacataaaattatgtgaagtaaagtataacataactgtttcttttctatgaaa1440
catgcctatttcaagtacatagtacactgcactgcagataaccggctgataaccagctct1500
yaacacatacaacctaatgattgaattaaaccatagtgtatatttttctaaatgtattct1560
taattaatcacattacaaccatcagtatttgggtgaacagcttcagcatccattagtttt.1620
tgagcaaagaactagaattcggagcattcaaatgatactagagaaaagacatgaagactg1680
tttatgagattggtccatctctgagaaatgtcaagatttaagaagagccgcaatttcaaa1740
accagggctacttcattgtggacctgaatctatttacccagggtcaaatcaaggatttgg1800
aacagaccatgggaacacaccactttcaatttttgaaatatttgcaaatacatgatgaga1860
tatcttggggatggaacccaagtctaaacagaaaatcaatgtatgtttcgtatctacctt1920
atagacatagtctgaaggtaattttagataatatttttaatattttgtttgacaccaaca1980
ttattcctgtctctgaatttatatgctacacataagcaatcattttattatacctattca2040
catgtaagtacttaacagttaaaaattgacataccattcatgcaataaaaaataatatgc2100
tgaaggtaactaagcagtatagcagcagcatcacaataaacaagctgttacaaaatagca2160
ataacaaacaaaggaaggcttccagtctccacctacgagtctgtattttaatttaaaagt2220
tactgtacgctgtattattattattttatttgagaagaaacatcagaagcagtcgaggga2280
ttaggaagtgggtcctctggggaagaggacatattcggctggatggcttctaaagtgttt2340
cctccagtcatctgcctcattaacaatattttttcttacaagcctctctttgattttata2400
aactgacatgatttcttgctctatgaatccatgctgctccagtccttcaataagctgatt2460
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
418
aaacattttcattatgtcttctgtaggcactttctctgcagggttaacaatgtcatcttc2520
attgccactattatcatgatcaccttgattctgaaccattttggctatttctccatcagt2580
caatgagtgaacaactgagccttaatatcaataacgtctataacattcttcaatgttcac2640
ttcatccagtttactgagggactctgaaggtatattttttgcatatgtaaagaggtcaga2700
caacattttattctcacttgatacacagaatccctcaaagtcaccaccttattaatcctc2760
atcactgagcatagttgcagacccagagggtatgctagacatgcatagctatgtatttag2820
ttcctgtgttccaagccttggcaaaagccaaaacagcatccttcatgctaagttcctttt2880
tagaaactttcatatttataccactattcactgatgctagctagcatggtattcaagaaa2940
gtattttttatattaattttcattgatctaaggatacctttgtcacacagctgaattaat3000
a 3001
<210> 217
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-27306-108polymorphicbase C
: or T
<220>
<221> misc
binding
_
<222> 1481 .1500
<223> 99-27306-108.misl,
<220>
<221> misc
binding
_
<222> 1502 .1521
<223> 99-27306-108.mis2, complement
<220>
<221> primer bind
<222> 1395..1415
<223> upstream ication
amplif primer
<220>
<221> primer bind
<222> 1822..1842
<223> downstream ification ement
ampl primer,
compl
<220>
<221> misc
binding
_
<222> 1489 .1513
<223> 99-27306-108robe
p
<400> 217
aggcactcat agccacttgtaaattgtaagagttaagaaggcctttgcct ctttattcag60
gaggtgctcg aaggaaatctggcttcttgtgagtttcctggaagttaggc tttgactgta120
caatgggagg aagggagtacatttatcttaatttttatttatttctcctt aatgcctttt180
aaatgatgtt ttaaaacaaaacgtacttatatttccattatacaaataaa gaaaggcaca240
ttcttgtctc atgctttatagggcggcttcagagctgcagttttcagact agttgatctt300
tatgttctaa aaaaattattgggtattccaaagaccttttgattttgtag ttatattgat360
caatatttac catattagaaattaaatcatccaaaaaattttaagttgtt tgtttattaa420
aatgacaaca caatgtgcattacgtgataacatattagtttcattaaaat aactatattt980
tccacaacct aaaagcaggtgagaagaaatggcgttgcttaatatttttg cctatctctt540
taatgactca cctaataaaataaagctttattttcatgtcagctttttca ttcaatatat600
cacaattcat tgttttgtttaaggtatatgaaaaaaatggcaagcctcac agagatatgg660
ataatggttg aaaaagcctttgcagataactatggatatcctttgttctt catacgaccc720
gaaagcttta caaatggatttttaaagtttcttgtgatgtgtaatctgaa acgatatgaa780
tacacttttg tactcttttttaatgaaaaggcactaatctatcttgcact tcgaataaat840
attttactca ccaatgattttatagcatcatgcattggtcatttggagaa tattgatttt900
ctgacatata aatcttccaaacattggcataatttattatctaatataag acatatcaca960
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
419
ttcaagtattcggaaactgtgaaactttgcttgatagataagttttccaaatttctactt1020
aatccttgaaagcttgagtttgctactggcaatagctactgtccgttgttttcccgaagt1080
gactggctcacttcattcatttttgaggaagtctgccaaatgcccaaatgtggtgaaact1140
tcatttctgtcagttgttctttcaagtagaagtggtgttccctaaaaaggaagaagctag1200
ttcagctcacagctccaacaatgcatgggtgcttctcctcaagaaaaccatcacatgctg1260
taggggctgacattctttcagaaaaggagacatgccaataaggctcaagatttaattaca1320
tgactaagttgtgtgacttcctcaggacattcattctcatgggaatctgaagttttattt1380
tttcccaggagtgtgaagtggtgaagacacgatagatgttagcacactcagagctatggc1440
ctcggcttctactgtggtaccatcccgtaaatatccacagtgaaaaaggatgacgacgtc1500
ytaaccatgccctgtgttttttaggaacactgtttactattatggaccctttgaaagctt1560
tgtgagcaccctctaagggtccgaaatcccacttcgagaaccacagccaatgagcaatgg1620
aaacgtgaacacagaagagccatatatttttaagactccttcagataaatctcactcccc1680
acccaacccactaagactctatccctgccttttaaccatccctgctatgatgggaaggat1740
aaggaactatactgatttacttttctatccaaattgtaatagtgggattggaaagagtaa1800
cttttcttctccactatactcccctagaacaagctcagtcagccacattgatgtacttgt1860
tatttttgtaaagtaagttgtagactctgacccgacaccaacaccacacccaatgtagag1920
ttctaagactttacatttattaaaaaatataatcctattatcgctacatctattaaaatt1980
tagtaaaaatatgtaatcctagtattgcttcttggaaaagttgtggcaatttaatgaaat2040
cacagatgcaaacctgtaatgcagtggctgaaacgcatctggaagattctcctctgcagt2100
ggctgaaacacatctggaagattcttcttcttctcctttttctttcttcactttccctag2160
aggtgagcacagtgactgacatataacagcagattgggatgcaataaatgtgtatacaat2220
aagttacttactatattgtatattaataacagggatgcaataaatatgtatacaataagt2280
tacttattttttccagctttatagaagtatactagacaaataagattagtatacattcaa2340
ggtgtgcaacatgatattttgatatacatatatcaaatgtggaatgattaccagaatcaa2400
attagttaacatatccatcactacaattagttaacatttgcatgtgtgtgtgtgtttgtg2460
tgtgtgagataaggatacttaagacccatctctcagcaaattataactgagcaatacaga2520
aacattaactgaaatcacaatgctgtatattaaattcccaaccaataggtgatttctgag2580
tgcatttgggtcacagcttttccacatcttattttcacatcctttttgttgtaaaaagat2640
ggggacttcttggaatttggcaattttgctttttgttttttatttaaaaaaaaaagttgt2700
tactggaataatgacccattatattctaaagttcatgacctggactttatttttggtgtc2760
aactatacttaggcattattagacacaaatagaacaaagaatcataaatatatttaccaa2820
aaaatagctaaaaaatcaaaataatagtttctgtacaggatgacacatttccctgtgcta2880
acagattttatatgttcttattataaacttatttttgaaatattttctgtgaaagccatt2940
ctgacattttcaatacttcagaagccagaataattctgtgtgtatttttcacttaaatag3000
t 3001
<210> 218
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-27312-58 . polymorphic base A or C
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-27312-58.misl,
<220>
<221> misc_binding
<222> 1502..1521
<223> 99-27312-58.mis2, complement
<220>
<221> primer bind
<222> 1445..1463
<223> upstream amplification primer
<220>
<221> primer bind
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
420
<222> 1940..1960
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-27312-58 probe
<220>
<221> misc_feature
<222> 83,95,495
<223> n=a, g, c or t
<400>
218
atcctcctgcctcagcctctcaagtagttgggaccacaggtgtgtgtcaccatgcctggc60
tgatttttcttttcgtttctttntctttaactttntttttttttttttttgaggcagagt120
cttgctctgttgcccaggctggagtgcagtggcgcgatcttggctcactgcaagctctgc180
ctcctgggtgcacgccattctcctgcctcagcctcccgagtagctgggactacaggcacc240
cgccaccacgcccagctaattttttgtgttttttaatagagagagatggggtttcaccgt300
gtttgctaggatggtctcgatctcctgaccttgtgatccacccgccttggcctcccaaat360
tgttgagattacaggtgtgagccaccgggcccggctgtctggctgattttttaaagtttt420
tgtagagatggtgtctccatatagcacccaggctggtcttaaactcctgggctcaagtga480
tccacctgcctcagnccttccaaattgctgggatgacaagtgtaagtcaccgctccactt540
ccatatcttgcctgaactattaaaatacctgttatctggccttccactcagcatttaatc600
cttctctgtgatctccatctggcagccaaataaacttttaaaaccacataaaatctatcc660
tgacattctcatgcttaaaatcttcaggtagcttgtcatcagtctcagaaataattaaaa720
atcctgtcccttgctgactaaacacaacttgctctcaccctgtctcataacagtctcttt780
tttgccttctgaacgttacaatgaaatgaatctatcatgccaaattattgtataactgta840
ttttctacgtctaaccaagaaccagtgagcctgagttaagaacagcctgactcgtttggg900
aaatacattatctttgtatagaaagaccatagtgtcctcacttgtattttgtctgaggag960
actaaaaatggctgtgttccatccaccatgcacccctcactgcattttaggtgttcagat1020
tatgtgagatactttgcaagttacaatgacctttcagaattaatgatttgttcccattca1080
ctgaagcaagcaaacactccagaacccctttttcataaaccgccctggacagaaggcttt1140
ctgatccaataatagactcagtcaggctcttcagaaagtagagaggaaatcaaaatctac1200
ccagtggaacaatccactactgaaaggcagttatcccttcaactcacatgcagattttta1260
ttatgttaaaggaaataaaacaaatattaacagctgtttttaaaatgtctactaatatgt1320
aaggcattagtcaaacaactttatgtacaattcttcaggatccacagaaagtcggcagct1380
tattacctgaattataatgttctatcaatattagctactgtcataaaaaattattcacaa1440
catcactgttacgatgtgatctccacattttacagagagaaatgtgatctccacattttg1500
mggagaggaaatggaagcttaaatggtaagatcacttatttttgttcagaagtttgataa1560
tcagcagatctagcatttaaactaaattgtactggctccagagtactaactgtggtcaca1620
ccacagtggccttaatttaaaatttcccactcctctttaccttgcaaagatgcttaccga1680
aggtgcttacgagcctttgtctttctgtatatgtgagattctcccctttgtgctgccagc1740
tcctgaagcttaaatatcctgacattttcagaattggtcattgccacttaaaatggggcc1800
caatgcacagtgtgctcaataagcatttgatgcaggaaataacgaaaatgctggcatgta1860
gcaggcatttcacagtgggccacaggagaatgaatgatattcgctgctgcacagtggtac1920
ctctaaaaacagaggcaaacaggttcttttcaccttaccgtttctatgatcgtgtttaag1980
caaactcatatagctttcattacatgtcagcgattgttctaagcaatcatgtattaactt2040
attaaattttctaaataactctcttggggtaaaaactataatattcatcttacaactgca2100
gaagctgagacagagacacattaaacttatccaagaccatatctgaaaataggagagaac2160
agagtcaaacccgggcaacctggctctgaatccagctctcgtcttgttggctgtgctgtc2220
ttttcagagactggcatctcctgtaagtgcaggtaaatcaaattcccagaagttaagtga2280
gaactggaaaatggtgagtaggaaaacatgttaatatcacaaggaattttaaatagttat2340
taaaacacagaaaggggcttgtatctccctaaattttgtagtgagcacagtgaatttctc2400
acctggcaagaattagaagtctctgtgaatgtataacagattatctgtgtccactctctt2460
tgactcccacactcagaaaactgaggctgacatttggatctaaaacatacagccacatat2520
tacatgctgctctcttacaaaggtttcaagagagacagacacaatttacaacacactgaa2580
gggtaacattttttgctagagatgaattttgcatggtgcccagcaggggaggaatgtaga2640
acacacggacattctctcttcagttctacccttaaatgatccttagaatctgaaaacagc2700
tatctcagaattaagtaaggatactattcttgagtatgatatgaatgactaaaaaacaat2760
attttatttaaaacaattgcttggatataaaatctctgaaattgagatttttatttaaaa2820
tacatatgaatttaataaacactttaaaacatctttattttcaaaggtaaacatgaagat2880
taagaagaaaggaaaaagtgttatacaggaaacgttcccataggaatttgacatatttgt2940
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
421
ggttttggcaattatacgtagaacctctggaatacatctacaaaacagat gttttagagg3000
g
3001
<210>
219
<211>
3001
<212>
DNA
<213> Sapiens
Homo
<220>
<221>
allele
<222>
1501
<223> base G
99-27323-372 or C
: polymorphic
<220>
<221> binding
misc
_ .1500
<222>
1481.
<223>
99-27323-372.misl,
<220>
<221> binding
misc_
<222> .1521
1502.
<223>
99-27323-372.mis2,
complement
<220>
<221>
primer
bind
<222> .1150
1132.
<223>
upstream
amplification
primer
<220>
<221>
primer
bind
<222> .1628
1610.
<223> ement
downstream
amplification
primer,
compl
<220>
<221> binding
misc_
<222> .1513
1489.
<223>
99-27323-372
probe
<400>
219
ttttaaagcacattttactgaaaggtttcctatttgttttaataaataat gccaaagata60
tggttatctactgtggtataacagaccaccccaacatttagtgacttaaa ataataatta120
ttttttgtgtccccaaatctgtactttgtgtagggcttggcaggaatggc tcatctctgt180
tccacaaggcatcgactggggtggcttggcagggaccggcattttcattt ccaaggcagc240
tccccgacacggctgattagtgctggctggcagtgtgttgagatctcaac tgcggctgtc300
attgggggccactctgagggaggcccctggattttttacagttaaataag ttttatacta360
catcacttcatttctttttccagaaacactggcagctaagctgcatttta tttgttggtt420
tcttcaataataaatatttcactatttcttctaatcctttgtttccactt attttatttc480
attcctcattttatcccttttttctaaattccattttattatacttaagg tgcttttaat540
atggttatcatactcctgatagtgttatttctttcttagtcttcttatat aagcgctata600
cgttcacattccatctcctttggttatctttccatttcttcaccgagcct ctttgctctc660
tttttttatagctggttcactcaaaatgtcttactttgccatttttgaaa tttattttca720
ttcttttatgtactgaataaaatttaaaaatactttatcatggtgggagg tacccgtgat780
gtccaaataagtgtttatattaattgttggggtttttttgtttgtgtgtt ttttgaaagg840
ttaagaaaatctcattcagaaagtaagttgtttaaaaattctggaccaaa tttaccacac900
atcaagcagatacttaccaagttgtttggtagacattagcagtatttact aatgtctgct960
tctccttgtaagcaaatgtatatctatatttacccctgttactaggaaag aaatcttgtc1020
tttggcagtggaaaacccatggagggtttaccggtttctctctgtaccct tgttgcaatg1080
atatggtaagcagagttgtgataaattggtttggtcaaacaaaattagag gtatctggct1140
tgcggagaacagctgctttgccatatggtctgagacccacagcagttctg tgtacatggg1200
aaataaacttttattgtattatgtctatgagaatgtgggtttgtttttta ctgtatcatg1260
attaatagagatgggttaataatttttatactatttctttttcctttgac cattaagaat1320
tccatgtgactatgagaatttgcaatacagtgccactctcctttgctttc attgatctac1380
gaaaacatgaaaagctataatctttagaattagtacatccagaacttttc ctgtctctat1440
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
422
tcctatctctttaattgatattccaggctctcatgagtccttgcagttaatccttttcat1500
stttgttatttatatttcttcaaactaaaggctgtattcaatggcaaatctatgcttggt1560
taaagacggagaagaggaatagaggtgagtctgacttgggagatcctttccatgctcccc1620
ctgattatggtaccaaagttgcagcacgtctttcaacagctcctttgcattgatattttg1680
ggaaacaattatttgttctgccttcttcctgcccagtgatatatttacacaggttggtga1740
tgacttgccaatatatttctgctgtagttaaattaatttatctctaactttttttaatct1800
tagtgatttcctaaatttcctgttgttacaattttgaatatgtgatttttatgggaatag1860
cagctttatcaactaaaatataagaaagttaaatgaagagcagctaactactatcataaa1920
ctaaaaatattaatataagctattaaacaaagggcagaaacatctactaaaaagtttatc1980
ctacataagaagtgcttagagcaaagatacaattataaataagaaggtacttaagactgt2040
gagtactttttaaataactcaaaagctgacacagttgagcaactcatttgtatatttgag2100
agcatctgataaattaaaaagtatcattatatgttaaatatgtagatggctggaaatata2160
tatgtgtatatatatatataggtatataaagtatgcaaatatcagcatgatatatttcct2220
aagcaaaaactaaaacttcattaagattttcaggaaaatgttactgagtatcttccatat2280
tcccttttcactaaaacataagatattttccattatataataccaagtgcatatcttaaa2340
tattatacatctcaactgcattaatctaatttcacatggctatacagaaatacacgagac2400
tgggtaatttatgaaagagagctttgattgactcacagttctgcagtgctggagaggcct2460
cgggaaacttagaatcataacagaagaaaagcaggagagatggagtgcaagcaagagaaa2520
ggccagatgcttataaaactatcagatctcctgagactcactccctgtcatgagaacagc2580
atgggggaaaagtcctccataatccaatcacctcccatcaggcttctcccttgacacatg2640
gtgattacaattcaaaatgagattgtgtggggacacagagccataccataccaccaactc2700
acattctacagctttcaattttctgacaattaaatatattattttagtctgggaatattt2760
gacacgctttgttactacagagcattaagagacagagtcttcattataaatgttagaata2820
tagttgacttgtttccataactactgtttgaatctgactttagagacacgttctttcaaa2880
tgcatgcatttgcatatactggaggatgggaagtatttggtacaagagtataagcctaga2940
aatgaatcaaagataggagtaaatttgggataattcaccagcacttctggtcaatggctt3000
c 3001
<210> 220
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-27335-191 : polymorphic base A or C
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-27335-191.misl,
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-27335-191.mis2, complement
<220>
<221> primer bind
<222> 1322..1342
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1768..1788
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-27335-191 probe
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
423
<400>
220
tctctgaaggatgagatcaccaaggaagtttagtagagagggagaacaaaaaagggacca60
gagaagagagaaaattctttaagtctgcatttattgcatttattaagtgtttatgtaact120
atgatcagttctgggcaatttatgagtgagcctctaaagtcaggtttccaaaagcaccag180
cttgaaagaactttcaagtacttatccaagtgtgccattaatcttgtgatgcttaatcag240
aactacaaaagaaacttttatctgaatcaaagtaaaaatgccaaataaatcacaattaga300
tttactgttatattttgtaattttctttttataattagtttttgatttataatatgttat360
tttctggttgttttttaaagaaactggaaaccttgatagcataatgtttttgatgacctg420
attcttttaaatatttctttcatatattgacctgttttgcccttaatatatacttgaact480
gtaaaagaggataactattaatagaaaacctcttataatgcaatgtaggtggtataaatg540
tttttaagatttattttgattaagaggcattaggttcttgtatccagtttaacttctcgt600
gttcttatatttaccaaaacttcctctgtctgaaattataatgacaatcttgcctgagtc660
cttaaaattttatatataaaattgaatgtttcctatttgtagtttttcttcattatctgg720
ttccataggtgaataaagatggattttttaaaaatacattttgctaattttattttttta780
ataggaaatgcctatattttctttgggactaagaaactctcatggatcatgtggaggttg840
cacttttgaataatgcatagttacttcctctaaggtttcttacaacttagtagtttaata900
aagcaagaaaaggaacaaaagaactgaagggctgaaaataaattatgggtgaaggagcat960
tgtgaggcccttgctgttttcataaggtcggattacttactaacttcatacacagatttt1020
tctctccaagagctttgctttttgtaatttgacctggatatttaacacaaaaattatagc1080
aaagaatagctattagactgtttgtataagtggattaatgaacttaatataagtacaaag1140
taaagaagacataggtatcaatagaaaaaaaaagcattcttcctggaattaaaagatttc1200
ttaaagttttttctgtttgtttactttgtaaatagaagatttataagggattaaacttat1260
gtttcactctagcttttagacctagtttgcttaagtcactatggaagaaattataggtca1320
tctaccttttttatggatgaacgtgagagctctttctcactcatcaaatttcaaacgttt1380
ttagaacaacaaaatataccttataaaaacataatattcattaaaaagagaaccttgatg1440
agaaatattagtctataagtttttgtgtgtggttttctttttttaatgtaagaaactact1500
mtaatgatgtattagagattgtaaacaatgaaaaacaaaatatcacaaaggcttatgttt1560
taaaaaatggttactttatatctgaactatcccaacaatagcctgacactcaaacaatct1620
acattgtgtagcagaacagttaaaattagtgcagacacctggaaacattccaagcattat1680
gattgctggccaaagacaatttcctttaaacaactaagaaaatatacatgaaattctagt1740
ttgaaatttatggaaaagaaaaatgctcatatagaaaagcagcagtctgaagaagattct1800
gcacacataggaaaaaagtcttaaaaattatttgaaaaagtgatgatgacagtgagtaaa1860
ttcaaattgcaaacattccctcaatatgaatattgcacttagcattatttagacctgtct1920
tgataatgttttcattctctaccctatagaaaatgaagaaaataattatcatatgacata1980.
tcaccatgcatatatttttcaataatctctgaatacaaagtaataattttataaaaatct2040
gatagtctcatattatattatatcactgaggccagcatggccagagaacctccgagctcc2100
attgtggaattgtgattgtctaataagagtttcatactaattaatccttactttacactc2160
tataaaatgcaactcaactgaacatagctaaatcctgtttcaaggtagagtaattcaata2220
ttgatagatactttctctacaattattaccaagaagataatttttttaagtggaaatacg2280
aaggctgccattgaatagcaatatctataatactcaagtgactatgcatgaaacactgat2340
cttgaagtttggtttagcctctatcaccaatgcttaccactattcataaatgcagttaaa2400
attgtataggtgtcattaatccagagagaaacagctgtctccattgatgtatcaattgtg2460
tagaagatagagatccatgagtctgtagtcaccattcccagttcactatatttaagaaat2520
atgggaataagtaaatgttatagtgtctaaaatattttaaaagatacttatgtgaaacta2580
ttttcccatatttcaaaaattatcatcaagtaacagttggcaacatattagatattattt2640
gaagactgtaggagttttgcatgctataataatgatttattttgtaattatcattaattt2700
tcatgagcaagtgtccatttgtaaataaaattgcttgattgtctacgagaagccatagat2760
ggacatagaccttggcttctattacttgtcactgatgtctttagcattaaatcctaggta2820
ggaatgaggacaatatgcctctcaggatgagtaaatctgattttttcaatgcgtattata2880
cttccttataatgacctggcagttattcgttctctactttaatgccatgactattcatca2940
tatgatgaattttctaaaagtcagtccatcttggtttactacatagatggaacctgcctc3000
a 3001
<210> 221
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-27345-189 : polymorphic base C or G
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
424
<220>
<221> misc_binding
<222> 1481..1500
<223> 99-27345-189.misl,
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-27345-189.mis2, complement
<220>
<221> primer bind
<222> 1672..1689
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1139..1159
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-27345-189 probe
<220>
<221> misc_feature
<222> 803
<223> n=a, g, c or t
<400>
221
atgaaatttttccattaggacaagttaatattggaagacaaggagagtaagtatgtactc60
tttgtcctgtgtaaatgaaagactcatgttgcatgctagctgttgtttatcttttaggac120
aagcagacaccaagaaagttctaatactaggaaatgaagccactgcttagttttctcatg180
aggtaagtgtaattttccagtaatcatatgatcttacatcatctactctattccctgtca240
acagtatatgttgttaaatttcatatttgtttagttgtaaatggattaaaataaagtttt300
atattgtaagcagctttaatactacttatttttacctgcatggaagacatgctccaaaaa360'
agtaggtttggtgtcatatgaaacacattcaaacggggaaaggaatttataaaatatttg420
acatgccaataagtctaatgtatacactctaaattttgcctattatttttattgtagttt480
ttatttttgtattttctatttcatatttctattttttgtgttatatccaagaaagttatg540
agaagtatgtaatgttagcattaataatgttatttttgtcacaagtgtctcaatttgaat600
aattaaacatatttttagtgcccaccatgagcaaatcatacctacagtagggacataaag660
aggtaatacataccaattctctgttgcaccccatctccacttgttaatgtactaaagacc720
aatggaatcaatgcatacaaactatctatgggttatgccagcaggaaacattggtgaagt780
cctgaaaacaggatgtgacttgngttgaagcaagtcaaaatctggctaagggactggcac840
caacttcctctccttttactgactgggtatactaatgtgatctaaatgatgtggtatgca900
ggcattgtagtacttcgtcttcagtaactccactctggatgaggccaatacaactactcc960
tgtagggtgaaggggtttcccattaagcaagtgtagtgctatggtagtgttcttctcatt1020
gctgcacagacagtgctgtttcgttttctttctatggttttaattgtaactgagatgtta1080
acattattacatagaaatctattagttcatttagactttcatttattcatttactcaaac1140
agaatttatcggtgtctgctgcatcaggcactgtgctagatgctgagctgacccaagaaa1200
tacagtatgcatgtcactcacgttgtgaagcttgcagttttccagaaaacaagcaaatgc1260
aacagaaaaattaccgtacgtattttataaaaattacaactacaagttctgataaatact1320
gaggaagggggcagggccagctttattgtttcccaggctgtgccatcattctgggtcctg1380
tagaaggacctgcttttggactaacactctgctggcacctcctgaaaattctgaatcatt1440
ttctagtgaaggacatcatagtttcagttttcactgggccctaaaaattatatagttgat1500
sctgagaagatgctaccgtagttataaaaaatgaaacacctaatttagatatggtaatat1560
gggaacacttactcagaaggtaattccaatccggttttaagtcataagtacagagtaaaa1620
ttaactccaaacccagttctgtccctactcatgagctaactagaactctagctaaatccg1680
tgtgggttacaagaaataacaaattacctggtggaagaagacatataggtattcaataca1740
tttacaaattcttttaaaaattttatgaagaaatcacttcataaaagcaggcaaaagata1800
taaaatttacaagataataaataaaataggccaataaaatattttaaaacggtctgtctc1860
aataatcattaatataaaaataatcaaatattggataatcaacttcacccataaaattgt1920
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
425
caataaacagtataatatccctagttggtatattggtcagtgttcttgttgcggggaaca1980
cttgcttaatcttgattgtatgggaatgcagtttattataagaaaaaaaaacttgataac2040
tcacagagttgggaaggctgtataagagaacaaagcttaaagctaagctcataggaatag2100
tgcctaaaactgtgctcagtaattgctctgaaaagaaaatcaccacaaatgttattagcc2160
cacatagcaaaagggaaagccattgttccttcctctgtactgatgcctcttctgaattgg2220
gaaatgtataaccactgcacccagtaggctgaccctcattccattacatctatcagcaaa2280
atgaattttgtaaagggctttcttcgtcaactctactgtcacacaataagcatcgtctgt2340
ttttaaaaagaaagataaattaaatgttttccaagttcaaaatgtgtacttataaaaaag2400
gaatagttaaaccacaaaatggaaaatatatttacatcttatttgacaacagatttatat2460
acctatacaagaactcctataagtcaacacttaaaaggaaaatagcacacacaacaaaca2520
cagaattacaatataaccccaatattccactgctcattatatatccaaaaaaacctgaaa2580
taagtacatctaaacaaatgtttattgcagctctattgacaatagccaaaagttggaaac2640
gacccaaaagctcatcagcagatgaatggacagacaaactgtggtatgggcatacggtgg2700
aatattatttaaccacagaaaggaatgaggtaccatcatgtgttacaatgtgaagaaagt2760
ttcgtaacattatgccaaattacaaattcttttaaaaattttacacaataagtcacattc2820
taaccagttatatgtattactcataatacataaatccttagagacagaaggccgactggt2880
ggtcgccagacactaggggagtcggggaggaggaacaacggcttaatggtaagtggcttt2940
catttggacaaatgaaaatgttttagaactagagagaggaagtggttacaaatattgtga3000
a 3001
<210> 222
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-27349-267 : polymorphic base G or A
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-27349-267.misl, complement
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-27349-267.mis2
<220>
<221> primer bind
<222> 1748..1767
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1337..1355
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-27349-267 probe
<220>
<221> misc_feature
<222> 182,848,1501,2206,2397
<223> n=a, g, c or t
<400> 222
gatgccaggc aatgtgcaaa tctgcagttg ctgcaccgtg cggtggctga gacttttcca 60
cataatttta agtgggaagt aggttaggtg gcaactttga acaagaaaaa tatgaagtga 120
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
426
taaatgtgcgtgtgcatgtttgggggtgggtgggtacgctcacatgcactcacgtgtgta180
angtgcatatcaggacctggacagctaaaggacaggatgtccaacttaaaaaaaaataga240
tttcacccaacaaatagttatgatttctcacatatatacatatatacatgatgttatcaa300
atgtaactaagctgaaaacatggaaatccccttactagagctcagaatttccaattcttc360
attgttttactttcactgaagtggtcagccatagcatatgcaaatctatgtcaaatgtag420
gtgaaacaaataccaataactggctgatgatcgagacaaattacacttatatacacacat480
atgcctgtacatatatagacatatatgcaatcatttccaacataataaagtacctatact540
ttaaatactacagcacctcataaaagggcatagaatttcatatcagaatctgtgtagcat600
tcttctttatatgcttctcactccactgctcctattgcaaaccaatagtaaatatatatt660
ttttctattttattttctacttaattattcatattcctcaataaatgtttagcacatttt720
aaaaaaattacatacctaacatgccagcaacaatgatgagctaaatagattttgtgctta780
gcttcataaaccaataactatttaaatagatttatatcgaaaaaatcccaaagacatatt840
ctttaaanttttgcttattactatatgagagaatctattctaggtctttaggggataaaa900
agattaatcttaccaagtaagactttatagtctcattggagagataagaccaacataaaa960
gtaaatctaatataaggaaaactaaggaaaaatattaaaatgacaataaaagtatactta1020
tattttaaagtaatttcaaaagaagaaattatttcagatgattcaattactttcaataaa1080
tcttttttgaatgttaggatagatgataaattttgctaggtactaggactaaaaagatga1140
atatggaaaatgtttgccctcaaggtgaataatgcattgtggagaaggtaattgttaatc1200
agagtattgaagaaagaggggaatgcagaaaagtgaagattcagaagaagttatttttct1260
gttcctgcctgagaatattctgaaattgagcaccttcaagcagcgatgaacacgtcaact1320
agggctgactgagtatgcgaagtgtgcttgaaatggaggggtaggatatgagagcgaaaa1380
gatgaagcagctgccaggggccttcaatagctcctgactgcctatctgtattatgttgga1440
taatttgaacttgaatgtgattaagggagcaacatgataagaaactatgatctaggatca1500
rtaatctcggtttagaacaaaggtggtttaggctaaaaagaatctagagttagaagcctg1560
ttggtaagttttattactggacagaagggagggaaatgagggaaagttatgaagggctca1620
tgttttagtaggatttaaagaaaaggacacaaaagacattgcagagacaagcttaacctt1680
agctaattcatggatatgggaacaagacagggagtagagtaaaaaccaaagctgaatgct1740
taaacttggttggcactgaagctggtacaattaaggtagaaacaaaagaattagaggaaa1800
taatttcaaagagcagataatgagttttgcgttgaacctattgggtttgaagaccaagtg1860
tgggtttgtggtggcatgttcattgggcaattagaagtctggaactaaaactcaggaaat1920
ggttgaagtggagatgaagatttgttaattttctgaagagaactgtgacctgaagtcatg1980
agatttaacaagattatcacgagagaaataagaaagaatgagatagtccagggaagatct2040
tagaaccctcatatttggagaagggaggtggtatacaaaaaaggagcaggcaggccaggc2100
acggtggctcacgcctgtaatcctagtactttgggaggccgaggtgggcagatcacgagg2160
tcaagagatcaaggccatcctggccaacatggtgaaaccctatctnttctaaaaatacaa2220
aaattagctgggcatggtggtgtgcacctgtagtaccagctacttgggaggctgaggcag2280
gagaatcacctgaacccaggaggcagaggttgcagtgagccgagatcatgccgctgcact2340
ccagcctgggtgccagagcaagactgtgtcaaaaaaaaaaaaaaaaaaaaaaaaaangga2400
aaagaaaaagaaaaagaaagcaggcaaaggaaacagaagaaaagtcaaggttttttttta2460
agaaaagtcaaaaggaacctacataaggacaacatgaggtcagattacagtgcataaaac2520
aatgtctcctttgtaacacaactcatttattagggaaaagccaatatttatgttttgctt2580
tcatctttaataggcatacaaggaatgttcacttactctcagacatttctatttttaaaa2640
tatgttttgttttaagctaaaacgttgatacctagaactatttttgcaaatattattcac2700
tgaagagtttcatgttactgtatgtatagtgatataattctagcaaattgctgtcataag2760
tatacattttatgaaattgatcttagacagaggtaattaagtttgacatcagtcttgcac2820
ttaaggagtttcaacaactatactgcaatatattcagcagcacaaggcatctggccacaa2880
aaagctacagaaatttggaggaggagaatttggtttctgtttggagaaccactgaagacc2940
cactgaaagaagaaacatctcagatattaactaaattgtgtggaccaatcccccttgcgc3000
t 3001
<210> 223
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-27352-197 . polymorphic base C or G
<220>
<221> misc_binding
<222> 1502 .1520
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
<223> 99-27352-197.misl, complement
427
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-27352-197.mis2,
<220>
<221> primer bind
<222> 1677..1697
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1250..1269
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489..1513
<223> 99-27352-197 probe
<220>
<221> misc_feature
<222> 365,1072,1760,2273,2939
<223> n=a, g, c or t
<400>
223
tgtatttttaaaaagtcttcggatgatgatggtgtgtagattgttttgagaaccactggt60
gccatgcattagcaacacaaagaatataaggctggttacaaacacttgtggaatagatgc120
caattcattaacattttttgtgtatcagaagcttcagggtaagtctcaagtagggtgaac180
ccggttcagggtcaaattatgtatagcaatatctgaaggatttcttgataagagacaatt240
gtttgttgttgttggtggtggtggttttgtttttgaaaaagaaatttgcgggcccggcac300
agtggctcatgcctgtaatcccagcactttgggaggcccaggtgggtggatcacgaggtc360
aaggnatcgagaccatcctggccaacatggtgaaaccccgtctctactaaaaatacaaag420
attagccaggcgtggtggcgggcgcctgtagtcccagctactcaggaggctgaggcagag480
gaatcagttgaacccaggaggcggaggttgcagtgagcctagatcgcaccactgcactgg540
ccacaaagcgagactccatctcaaaagaaaaaaaaaaggaaaaagaaatttgcttagaca600
gatcaaagagcctatgccctgttcttcccagtgtagggctgttttttgaccggaacatgg660
actgaaagtgcatctcatgttctagaggccatggcaatttgcggcacgtaagatcaccaa720
tatcttcttggtagggatagcactcttcccataatttgaacttcagaatatcgtgtaggc780
tgtaacactaccttgctcagtgcttggcatacactaggtgcttaacagtgattagaatcc840
cttcactgtaactgtcttgttggtatgaaaatacaattttaaaaacagaaaaataaaaca900
aacctctactttagatcatggcgtgctaaaacatccagtaaggagtgttctcttatttat960
ttatttatttttcctggagctcctgggcctgcagtggagaacaatgtgtccgcagttatt1020
tcctacttttctaaggtagtgagaagaatgctgaagctatgcacttaaagcnaattatta1080
gtaacttaaatggcattccaagagaacagagaatccaaactcagtgcttatgttttaaaa1140
acaatgaagcaaagctataatgttggcacactttgcagcactttgttatctatttgtcta1200
cacatttcaggaaaatgtttctggtttgaaagttcaaaacaagctaaagcttcaaacgga1260
ggctgtgaggttctttattcttttgttttaatggtagcataacgacataggacatctgag1320
ctcatgctgtacagcgacatcctttagccgtttccattagacatttatgcctggtattct1380
taaatgaaacataaaatattggtatgtatttttccctgacaggatatgtttgagatattg1440
ctgtaagatgtaatcaaattttaaaggcgataggagccctaaaaaaggaagaatcattca1500
sgttttctaatcacagccatgtgagtaatggcatctggcgactcgggaacgcctgctaag1560
ttttagtacttgtctgaaactagctaccacgtgattgcttagctgcctggtctttttaag1620
gttgcctgaaagggctctgctataaacttacttatttatcctatttattggatgcaccca1680
catcacataatagtctctgggtacatttacaagggtaataaaagaggctatacagttctt1740
tcttggcaattggatagagnacctagagttcaaaggagatacaagtgtatgtaattcagc1800
tgttgcacttttctttacaatttttaacatcttatatttaaatttttttttagggctgtg1860
aatcaataaaataacaaaaaaagagtatatgctttcaactgagacgttaaagaaaataaa1920
attacagagagccttttacagttttcttccaggcagtccacactaaggggcaattccttt1980
aggacgagcactgtgttggaggctctgttttcataatcagaatagcacatcccgtgtgaa2040
gaagaggctttgagtccacattcttcctggatttcacatccgattaatgaggatgccagg2100
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
428
caatgtgcaaatctgcagttgctgcaccgtgcggtggctgagacttttccacataatttt2160
aagtgggaagtaggttaggtggcaactttgaacaagaaaaatatgaagtgataaatgtgc2220
gtgtgcatgtttgggggtgggtgggtacgctcacatgcactcacgtgtgtaangtgcata2280
tcaggacctggacagctaaaggacaggatgtccaacttaaaaaaaaatagatttcaccca2340
acaaatagttatgatttctcacatatatacatatatacatgatgttatcaaatgtaacta2400
agctgaaaacatggaaatccccttactagagctcagaatttccaattcttcattgtttta2460
ctttcactgaagtggtcagccatagcatatgcaaatctatgtcaaatgtaggtgaaacaa2520
ataccaataactggctgatgatcgagacaaattacacttatatacacacatatgcctgta2580
catatatagacatatatgcaatcatttccaacataataaagtacctatactttaaatact2640
acagcacctcataaaagggcatagaatttcatatcagaatctgtgtagcattcttcttta2700
tatgcttctcactccactgctcctattgcaaaccaatagtaaatatatattttttctatt2760
ttattttctacttaattattcatattcctcaataaatgtttagcacattttaaaaaaatt2820
acatacctaacatgccagcaacaatgatgagctaaatagattttgtgcttagcttcataa2880
accaataactatttaaatagatttatatcgaaaaaatcccaaagacatattctttaaant2940
tttgcttattactatatgagagaatctattctaggtctttaggggataaaaagattaatc3000
t 3001
<210> 224
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-27353-105 : polymorphic base T or C
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-27353-105.misl, complement
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-27353-105.mis2
<220>
<221> primer bind
<222> 1584..1604
<223> upstream amplification primer, complement
<220>
<221> primer bind
<222> 1085..1105
<223> downstream amplification primer
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-27353-105 probe
<220>
<221> misc_feature
<222> 794,1501,2189,2702
<223> n=a, g, c or t
<400> 224
tggagatgct ttggttattg catttttcag gatcacctga gacctcattt aagaattttt 60
ttttcattca ttctctgaaa gagttcccta tttgatttcc tttgggtgag gcaatgcgat 120
aaataggatg agcatagaat ttagagatgg atttacctgc cttatcatat gaagcctacc 180
attcacttag atatacaatt ttgagcctat tattattcat tccttagcct gactcctact 240
tcgtaaaaaa tacaggtaaa atccctgcct acagaagttt tgtaagtatt aaattaaatt 300
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
429
ttatatataaatgttgtatatatgtatatacacagtatatacatataaagtctagcgcag360
agtttcaaatttggttgctttgaagaatctactatgaattctgtaagtctgggcaggagc420
ccaggcatctgtatttttaaaaagtcttcggatgatgatggtgtgtagattgttttgaga480
accactggtgccatgcattagcaacacaaagaatataaggctggttacaaacacttgtgg540
aatagatgccaattcattaacattttttgtgtatcagaagcttcagggtaagtctcaagt600
agggtgaacccggttcagggtcaaattatgtatagcaatatctgaaggatttcttgataa660
gagacaattgtttgttgttgttggtggtggtggttttgtttttgaaaaagaaatttgcgg720
gcccggcacagtggctcatgcctgtaatcccagcactttgggaggcccaggtgggtggat780
cacgaggtcaaggnatcgagaccatcctggccaacatggtgaaaccccgtctctactaaa840
aatacaaagattagccaggcgtggtggcgggcgcctgtagtcccagctactcaggaggct900
gaggcagaggaatcagttgaacccaggaggcggaggttgcagtgagcctagatcgcacca960
ctgcactggccacaaagcgagactccatctcaaaagaaaaaaaaaaggaaaaagaaattt1020
gcttagacagatcaaagagcctatgccctgttcttcccagtgtagggctgttttttgacc1080
ggaacatggactgaaagtgcatctcatgttctagaggccatggcaatttgcggcacgtaa1140
gatcaccaatatcttcttggtagggatagcactcttcccataatttgaacttcagaatat1200
cgtgtaggctgtaacactaccttgctcagtgcttggcatacactaggtgcttaacagtga1260
ttagaatcccttcactgtaactgtcttgttggtatgaaaatacaattttaaaaacagaaa1320
aataaaacaaacctctactttagatcatggcgtgctaaaacatccagtaaggagtgttct1380
cttatttatttatttatttttcctggagctcctgggcctgcagtggagaacaatgtgtcc1440
gcagttatttcctacttttctaaggtagtgagaagaatgctgaagctatgcacttaaagc1500
yaattattagtaacttaaatggcattccaagagaacagagaatccaaactcagtgcttat1560
gttttaaaaacaatgaagcaaagctataatgttggcacactttgcagcactttgttatct1620
atttgtctacacatttcaggaaaatgtttctggtttgaaagttcaaaacaagctaaagct1680
tcaaacggaggctgtgaggttctttattcttttgttttaatggtagcataacgacatagg1740
acatctgagctcatgctgtacagcgacatcctttagccgtttccattagacatttatgcc1800
tggtattcttaaatgaaacataaaatattggtatgtatttttccctgacaggatatgttt1860
gagatattgctgtaagatgtaatcaaattttaaaggcgataggagccctaaaaaaggaag1920
aatcattcacgttttctaatcacagccatgtgagtaatggcatctggcgactcgggaacg1980
cctgctaagttttagtacttgtctgaaactagctaccacgtgattgcttagctgcctggt2040
ctttttaaggttgcctgaaagggctctgctataaacttacttatttatcctatttattgg2100
atgcacccacatcacataatagtctctgggtacatttacaagggtaataaaagaggctat2160
acagttctttcttggcaattggatagagnacctagagttcaaaggagatacaagtgtatg2220
taattcagctgttgcacttttctttacaatttttaacatcttatatttaaattttttttt2280
agggctgtgaatcaataaaataacaaaaaaagagtatatgctttcaactgagacgttaaa234.0
gaaaataaaattacagagagccttttacagttttcttccaggcagtccacactaaggggc.2400
aattcctttaggacgagcactgtgttggaggctctgttttcataatcagaatagcacatc2460
ccgtgtgaagaagaggctttgagtccacattcttcctggatttcacatccgattaatgag2520
gatgccaggcaatgtgcaaatctgcagttgctgcaccgtgcggtggctgagacttttcca2580
cataattttaagtgggaagtaggttaggtggcaactttgaacaagaaaaatatgaagtga2640
taaatgtgcgtgtgcatgtttgggggtgggtgggtacgctcacatgcactcacgtgtgta2700
angtgcatatcaggacctggacagctaaaggacaggatgtccaacttaaaaaaaaataga2760
tttcacccaacaaatagttatgatttctcacatatatacatatatacatgatgttatcaa2820
atgtaactaagctgaaaacatggaaatccccttactagagctcagaatttccaattcttc2880
attgttttactttcactgaagtggtcagccatagcatat~gcaaatctatgtcaaatgtag2940
gtgaaacaaataccaataactggctgatgatcgagacaaattacacttatatacacacat3000
a 3001
<210> 225
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-27360-142 : polymorphic base G or T
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-27360-142.misl
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
430
<221> misc_binding
<222> 1502 .1521
<223> 99-27360-142.mis2, complement
<220>
<221> primer bind
<222> 1361..1381
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1793..1812
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-27360-142 probe
<400> 225
ttgtttcataatcagataccattaggtggtctgtgttcactgtgatgctggtgaatccac60
actctcaatgtcgcacacctgtctgtgttttgacttgcacttgtcacatgaggtcaggtg120
tggaattttccacttgtggtgtcatgtgggcactcaaacaatttcggattttggagcatt180
tcagattttcagattaggaatgctcaatttgtatctaactttctaaacctgtgaatatga240
gactgtatttatctatctcaagaacaaacatcaaaatatgtccatcagtgatagattgga300
ttaagaaaatgtggcacatatacaccaaggaatactatgcatccataaaaaggatgagtt360
catgtcctttgtagggacatggatgaagctggaaaccatcattctcagcaaactatcgca420
aggacaaaaaaccaaacactgaatgttctcactcataggtggcaattgaacaatgagaac480
acttggacatcggaaggggaacatcacataccagggcctgttgtggggtggggggagggg540
ggagggatagcattaggagatatacctaatgtaaatgacgagttaatgggtgcagcacac600
caacatggcacatgtatacatatgtaacaaacctgcacattgtgcacatgtaccctagaa660
cttaaagtataataaaaaaatatggtagctgtctgaatat.tatctaaatacataggatat720
agaactcccattatgagttgtaaaattgtaacactttgagaagtaaagaaggatggagta780
aagattgaaggttggaaatggaggcaacattctctgatatgcttttccctgatataatat840.
ttgacatacaatcaatacaaacattttgctgatacaataatagctagagatattattatg900
tctttgtaacagagagatgtttaatatgaaataaatgatgcatagtagatagcttaattt960
gcttggtggcgaaaaacactgcctaaatcctttggggctgaaatttgctgatttcaaaat1020
gtatgccaatcacttaaaccattttaaaatttcccttttcttataataaattacaattat1080
taaaatatcacccataagaattgaaaatcaaataaatttttgaattatacttcatgtatt1140
cttataaagaaatggaatcaggaatatgtttcaaaaagatctttgtcaattataactatc1200
attgtattactagggtttcattaaaactggattttctctactttttttgtattttggtta1260
atgagttatttgtgatttattctatcttaattaattttgccttctttttaaatatatctg1320
gaaatttaagagtgtaaaaagtgacaattaaaaatctttacataaccaaaagtagatcaa1380
ggttacatttcgctaggttggcaataaaattatccatataattacataattcattcccct1940
aaaatattattttggtaagttacttaaaaattttggcacatcttgtgttccttttgaaga1500
kaaatcatcctatatatttcaatatattttagatttttttctaactccatctttgtttta1560
agaaaaatcaaagtttataaactatgtctatatttacaaaatcactgtgtcagagcatga1620
cttttaatcatctctgcactttaacacaggccttaggatatttacaaaaattggagaatc1680
aaaattagagagttgcaaacacccttgaaatccatctagtccagtcatctagctctccac1740
ttcttagtaccacaggctaaggagacagactgagcagtcaaggtaacaagcccctctacc1800
ctttctttgtacaaaacaatttcagtgtttttgaagtatttgtaacaatgttcttagcaa1860
cttcattataccatttaacaagaatacattgaaaatcaattccccaacactcattttgta1920
cgctaattttgtaagatcctgaaaagtttcactattttatggtttcatgtgttacagatg1980
aaaaaaaaactagaattcaaattttctgagtttttttttacaatattttatgattacaaa2040
gttagaagactaagaataaaatggcctaatttccataatgtgagtggtaaatgcagagca2100
ctggcctaaagaaaatatttcaaaaaattagtcatcttttccttaatttttttccaacct2160
atgatctgttgaatgagcattttgcatatataaataaataaattactttgtaaataatct2220
tgactggtttctgttgaccacagtaacccactgcacagcacagcctgtaatttctatgaa2280
cctagggaaatgtatttaagtttattttttgattacacaggtcctcattgtgtaactaaa2340
cattgcatagaatatgccagtgatgatggagaaaagctgtcaaaatcaatatttagggga2400
gaggtagctgctggcagctctgacacattgaaaaagttcagtgactcaagtacaaagaca2460
ggagaaaatcattcaacaaaacccctgaaatgtgtacttgtttttcctgacctacacatt2520
ttaattccaaaaagagtgggaggcacataattatttttgtcaacatagattcatcaaaca2580
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
431
cagggcaaatatattcagaacaatggagatatttccttcctgccaattcaagaattatta2640
atttgcctgaggaaaacgtttacatttatgatggtatatacacatgtctacacacacata2700
tgcatatgtaaaagaaaagcgtatcaaaatctaactgtgccggaaagtaggacacaagtg2760
ttagctgcattcacaatgacattgcagtgacctcatagcttgctttgccacagtttgctg2820
cctttttcattgttgttcaaaggaagataaatttcaatatttcccttgcttgcataacat2880
ggtgtcgcattccagactgttggtagtgtttccacatataaattattggtctagcacttc2940
acagaatctggtacgctgctattttcagcagtctatgcttcctcccagcctcctccttgg3000
t 3001
<210> 226
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-27361-181 : polymorphic base A or G
<220>
<221> misc_binding
<222> 1482 .1500
<223> 99-27361-181.mis1
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-27361-181.mis2, complement
<220>
<221> primer bind
<222> 1322..1340
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1815..1834
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-27361-181 probe
<400> 226
gtgactcaag tacaaagaca ggagaaaatc attcaacaaa acccctgaaa tgtgtacttg 60
tttttcctga cctacacatt ttaattccaa aaagagtggg aggcacataa ttatttttgt 120
caacatagat tcatcaaaca cagggcaaat atattcagaa caatggagat atttccttcc 180
tgccaattca agaattatta atttgcctga ggaaaacgtt tacatttatg atggtatata 240
cacatgtcta cacacacata tgcatatgta aaagaaaagc gtatcaaaat ctaactgtgc 300
cggaaagtag gacacaagtg ttagctgcat tcacaatgac attgcagtga cctcatagct 360
tgctttgcca cagtttgctg cctttttcat tgttgttcaa aggaagataa atttcaatat 420
ttcccttgct tgcataacat ggtgtcgcat tccagactgt tggtagtgtt tccacatata 480
aattattggt ctagcacttc acagaatctg gtacgctgct attttcagca gtctatgctt 540
cctcccagcc tcctccttgg tggtatgact gttacagaaa cattagaggg aacagaaatg 600
ctgccagtgc acaatgtgag tggtattatg aggaatcaga ttgctaaaag catgcatatt 660
tgatgaagca agctaaacaa ggttatactg tttaatagcc taaaaaggca aataataata 720
tatgagaaat catttctata tctgtaggtg taagaaccca aagttagaaa aaaacatctt 780
ttgtcgggat taaggaaatt tattcaatga catcatagca aataaaatca gattttttta 840
tgtgagtaaa ctattaatgc atagcagaat taataatctt gtagcaatga taccaaatta 900
attttatgtt ttaagcctat gatataagtt agtttccaag gacaaagcag tgtgactaaa 960
gccctctgta aaatatcatt tcctaaataa taacaataca cctgtttgtt tttacacttt 1020
taaaattttt acctctctga ataattgaga atttgaaatc atcacacaag gaaagcaata 1080
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
432
tgctttttatttgcatatagcatgttcttttcattaaaaatgtaatatggtgagaggtaa1140
acaaatctgcccaaaaaaagtgtgcaaacctgccagcctaagtggtacttcttcttaaaa1200
attgtactgattttatttaacaaaaagttcaagtgataattctaaataaatagaattgca1260
ttgtggaacatatgttatcacattaatcatttgctcctactgctatttcatacttggtgg1320
tcattcttatgccatatctgtaattatgacatttttctttactctaatgtcaactgatta1380
ctgatgggcccagaaatggctttctgttaacaagcctggagcagctttgtgcaaaaaggc1940
ttttgggaataaagaattgatttgtgcatcttgcaaacagaagaaatttgggataactca1500
rctagtgactagaagaatcccttctctcagagtaaattccagtgaccatagagtatggat1560
tgttgaccattcttgacatgccattggtcatggtgatggacattgcatgcctgtcccaag1620
acggacattactgatcatgacaatgtttgaaataggaaaacaggctaatagagttaaagt1680
gaattgcttgtagtctcacagctaataagtgacaaagcaatcattggaaactaattctgt1740
ttgttttgcttttgaatggaagaatgttagatcctaatgtataatgtttagttcaatgca1800
tgtcatgataaatagacatttaccaaaagcatacatttgtcaaagctctgaagtgtttgg1860
ctgtgaatggagactcaagacttattactcaaaccaatattcatacagtcttctcctgtt1920
gacattcatgctaatatttttatctattttataaccgaagtgcttttgtatatttttgat1980
tataattttctgagtagaagctgtccttgaataacattttcaagacaaactacacaatta2040
ttgtagtagaaatatggattcctttccaggtggtatttgagatcactagaggacagtaag2100
gatttgtagaggtcatttgtttttttaaaaaaaatttaataaccctctttcacctttccc2160
taaagaccctaaatctgaggaatcaacagggcagcagatctgtatatttttttctaagag2220
aaaatgtaaataaaggatttctagatgaaaaaaaaaaaaaaaaaaaaaaaaaaaatttaa2280
taaaaagcatttatagttgtaatttattttaatttccagtatgtacgtatttaaagcaag2340
tatagataaaatttactttgtgatagcatcaatgtttaattaatcatttgctttttcaat2400
cttgaaagctagtgatgtttacattttctgtttcaaatcaaccatttttaacttatatta2460
catctacaagaggtaagaataaaaaaattgaaatgacaaaaaaggattatcaaaattatt2520
acgatgtggaaaacaatcttgagcgtaatctgtagctgagtaaatagcagaatgtgaagc2580
attatgaattattttatagactttggaaaatatgaacaaatataattgtttatatttaca2640
aaatgtctcctatttctatacttcctagatcaagctgtgttcattattatggtgccgctg2700
ccgcctagttagcctatcactatctagagtcatcagctttccttaaagcccttttctctc2760
ctccccttaaagcccttttctctcctcccattaaagccctttactctcctcccctcacct2820
aaagtaagttaaatacatttactcacagaactagaagtgggtggactggctaatgaatgg2880
tttagctttgaaattatacttacagaaaatattagattaaattatgggaaaacatttccc2940
caaatgatttttctagtactatgcctacaagctttgtgcttcaaaacagtagtgagaaca3000
a 3001
<210> 227
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-27365-421 : polymorphic base C or T
<220>
<221> misc_binding
<222> 1482..1500
<223> 99-27365-921.mis1
<220>
<221> misc_binding
<222> 1502 .1521
<223> 99-27365-421.mis2, complement
<220>
<221> primer bind
<222> 1081..1099
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1590..1609
<223> downstream amplification primer, complement
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
433
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-27365-421 probe
<400>
227
tcttttctttcttttctttctttctcaatctcaccctgtcatccaggctgaagtacagtg60
gcacaaatgtagctcactgcaaactcaacctcctgggctcaagcaatatttctgcctcag120
cctcctgagtagctaagactacaagtgtgtgcctggctttttttttttttttcttcttct180
tcttctttaacgttttgtagagatgaggttttactatgttgcccaggttggtaaattcct240
tagctcaggcgatcttcccacctcagccttccaaaatgctggatttacaagcatgagcca300
ctgcatcctactcaatatcagtttatttttatgagctcaccagtcatggatgaaaactga360
ctcctggagaaggggttaaaaagagaatgcaagatgaatgtttgactccttccttttctt420
ctataagttttcagaataatgcctttttttttccctaagagtcctgatcctaggtaccag480
tagtgctcattccttttgagtgggtcagcgtttctagtcattttctgtgggccggatgag540
ggtatctttattttttttttaataagagatgccattcatctgatttttattgataataca600
ggtgttctcttaaaattttttctctcttaattatgtatttatttctctcatgtcaaaatt660
ccagttcccagtaacacagacatttgttttcatctaaatacatacacagtagtctctgtg720
tgagaataccagacattggaagagagtcacttactgatcagggagtcctgagcagatctt780
accaaggagagatataaacttctatagtgtaagcttttgagcttacactatacaattttg840
ggaatgggagttagttatctgttaaaacagttaacagcttctttaatacataaagtatct900
aatgcttttgccgtaccctgcttaaaagtttgtaatatcaatcggtactgtgaataaatt960
acttaccattctgcattgcaatggatatcatgacttgaatagcaatagatacatgtattg1020
agatctgtgtgaagggtcaaatacaaggaaggattttgtagtactggactagaaaatatt1080
ttatcctaagtggaaacagaacatatgggcatgtaagcagcttgagcatgtacttcaatt1140
ccctggtaagaaatctcctcttgaaaatttgagtcagatagtctgaagtgttctgctgga1200
atgaaatcaatatatgaaatttaaaatgttggagtaatctgcacttaggtaaccatgcag1260
tgcagtgacttcatgggtgccttcagattagaacaatataaaatttgaggagcaaaagtg1320
caaacatttgagaaatgctcatagttaagtggtgattgctgaggagatttaaaagaaaga1380
aatacaaaattaatcatagaagaaagaagataatatagtgccaaaaaacccacaagagaa1440
atagtttaagaagtgaataatacattaaataagacagagaaatcagcaatacaagacaac1500
ygaatttaaaacttaacagattatttgtgacctgaccactgagtaaaaatactcagtaaa1560
gtggttggaatggaaacagtattgtttctcaagggtacaataaaagacaatgacttggag1620
aggtgactgcaaaacagagtgacaagattctaagtagagccataagactcactgtgaaaa1680
caaatgtcctgctctatttggttctaaaattcattatctgcaaaagttctacaatgctga1740
ggggccatattttgtttgtatgtttcaactcatactttacctctgctgcctcacaatagc1800
ctgcaaaaatagccactgccccacaataccttggaagtaggaactgcgcctcacgcaggc1860
cgcctacaggacagggaagcagctggagacccatgagatggctgaaccaaacagaatcca1920
gaccgggcttgctttggaaatgtggggcaagaaataccaattaaataaggcagtgagtgg1980
tgggaactaaactaaaatgccatctggtaggtcatggatggagagaaccacggggctatc2040
gataagccaaagctgcaagctgtcagtgactctgtgaagaaaccgaaagtcaatgcgtgc2100
agcgagaagagggtgattgaggaagtgctgcagcatggctatgggcgatagaaagactgc2160
agctcttgactcaagcacggagggaggaggtggttttgaaacagcctcggatgctgacag2220
attgccttctgtagctctaagtccttaaaataacccaactcggtggctgtgtgtggtttt2280
gtttgttttgtttgacccaaatagcttggaagactcagacatcttctgtagtctcggttc2340
tagcagtgccagagctagatgaacctggtagtttaaattttcaaagggttggtaaacgat2400
gtatggtaagcaggaaagaaaggataatgagcacagtaagaggaactaggggaaaggtac2460
tttggtgaggctgaaactgcttcagttcccgctctgcctctctctctcatgaatcactat2520
gacctgaatagggagaaaacgaacgcacatgttggaaatcaggttgagcggatttcacgt2580
catttccacatagcaccctatccagtgagaggaaattatctgcctctttgtgaaagtgac2640
agggatgtgcaggcacagtgcaattccttggggaagtgagggcagtgtctgcatatagtt2700
atcaagcaagaaattgttgagtgttgcgattgcaaagaaaagaacagaattgagaacacc2760
cgagtctttatcgatcaagccccagaatagcagtcatgacagggcaggttatgagtttag2820
ccagctgtgtgaggtaacaaggcctcctacagctcttcttttgggagcttcagttgagtg2880
ataagtcatcctctctctagagtaaggcagtagcaggaaacagctgtatgccaattgtaa2940
attctcccacatttcagtggagatgtagtccaggtcttacttgcccctgtggattatcta3000
a 3001
<210> 228
<211> 526
<212> DNA
<213> Homo Sapiens
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
434
<220>
<221> allele
<222> 484
<223> 99-27680-484 . polymorphic base G or T
<220>
<221> misc_binding
<222> 464. 483
<223> 99-27680-484.misl,
<220>
<221> misc_binding
<222> 485. 504
<223> 99-27680-484.mis2, complement
<220>
<221> primer bind
<222> 1..18
<223> upstream amplification primer
<220>
<221> primer bind
<222> 509..526
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 472. 496
<223> 99-27680-484 probe
<220>
<221> misc_feature
<222> 57
<223> n=a, g, c or t
<400> 228
ggagacaaaa aatcacggca aattacaaat tataaaagct aaaaattacc tcaaatntta 60
taaaatccag tatactaata ccttgaaata cctctataat aacatttttt atgtatttta 120
gctatatact ttaaaattgt ttttattgtg gtaaataaat ataaaatctg ccatagtaac 180
catcttgaag tgtacaattc agtgacattc agtgcattta tgatgttgtg caaccatcac 240
cactagctgt ttccataata gagcctggaa gagctattca cttaaaacac gacgggaaga 300
acaccacctt gagttgtaca gtgccaaggc ccagaacatg ctgccctctt tcacttccaa 360
gctttggcac aatttttccc tctgccagaa gtgccctaat tcaaaccctt ctgctgttcc 420
tactcacttc tcagtcccaa cccaggtaga tgtttgaagc ccttatggaa tccccccaga 480
ttakattggg tgcccttcct ctgtgcttct actccacact tactca 526
<210> 229
<211> 3001
<212> DNA
<213> Homo Sapiens
<220>
<221> allele
<222> 1501
<223> 99-27912-272 : polymorphic base C or T
<220>
<221> misc_binding
<222> 1481 .1500
<223> 99-27912-272.misl,
<220>
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
435
<221> misc_binding
<222> 1502..1521
<223> 99-27912-272.mis2, complement
<220>
<221> primer bind
<222> 1230..1250
<223> upstream amplification primer
<220>
<221> primer bind
<222> 1659..1679
<223> downstream amplification primer, complement
<220>
<221> misc_binding
<222> 1489 .1513
<223> 99-27912-272 probe
<220>
<221> misc_feature
<222> 1929,2531,2954
<223> n=a, g, c or t
<400> 229
tccaagaagagtcagtgtttcagtttgaacccaaatactggaaaaaagccaatctagttc60
aagagcagttggtcaagaagaatttcctcttatatgggagatagtcagctttttgttcta120
ttcaaacgtctaactgaatgaggaccgcccacacgaaaaagagcaagttgctttactcac180
tctgctgattgaaatgttatctcatccagaaacatcctcataaacacaccagtaataatg240
tttgaccaaatatctggacaccttttggttcaggcaagttgacacataaaattaatcatg300
acaactttcaatagggaatttcacagtttgcatctagaacacctagaactccataatggc360
aaagacgaagactttgggtctatgtgttcttagtgggaagcactgtgtttggtctataat420
gagcattaaggaatgcagaataaactatgcattaacattgaaaaaactatatttgacaag480
ttaatgataataaacatcttggtaaaaatgtgtatttcttttaatagaaaattttaaaga540
attatcctaagtgaaaatatattaggttatgttttatttattttattttattttatttat600
ttattttttgagatggaggagtctcgctgtgtcgcccaggctggagtgcagtggcgtgat660
ctgggctcactgcaagctctgcctcccaggttcacgccattctcctgcctcagcctcccg720
agtagctgggactaggggcgcccaccaccatgcccggctaattttgtttttgtattttta780
gcagagacggggtttcactgtgttagccaggatggtctcaatctctgacctcgtgatctg840
cccacctcagcctcccaaagtgctgggattacaggcgtgagccaccacgcccggcctaga900
tgatgtttttaattaattaatcagatttcttaaaaatatataatttgtctggctccttta960
tttcagttagtctttaatctctaaagcaatgaagttattcaaccataactcaagtaacaa1020
agtgtccggacatatttggaaaatccatctaagagaaatgaaactatgaacatttatata1080
cctccattaaaaatgtgtctaattcaaatattaaaaatctgaatttataagaattttagt1140
ggttttaatatctgctgatttgtcttttaataactttcagaattaattttgtgtaaatat1200
tttccttttctctttttttttcccagacataagccccacaaggtgaaaaggcatgcagat1260
aaagagtatgccttttctttttcagtgtctggcaaaagaataattgtaaaattaagagga1320
ttcttaatctttgacttttgttcaatgttgtctcatccatccagtttttcctgtgctata1380
agacttagatctgtaatgttaataattaattacttaaaaggtaatgtctatgctcaaaca1440
acctataatgttacccctaaaacaatgagaaacaatgacaagttaactaatatggatcct1500
ytaaattgtgtgaatgtgtgctgtaagactgaagttgtagttgtttcttagatttaacac1560
agagctacctccttgactataaacttttgttgctatgttgggaaatcagtttggccttaa1620
attgtcttctgtgaataataaaactttccttggagactggattcatggcaaattctcttt1680
aggaaaacatgcttgaatttgacacatttgtaaaaccatcgctctttgggactactggct1740
tctgacctctgaatcctagtaattattctaaggccacaaatgtaccaaatattgtccaga1800
agagccgttcactggctccttacttcgtcagtcccattgcttgtagaaactgtgcttctt1860
atatcctggttagaggtctccaggctatggtcttcctacttggttatctcaagctacagc1920
tgctcctangttggtgcctccaacaacagttttaacagacttcattttctatgggagact1980
catgcctgaactcaacttctctatgtctaggtagtgtccacatgcagatattgatataat2040
gtatattcctttatcctttatgttttataagaggagaagggtaccaaaacacttaggggg2100
tgataatgactagattgaatacatttatattggatgttatctaaggaagaggctttcaat2160
tttcatacaatgtgggagagagctaataagtaaaaaggaaagagttgaaacaatatctct2220
aacaatattggttcatagggaataataagaaaatgggaattgtttgtggaaaaatgctat2280
CA 02361408 2001-08-08
WO 00/58510 PCT/IB00/00435
436
cacataggttgacctaaaattttaaataattaaactcttttgatacactt ttgtttctat2340
cttttccccaaatgaccagcataaaaacctattgattaagcaaatcaagt ttgttagact2400
gtagcagtagggaaaaaaaacaaccttgacagagtctcattggagtctct aagtagtgat2960
actattgaagtatatagatgctttagagcctgggatatgtgatttaaggg tagatatttc2520
aaggtgtgganctagttggaattgggaaaattttatataataaaatacct ttggttttgc2580
aggcacagcaaagaagtgagaatcttgaagtaagccctaattagcaaact tggtttaata2640
gacaagtggtttagttggttcatattcttattttccaggaacaagtaatt cctggaacaa2700
taatacaagttatttttacttgatcttggtataagtatgcttagtcctag tatggtttaa2760
cacaggacaggaactatgctagtttaagttcttggtcttaaactgaccta ttataccatc2820
ccagtttttagagagctatataaaaaactaaggatttttttctcagctat ctaccatttc2880
caaaacacaaattttcaccaaaacacaaattcacagatgcaagattctac catagtcaat2940
atttactatagagntcctagtgtaagaggaatcatgattggactctggta tcccattgga3000
g 3001
<210>
230
<211>
18
<212>
DNA
<213>
Artificial
Sequence
<220>
<223> PrimerPU
sequencing
oligonucleotide
<400>
230
tgtaaaacgacggccagt 18
<210>
231
<211>
18
<212>
DNA
<213>
Artificial
Sequence
<220>
<223> PrimerRP
sequencing
oligonucleotide
<400>
231
caggaaacagctatgacc 18
