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CA 02330022 2000-11-30
WO OOI62'I36 PCT/US00/08020
LOW ADENOSINE ANTI~ENSE OLIGONUCLEOTIDE, COMPOSITIONS, KIT
& METHOD FOR TREATMENT OF AIRWAY DISORDERS ASSOCIATED
WITH BRONCHOCONSTRICTION, LUNG INFLAMMATION,
ALLERGY(llES) & SURFACTANT DEPLETION
BACKGROUND OF THE INVENTION
Field of the Invention
This patent relates to a composition comprising oligonucleotides (oligos) that
are anti-sense to
adenine receptors, and contain low amounts of or no adenosine (A). These
agents are suitable for the
treatment, among others, of pulmonary diseases associated with inflammation,
impaired airways,
including lung disease and diseases whose secondary effects afflict the lungs
of a subject. Examples of
these diseases are allergies, asthma, impeded respiration, allergic rhynitis,
pain, cystic fibrosis, and
cancers such as leukemias, e.g. colon cancer, and the like. The present agent
may be administered
prophylactically or therapeutically in conjunction with other therapies, or
may be utilized as a
substitute for therapies that have significant, negative side effects.
Backstround o~'the Invention
Respiratory ailments, associated with a variety of diseases and conditions,
are extremely
common in the general population, and more so in certain ethnic groups, such
as African Americans.
In some cases they are accompanied by inflammation, which aggravates the
condition of the lungs.
Asthma, for example, is one of the most common diseases in industrialized
countries. In the United
States it accounts for about I% of all health care costs. An alarming increase
in both the prevalence
and mortality of asthma over the past decade has been reported, and asthma is
predicted to be the
preeminent occupational lung disease in the next decade. While the increasing
mortality of asthma in
industrialized countries could be attributable to the depletion reliance upon
beta agonises in the
treatment of this disease, the underlying causes of asthma romain poorly
understood.
Adenosine may constitute an important mediator in the lung for various
diseases, including
bronchial asiltma. Its potential role was suggested by the finding that
asthmatics respond favorably to
aerosolized adenosine with marked bronchoconstriction whereas normal
individuals do not. An
asthmatic rabbit animal model, the dust mite allergic rabbit model for human
asthma, responded in a
similar fashion to aerosolized adenosine with marked bronchoconstriction
whereas non-asthmatic
rabbits showed no response. More recent work with this animal model suggested
that adenosine-
induced bronchoconstriction and bronchial hyperresponsiveness in asthma may be
mediated primarily
through the stimulation of adenosine receptors. Adenosine has also been shown
to cause adverse
effects, including death, when administered therapeutically for other diseases
and conditions in
subjects with previously undiagnosed hyper reactive airways.
A handful of medicaments have been available for the treatment of respiratory
diseases and
conditions, although in general they all have limitations. Theophyliine, an
important drug in the
treatment of asthma, is a known adenosine receptor antagonist which was
reported to eliminate
adenosine-mediated bronchoconstriction in asthmatic rabbits. A selective
adenosine A, receptor
antagonist, 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX) was also reported to
inhibit adenosine-
mediated bronchoconstriction and bronchial hyperresponsiveness in allergic
rabbits. The therapeutic
and preventative applications of currently available adenosine A, receptor-
specific antagonists are,
nevertheless, limited by their toxicity. Theophylline, for example, has been
widely used in the
treatment of asthma, but is associated with frequent, significant toxicity
resulting from its narrow
therapeutic dose range. DPCPX is fat too toxic to be useful clinically, The
fact that, despite decades of
extensive research, no specific adenosine receptor antagonist is available for
clinical use attests to the
general toxicity of these agents. Anti-sense oligonucleotides have received
considerable theoretical
consideration as potential useful pharmacological agents in human disease.
Their practical application
in actual models of human disease, however, has been somewhat elusive. One
important impediment to
their effective application has been a difficulty in finding an appropriate
route of administration to
CA 02330022 2000-11-30
WO 00/62736 2 PCT/US00!(1R(120
deliver them to their site of action. Many in vivo experiments were conducted
by administering anti-
sense oligonucleotides directly to specific regions of the brain. These
applications, however,
necessarily have limited clinical utility due to their invasive nature.
Although anti-sense
oligonucleotides have received considerable theoretical consideration for
their potential use as
pharmacological agents in human disease, fording practical and effective
applications for these agents
in actual models of human disease, however, have been few and far between,
particularly because they
had to be administered in large doses. Another important consideration in the
phartnacoiogic
application of these molecules is their route of administration. Many in vivo
applications have involved
the direct administration of anti-sense oligonucleotides to limited regions of
the brain. Such
applications, however, have limited clinical utility due to their invasive
nature. The systemic
administration of anti-sense oligonucleotides as pharmacological agents has
been found to have also
significant problems, not the least of which being an inherent difficulty in
targeting disease-involved
nssues. That is, the necessary dilution of the anti-sense oligonucleotide in
the circulatory system makes
extremely difficult to attain a therapeutic dose at the target tissue by
intravenous or oral administration.
The bioavailabiiity of orally administered anti-sense oligonucleotides is very
low, of the order of less
than about 5%. Anti-sense oligonueleotides have been used in therapy by many,
including the present
inventor, who in his previous work successfully treated various diseases and
conditions by direct
administration of these agents to the lung. In many instances, other workers
have had to face the
difficulties associated with the delivery of DNA molecules to a desired
target. Thus, the route of
administration may be of extreme importance for treating generalized diseases
and conditions as well
as those which are localized. In contrast, up to the present time, the
delivery of anti-sense agents to the
lung has been relatively undeveloped. As described by the present inventor in
more detail below, the
lung is an excellent target for the direct administration of anti-sense
oligonucleotides and provides a
non-invasive and a tissue-specific route.
Clearly, there exist presently no effective therapies for treating these
ailments, or at least no
therapies which are effective and devoid of significant detrimental side
effects. Accordingly, there is
still a need for an agent for the treatment of adenosine mediated ailments
afflicting the pulmonary and
respiratory ailments affecting the lung airways, including respiratory
problems, bronchoconstriction,
inflammation, allergy(ies), depletion or hyposecretion of surfactant, ere.,
which is highly effective and
sufficiently selective to avoid detrimental side effects produced by other
therapies. In addition, there is
a definite need for making available a delivery method that will require low
amounts of therapeutic
agents and will be effective for the rapid and targeted access of tissue genes
of tnRNAs and the
reversal of untoward effects afflicting a subject.
SiJN>1~IARY OF THIS INVENTION
The present invention generally relates to a pharmaceutical or veterinary
composition,
comprising an anti-sense oligonueleotide(s) (oligo(s)) which is (are)
effective for alleviating
bronchoconstriction and/or lung inflammation, allergy(ies), and\or surfactant
depletion andlor
hyposecretion, when administered to a mammal, the oligo containing about 0 to
about 15% adenosine
(A) and being anti-sense to a target selected from the group consisting of the
initiation codon, the
coding region, the 5'-end and the 3'-end genomic flanking regions, the 5' and
3' intron-exon junctions,
and regions within 2 to 10 nucleotides of the junctions of a gene encoding a
target polypeptide
associated with lung airway dysfunction or anti-sense to the polypeptide mRNA;
combinations of the
oligos; and mixtures of the oligos; and a pharmaceutically or vcterinarily
acceptable carrier or diluent.
The targets are typically molecules associated with airway disease, cancer,
etc., such as transcription
factors, stimulating and activating peptide factors, cytokines, cytokine
receptors, chemokines,
chemokine receptors, adenosine receptors, bradykinin receptors, endogenously
produced specific and
non-specific enzymes, immunoglobulins and antibodies, antibody receptors,
central nervous system
(CNS) and peripheral nervous and non-nervous system receptors, CNS and
peripheral nervous and
non-nervous system peptide transmitters, adhesion molecules, defensins, growth
factors, vasoactive
peptides and receptors, binding proteins, and malignancy associated proteins,
among others. Examples
CA 02330022 2000-11-30
WO 00/62736 PCT/US00/08020
are oligo(s) targeted to adenosine receptors) and it(they) are typically
present in the composition in an
amount effective to reduce adenosine mediated effect(s), such as airway
obstruction, inflammation,
allergy(ies), and sufactant depletion, among others. The adenosine receptor is
preferably selected from
the group consisting of the adenosine A,, Air, and A~ receptors, and in some
instances even adenosine
S AZ, receptors. The oligo of the invention may be applied to the preparation
of a medicament for (a)
reducing adenosine-mediated bronchoconstriction, impeded respiration,
inflammation, allergy(ies),
depletion production of surfactant, and other detrimental pulmonary effects in
a subject in need of
treatment, and/or for (b) treating specific diseases and conditions such as
asthma, cystic fibrosis,
allergic rhynitis, COPD, etc. For the fast time this invention provides the
targeted administration of
l0 one or mote oligonucleotides directly into the repiratory system. The
oligos tray be directed to any
target and are intended for fast delivery through the mucosal tissue of the
lungs for hybridization to a
desired target polynucleotide, e, g. mRNA, to prevent gene transcription and
translation, such that
protein expression will be reduced, hampered, or completely stopped. Thus,
this invention also
provides a more general method for administering oligonucleotides that are
anti-sense to targeted genes
IS and mRNAs associated with any type of diseases, by direct administration
into the respiratory system,
e. g. by inhalation, by introduction of a solution or aerosol into the
respiratory airways, and/or directly
into the lung.
The present oligos, moreover, are suitable for reducing effects mediated by a
variety of target
proteins and genes, for example adenosine-mediated effects, including
pulmonary, respiratory, and
20 other associated effects, e. g, bronchoconstnction, inflammation, immune
mediated reactions,
allergy(ies) and other airway problems, which may be caused by different
conditions, including cancer.
Examples of diseases and conditions, which may be treated preventatively,
prophylactically and
therapeutically with the agent of this invention, are pulmonary
vasoconstriction, inf<ammation,
allergies, asthma, impeded respiration, respiratory distress syndrome, pain,
cystic fibrosis, allergic
25 rhynitis, pulmonary hypertension, pulmonary vasoconstriction, emphysema,
chronic obstructive
pulmonary disease (COPD), bronchitis, and cancers such as leukemias,
lymphomas, carcinomas, and
the like, e.g. colon cancer, breast cancer, lung cancer, pancreatic cancer,
hepatocellutar carcinoma,
kidney cancer, melanoma, hepatic metastases, etc., as well as all types of
cancers which may
metastasize or have metastasized to the tung(s), including breast and prostate
cancer. The present
30 agents are also suitable for administration before, during and after other
treatments, including
radiation, chemotherapy, antibody therapy, phototherapy and cancer, and other
types of surgery. 'the
present agent is effectively administered prophylactically and therapeurically
in conjunction with other
therapies, or by itself for conditions without known therapies or as a
substitute for therapies that have
significant negative side effects. The oligo(s) may be administered by any
means known to a subject,
35 e. g. to the lungs of the subject, more generally through any and all
systemic and topical routes. This
oligonucleotide(s) (oligo(s)) employed are anti-sense to to a target DNA or
RNA, e. g. an adenosine
receptor DNA or RNA, and preferably consist essentially of up to about I 5%
adenosine (A), and more
preferably contain no adenosine. The oligos are provided in the form of
specific compositions and
formulations, with a carrier or diluent, and optionally with other therapeutic
agents and additives which
40 are used for administration by specific routes, e.g. into the respiratory
system, topically, transdermally,
parenterally, by implantation, and the Like. The oligo is also provided as a
capsule or carnidge, and in
the form of a kit. The oligos of the invention may be produced by selection of
speciGe targeted
segments of the gene or ntRNA encoding the adenosine receptor as described
below. In one preferred
embodiment, the selection is made to obtain oligos that consisting essentially
of less than about i5%
45 adenosine (A). This may be done by selecting the target as done above,
which includes genes, genomic
flanking regions, RNAs and polypeptide associated with an ailment afflicting
the lung airways,
obtaining the sequence of a mRNA(s) corresponding to the target genes) and/or
their genomic
flanking regions) and/or the juxta-membrane regions thereof, and mRNA(s)
encoding the target
polypeptide(s), selecting at least one segment of the mRNA(s), and
synthesizing one or more anti-sense
50 oligonucleotide(s) to the selected mRNA segment(s), and subsfituting, if
necessary, an alternative, e. g.
CA 02330022 2000-11-30
WO 00/62736 PCTlUS001118020
4
a universal bases) or other bases) for one or more A to reduce the proportion
of A present in the
oligonucleotide to less than about 1S%, and down to no adenosine. Similarly,
alternative and/or
universal bases may be substituted for adenosine, e. g. specific adenosine A1,
A2b and A3 receptor
antagonists or A2a receptor agonists, theophilline, enprophylline, and many
other adenosine receptor
S antagonists known in the an as well as agonises with significantly reduced
agonise activity with respect
to adenosine, e. g. less than 0.5%, less than 0.3%, and the like.
The invention will now be described in general in conceptual and experimental
terms, with
reference to specific examples. Other obaects, advantages and features of the
present invention will
become apparent to those skilled in the an from the description that follows.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
This invention arose from a desire by the inventor to improve an prior art
treatments for
pulmonary and other diseases, which technology is generally frought with
detrimental side effects and
by the need of administering high doses of therapeutical agents. The present
invention arises from the
inventor's own discovery that adenosine receptor targeted anti-sense
oligonucleotides (oligos) may be
IS utilized therapeutically in the treatment of diseases or conditions which
impair respiration, cause
inflammation and/or allergy(ies), constrict bronchial tissue, obstruct the
lung airways, depletion
surfactant secretion, or otherwise impede normal breathing. In general, many
diseases and conditions
are associated with or cause inflammation, constrict bronchial tissue or the
lung airways, depletion
secretion of surfactant, augment allergy(ies), or otherwise impede normal
breathing. 'This treatment is
selective for specific targets associated with or mediating these symptoms,
and the agents are
administered in up to 1000-fold lower doses than those seen in the art. The
inventor, in addition,
wanted to provide a treatment which would improve the outcome and life style
of patients undergoing
other procedures or being administered other therapies, including antibody
therapy, chemotherapy,
radiation, phototherapy, and surgery e.g. cancer surgery, and that could be
effectively administered
preventatively, prophylacticaliy or therapeutically- He reasoned that he could
further improve on this
discovery by selecting oligos of reduced adenosine content, or reducing the
adenosine content of
otherwise targeted anti-sense oligos corresponding to endogenous
polynucleotide sequences: The
present invention is premised on the discovery by the inventor that
oligonucleotides are metabolized in
vivo to their mononucleotides. Adenosine (A)-containing ohgonucleotides break
down and release
adenosine which, in turn, activates adenosine receptors, thereby causing
bronchoconstriction,
inflatnmation, surfactant depletion, allergy(ies), and the like. He, thus,
conceived of employing low
adenosine-free adenosine oligos to avoid these side effects upon their
administration. He succeeded in
this endeavor and is providing in this patent novel and improved compositions,
formulations and
methods which afford greatly improved results when compared with previously
known treatments for
3S preventing and alleviating bronchoconstriction, allergy(ies), inflammation,
breathing difficulties,
surfactant depletion and blockage of airways, as well as for other conditions
which affect the lung
directly or indirectly. In different embodiments, one or more nucleic acids of
the invention may be
formulated atone, and/or with one or more surfactant components and/or with a
carrier, andlor with
other therapeutic agents and/or formulation agents known in the art. The
compositions of this
invention, thus, may be incorporated into a variety of formulations for
systemic and topical
administration. Moreover, the inventor also provides a broad method for
delivery of anti-sense
oligonucleotides (oligos) through the respiratory system, as a fast means of
starting treatment to
address acute attacks of asthma and other diseases and conditions that have a
rapid onset. In addition,
the present agents have long halflives and may be administered at very low
doses. This makes them
4S ideal for once a week type therapies. In the past, anti-sense
oligonueleotides received considerable
theoretical consideration as being potentially useful as pharmacologic agents
for the treatment of
human disease. Wagner, R., Nature 372: 333-335 ( 1994) However, it has been
difficult to actually
apply these molecules to allemating and curing human diseases. One important
consideration in the
phacmacologic application of these molecules has been the failure of various
routes of administration
to deliver the compounds to its target while avoiding invading the circulation
and, therefore, other
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WO 00/62736 PCT/US(1(1/OR1120
untargeted tissues which, thus, produces a plethora of side effects. Most in
vivo experiments utilizing
anti-sense oligonucleotides involved a direct application of the oligo to
limited regions of the brain.
See, Wahlestedt, C., Trends in Pharmacol. Sri. I5: 42-46 (1994); Lai, J. et
al., Neuroreport S: 1049-
1052 ( t 994); Standifer, K., et al., Neuron 12: 805-810 ( 1994}; Akabayashi,
A., et al,, Brain Res. 21:
5 55-61 (1994). Others applied them into the spinal fluid. See, e.g, Tseng,
1.., et al., European J.
Pharmacol. 258: RI-3 (1994); Raffa, R., et al., European J. Phatmtacol. 258:
R5-7 (1994); Gillardon,
F., et al., European J. Neurosci. 6: 880-884 ( 1994). Such applications,
clearly, have no practical
clinical utility due to their invasive nature. Thus, the systemic
administration of anti-sense
oligonucleotides poses significant problems with respect to their
pharmacologic application, not the
least of which is the difficulty in selectively targeting disease-involved
tissues. The systemic
administration of anti-sense oligonucleotides also poses significant problems
with respect to their
pharmacologic application, not the least of which is the difficulty in
selectively targeting disease-
involved tissues.
The respiratory system, and in particular the lung, as the ultimate port of
entry into the
I S organism, however, is an excellent route of administration for anti-sense
oligonucleotides. This is so
not only for the treatment of lung disease, but also when utilizing the lung
as a means for delivery,
particularly because of its non-invasive and tissue-specific nature. Thus,
local delivery of antisense
oligonucleotides directly to the target tissue enables the therapeutic use of
these compounds.
Fomivirsen (ISIS 2302) is an example of a local drug delivery into the eye to
treat cytomegalovirus
(CMV) retinitis, for which a new drug application has been filed by ISIS. The
administration of a drug
through the Iang offers the further advantage that inhalation is non-invasive
whereas direct injection in
to the vitreous of the eye is invasive. The composition and formulations of
this invention are highly
efficacious for preventing and treating diseases and conditions associated
with bronchoconstriction,
difficult breathing, impeded and obstructed lung ainrvays, allergy(ies),
inflammation and surfactant
depletion, among others. Examples of diseases and conditions which are
suitably treated by the
present method are diseases and conditions, including Acute Respiratory
Distress Syndrome CARDS),
asthma, adenosine administration e.g. in the treatment of SupraVentricular
Tachycardia (SVT) and
other arrhythmias, and in stress tests to hyper-sensitized individuals,
ischemia, renal damage or failure
induced by certain drugs, infantile respiratory distress syndrome, pain,
cystic fibrosis, pulmonary
hypertension, pulmonary vasoconstriction, emphysema, chronic obstructive
pulmonary disease
(COPD), lung transplantation rejection, pulmonary infections, and cancers such
as leukemias,
lymphomas, carcinomas, and the like, including colon cancer, breast cancer,
lung cancer, pancreatic
cancer, hepatoceilular carcinoma, kidney cancer, melanoma, hepatic metastases,
ere., as well as all
types of cancers which rnay metastasize or have metastasized to the lung(s),
including breast and
prostate cancer. The invention will be described with respect to the adenosine
receptors as targets, but
is similarly applicable to any other target with respect to the pulmonary
administration of anti-sense
oligos. The examples provided below show a complete inhibition of such
adenosine receptor
associated symptoms in a rabbit model for human bronchoeonstriction,
allergy(ies) and inflammation
as well as the elimination of the ability of the adenosine receptor agonist
par excellence, adenosine, to
cause bronchoeonstriction in hyper-responsive monkeys, which are animal models
for human hyper-
responsiveness to adenosine receptor agonists. The pharmaceutical composition
and formulations of
the invention, therefore, are suitable for preventing and alleviating the
symptoms associated with
stimulation of adenosine receptors, such as the adenosine A, receptors. The
compositions and
formulations of this invention, thus, are also suitable for prevent the
untoward side effects of
adenosine-mediated hyperresponsiveness in certain individuals, which are
generally seen in diseases
affecting respiratory activity.
The method of the present invention may be used to neat airway diseases and
conditions in a
subject of any kind and for any reason, with the intention that the adenosine
content of anti-sense
compounds be minimized, reduced or eliminated so as to prevent its liberation
upon anti-sense
degradation. Examples of diseases and conditions, which may be treated
preventatively,
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WO 00/62736 PCTlUS11111t1802(1
prophyiacticaliy and therapeutically with the compositions and formulations of
this invention, are
pulmonary vasoconstriction, inflammation, allergies, asthma, allergic
rhynitis, impeded respiration,
Acute Respiratory Distress Syndrome CARDS), renal damage and failure
associated with ischemia as
well as the administration of certain drugs, side effects associated with
adenosine administration e.g. in
SupraVentricular Tachycardia (SVT) and in adenosine stress tests, infantile
Respiratory Distress
Syndrome (infantile RUS), ARDS, pain, cystic fibrosis, pulmonary hypertension,
pulmonary
vasoconstriction, emphysema, chronic obstructive pulmonary disease (COPD),
lung transplantation
rjejection, pulmonary infections, and cancers such as leukemias, lymphomas,
carcinomas, and the like,
e.g. colon cancer, breast cancer, lung cancer, pancreatic cancer,
hepatocellular carcinoma, kidney
IO cancer, melanoma, metastatic cancer such as hepatic metastases, lung,
breast and prostate metastases,
among others. The present compositions and formulations are suitable for
administration before,
during and after other treatments, including radiation, chemotherapy, antibody
therapy, phototherapy
and cancer, and other types of surgery. The present compositions and
formulations tray also be
administered effectively as a substitute for therapies that have significant
negative side effects.The
terms "anti-sense" oligonucleotides generally refers to small, synthetic
oligonucleotides, resembling
single-stranded DNA, which in this patent are applied to the inhibition of
gene expression by
inhibition of a target messenger RNA (mRNA). See, Milligan, 1. F. et al., 1.
Med. Chem. 36(14),
1923-1937 (1993), the relevant portion of which is hereby incorporated in its
entirety by reference. For
consistency=s sake, all RNAs and oligonucleotides are represented in this
patent by a single strand in
the 5' to 3' direction, when read from left to right, although their
complementary sequences) is (are)
also encompassed within the four corners of the invention. In addition, all
nucleotide bases and amino
acids are represented utilizing the recommendations of the CUPAC-IUB
Biochetrueal Nomenclature
Commission, or by the known 3-letter code (for amino acids). Nucleotide
sequences ate presented
herein by single strand only, in the 5' to 3' direction, from left to right.
In addition, nucleotide and
amino acids are represented herein in the manner recommended by the IUPAC-IUB
Biochemical
Nomenclature Commission, or (for amino acids) by three letter code, in
accordance with 37 CFR '
1.822 and established usage. See, e.g., PatentIn User Manual, 99-102 (Nov.
1990) (U.S. Patent and
Trademark Office, Office of the Assistant Commissioner for Patents,
Washington, D.C. 20231); U.S.
Patent No. 4,871,670 to Hudson et al. at col. 3, lines 20-43. The present
method utilizes anti-sense
agents to inhibit or down-regulate gene expression of target genes, including
those listed in Tables l
and 2 below. This is generally attained by hybridization of the anti-sense
oligonucleotides to coding
(sense) sequences of a targeted messenger RNA (rnRNA), as is known in the art.
The exogenously
administered agents of the invention decrease the levels of mRNA and protein
encoded by the target
gene and/or cause changes in the growth characteristics or shapes of the thus
treated cells. See,
Milligan et al. (1993); Helene, C. and Toulme,1. Biochim. Biophys. Acta 1049,
99-125 (1990); Cohen,
J. S. D., Ed., Oligodeoxynucleotides as Anti-sense Inhibitors of Gene
Expression; CRC Press: Boca
Raton, FL (1987), the relevant portion of which is hereby incorporated in its
entirety by reference. As
used herein, "anti-sense oligonucleotide or asnti-sense oligo" is generally a
short sequence of synthetic
nucleotide that (1) hybridizes to any segment of a mRNA encoding a targeted
protein under
appropriate hybridization conditions, and which (2) upon hybridization causes
a decrease in gene
expression of the targeted protein. The terms "desAdenosine" (desA) and "des-
thymidine" (desT) refer
to oligonucleotides substantially lacking either adenosine (dcsA) or lhymidine
(desT). In some
instances, the des A or des T sequences are naturally occurring, and in others
they may result from
substitution of an undesirable nucleotide (A) by another lacking its
undesirable activity, such as acting
as an agonist or having a triggering effect at the adenosine A receptor(s). In
the present context, the
substitution is generally accomplished by substitution of A with a "universal
or alternative base",
presently known in the art or to be ascertained at a later time. As used
herein, the terms "prevent",
"preventing", "treat" or "treating" refer to a preventative, prophylactic,
maintenance, or therapeutic
treatment which decreases the likelihood that the subject adnlinistered such
treatment will manifest
symptoms associated with adenosine receptor stimulation. The term "down-
regulate" refers to inducing
CA 02330022 2000-11-30
WO 00/G273G PCTlUS00/08020
a decrease in production, secretion or availability and, thus, a decrease in
concentration, of intracellular
target product, be it a receptor e. g. adenosine A" A=b, A" bradykinin 2B,
GATA-3, or other receptors,
or an increase in concentration of the adenosine Al, receptor. The present
technology relies on the
design of anti-sense oligos targeted to mRNAs associated with ailments
involving lung airway
pathology(ies), and on their modification to reduce the occurrence of
undesirable side effects caused by
their release of adenosine upon breakdown, while preserving their activity and
efficacy for their
intended purpose. In this manner, the inventor targets a specific gene to
design one or more anti-sense
oligonucleotide(s) (oligos) that selectively bmd(s) to the corresponding
ntRNA, and then reduces, if
necessary, their content of adenosine via substitution with an alternative or
a universal base, or an
adenosine analog incapable of significantly, or having substantially reduced
ability for, activating or
antagonizing adenosine A,, Alb or A, receptors or which may act as an agonist
at the adenosine A,~,
receptor. Any number of adenosines present may be substituted by an
alternative andlor universal base,
such as heteroaromatic bases, which binds to a thymidine base but has less
than about 0.3 of the
adenosine base agonist or antagonist activity at the adenosine A" Az" Alb and
A, receptors. Based on
his prior experience in the field, the inventor reasoned that in addition to
"downregulating" specific
genes, he could increase the effect of the agents) administered by either
selecting segments of RNA
that are devoid, or have a low content, of thymidine (T) or, alternatively,
substitute one or more
adenosine(s) present in the designed oligonucleotide(s) with other nucleotide
bases, so called universal
bases, which bind to thymidine but lack the ability to activate adenosine
receptors and otherwise
exercise the constricting effect of adenosine in the lungs, etc. Given that
adenosine (A) is a nucleotide
base complementary to thymidine (T), when a T appears in the RNA, the anti-
sense oligo will have an
A at the same position.
In one aspect of this invention, the anti-sense oligonucleotide has a sequence
which
specifically binds to a portion or segment of a mRNA molecule which encodes a
protein associated
with impeded breathing, siiergy(ies), lung inflammation, depletion of lung
surfactant or lowering of
lung surfactant, airway obstruction, bronchitis, and the like. One effect of
this binding i5 to reduce or
even prevent the translation of the corresponding mRNA and, thereby, reduce
the available amount of
target protein in the subject=s lung. In one preferred embodiment of this
invention, the phosphodiester
residues of the anti-sense oligonucleotide are modified or substituted.
Chemical analogs of
oligonucleotides with modified or substituted phosphodiester residues, e.g.,
to the methylphosphonate,
the phosphotriester, the phosphorothioate, the phosphorodlthioate, or the
phosphoramidate, a=
methoxy ethyl and similar modifications, which increase the in vivo stability
of the oligonucleotide are
particularly preferred. The naturally occurring phosphodiester linkages of
oligonucleotides are
susceptible to some degree of degradation by cellular nucleases. Many of the
residues proposed herein,
on the contrary, are highly resistant to nuclease degradation. See, Milligan
et al,; Cohen, J. S. D., supra.
In another preferred embodiment of the invention, the oligonucleotides may be
protected from
degradation by adding a "3'-end cap" by which nuclease-resistant linkages are
substituted for
phosphodiester linkages at the 3' end of the oligonucleotide. See, Tidd, D. M.
and Warenius, H.M., Be.
J. Cancer 60: 343-350 (1989); Shaw, J.P et al., Nucleic Acids Res. 19: 747-750
(1991), the relevant
section of which are incorporated in their entireties herein by reference.
Phosphoramidates,
phosphorothioates, and methylphosphonate linkages all function adequately in
this manner for the
purposes of this invention, as do a' modifications, such as a' methoxy ethyl,
and the like. The more
extensive the modification of the phosphodiester backbone the more stable the
resulting agent, and in
many instances the higher their RNA affinity and cellular petTneation. See,
Milligan, et al., supra. In
addition, a plurality of substitutions to the carbohydrate ring are also known
to improve stability of
nucleic acids. Thus, the number of residues which may be modified or
substituted will vary depending
on the need, target, and route of administranon, and may be from 1 to all the
residues, to any number in
between. Many different methods for replacing the entire phosphodiester
backbone with novel linkages
are known, See, Millikan et al, supra. Preferred backbone analogue residues
include phosphoramidate,
phosphorothioate, methylphosphonate, phosphorotriester, phosphotriester,
thiofotmacetal,
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phosphorodithioate, phosphoramidate, fortrlacetal, trifortnacetal, thioether,
carbamate,
boranophosphate, 3'-thioformacetal, 5'-thioether, carbonate, Cs-substituted
nucleotides, 5'-N-
carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, 2'-O
methyl, sulfoxide, sulfide,
hydroxylamine, methylene(methylimino) (MMI), methoxymethyl (MOM), and
methoxyethyl(MOE),
and methyleneoxy(methylimino) (MOMI) residues, and combinations thereof.
Phosphorothioate and
methylphosphonate-modified oligonucleotides are particularly preferred due to
their availability
through automated oligonucleotide synthesis. See, Millikan et al, supra. Where
appropriate, the agent
of this invention may be administered in the form of their pharmaceutically
acceptable salts, or as a
mixture of the anti-sense ohgonucleotide and its salt. In another embodiment
of this invention, a
mixture of different anti-sense oligonucleohdes or their pharmaceutically
acceptable salts is
administered. A single agent of this invention has the capacity to attenuate
the expression of a target
mRNA and/or various agents to enhance or attenuate the activity of a pathway.
By means of example,
the present method may be practiced by identifying all possible
deoxyribonucleotide segments which
ate low in thymidine (T) or deoxynucleotide segments low in adenosine (A) of
about 7 or more
mononucleotides, preferably up to about 60 mononucleotides, more preferably
about 10 to about 36
mononucleotides, and still more preferably about 12 to about 21
mononucleotides, in a target mRNA
or a gene, respectively. This may be attained by searching for mononucleotide
segments within a target
sequence which are low in, or lack thymidine (RNA), a nucleotide which is
complementary to
adenosine, or that are low in adenosine (gene), that are 7 or more nucleotides
long. In most cases, this
search typically results in about 10 to 30 such sequences, i.e. naturally
Lacking or having less than
about 40% adenosine, anti-sense oligonucleotides of varying lengths for a
typical target mRNA of
average length, i.e., about 1800 nucleotides long. Those with high content of
1' or A, respectively, may
be fixed by substitution of a universal base for one or more As. The agents)
of this invention may be
of any suitable length, including but not limited to, about 7 to about 60
nucleotides long, preferably
about 12 to about 45, more preferably up to about 30 nucleotides long, and
still more preferably up to
about 21, although they may be of other lengths as well, depending on the
particular target and the
mode of delivery. The agents) of the invention may be directed to any and all
segments of a target
RNA. One preferred group of agents) includes those directed to an mRNA region
containing a
junction between an introit and an exon. Where the agent is directed to an
intron/exon junction, it may
either entirely overlie the junction or it may be sufficiently close to the
junction to inhibit the splicing-
out of the intervening exon during processing of precursor mRNA to mature
mRNA, e.g. with the 3' or
5' terminus of the anti-sense oligonucleotide being positioned within about,
for example, within about
2 to 10, preferably about 3 to 5, nucleotide of the intron/exon junction. Also
preferred are anti-sense
oligonucleotides which overlap the initiation codon, and those near the 5' and
3' termini of the coding
region. The flanking regions of the exons may also be targeted as well as the
spliced segments in the
precursor mRNAs. The mRNA sequences of the adenosine receptors and of many
other targets are
derived from the DNA base sequence of the gene expressing either receptors, e.
g, the adenosine
receptors, the enzymes, factors, or other targets associated with airway
disease. For example, the
sequence of the genomic human A, adenosine receptor is known and is disclosed
in U.S. Patent No.
5,320,963 to Stiles, G., et al. The A, adenosine receptor has been cloned,
sequenced and expressed in
rat (see, Zhou, F., et al., P.N.A.S. (USA) 89: 7432 ( 1992)) and human (see,
Jacobson, M. A., et al.,
U.K, Patent Application No. 9304582.1 ( 1993)). The sequence of the adenosine
A2h receptor gene is
also known. See, Salvatore, C. A., Luneau, C. J., Johnson, R. G. and Jacobson,
M., Genomics ( 1995),
the relevant portion of which is hereby incorporated in tts entirety by
reference. The sequences of
many of the remaining exemplary target genes are also known. See, GenBank,
NIH. The sequences of
those genes whose sequences are not yet available may be obtained by isolating
the target segments
applying technology known in the art. Once the sequence of the gene, its RNA
andlor the protein are
known, an anti-sense oligonucleotides may be produced according to this
invention as described above
to reduce the production of the targeted protein in accordance u~irh standard
techniques. The sequences
for the adenosine A" bradykinin, and other genes as well as methods for
preparation of
CA 02330022 2000-11-30
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oligonucleotides are also known as those of many other target genes and mRNAs
for which this
invention is suitable. Thus, anti-sense oligonucleotides that downregulate the
production of target
sequences associated with airway disease, including the adenosine A,, A" Aip,
A3, bradykinin, GATA-
3, COX-2, and many other receptors, may be produced in accordance with
standard techniques.
Examples of diseases and conditions which are suitably treated by the present
method are diseases and
conditions, including Acute Respiratory Distress Syndrome CARDS), asthma,
adenosine administration
e.g. in the treatment of SupraVentricular Tachycardia (SVT) and other
arrhythmias, and in stress tests
to hyper-sensitized individuals, ischemia, renal damage or failure induced by
certain drugs, infantile
respiratory distress syndrome, pain, cystic fibrosis, pulmonary hypertension,
pulmonary
vasoconstriction, emphysema, chronic obstructive pulmonary disease (COPD),
pulmonary
transplantation rejection, pulmonary infections, and cancers such as
leukemias, lymphomas,
carcinomas, and the like, including colon cancer, breast cancer, lung cancer,
pancreatic cancer,
hepatocellular carcinoma, kidney cancer, melanoma, hepatic metastases, etc.,
as well as all types of
cancers which may metastasize or have metastasized to the lung(s), including
breast and prostate
I S cancer.
The adenosine receptors discussed above are mere examples of the high power of
the
inventor=s technology. In fact, a large number of genes may be targeted in a
similar manner by the
present agent(s), to reduce or down-regulate protein expression. By means of
example, if the target
disease or condition is one associated with impeded or reduced breathing,
bronchoconstriction, chronic
ZO bronchitis, pulmonary bronchoconstriction and/or hypertension, chronic
obstructive pulmonary disease
(COPD), pulmonary transplantation rejection, pulmonary infections, allergy,
asthma, cystic fibrosis,
respiratory distress syndrome, cancers, which either directly or by metastasis
afflict the lung, the
present method may be applied to a list of potential target mRNAs, which
includes the targets listed in
Table 1 and Table 2 below, among others. The anti-sense agents) of the
invention have a low A
25 content to prevent its liberation upon in vivo degradation of the agent(s).
For example, if the system is
the pulmonary or respiratory system, a large number of genes is involved in
different functions,
including those listed in Table 1 below.
Table 1: Pulmonary Disease or Condition Pulmonary and Inflammation Targets
Nf6B Transcription Interleukin-8 Receptor (IL-8
Factor R)
30Interleukin-5 ReceptorInterleukin-4 Receptor (IL-4R)
(IL-SR)
Interleukin-3 ReceptorInterleukin-lp (IL-1(i)
(IL-3R)
Interieukin-1 p ReceptorEotaxin
(IL-1 ~3R)
Tryptase Major Basic Protern
p2-adrenergic ReceptorEndothelin Receptor A
Kinase
35Endothelin Receptor Preproendothelin
B
Bradykinin B2 ReceptorIgE (High Affinity Receptor)
(B2BR)
Interleukin-1 (IL-1) Interleukin 1 Receptor (IL-1
R)
Interleukin-9 (IL-9) Interleukin-9 Receptor (IL-9
R)
lnterleukin-11 (IL-11)Interleukin-11 Receptor (IL-11
R)
40Inducible Nitric OxideCyclooxygenase (COX)
Synthase
Intracellular Adhesion
Molecule 1 (ICAM-1)
Vascular Cellular
Adhesion Molecule
Substance P (VCAM)
Rantes Endothelial Leukocyte Adhesion
Molecule Endothelia
ETA Receptor (SLAM-1)
45Cyclooxygenase2 (COX-2)GM-CSF, f?ndothelin-I
Monocyte Activating Neutrophil Chemotactic Factor
Factor
Neutrophil Elastase Vefensin 1,2,3
''
Muscarinic AcetylcholinePlatelet Activating Factor
Receptors
Tumor Necrosis Factor S-lipoxygenase
a
50Phosphodiesterase IV Substance P
Substance P Receptor Histamine Receptor
Chymase CCR-I CC Chemokine Receptor
Interleukin-2 (IL-2) Interleukin-4 (IL-4)
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Interleukin-12 (IL-12)Interleukin-5 (IL-S)
lnterleukin-6 (IL-6) lnterleukin-7 (iI_-7)
lnterleukin-8 (IL-8) lnterleukin-12 Receptor (IL-12R)
Interleukin-7 ReceptorInterleukin-1 (IL-1)
(IL-?R)
5 Interleukin-14 ReceptorInterleukin-14
{IL-l4R)
CCR-2 CC Chemokine CCR-3 CC Chemokine Receptor
Receptor
CCR-4 CC Chemokine CCR-5 CC Chemokine Receptor
Receptor
Prostanoid Receptors GATA-3 Transcription Factor
Neutrophil Adherence MAP Kinase
Receptor
!0lnterleukin-15 (IL-15)Interleukin-15 Receptor (IL-15R)
Interleukin-11 (IL-11)Interleukin-I1 Receptor (IL-IIR)
NFAT Transcription STAT 4
Factors
MiP-I a MCP-2
MCP-3 MCP-4
15Cyclophillin (A, B, Phosphotipase A2
etc.)
Basic Fibroblast GrowthMetalloproteinase
Factor
CSBP/p38 MAP Kinase 'Cryptase Receptor
PDG2 lnterleukin-3 (IL-3)
lnterleukin-10 (IL-10)Cyclosporin A - Binding Protein
20FK506-Binding Protein a4p1 Selectin
Fibronectin a4ji7 Selectin
Table 1: Pulmonary
Disease or Condition
Pulmonary and Inflammation
Targets
cMad CAM-1 LFA-1 (CDlla/CD18)
PECAM-I LFA-1 Selectin
25C3bi PSGL-1
E-Selectin P-Selectin
CD-34 L-Selectin
p150,95 Mac-1 (CDIIb/CI)18)
Fucosyl transferase VLA-4
30STAT-1 STAT-2
CD-181CD 11 a CD 11 b/CD 18
1CAM2 and ICAM3 C5a
CCR3 (Eotaxin Receptor)CCR1, CCR2, CCR4, CCRS
LTB-4 AP-1 Transcription Factor
35Protein kinase C Cysteinyl Leukotriene Receptor
Tachykinnen Receptors 16B Kinase 1 & 2
(tach R)
Interleukin-2 Receptor(e.g., Substance P, NK-1 & NK-3
(IL-2R) Receptors)
STAT 6 c-mas
NF-Interteukin-6 (NF-IL-6)Interteukin-t0 Receptor (IL-lOR)
40Interleukin-3 (IL-3) lnterleukin-2 Receptor (IL-2R)
Interleukin-13 (IL-13)Interleukin-12 Receptor (IL-12R)
Interleukin-14 (1L-14)lnterleukin-6 Receptor (IL-6R)
Interleukin-16 (IL-16)Interleukin-13 Receptor (IL-13R)
Medullasin Interleukin-16 Receptor (IL-16R)
45Adenosine A, Receptor Tryptase-I
(A, R)
Adenosine AZb ReceptorAdenosine A, Receptor (A, R)
(Aib R)
(I Tryptase STAT-3 '
Adenosine Ai, ReceptorlgE Receptor p Subunit (IgE R
(A2, R) p)
Fc-epsilon receptor IgE Receptor a Subunit (IgE R
CD23 antigen a)
50IgE Receptor Fe Epsilon
Receptor (IgERFc l;
R) Substance P Receptor
Histidine decarboxylaseTryptase-1
Prostaglandin D SynthaseEosinophil Cationic Protein
Eosinophil Derived Eosinophil Peroxidase
Neurotoxin
Endothelial Nitric Endothelial Monocyte Activating
Oxide Synthase Factor
55Neutrophil Oxidase Cathepsin G
Factor
Macrophage InflammatoryInterleukin-8 Receptor a Subunit
Protein-i- (IL-8 Ra)
Aloha/Rantes Receptor Endotllelin Receptor ET-B
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11
These genes, and others, are involved in the normal functioning of respiration
as well as in
diseases associated with respiratory pathologies, including cystic fibrosis,
asthma, pulmonary
hypertension and vasoconstriction, chronic obstructive pulmonary disease
(COPD), pulmonary
transplantation rejection, pulmonary infections, chronic bronchitis,
respiratory distress syndrome
CARDS), allergic rhinitis, lung cancer and lung metastatic cancers and other
airway diseases, including
those with inflammatory response.
Anti-sense oligos to the target receptors, e. g. the adenosine A" AZ" Aib, and
A~ receptors,
CCR3 (chemokine receptors), bradykinin 2B, CAM (vascular cell adhesion
molecule), and eosinophil
receptors, among others, have been shown to be effective m down-regulating the
expression of their
genes. Some of these act to alleviate the symptoms or reduce respiratory
ailments and/or inflammation,
for example, by "down regulation" of the adenosine A" A~" AZe, and/or A,
receptors and CCR3,
bradykinin 2B, VCAM (vascular cell adhesion molecule) and eosinophil
receptors. These agents may
be utilized by the present method alone or in conjunction with anti-sense
oligos targeted to other genes
to validate pathway and/or networks in which they are involved. For better
results, the oligos are
IS preferably administered directly into the respiratory system, e.g., by
inhalation or other means, of the
experimental animal, so that they may reach the lungs without widespread
systemic dissemination.
This permits the use of low agent doses as compared with those administered
systemically of by other
generalized routes and, consequently, reduces the number and degree of
undesirable side effects
resulting from the agent=s widespread distribution in the body. 'IZte agents)
of this invention has
(have) been shown to reduce the amount of receptor protein expressed by the
tissue. These agents,
thus, rather than merely interacting with their targets, a g. a receptor,
lower the number of target
proteins that other drugs may interact with. In this manner, the present
agents) affords) extremely
high efficacy with low toxicity. Anti-sense oligonucleotides to the A, , A~b,
A,, bradykinin B2, GATA-
3, CAM (vascular cell adhesion molecule), eosinophil receptors, and COX-2
receptors, among others,
have been shown to be affective in the down-regulation of the respective
receptor proteins in the cell.
One novel feature of this treatment, as compared to traditional treatments for
adenosine-mediated
bronchoconstriction, is that administration is direct to the lungs, or in situ
to other tissues, organs or
systems of the body. Additionally, a receptor protein itself is reduced in
amount, rather than merely
interacting with a drug, and toxicity is reduced. Other proteins that may be
targeted with anti-sense
agents for the treatment of lung conditions include, but are not Limited to:
CCR3 (chemokine)
receptors, human A2, adenosine receptor, human Azb adenosine receptor, human
IgE receptor [3, human
Fc-epsilon receptor CD23 antigen, human histidine decarboxylase, human beta
tryptase, human
tryptase-I, human prostaglandin D synthase, human cyclooxigenase-2, human
eosinophil cationic
protein, human eosinophil derived neurotoxin, human eosinophil peroxidase,
human intercellular
adhesion molecule-I (ICAM-1), human vascular cell adhesion molecule-1 (VCAM-
i), human
endothelial leukocyte adhesion molecule-1 (SLAM-1), human P selectin, human
endothelial monocyte
activating factor, human IL-3, human IL-4, human IL.-5, human IL-6, human IL-
8, human monocyte-
derived neutrophil chemotactic factor, human neutrophil elastase, human
neutrophil oxidase factot,
human cathepsin G, human defensin 1, human defensin 3, human macrophage
inflammatory protein-1-
alpha, human muscarinic acetylcholine receptor HM3, human fibronectin, human
GM-CSF, human
tumor necrosis factor a, human leukotriene C4 synthase, hunu3n major basic
protein, and human
endothelia t. Although not intended to be exclusive, a more extensive list of
genes is provided below.
Some of these act to alleviate the symptoms or reduce respiratory ailments
and/or inflammation, for
example, by "down regulation" of the adenosine A,, AI" A2b, and/or A,
receptors and CCR3,
bradykinin 2B, VCAM (vascular cell adhesion molecule) and eosinophil
receptors. These agents are
preferably administered directly into the respiratory system, e.g., by
inhalation or other means, so that
they may reach the lungs without widespread systemic dissemination. 'This
permits the use of
substantially lower doses of the agent of the invention as compared with those
administered by the
prior art, systemically or by other generalized routes and, consequently,
reduce undesirable side effects
SO resulting from the agent=s widespread distribution in the body. The agents)
of this invention has
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12
(have) been shown to reduce the amount of receptor protein expressed by the
tissue. These agents,
thus, rather than merely interacting with their targets, e.g. a receptor,
lower the number of target
proteins that other drugs may interact with. In this manner, the present
agents) affords) extremely
high efficacy with low toxicity. In these latter targeu, and in target genes
in general, it is particularly
imperative to eliminate or reduce the adenosine content of the corresponding
anti-sense
oligonucIeotide to prevent their breakdown products from liberating adenosine.
As used herein, the term "treat" or "treating" asthma refers to a treatment
which decreases the
likelihood that the subject administered such treatment will manifest symptoms
of the lung disease.
The term "dowttregulate" refers to inducing a decrease in production,
secretion or availability (and thus
a decrease in concentration) of the targeted intracellular protein. The
present invention is concerned
primarily with the treatment of human subjects. However, the agents and
methods disclosed here may
also be employed for veterinary purposes, such as is the case in the treatment
of other mammals, such
as cattle, horses, wild animals, zoo animals, and domestic animals, e. g. dogs
and cats. Targeted
proteins are preferably mammalian and more preferably of the same species as
the subject being
treated. In general, "anti-sense" refers to the use of small, synthetic
oligonucleotides, resembling
single-stranded DNA, to inhibit gene expression by inhibiting the function of
the target messenger
RNA (mRNA). Milligan, J. F. et al., J. Med. Chem. 36(14), 1923-1937 (1993). 1n
the present
invention, inhibition of gene expression of the A, or A3 adenosine receptor is
desired. Gene expression
is inhibited through hybridization to coding (sense) sequences in a specific
messenger RNA (mRNA)
target by hydrogen bonding according to Watson-Crick base pairing rules. The
mechanism of anti-
sense inhibition is that the exogenously applied oligonucleotides decrease the
mRNA and protein levels
of the target gene or cause changes in the growth Characteristics or shapes of
the cells. Id. See, also
Nelene, C, and Toulme, J., Biochim. Biophys. Acta 1049, 99-125 (1990); Cohen,
J. S. D., Ed.,
Oligodeoxynucleotides as Anti-sense Inhibitors of Gene Expression; CRC Press:
Boca Raton, FL
( 1987). As used herein, "anti-sense oligonucleotide" is defined as a short
sequence of synthetic
nucleotide that (1) hybridizes to any coding sequence in an mRNA which codes
for the targeted
protein, according to hybridization conditions described below, and (2) upon
hybridization causes a
decrease in gene expression of the A, or A, adenosine receptor. The receptors
discussed above are
mere examples of the high power of the present technology. In fact, a large
number of genes may be
targeted in a similar manner by practicing the present methods, to
significantly down-regulate or
obliterate protein expression and observe any changes wrought to one or more
functions within a
system, e.g. the respiratory system and other lung disease associated targets.
By means of example, in
the respiratory system, the targets may be associated With difficulties of
breathing,
bronchoconstriction, inflammation, allergic rhynitis, chronic bronchitis,
surfactant depletion, and
others associated with diseases and conditions such as chronic obstructive
pulmonary disease (COPD),
pulmonary transplantation rejection, pulmonary infections, inhalation bums,
Acute Respiratory
Distress Syndrome (ARDS), cystic fibrosis, pulmonary fibrosis, radiation
pulmonitis, tonsilitis,
emphysema, dental pain, oral inflammation, joint pain, esophagitis, cancers
afflicting the respiratory
system either directly such as Lung cancer, esophageal cancer, and the like,
or indirectly by means of
metastases, among others. These functions are of great interest because of
their association with
respiratory dysfunction, as is the case in asthma, allergies, allergic
rhinitis, pulmonary
bronchoconstriction and hypertension, chronic obstructive pulmonary disease
(COPD), pulmonary
transplantation rejection, pulmonary infections, allergy, asthma, cystic
fibrosis (CF), Acute Respiratory
Distress Syndrome CARDS) as well as infantile and pregnancy-related RDS,
cancer, ere., which either
directly or by metastasis afflict the lung, the present anti-sense
oligonucleotides may be directed to a
list of target mRNAs, which includes the targets listed in Table I above,
among others.
The oligos of this invention may be obtained by first selecting fragments of a
target nucleic
acid having at least 4 contiguous nucleic acids selected from the group
consisting of G and C and/or
having a specific type and/or extent of activity, and then obtaining a first
oligonucleotide 4 to 60
nucleotides long which comprises the selected fragment and has a thymidine (T)
nucleic acid content
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13
of up to and including about 15%, preferably, about 12%, about 10%, about 7%,
about 5%, about 3%,
about 1%, and more preferably no thymidine. The latter step may be conducted
by obtaining a second
oligonucleotide 4 to GO nucleotides long comprising a sequence which is anti-
sense to the selected
fragment, the second oligonucleotide having an adenosine base content of up to
and including about
15%, preferably about 12%, about t0%, about 7%, about 5%, about 3%, about I%,
and more
preferably no adenosine. When the selected fragment comprises at (east one
thymidine base, an
adenosine base may be substituted in the corresponding anti-sense nucleotide
fragment with a universal
base selected from the group consisting of heteroaromatic bases which bind to
a thymidine base but
have less than about bout 10%, preferably less than about 1%, and more
preferably less than about
0.3% of the adenosine base agonist activity at the adenosine A" Aza, A2,, and
A, receptors, and
heteroaromatic bases which have no activity at the adenosine A2°
receptor, when validating in the
respiratory system. Other adenosine activities in other systems may be
detetmmed in other systems, as
appropriate. The analogue heteroaromatic bases may be selected from all
pyrimidines and purines,
which may be substituted by O, halo, NH2, SH, SO, SOi, SO,, OOOH and branched
and fused primary
and secondary amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
aryl, heteroaryl, alkoxy,
alkenoxy, acyl, cycloacyl, arylacyl, alkynoxy, cycloalkoxy, aroyl, arylthio,
arylsulfoxyl,
halocycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkynylcycloalkyl,
haloaryl, alkylaryl, alkenylaryl,
alkynylaryl, arylaIkyl, arytalkenyl, arylalkynyl, arylcycloalkyl, which may be
further substituted by O,
halo, NH2, primary, secondary and tertiary amine, SH, SO, SO;, SO" cycloalkyl,
heterocyeloalkyl and
heteroaryl. The pyrimidines and purines may be substituted at all positions as
is known in the art, but
preferred are those which are substituted at positions I, 2, 3, 4, 7 and/or 8.
More preferred are
pyrimidines and purines such as theophylline, caffeine, dyphylline,
etophylline, acephylline piperazine,
bamifylline, enprofylline and xantine having the chemical formula
0
~L i~
Ir,N/1 fC/M~ 3
OsC~.7 jC,~l~~
!! N
R
wherein R' and R2 are independently H, alkyl, alkenyl or alkynyl and R' i.s H,
aryl, dicycloalkyl,
dicycloalkenyl, dicycloalkynyl, cycloalkyl, cyeloalkenyl, cycloalkynyl, O-
cycloalkyl, O-cycloalkenyl,
O-cycloalkynyl, NH2-alkylamino-kctoxyalkyloxy-aryl, mono and dialkylaminoalkyl-
N-alkylamino-
SOIaryI, among others. Similar modifications in the sugar arc also embodiments
of this invention.
Reduced adenosine content of the anti-sense oligos corresponding to the
thymidines (T') present in the
target RNA serves to prevent the breakdown of the oligos into products that
free adenosine into thZ
system, e.g. the lung, brain, heart, kidney, ere., tissue environment and,
thereby, to prevent any
unwanted effects due to it. By means of example, the Nf6B transcription factor
may be selected as a
target, and its rnRNA or DNA searched for low thymidine (T) or desthymidine
(desT) fragments. Only
desT segments of the mRNA or DNA are selected which, in rum, will produce desA
anti-sense as their
complementary strand. When a number of RNA des'f segments are found, the
sequence of the anti.
sense segments may be deduced. Typically, about 10 to 30 and even larger
numbers of desA apti-sense
sequences may be obtained. These anti-sense sequences may include some or all
desA anti-sense
oligonucleotide sequences corresponding to desT segments of the mRNA of the
target, such as anyone
of those shown in Table I above, in Table 2 below, and others associated with
functions of the brain,
cardiovascular and renal systems, and many others. When this occurs, the anti-
sense oligonucleotides
found are said to be 100% A-free. For each of the original desA anti-sense
oligonucleotide sequences
corresponding to the target gene, e_g. the NF6B transcription factor,
typically about 10 to 30 sequences
may be found within the target gene or RNA which have a low content of
thymidine (RNA). In
accordance with this invention, the selected fragment sequences may also
contain a small number of
thymidine (RNA) nucleotides within the secondary or tertiary or quaternary
sequences. In some cases,
CA 02330022 2000-11-30
WO 00162736 PCT/US00/08020
1.t
a large adenosine content may suffice to render the anti-sense oligonucleotide
less active or even
inactive against the target. In accordance with this invention, these so
called "non-fully desA"
sequences may preferably have a content of adenosine of less than about 15%,
about 12%, about 10%,
about 7%, about 5%, and about 2% adenosine. Most preferred is no adenosine
content (0%). In some
instances, however, a higher content of adenosine is acceptable and the
oligonucleotides still fail to
show detrimental "adenosine activity". A particular important embodiment is
that where the adenosine
nucleotide is "fixed" or replaced by a "Universal or alternative" base that
may base-pair with similar or
equal affinity to two or more of the four nucleotide present in natural DNA:
A, G, C, and T.
A universal or alternative base is defined in this patent as any compound,
more commonly an
adenosine analogue, which has substantial capacity to hybridize to thymidine,
while at the same time
having reduced, or substantially lacking, ability to bind adenosine receptors
or other molecules through
which adenosine may exert an undesirable side effect in the experimental
animal or in a cell system.
Alternatively, adenosine analogs which completely fail to activate, or have
significantly reduce ability
for activating, adenosine receptors, such as the adenosine A" ,4z6 andlor A,
receptors, most preferably
A, receptors, and those that may even act as agonists of the adenosine Az"
receptor, may be used. One
example of a universal base is a-deoxyribofuranosol-(5-nitroittdole), and an
artisan will know how to
select others. This "fixing" step generates further novel sequences, different
from those anti-sense to
the ones found in nature, that permits the anti-sense ohgonucleotide to bind,
preferably equally well,
with the target RNA. Other examples of universal or alternative bases are 2-
deoxyribosyl-(S-
ZO nitroindole). Other examples of universal bases are 3 - nitropyrrole - 2' -
deoxynucleoside, 5 - nitro-
indole, 2 - deoxyribosyl - (5 - nitroindole), 2-deoxyribofuranosyl - (5-
nitroindole), 2' - deoxyinosine, 2'
-deoxynebularine, 6H, 8H-3,4-dihydropyrimido [ 4, 5 - c] oxazine - 7 - one and
2 - amino - 6 -methoxy
aminopurine. In addition to the above, Universal bases which may be
substituted for any other base
although with somewhat reduced hybridization potential, include 3 -
nitropyrrole 2' - deoxynucleoside
2 - deoxyribofuranosyl - (5 - nitroindole), 2' - deoxyinosine and 2' -
deoxynebularine (Glen Research,
Sterling, VA). More specific mismatch repairs may be made using "P"
nucleotide, 6H, 8H - 3, 4 -
dihydropyrimido [4,5 - c] [l, 2] oxazin - 7 - one, which base pairs with
either guanine (G) or adenine
(A) and "K" nucleotide, 2 - amino - 6 - methoxyaminopurine, which base pairs
with either cytidine (C)
or thymidine (T), among others. Others which are known in the art or will
become available are also
suitable. See, for example, Loakes, D. and Brown, D. M., Nucl. Acids Res.
22:4039-4043 (1994);
Ohtsuka, E. et al., 1. Biol. Chem.260(5):2605-2608 (1985); Lin, P.K.T. and
Brown, D. M., Nucleic
Acids Res. 20(19):5149-5152 (1992; Nichols, R. et al., Nature 369(b480): 492-
493 (1994); Rahmon ,
M. S. and Humayun, N. Z., Mutation Research 377 (2): 263-8 (1997); Amosova,
O., et al., Nucleic
Acids Res. 25 (!0): 1930-1934 (1997); Loakes D. & Brown, D. M., Nucleic Acids
Res. 22 (20): 4039-
4043 ( 1994), the entire sections relating to universal bases and their
preparation and use in nucleic acid
binding being incorporated herein by reference. When non-fully desT sequences
are found in the
naturally occurring target, they typically are selected so that about 1 to 3
universal base substitutions
will suffice to obtain a 100% "desA" anti-sense oligonucleotide. 'thus, the
present method provides
either anti-sense oligonucleotides to different targets which are low in, or
devoid of, A content, as well
as anti-sense oligonucleotides where one or more adenosine nucleotides, e. g.
about 1 to 3, or more,
may be "fixed" by replacement with a "Universal" or "replacement" base.
Universal bases are known
in the art and need not be listed herein. An artisan will know which bases may
act as universal bases,
and replace them for A. Table 2 below provides a selected number of targets to
which the agents of the
invention are effectively applied. Others, however, may also be targeted.
Table 2: Cancer Targets
Transforming Therapy
Onco2enes Targets
ras thymidylate synihetase
src thymidylate synthetase
myc dihydrofolate redurtase
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bcl-2 thymidine kinase
deoxycytidine kinase
ribonucleotide reductase
Angiogenesis factors Adhesion Molecules
5 Oncogenes Folate Pathway Enzymes
DNA repair genes (One Carbon Pool)
Telomerase
HMG CoA Reductase
Farnesyl Transferase
10 Glucose-6-Phosphate Transferase
A group of preferred targets for the treatment of cancer are genes associated
with any of
different types of cancers, or those generally known to be associated with
malignancies, whether they
are regulatory or involved in the production of RNA and/or proteins. Examples
are transforming
oncogenes, including, but not limited to, ras, src, myc, and BGL-2, among
others. Other targets are
15 those to which present cancer chemotherapeutic agents are directed to, such
as various enzymes,
primarily, although not exclusively, thymidylate synthetase, dihydrofolate
reductase, thymidine kinase,
deoxycytidine kinase, ribonucleotide reductase, and the like. The present
technology is particularly
useful in the treatment of cancer ailments given that traditional cancer
therapies are naught with the
unresolved problem of selectively killing cancer cells while preserving normal
living cells from the
devastating effects of treatments such as chemotherapy, radiotherapy, and the
like. The present
technology provides the abiiiry of selectively attenuating or enhancing a
desired pathway or target.
This approach provides a significant advantage over standard treatments of
cancer because it permits
the selection of a pathway, including primary, secondary and possibly tertiary
targets, which are not
generally expressed simultaneously in normal cells. Thus, the present agent
may be administered to a
subject to cause a selective increase in toxicity within tumor cells that, for
instance, express all three
targets while normal cells that may expresses only one or two of the targets
will be significantly less
affected or even spared. A group of preferred targets for the treatment of
cancers are genes associated
with different types of cancers, or those generally known to be associated
with malignancies, whether
they are regulatory or involved in the production of RNA and/or proteins.
Examples are transfotining
oncogenes, including, but not limited to, ras, src, myc, and BCL-2, among
others. Other targets are
those to which present cancer chemotherapeutic agents are directed to, such as
various enzymes,
primarily, although not exclusively, thymidylate synthetase, dihydrofolate
reductase, thymidine kinase,
deoxycytidine kinase, ribonucleotide reductase, and the like.
In one embodiment, at least one of the mRNAs to which the oligo of the
invention is targeted
encodes a protein such as transcription factors, stimulating and activating
factors, intracellular and
extracellular receptors and peptide transmitters in general, interleukins,
interleukin receptors,
chemokines, chemokine receptors, endogenously produced specific and non-
specific enzymes,
immunoglobulins, antibody receptors, central nervous system ((.'NS) and
peripheral nervous and non
nervous system receptors, CNS and peripheral nervous and non-nervous system
peptide transmitters,
adhesion molecules, defensines, growth factors, vasoactive peptides and
receptors, and binding
proteins, among others; or the mRNA is corresponding to an oncogene and other
genes associated with
various diseases or conditions. Examples of target proteins are eotaxin, major
basic protein,
preproendothelin, eosinophil cationic protein, P-selectin, STAT 4, MIP-la, MCP-
2, MCP-3, MCP-4,
STAT 6, c-mas, NF-IL-6, cyclophillins, PDG2, cyclosporin A-binding protein,
FKS-binding protein,
fibronectin, L<:A-1 (CDlla/CD18), PECAM-1, C3bi, PSGL-1,CD-34, substance P,
p150,95, Mac-I
(CD1 IblCDlB), VLA-4, CD-18/CDlla, CDI Ib/CD18, CSa, CCRI, CCR2, CCR4, CCRS,
and LT'B-4,
among others. Others are, however, suitable, as well. In another embodiment,
at least one of the
mRNAs to which the oligo is targeted encodes intracellular and extracellular
receptors and peptide
transmitters such as sympathomimetic receptors, parasympathetic receptors,
GABA receptors,
adenosine receptors, bradykinin receptors, insulin receptors, glucagon
receptors, prostaglandin
receptors, thyroid receptors, androgen receptors, anabolic receptors, estrogen
receptors, progesterone
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16
receptors, receptors associated with the coagulation cascade, adenohypophyseal
receptors,
adenohypophyseal peptide transmitters, and histamine receptors (HisR), among
others. However others
are also contemplated. The encoded sympathomimetic receptors and
parasympathomimetic receptors
include acetytcholinesterase receptors (AcChaseR) acetyleholine receptors
(AcChR), atropine
S receptors, muscarinic receptors, epinephrine receptors (EpiR), dopamine
receptors (DOPAR), and
norepinephrine receptors (NEpiR), among others. Further examples of encoded
receptors are adenosine
A, receptor, adenosine AzB receptor, adenosine A, receptor, endothelia
receptor A, endothelia receptor
B, IgE high affinity receptor, muscarinic acetylcholine receptors, substance P
receptor, histamine
receptor, CCR-1 CC ehemokine receptor, CCR-2 CC chemokine receptor, CCR-3 CC
chemokine
receptor (Eotaxin Receptor), interleukin-lp receptor (IL-1(3R), interleukin-I
receptor (IL-1R),
interleukin-Iii receptor (IL-l~iR), inttrleukin-3 receptor (IL-3R), CCR-4 CC
chemokine receptor,
cysteinyl leukotriene receptors, prostanoid receptors, GATA-3 transcription
factor receptor,
interleukin-I receptor (IL-1R), interieukin-4 receptor (IL-4R), interleukin-5
receptor (IL-SR),
interleukin-8 receptor (IL-8R), interleukin-9 receptor (IL-9R), intetleukin-11
receptor (IL-I1 R),
bradykinin B2 receptor, sympathomimetic receptors, parasympathomimetic
receptors, GAGA
receptors, adenosine receptors, bradykinin receptors, insulin receptors,
giucagon receptors,
prostaglandin receptors, thyroid receptors, androgen receptors, anabolic
receptors, estrogen receptors,
progesterone receptors, receptors associated with the coagulation cascade,
adenohypophyseal
receptors, and histamine receptors (HisR). Others are also contemplated even
though not listed herein.
The encoded enzymes for development of the oligos of the invention include
synthetases, kinases,
oxidases, phosphatases, reductases, polysaccharide, triglyceride, and protein
hydrolases, esterases,
elastases, and , polysaccharide, triglyceride, lipid, and protein syathases,
among others. Examples of
target enzymes are tryptase, inducible nitric oxide synthase, cyclooxygenase
(Cox), MAP kinase,
eosinophil peroxidase, ~i2-adrenergic receptor kinase, ieukotriene c-4
synthase, S-lipooxygenase,
2S phosphodiesterase IV, metalloproteinase, tryptase, CSHP/p38 MAP kinase,
neutrophil elastase,
phospholipase A2, cyclooxygenase 2 (Cox-2), fucosyl transferase, chymase,
protein kinase C,
thynudylate synthetase, dihydrofolate reductase, thymidinc kinase,
deoxycytidine kinase, and
ribonucleotide reductase, among others. Any enzyme associated with a disease
or condition, however,
is suitable as a target for this invention. Suitable encoded factors for
application of this invention are,
among others, Nf6B transcription factor, granulocyte macrophage colony
stimulating factor (CiM-
CSF), AP-1 transcription factor, GATA-3 transcription factor, monoeyte
activating factor, neutrophil
chemotactic factor, granulocyte/macrophage colony-stimulating-factor (G-CSF),
NEAT transcription
factors, platelet activating factor, tumor necrosis factor a (TNF a), and
basic fibroblast growth factor
(BFGF). Additional factors are also within the invention even though not
specifically mentioned.
Suitable adhesion molecules for use with this invention include intracellular
adhesion molecules 1
(ICAM-1), 2 (ICAM-2) and 3 (ICAM-3), vascular cellular adhesion molecule
(VCAM), endothelial
leukocyte adhesion molecule-1 (ELAM-1), neutrophil adherence receptor, mad CAM-
1, and the like.
Other known and unknown factors (at this time) may also be targeted herein.
Among the cytokines,
lymphokines and chemokines preferred are interleukin-I (IL-I), interleukin-I(i
(IL-lei), interleukin-3
(IL-3), interteukin-~t (IL-4), interleukin-5 (IL-S), interleukin-8 (IL-8),
interleukin-9 (IL-9), interleukin-
I I (IL-Il),CCR-S CC chemokine, and Rantes. Others, however, may also be
targeted, as they are
known to be involved in specific diseases or conditions to be treated, or for
their generic activities,
such as inflammation. Examples of defensins for the practice of this invention
are defensin 1, defensin
2, and defensin 3, and of selectins are a4(31 selectin, a4p7 selectin, LFA-l
selectin, E-selectin, P-
selectin, and L-selectin. Examples of oncogenes, although not an all inclusive
list, are ras, src, myc,
and bcBCL. Others, however, are also suitable for use with this invention.
The agents administered in accordance with this invention are preferably
designed to be anti-
sense to target genes and/or mRNAs related in origin to the species to which
it is to be administered.
When treating humans, the agents are preferably designed to be anti-sense to a
human gene or RNA.
The agents of the invention encompass oligonucleotides which arc anti-sense to
naturally occurring
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DNA and/or RNA sequences, fragments thereof of up to a length of one ( 1 )
base less than the targeted
sequence, preferably at least about 7 nucleotides long, oligos having only
over about 0.02%, more
preferably over about 0.1%, still more preferably over about
1°i°, and even more preferably over about
4% adenosine nucleotides, and up to about 30%, more preferably up to about
15%, still more
S preferably up to about I0% and even more preferably up to about S%,
adenosine nucleotide, or lacking
adenosine altogether, and oligos in which one or more of the adenosine
nucleotides have been replaced
with so-called universal bases, which may pair up with thymidine nucleotides
but fail to substantially
trigger adenosine receptor activity. Examples of human sequences and
fragments, which are not
limiting, of anti-sense oligonucleotide of the invention are the following
fragments as well as shorter
segments of the fragments and of the full gene or mRNA coding sequences, exons
and intron-exon
junctions encompassing preferably 7, 10, IS, 18 to 21, 24, 27, 30, n-t
nucleotides for each sequence,
where n is the sequence=s total number of nucleotides. These fragments may be
selected from any
portion of the longer oligo, for example, from the middle, S'- end, 3'- end or
starting at any other site of
the original sequence. Of particular importance are fragments of low adenosine
nucleotide content, that
1 S is, those fragments containing less than or about 30%, preferably less
than or about 1 S%, more
preferably less than or about 10%, and even more preferably Less than or about
5%, and most
preferably those devoid of adenosine nucleotide, either by choice or by
replacement with a universal
base in accordance with this invention. The agent of the invention includes as
a most preferred group
sequences and their fragments where one or more adenosines present in the
sequence have been
replaced by a universal base (B), as exemplified here. Similarly, also
encompassed are all shorter
fragments of the B-containing fragments designed by substitution of B(s) for
adenosine(s) (A(s))
contained in the sequences, fragments thereof or segments thereof, as
described above. A limited list of
sequences and fragments is provided below.
Some of the examples of anti-sense oligonucleotide sequence fragments target
the initiation
codon of the respective gene, and in some cases adenosine is substituted with
a universal or alternative
base adenosine analogue denoted as "B", which lacks ability to bind to the
adenosine A, andlor A,
receptors. In fact, such replacement nucleotide acts as a "spacer. Many of the
examples shown below
provide one such sequence and many fragments overlapping the initiation codon,
preferably wherein
the number of nucleotides n is about 7, about 10, about 12, about 15, about
18, about 21 and up to
about 28, about 3S, about 40, about 50, about 60.
CA 02330022 2001-11-27
SEQUENCE LISTING
<110> EAST CAROLINA UNIVERSITY
<120> LOW ADENOSINE ANTI-SENSE OLIGONUCLEOTIDE, COMPOSITIONS, KIT & METHOD
FOR TREATMENT OF AIRWAY DISORDERS ASSOCIATED WITH BRONCHOCONSTRICTION, LUNG
INFLAMMATION, ALLERGY(IES) AND SURFACTANT DEPLETION
<130> 08-892198CA
<140> 2,330,022
<141> 2000-03-24
<150> US 60/127,958
<151> 1999-04-06
<160> 3111
<170> PatentIn version 3.0
<210> 1
<211> 21
<212> DNA
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gatggagggc ggcatggcgg g 21
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<223> mismatch molecule
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gtagcaggcg gggatggggg c 21
1
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gttgttgggc atcttgcc
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gtacttgcgg atctaggc
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gtgggcctag ctctcgcc 1g
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ctcgtcgccg tcgccggcgg g 21
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gggtggtgct attgtcgggc
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ggcccagggc cagcc 15
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ggccgggcca gccgggcccg g 21
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gcggcctgga aagctgagat ggagggcggc atggcgggca caggctgggc 50
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cggcctggaa agctgagatg gagggcggca tggcgggcac aggctgggc 49
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cctggaaagc tgagatggag ggcggcatgg cgggcacagg ctgggc 46
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ctggaaagct gagatggagg gcggcatggc gggcacaggc tgggc 45
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tggaaagctg agatggaggg cggcatggcg ggcacaggct gggc 44
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ggaaagctga gatggagggc ggcatggcgg gcacaggctg ggc 43
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gaaagctgag atggagggcg gcatggcggg cacaggctgg 9c 42
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aaagctgaga tggagggcgg catggcgggc acaggctggg c 41
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aagctgagat ggagggcggc atggcgggca caggctgggc 40
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agctgagatg gagggcggca tggcgggcac aggctgggc 39
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gctgagatgg agggcggcat ggcgggcaca ggctgggc 38
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ctgagatgga gggcggcatg gcgggcacag gctgggc 37
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tgagatggag ggcggcatgg cgggcacagg ctgggc 36
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gagatggagg gcggcatggc gggcacaggc tgggc 35
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agatggaggg cggcatggcg ggcacaggct gggc 34
<210> 28
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gatggagggc ggcatggcgg gcacaggctg ggc 33
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atggagggcg gcatggcggg cacaggctgg gc 32
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tggagggcgg catggcgggc acaggctggg c
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ggagggcggc atggcgggca caggctgggc 30
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gagggcggca tggcgggcac aggctgggc 29
<210> 33
<211> 28
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agggcggcat ggcgggcaca ggctgggc 2g
<210> 34
<211> 27
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gggcggcatg gcgggcacag gctgggc 27
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ggcggcatgg cgggcacagg ctgggc 26
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gcggcatggc gggcacaggc tgggc 25
<210> 37
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<212> DNA
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cggcatggcg ggcacaggct gggc 24
<210> 38
<211> 23
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ggcatggcgg gcacaggctg ggc 23
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<213> mammalian
<400> 39
gcatggcggg cacaggctgg gc 22
<210> 40
<211> 21
<212> DNA
<213> mammalian
<400> 40
catggcgggc acaggctggg c 21
<210> 41
<211> 20
<212> DNA
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atggcgggca caggctgggc 20
<210> 42
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tggcgggcac aggctgggc 19
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<400> 43
ggcgggcaca ggctgggc
18
<210> 44
<211> 17
<212> DNA
<213> mammalian
<400> 44
gcgggcacag gctgggc 17
<210> 45
<211> 16
<212> DNA
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cgggcacagg ctgggc 16
<210> 46
<211> 15
<212> DNA
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gggcacaggc tgggc 15
<210> 47
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<212> DNA
<213> mammalian
<400> 47
ggcacaggct gggc 14
<210> 48
<211> 13
<212> DNA
<213> mammalian
<400> 48
gcacaggctg ggc 13
<210> 49
<211> 12
' <212> DNA
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<400> 49
cacaggctgg gc 12
<210> 50
<211> 11
<212> DNA
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13
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acaggctggg c 11
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caggctgggc 10
<210> 52
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aggctgggc 9
<210> 53
<211> 51
<212> DNA
<213> mammalian
<400> 53
ggcggcctgg aaagctgaga tggagggcgg catggcgggc acaggctggg c 51
<210> 54
<211> 50
<212> DNA
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ggcggcctgg aaagctgaga tggagggcgg catggcgggc acaggctggg 50
<210> 55
<211> 49
<212> DNA
<213> mammalian
<400> 55
ggcggcctgg aaagctgaga tggagggcgg catggcgggc acaggctgg 49
<210> 56
<211> 48
<212> DNA
<213> mammalian
<400> 56
ggcggcctgg aaagctgaga tggagggcgg catggcgggc acaggctg 48
<210> 57
<211> 47
<212> DNA
<213> mammalian
<400> 57
ggcggcctgg aaagctgaga tggagggcgg catggcgggc acaggct 47
<210> 58
<211> 46
<212> DNA
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ggcggcctgg aaagctgaga tggagggcgg catggcgggc acaggc 46
<210> 59
<211> 45
<212> DNA
<213> mammalian
<400> 59
ggcggcctgg aaagctgaga tggagggcgg catggcgggc acagg 45
<210> 60
<211> 44
<212> DNA
<213> mammalian
<400> 60
ggcggcctgg aaagctgaga tggagggcgg catggcgggc acag 44
<210> 61
<211> 43
<212> DNA
<213> mammalian
<400> 61
ggcggcctgg aaagctgaga tggagggcgg catggcgggc aca 43
<210> 62
<211> 42
<212> DNA
<213> mammalian
4
16
CA 02330022 2001-11-27
<400> 62
ggcggcctgg aaagctgaga tggagggcgg catggcgggc ac 42
<210> 63
<211> 41
<212> DNA
<213> mammalian
<400> 63
ggcggcctgg aaagctgaga tggagggcgg catggcgggc a 41
<210> 64
<211> 40
<212> DNA
<213> mammalian
<400> 64
ggcggcctgg aaagctgaga tggagggcgg catggcgggc 40
<210> 65
<211> 39
<212> DNA
<213> mammalian
<400> 65
ggcggcctgg aaagctgaga tggagggcgg catggcggg 39
<210> 66
<211> 38
<212> DNA
<213> mammalian
17
t I
CA 02330022 2001-11-27
<400> 66
ggcggcctgg aaagctgaga tggagggcgg catggcgg 38
<210> 67
<211> 37
<212> DNA
<213> mammalian
<400> 67
ggcggcctgg aaagctgaga tggagggcgg catggcg 37
<210> 68
<211> 36
<212> DNA
<213> mammalian
<400> 68
ggcggcctgg aaagctgaga tggagggcgg catggc 36
<210> 69
<211> 35
<212> DNA
<213> mammalian
<400> 69
ggcggcctgg aaagctgaga tggagggcgg catgg 35
<210> 70
<211> 34
<212> DNA
<213> mammalian
18
CA 02330022 2001-11-27
<400> 70
ggcggcctgg aaagctgaga tggagggcgg catg 34
<210> 71
<211> 33
<212> DNA
<213> mammalian
<400> 71
ggcggcctgg aaagctgaga tggagggcgg cat 33
<210> 72
<211> 32
<212> DNA
<213> mammalian
<400> 72
ggcggcctgg aaagctgaga tggagggcgg ca 32
<210> 73
<211> 31
<212> DNA
<213> mammalian
<400> 73
ggcggcctgg aaagctgaga tggagggcgg c 31
<210> 74
<211> 30
<212> DNA
<213> mammalian
19
CA 02330022 2001-11-27
<400> 74
ggcggcctgg aaagctgaga tggagggcgg 30
<210> 75
<211> 29
<212> DNA
<213> mammalian
<400> 75
ggcggcctgg aaagctgaga tggagggcg 29
<210> 76
<211> 28
<212> DNA
<213> mammalian
<400> 76
ggcggcctgg aaagctgaga tggagggc 2g
<210> 77
<211> 27
<212> DNA
<213> mammalian
<400> 77
ggcggcctgg aaagctgaga tggaggg 27
<210> 78
<211> 26
<212> DNA
<213> mammalian
CA 02330022 2001-11-27
<400> 78
ggcggcctgg aaagctgaga tggagg
26
<210> 79
<211> 25
<212> DNA
<213> mammalian
<400> 79
ggcggcctgg aaagctgaga tggag 25
<210> 80
<211> 24
<212> DNA
<213> mammalian
<400> 80
ggcggcctgg aaagctgaga tgga 24
<210> 81
<211> 23
<212> DNA
<213> mammalian
<400> 81
ggcggcctgg aaagctgaga tgg 23
<210> 82
<211> 22
<212> DNA
<213> mammalian
21
CA 02330022 2001-11-27
<400> 82
ggcggcctgg aaagctgaga tg 22
<210> 83
<211> 21
<212> DNA
<213> mammalian
<400> 83
ggcggcctgg aaagctgaga t 21
<210> 84
<211> 20
<212> DNA
<213> mammalian
<400> 84
ggcggcctgg aaagctgaga 20
<210> 85
<211> 19
<212> DNA
<213> mammalian
<400> 85
ggcggcctgg aaagctgag 19
<210> 86
<211> 18
<212> DNA
<213> mammalian
22
CA 02330022 2001-11-27
<400> 86
ggcggcctgg aaagctga 18
<210> 87
<211> 17
<212> DNA
<213> mammalian
<400> 87
ggcggcctgg aaagctg 17
<210> 88
<211> 16
<212> DNA
<213> mammalian
<400> 88
ggcggcctgg aaagct 16
<210> 89
<211> 15
<212> DNA
<213> mammalian
<400> 89
ggcggcctgg aaagc 15
<210> 90
<211> 14
<212> DNA
<213> mammalian
23
CA 02330022 2001-11-27
<400> 90
ggcggcctgg aaag 14
<210> 91
<211> 13
<212> DNA
<213> mammalian
<400> 91
ggcggcctgg aaa
13
<210> 92
<211> 12
<212> DNA
<213> mammalian
<400> 92
ggcggcctgg as
12
<210> 93
<211> 11
<212> DNA
<213> mammalian
<400> 93
ggcggcc~gg a
11
<210> 94
<211> 10
<212> DNA
<213> mammalian
24
CA 02330022 2001-11-27
<400> 94
ggcggcctgg 10
<210> 95
<211> 50
<212> DNA
<213> mammalian
<400> 95
gcggcctgga aagctgagat ggagggcggc atggcgggca caggctgggc 50
<210> 96
<211> 49
<212> DNA
<213> mammalian
<400> 96
gcggcctgga aagctgagat ggagggcggc atggcgggca caggctggg 49
<210> 97
<211> 48
<212> DNA
<213> mammalian
<400> 97
gcggcctgga aagctgagat ggagggcggc atggcgggca caggctgg 48
<210> 98
<211> 47
<212> DNA
<213> mammalian
CA 02330022 2001-11-27
<400> 98
gcggcctgga aagctgagat ggagggcggc atggcgggca caggctg 47
<210> 99
<211> 46
<212> DNA
<213> mammalian
<400> 99
gcggcctgga aagctgagat ggagggcggc atggcgggca caggct 46
<210> 100
<211> 45
<212> DNA
<213> mammalian
<400> 100
gcggcctgga aagctgagat ggagggcggc atggcgggca caggc 45
<210> 101
<211> 44
<212> DNA
<213> mammalian
<400> 101
gcggcctgga aagctgagat ggagggcggc atggcgggca cagg 44
<210> 102
<211> 43
<212> DNA
<213> mammalian
26
CA 02330022 2001-11-27
<400> 102
gcggcctgga aagctgagat ggagggcggc atggcgggca cag 43
<210> 103
<211> 42
<212> DNA
<213> mammalian
<400> 103
gcggcctgga aagctgagat ggagggcggc atggcgggca ca 42
<210> 104
<211> 41
<212> DNA
<213> mammalian
<400> 104
gcggcctgga aagctgagat ggagggcggc atggcgggca c 41
<210> 105
<211> 40
<212> DNA
<213> mammalian
<400> 105
gcggcctgga aagctgagat ggagggcggc atggcgggca 40
<210> 106
<211> 39
<212> DNA
<213> mammalian
27
CA 02330022 2001-11-27
<400> 106
gcggcctgga aagctgagat ggagggcggc atggcgggc 39
<210> 107
<211> 38
<212> DNA
<213> mammalian
<400> 107
gcggcctgga aagctgagat ggagggcggc atggcggg 3g
<210> 108
<211> 37
<212> DNA
<213> mammalian
<400> 108
gcggcctgga aagctgagat ggagggcggc atggcgg 37
<210> 109
<211> 36
<212> DNA
<213> mammalian
<400> 109
gcggcctgga aagctgagat ggagggcggc atggcg
36
<210> 110
<211> 35
<212> DNA
<213> mammalian
28
CA 02330022 2001-11-27
<400> 110
gcggcctgga aagctgagat ggagggcggc atggc 35
<210> 111
<211> 34
<212> DNA
<213> mammalian
<400> 111
gcggcctgga aagctgagat ggagggcggc atgg ~ 34
<210> 112
<211> 33
<212> DNA
<213> mammalian
<400> 112
gcggcctgga aagctgagat ggagggcggc atg 33
<210> 113
<211> 32
<212> DNA
<213> mammalian
<400> 113
gcggcctgga aagctgagat ggagggcggc at 32
<210> 114
<211> 31
<212> DNA
<213> mammalian
29
CA 02330022 2001-11-27
<400> 114
gcggcctgga aagctgagat ggagggcggc a 31
<210> 115
<211> 30
<212> DNA
<213> mammalian
<400> 115
gcggcctgga aagctgagat ggagggcggc 30
<210> 116
<211> 29
<212> DNA
<213> mammalian
<400> 116
gcggcctgga aagctgagat ggagggcgg 29
<210> 117
<211> 28
<212> DNA
<213> mammalian
<400> 117
gcggcctgga aagctgagat ggagggcg 2g
<210> 118
<211> 27
<212> DNA
<213> mammalian
CA 02330022 2001-11-27
<400> 118
gcggcctgga aagctgagat ggagggc 2~
<210> 119
<211> 26
<212> DNA
<213> mammalian
<400> 119
gcggcctgga aagctgagat ggaggg 26
<210> 120
<211> 25
<212> DNA
<213> mammalian
<400> 120
gcggcctgga aagctgagat ggagg 25
<210> 121
<211> 24
<212> DNA
<213> mammalian
<400> 121
gcggcctgga aagctgagat ggag 24
<210> 122
<211> 23
<212> DNA
<213> mammalian
31
CA 02330022 2001-11-27
<400> 122
gcggcctgga aagctgagat gga 23
<210> 123
<211> 22
<212> DNA
<213> mammalian
<400> 123
gcggcctgga aagctgagat gg 22
<210> 124
<211> 21
<212> DNA
<213> mammalian
<400> 124
gcggcctgga aagctgagat g 21
<210> 125
<211> 20
<212> DNA
<213> mammalian
<400> 125
gcggcctgga aagctgagat 20
<210> 126
<211> 19
<212> DNA
<213> mammalian
32
CA 02330022 2001-11-27
<400> 126
gcggcctgga aagctgaga
19
<210> 127
<211> 18
<212> DNA
<213> mammalian
<400> 127
gcggcctgga aagctgag 1g
<210> 128
<211> 17
<212> DNA
<213> mammalian
<400> 128
gcggcctgga aagctga 17
<210> 129
<211> 16
<212> DNA
<213> mammalian
<400> 129
gcggcctgga aagctg 16
<210> 130
<211> 15
<212> DNA
<213> mammalian
33
CA 02330022 2001-11-27
<400> 130
gcggcctgga aagct 15
<210> 131
<211> 14
<212> DNA
<213> mammalian
<400> 131
gcggcctgga aagc 14
<210> 132
<211> 13
<212> DNA
<213> mammalian
<400> 132
gcggcctgga aag 13
<210> 133
<211> 12
<212> DNA
<213> mammalian
<400> 133
gcggcctgga as 12
<210> 134
<211> 11
<212> DNA
<213> mammalian
34
CA 02330022 2001-11-27
<400> 134
gcggcctgga a 11
<210> 135
<211> 10
<212> DNA
<213> mammalian
<400> 135
gcggcctgga 10
<210> 136
<211> 49
<212> DNA
<213> mammalian
<400> 136
cggcctggaa agctgagatg gagggcggca tggcgggcac aggctgggc 49
<210> 137
<211> 48
<212> DNA
<213> mammalian
<400> 137
cggcctggaa agctgagatg gagggcggca tggcgggcac aggctggg 48
<210> 138
<211> 47
<212> DNA
<213> mammalian
CA 02330022 2001-11-27
<400> 138
cggcctggaa agctgagatg gagggcggca tggcgggcac aggctgg 47
<210> 139
<211> 46
<212> DNA
<213> mammalian
<400> 139
cggcctggaa agctgagatg gagggcggca tggcgggcac aggctg 46
<210> 140
<211> 45
<212> DNA
<213> mammalian
<400> 140
cggcctggaa agctgagatg gagggcggca tggcgggcac aggct 45
<210> 141
<211> 44
<212> DNA
<213> mammalian
<400> 141
cggcctggaa agctgagatg gagggcggca tggcgggcac aggc 44
<210> 142
<211> 43
<212> DNA
<213> mammalian
36
CA 02330022 2001-11-27
<400> 142
cggcctggaa agctgagatg gagggcggca tggcgggcac agg 43
<210> 143
<211> 42
<212> DNA
<213> mammalian
<400> 143
cggcctggaa agctgagatg gagggcggca tggcgggcac ag 42
<210>144
<211>41
<212>DNA
<213>mammalian
<400> 144
cggcctggaa agctgagatg gagggcggca tggcgggcac a 41
<210> 145
<211> 40
<212> DNA
<213> mammalian
<400> 145
cggcctggaa agctgagatg gagggcggca tggcgggcac 40
<210> 146
<211> 39
<212> DNA
<213> mammalian
37
CA 02330022 2001-11-27
<400> 146
cggcctggaa agctgagatg gagggcggca tggcgggca 39
<210> 147
<211> 38
<212> DNA
<213> mammalian
<400> 147
cggcctggaa agctgagatg gagggcggca tggcgggc 38
<210> 148
<211> 37
<212> DNA
<213> mammalian
<400> 148
cggcctggaa agctgagatg gagggcggca tggcggg 37
<210> 149
<211> 36
<212> DNA
<213> mammalian
<400> 149
cggcctggaa agctgagatg gagggcggca tggcgg 36
<210> 150
<211> 35
<212> DNA
<213> mammalian
38
CA 02330022 2001-11-27
<400> 150
cggcctggaa agctgagatg gagggcggca tggcg 35
<210> 151
<211> 34
<212> DNA
<213> mammalian
<400> 151
cggcctggaa agctgagatg gagggcggca tggc 34
<210> 152
<211> 33
<212> DNA
<213> mammalian
<400> 152
cggcctggaa agctgagatg gagggcggca tgg 33
<210> 153
<211> 32
<212> DNA
<213> mammalian
<400> 153
cggcctggaa agctgagatg gagggcggca tg 32
<210> 154
<211> 31
<212> DNA
<213> mammalian
39
CA 02330022 2001-11-27
<400> 154
cggcctggaa agctgagatg gagggcggca t
31
<210> 155
<211> 30
<212> DNA
<213> mammalian
<400> 155
cggcctggaa agctgagatg gagggcggca 30
<210> 156
<211> 29
<212> DNA
<213> mammalian
<400> 156
cggcctggaa agctgagatg gagggcggc 29
<210> 157
<211> 28
<212> DNA
<213> mammalian
<400> 157
cggcctggaa agctgagatg gagggcgg 2g
<210> 158
<2~11> 27
<212> DNA
<213> mammalian
CA 02330022 2001-11-27
<400> 158
cggcctggaa agctgagatg gagggcg 2~
<210> 159
<211> 26
<212> DNA
<213> mammalian
<400> 159
cggcctggaa agctgagatg gagggc 26
<210> 160
<211> 25
<212> DNA
<213> mammalian
<400> 160
cggcctggaa agctgagatg gaggg 25
<210> 161
<211> 24
<212> DNA
<213> mammalian
<400> 161
cggcctggaa agctgagatg gagg 24
<210> 162
<211> 23
<212> DNA
<213> mammalian
41
CA 02330022 2001-11-27
<400> 162
cggcctggaa agctgagatg gag 23
<210> 163
<211> 22
<212> DNA
<213> mammalian
<400> 163
cggcctggaa agctgagatg ga 22
<210> 164
<211> 21
<212> DNA
<213> mammalian
<400> 164
cggcctggaa agctgagatg g 21
<210> 165
<211> 20
<212> DNA
<213> mammalian
<400> 165
cggcctggaa agctgagatg 20
<210> 166
<211> 19
<212> DNA
<213> mammalian
42
CA 02330022 2001-11-27
<400> 166
cggcctggaa agctgagat 19
<210> 167
<211> 18
<212> DNA
<213> mammalian
<400> 167
cggcctggaa agctgaga 18
<210> 168
<211> 17
<212> DNA
<213> mammalian
<400> 168
cggcctggaa agctgag 17
<210> 169
<211> 16
<212> DNA
<213> mammalian
<400> 169
cggcctggaa agctga 16
<210> 170
<211> 15
<212> DNA
<213> mammalian
43
CA 02330022 2001-11-27
<400> 170
cggcctggaa agctg 15
<210> 171
<211> 14
<212> DNA
<213> mammalian
<400> 171
cggcctggaa agct 14
<210> 172
<211> 13
<212> DNA
<213> mammalian
<400> 172
cggcctggaa agc 13
<210> 173
<211> 12
<212> DNA
<213> mammalian
<400> 173
cggcctggaa ag 12
<210> 174
<211> 11
<212> DNA
<213> mammalian
44
CA 02330022 2001-11-27
<400> 174
cggcctggaa a 11
<210> 175
<211> 10
<212> DNA
<213> mammalian
<400> 175
cggcctggaa 10
<210> 176
<211> 48
<212> DNA
<213> mammalian
<400> 176
ggcctggaaa gctgagatgg agggcggcat ggcgggcaca ggctgggc 48
<210> 177
<211> 47
<212> DNA
<213> mammalian
<400> 177
ggcctggaaa gctgagatgg agggcggcat ggcgggcaca ggctggg 47
<210> 178
<211> 46
<212> DNA
<213> mammalian
CA 02330022 2001-11-27
<400> 178
ggcctggaaa gctgagatgg agggcggcat ggcgggcaca ggctgg 46
<210> 179
<211> 45
<212> DNA
<213> mammalian
<400> 179
ggcctggaaa gctgagatgg agggcggcat ggcgggcaca ggctg 45
<210> 180
<211> 44
<212> DNA
<213> mammalian
<400> 180
ggcctggaaa gctgagatgg agggcggcat ggcgggcaca ggct 44
<210> 181
<211> 43
<212> DNA
<213> mammalian
<400> 181
ggcctggaaa gctgagatgg agggcggcat ggcgggcaca ggc 43
<210> 182
<211> 42
<212> DNA
<213> mammalian
46
CA 02330022 2001-11-27
<400> 182
ggcctggaaa gctgagatgg agggcggcat ggcgggcaca gg 42
<210> 183
<211> 41
<212> DNA
<213> mammalian
<400> 183
ggcctggaaa gctgagatgg agggcggcat ggcgggcaca g 41
<210> 184
<211> 40
<212> DNA
<213> mammalian
<400> 184
ggcctggaaa gctgagatgg agggcggcat ggcgggcaca 40
<210> 185
<211> 39
<212> DNA
<213> mammalian
<400> 185
ggcctggaaa gctgagatgg agggcggcat ggcgggcac 39
<210> 186
<211> 38
<212> DNA
<213> mammalian
47
CA 02330022 2001-11-27
<400> 186
ggcctggaaa gctgagatgg agggcggcat ggcgggca 38
<210> 187
<211> 37
<212> DNA
<213> mammalian
<400> 187
ggcctggaaa gctgagatgg agggcggcat ggcgggc 37
<210> 188
<211> 36
<212> DNA
<213> mammalian
<400> 188
ggcctggaaa gctgagatgg agggcggcat ggcggg 36
<210> 189
<211> 35
<212> DNA
<213> mammalian
<400> 189
ggcctggaaa gctgagatgg agggcggcat ggcgg 35
<210> 190
<211> 34
<212> DNA
<213> mammalian
48
CA 02330022 2001-11-27
<400> 190
ggcctggaaa gctgagatgg agggcggcat ggcg 34
<210> 191
<211> 33
<212> DNA
<213> mammalian
<400> 191
ggcctggaaa gctgagatgg agggcggcat ggc 33
<210> 192
<211> 32
<212> DNA
<213> mammalian
<400> 192
ggcctggaaa gctgagatgg agggcggcat gg 32
<210> 193
<211> 31
<212> DNA
<213> mammalian
<400> 193
ggcctggaaa gctgagatgg agggcggcat g 31
<210> 194
<211> 30
<212> DNA
<213> mammalian
49
CA 02330022 2001-11-27
<400> 194
ggcctggaaa gctgagatgg agggcggcat 30
<210> 195
<211> 29
<212> DNA
<213> mammalian
<400> 195
ggcctggaaa gctgagatgg agggcggca 29
<210> 196
<211> 28
<212> DNA
<213> mammalian
<400> 196
ggcctggaaa gctgagatgg agggcggc 2g
<210> 197
<211> 27
<212> DNA
<213> mammalian
<400> 197
ggcctggaaa gctgagatgg agggcgg 27
<210> 198
<211> 26
<212> DNA
<213> mammalian
CA 02330022 2001-11-27
<400> 198
ggcctggaaa gctgagatgg agggcg 26
<210> 199
<211> 25
<212> DNA
<213> mammalian
<400> 199
ggcctggaaa gctgagatgg agggc 25
<210> 200
<211> 24
<212> DNA
<213> mammalian
<400> 200
ggcctggaaa gctgagatgg aggg 24
<210> 201
<211> 23
<212> DNA
<213> mammalian
<400> 201
ggcctggaaa gctgagatgg agg 23
<210> 202
<211> 22
<212> DNA
<213> mammalian
51
CA 02330022 2001-11-27
<400> 202
ggcctggaaa gctgagatgg ag 22
<210> 203
<211> 21
<212> DNA
<213> mammalian
<400> 203
ggcctggaaa gctgagatgg a 21
<210> 204
<211> 20
<212> DNA
<213> mammalian
<400> 204
ggcctggaaa gctgagatgg 20
<210> 205
<211> 19
<212> DNA
<213> mammalian
<400> 205
ggcctggaaa gctgagatg 19
<210> 206
<211> 18
<212> DNA
<213> mammalian
52
CA 02330022 2001-11-27
<400> 206
ggcctggaaa gctgagat 18
<210> 207
<211> 17
<212> DNA
<213> mammalian
<400> 207
ggcctggaaa gctgaga 17
<210> 208
<211> 16
<212> DNA
<213> mammalian
<400> 208
ggcctggaaa gctgag 16
<210> 209
<211> 15
<212> DNA
<213> mammalian
<400> 209
ggcctggaaa gctga 15
<210> 210
<211> 14
<212> DNA
<213> mammalian
53
CA 02330022 2001-11-27
<400> 210
ggcctggaaa gctg 14
<210> 211
<211> 13
<212> DNA
<213> mammalian
<400> 211
ggcctggaaa get 13
<210> 212
<211> 12
<212> DNA
<213> mammalian
<400> 212
ggcctggaaa gc 12
<210> 213
<211> 11
<212> DNA
<213> mammalian
<400> 213
ggcctggaaa g 11
<210> 214
<211> 10
<212> DNA
<213> mammalian
54
CA 02330022 2001-11-27
<400> 214
ggcctggaaa
<210> 215
<211> 47
<212> DNA
<213> mammalian
<400> 215
gcctggaaag ctgagatgga gggcggcatg gcgggcacag gctgggc 47
<210> 216
<211> 46
<212> DNA
<213> mammalian
<400> 216
gcctggaaag ctgagatgga gggcggcatg gcgggcacag gctggg 46
<210> 2I7
<211> 45
<212> DNA
<213> mammalian
<400> 217
gcctggaaag ctgagatgga gggcggcatg gcgggcacag gctgg 45
<210> 218
<211> 44
<212> DNA
<213> mammalian
CA 02330022 2001-11-27
<400> 218
gcctggaaag ctgagatgga gggcggcatg gcgggcacag gctg 44
<210> 219
<211> 43
<212> DNA
<213> mammalian
<400> 219
gcctggaaag ctgagatgga gggcggcatg gcgggcacag get 43
<210> 220
<211> 42
<212> DNA
<213> mammalian
<400> 220
gcctggaaag ctgagatgga gggcggcatg gcgggcacag gc 42
<210> 221
<212> 41
<212> DNA
<213> mammalian
<400> 221
gcctggaaag ctgagatgga gggcggcatg gcgggcacag g 41
<210> 222
<211> 40
<212> DNA
<213> mammalian
56
CA 02330022 2001-11-27
<400> 222
gcctggaaag ctgagatgga gggcggcatg gcgggcacag 40
<210> 223
<211> 39
<212> DNA
<213> mammalian
<400> 223
gcctggaaag ctgagatgga gggcggcatg gcgggcaca 39
<210> 224
<211> 38
<212> DNA
<213> mammalian
<400> 224
gcctggaaag ctgagatgga gggcggcatg gcgggcac 38
<210> 225
<211> 37
<212> DNA
<213> mammalian
<400> 225
gcctggaaag ctgagatgga gggcggcatg gcgggca 37
<210> 226
<211> 36
<212> DNA
<223> mammalian
57
CA 02330022 2001-11-27
<400> 226
gcctggaaag ctgagatgga gggcggcatg gcgggc 36
<210> 227
<211> 35
<212> DNA
<213> mammalian
<400> 227
gcctggaaag ctgagatgga gggcggcatg gcggg 35
<210> 228
<211> 34
<212> DNA
<213> mammalian
<400> 228
gcctggaaag ctgagatgga gggcggcatg gcgg 34
<210> 229
<211> 33
<212> DNA
<213> mammalian
<400> 229
gcctggaaag ctgagatgga gggcggcatg gcg 33
<210> 230
<211> 32
<212> DNA
<213> mammalian
58
CA 02330022 2001-11-27
<400> 230
gcctggaaag ctgagatgga gggcggcatg gc 32
<210> 231
<211> 31
<212> DNA
<213> mammalian
<400> 231
gcctggaaag ctgagatgga gggcggcatg g 31
<210> 232
<211> 30
<212> DNA
<213> mammalian
<400> 232
gcctggaaag ctgagatgga gggcggcatg 30
<210> 233
<211> 29
<212> DNA
<213> mammalian
<400> 233
gcctggaaag ctgagatgga gggcggcat 29
<210> 234
<211> 28
<212> DNA
<213> mammalian
59
CA 02330022 2001-11-27
<400> 234
gcctggaaag ctgagatgga gggcggca 28
<210> 235
<211> 27
<212> DNA
<213> mammalian
<400> 235
gcctggaaag ctgagatgga gggcggc 27
<210> 236
<211> 26
<212> DNA
<213> mammalian
<400> 236
gcctggaaag ctgagatgga gggcgg 26
<210> 237
<211> 25
<212> DNA
<213> mammalian
<400> 237
gcctggaaag ctgagatgga gggcg 25
<210> 238
<211> 24
<212> DNA
<213> mammalian
CA 02330022 2001-11-27
<400> 238
gcctggaaag ctgagatgga gggc 24
<210> 239
<211> 23
<212> DNA
<213> mammalian
<400> 239
gcctggaaag ctgagatgga ggg 23
<210> 240
<211> 22
<212> DNA
<213> mammalian
<400> 240
gcctggaaag ctgagatgga gg 22
<210> 241
<211> 21
<212> DNA
<213> mammalian
<400> 241
gcctggaaag ctgagatgga g 21
<210> 242
<211> 20
<212> DNA
<213> mammalian
61
CA 02330022 2001-11-27
<400> 242
gcctggaaag ctgagatgga 20
<210> 243
<211> 19
<212> DNA
<213> mammalian
<400> 243
gcctggaaag ctgagatgg 19
<210> 244
<211> 18
<212> DNA
<213> mammalian
<400> 244
gcctggaaag ctgagatg 18
<210> 245
<211> 17
<212> DNA
<213> mammalian
<400> 245
gcctggaaag ctgagat 17
<210> 246
<211> 16
<212> DNA
<213> mammalian
62
CA 02330022 2001-11-27
<400> 246
gcctggaaag ctgaga 16
<210> 247
<211> 15
<212> DNA
<213> mammalian
<400> 247
gcctggaaag ctgag 15
<210> 248
<211> 14
<212> DNA
<213> mammalian
<400> 248
gcctggaaag ctga 14
<210> 249
<211> 13
<212> DNA
<213> mammalian
<400> 249
gcctggaaag ctg 13
<210> 250
<211> 12
<212> DNA
<213> mammalian
63
CA 02330022 2001-11-27
<400> 250
gcctggaaag ct 12
<210> 251
<211> 11
<212> DNA
<213> mammalian
<400> 251
gcctggaaag c 11
<210> 252
<211> 10
<212> DNA
<213> mammalian
<400> 252
gcctggaaag 10
<210> 253
<211> 46
<212> DNA
<213> mammalian
<400> 253
cctggaaagc tgagatggag ggcggcatgg cgggcacagg ctgggc 46
<210> 254
<211> 45
<212> DNA
<213> mammalian
64
CA 02330022 2001-11-27
<400> 254
cctggaaagc tgagatggag ggcggcatgg cgggcacagg ctggg 45
<210> 255
<211> 44
<212> DNA
<213> mammalian
<400> 255
cctggaaagc tgagatggag ggcggcatgg cgggcacagg ctgg 44
<210> 256
<211> 43
<212> DNA
<213> mammalian
<400> 256
cctggaaagc tgagatggag ggcggcatgg cgggcacagg ctg 43
<210> 257
<211> 42
<212> DNA
<213> mammalian
<400> 257
cctggaaagc tgagatggag ggcggcatgg cgggcacagg ct 42
<210> 258
<211> 41
<212> DNA
<213> mammalian
CA 02330022 2001-11-27
<400> 258
cctggaaagc tgagatggag ggcggcatgg cgggcacagg c 41
<210> 259
<211> 40
<212> DNA
<213> mammalian
<400> 259
cctggaaagc tgagatggag ggcggcatgg cgggcacagg 40
<210> 260
<211> 39
<212> DNA
<213> mammalian
<400> 260
cctggaaagc tgagatggag ggcggcatgg cgggcacag 39
<210> 261
<211> 38
<212> DNA
<213> mammalian
<400> 261
cctggaaagc tgagatggag ggcggcatgg cgggcaca 38
<210> 262
<211> 37
<212> DNA
<213> mammalian
66
CA 02330022 2001-11-27
<400> 262
cctggaaagc tgagatggag ggcggcatgg cgggcac 37
<210> 263
<211> 36
<212> DNA
<213> mammalian
<400> 263
cctggaaagc tgagatggag ggcggcatgg cgggca 36
<210> 264
<211> 35
<212> DNA
<213> mammalian
<400> 264
cctggaaagc tgagatggag ggcggcatgg cgggc 35
<210> 265
<211> 34
<212> DNA
<213> mammalian
<400> 265
cctggaaagc tgagatggag ggcggcatgg cggg 34
<210> 266
<211> 33
<212> DNA
<213> mammalian
67
CA 02330022 2001-11-27
<400> 266
cctggaaagc tgagatggag ggcggcatgg cgg 33
<210> 267
<211> 32
<212> DNA
<213> mammalian
<400> 267
cctggaaagc tgagatggag ggcggcatgg cg 32
<210> 268
<211> 31
<212> DNA
<213> mammalian
<400> 268
cctggaaagc tgagatggag ggcggcatgg c 31
<210> 269
<211> 30
<212> DNA
<213> mammalian
<400> 269
cctggaaagc tgagatggag ggcggcatgg 30
<210> 270
<211> 29
<212> DNA
<213> mammalian
68
CA 02330022 2001-11-27
<400> 270
cctggaaagc tgagatggag ggcggcatg 29
<210> 271
<211> 28
<212> DNA
<213> mammalian
<400> 271
cctggaaagc tgagatggag ggcggcat 28
<210> 272
<211> 27
<212> DNA
<213> mammalian
<400> 272
cctggaaagc tgagatggag ggcggca 27
<210> 273
<211> 26
<212> DNA
<213> mammalian
<400> 273
cctggaaagc tgagatggag ggcggc 26
<210> 274
<211> 25
<212> DNA
<213> mammalian
69
CA 02330022 2001-11-27
<400> 274
cctggaaagc tgagatggag ggcgg 25
<210> 275
<211> 24
<212> DNA
<213> mammalian
<400> 275
cctggaaagc tgagatggag ggcg 24
<210> 276
<211> 23
<212> DNA
<213> mammalian
<400> 276
cctggaaagc tgagatggag ggc 23
<210> 277
<211> 22
<212> DNA
<213> mammalian
<400> 277
cctggaaagc tgagatggag gg 22
<210> 278
<211> 21
<212> DNA
<213> mammalian
CA 02330022 2001-11-27
<400> 278
cctggaaagc tgagatggag g 21
<210> 279
<211> 20
<212> DNA
<213> mammalian
<400> 279
cctggaaagc tgagatggag 20
<210> 280
<211> 19
<212> DNA
<213> mammalian
<400> 280
cctggaaagc tgagatgga 19
<210> 281
<211> 18
<212> DNA
<213> mammalian
<400> 281
cctggaaagc tgagatgg 18
<210> 282
<211> 17
<212> DNA
<213> mammalian
71
CA 02330022 2001-11-27
<400> 282
cctggaaagc tgagatg 1~
<210> 283
<211> 16
<212> DNA
<213> mammalian
<400> 283
cctggaaagc tgagat 16
<210> 284
<211> 15
<212> DNA
<213> mammalian
<400> 284
cctggaaagc tgaga 15
<210> 285
<211> 14
<212> DNA
<213> mammalian
<400> 285
cctggaaagc tgag 14
<210> 286
<211> 13
<212> DNA
<213> mammalian
72
CA 02330022 2001-11-27
<400> 286
cctggaaagc tga 13
<210> 287
<211> 12
<212> DNA
<213> mammalian
<400> 287
cctggaaagc tg 12
<210> 288
<211> 11
<212> DNA
<213> mammalian
<400> 288
cctggaaagc t 11
<210> 289
<211> 10
<212> DNA
<213> mammalian
<400> 289
cctggaaagc 10
<210> 290
<211> 45
<212> DNA
<213> mammalian
73
CA 02330022 2001-11-27
<400> 290
ctggaaagct gagatggagg gcggcatggc gggcacaggc tgggc 45
<210> 291
<211> 44
<212> DNA
<213> mammalian
<400> 291
ctggaaagct gagatggagg gcggcatggc gggcacaggc tggg 44
<210> 292
<211> 43
<212> DNA
<213> mammalian
<400> 292
ctggaaagct gagatggagg gcggcatggc gggcacaggc tgg 43
<210> 293
<211> 42
<212> DNA
<213> mammalian
<400> 293
ctggaaagct gagatggagg gcggcatggc gggcacaggc tg 42
<210> 294
<211> 41
<212> DNA
<213> mammalian
74
CA 02330022 2001-11-27
<400> 294
ctggaaagct gagatggagg gcggcatggc gggcacaggc t 41
<210> 295
<211> 40
<212> DNA
<213> mammalian
<400> 295
ctggaaagct gagatggagg gcggcatggc gggcacaggc 40
<210> 296
<211> 39
<212> DNA
<213> mammalian
<400> 296
ctggaaagct gagatggagg gcggcatggc gggcacagg 39
<210> 297
<211> 38
<212> DNA
<213> mammalian
<400> 297
ctggaaagct gagatggagg gcggcatggc gggcacag 38
<210> 298
<211> 37
<212> DNA
<213> mammalian
CA 02330022 2001-11-27
<400> 298
ctggaaagct gagatggagg gcggcatggc gggcaca 3~
<210> 299
<211> 36
<212> DNA
<213> mammalian
<400> 299
ctggaaagct gagatggagg gcggcatggc gggcac 36
<210> 300
<211> 35
<212> DNA
<213> mammalian
<400> 300
ctggaaagct gagatggagg gcggcatggc gggca 35
<210> 301
<211> 34
<212> DNA
<213> mammalian
<400> 301
ctggaaagct gagatggagg gcggcatggc gggc 34
<210> 302
<211> 33
<212> DNA
<213> mammalian
76
CA 02330022 2001-11-27
<400> 302
ctggaaagct gagatggagg gcggcatggc ggg 33
<210> 303
<211> 32
<212> DNA
<213> mammalian
<400> 303
ctggaaagct gagatggagg gcggcatggc gg 32
<210> 304
<211> 31
<212> DNA
<213> mammalian
<400> 304
ctggaaagct gagatggagg gcggcatggc g 31
<210> 305
<211> 30
<212> DNA
<213> mammalian
<400> 305
ctggaaagct gagatggagg gcggcatggc 30
<210> 306
<211> 29
<212> DNA
<213> mammalian
77
CA 02330022 2001-11-27
<400> 306
ctggaaagct gagatggagg gcggcatgg 29
<210> 307
<211> 28
<212> DNA
<213> mammalian
<400> 307
ctggaaagct gagatggagg gcggcatg 28
<210> 308
<211> 27
<212> DNA
<213> mammalian
<400> 308
ctggaaagct gagatggagg gcggcat 27
<210> 309
<211> 26
<212> DNA
<213> mammalian
<400> 309
ctggaaagct gagatggagg gcggca 26
<210> 310
<211> 25
<212> DNA
<213> mammalian
78
CA 02330022 2001-11-27
<400> 310
ctggaaagct gagatggagg gcggc 25
<210> 311
<211> 24
<212> DNA
<213> mammalian
<400> 311
ctggaaagct gagatggagg gcgg 24
<210> 312
<211> 23
<212> DNA
<213> mammalian
<400> 312
ctggaaagct gagatggagg gcg 23
<210> 313
<211> 22
<212> DNA
<213> mammalian
<400> 313
ctggaaagct gagatggagg gc 22
<210> 314
<211> 21
<212> DNA
<213> mammalian
79
CA 02330022 2001-11-27
<400> 314
ctggaaagct gagatggagg g 21
<210> 315
<211> 20
<212> DNA
<213> mammalian
<400> 315
ctggaaagct gagatggagg 20
<210> 316
<211> 19
<212> DNA
<213> mammalian
<400> 316
ctggaaagct gagatggag 19
<210> 317
<211> 18
<212> DNA
<213> mammalian
<400> 317
ctggaaagct gagatgga 18
<210> 318
<211> 17
<212> DNA
<213> mammalian
CA 02330022 2001-11-27
<400> 318
ctggaaagct gagatgg 1~
<210> 319
<211> 16
<212> DNA
<213> mammalian
<400> 319
ctggaaagct gagatg 16
<210> 320
<211> 15
<212> DNA
<213> mammalian
<400> 320
ctggaaagct gagat 15
<210> 321
<211> 14
<212> DNA
<213> mammalian
<400> 321
ctggaaagct gaga 14
<210> 322
<211> 13
<212> DNA
<213> mammalian
81
CA 02330022 2001-11-27
<400> 322
ctggaaagct gag 13
<210> 323
<211> 12
<212> DNA
<213> mammalian
<400> 323
ctggaaagct ga 12
<210> 324
<211> 11
<212> DNA
<213> mammalian
<400> 324
ctggaaagct g 11
<210> 325
<211> 10
<212> DNA
<213> mammalian
<400> 325
ctggaaagct 10
<210> 326
<211> 44
<212> DNA
<213> mammalian
82
CA 02330022 2001-11-27
<400> 326
tggaaagctg agatggaggg cggcatggcg ggcacaggct gggc 44
<210> 327
<211> 43
<212> DNA
<213> mammalian
<400> 327
tggaaagctg agatggaggg cggcatggcg ggcacaggct ggg 43
<210> 328
<211> 42
<212> DNA
<213> mammalian
<400> 328
tggaaagctg agatggaggg cggcatggcg ggcacaggct gg 42
<210> 329
<211> 41
<212> DNA
<213> mammalian
<400> 329
tggaaagctg agatggaggg cggcatggcg ggcacaggct g 41
<210> 330
<211> 40
<212> DNA
<213> mammalian
83
CA 02330022 2001-11-27
<400> 330
tggaaagctg agatggaggg cggcatggcg ggcacaggct 40
<210> 331
<211> 39
<212> DNA
<213> mammalian
<400> 331
tggaaagctg agatggaggg cggcatggcg ggcacaggc 39
<210> 332
<211> 38
<212> DNA
<213> mammalian
<400> 332
tggaaagctg agatggaggg cggcatggcg ggcacagg 38
<210> 333
<211> 37
<212> DNA
<213> mammalian
<400> 333
tggaaagctg agatggaggg cggcatggcg ggcacag 37
<210> 334
<211> 36
<212> DNA
<213> mammalian
84
CA 02330022 2001-11-27
<400> 334
tggaaagctg agatggaggg cggcatggcg ggcaca 36
<210> 335
<211> 35
<212> DNA
<213> mammalian
<400> 335
tggaaagctg agatggaggg cggcatggcg ggcac 35
<210> 336
<211> 34
<212> DNA
<213> mammalian
<400> 336
tggaaagctg agatggaggg cggcatggcg ggca 34
<210> 337
<221> 33
<212> DNA
<213> mammalian
<400> 337
tggaaagctg agatggaggg cggcatggcg ggc 33
<210> 338
<211> 32
<212> DNA
<213> mammalian
CA 02330022 2001-11-27
<400> 338
tggaaagctg agatggaggg cggcatggcg gg 32
<210> 339
<211> 31
<212> DNA
<213> mammalian
<400> 339
tggaaagctg agatggaggg cggcatggcg g 31
<210> 340
<211> 30
<212> DNA
<213> mammalian
<400> 340
tggaaagctg agatggaggg cggcatggcg 30
<210> 341
<211> 29
<212> DNA
<213> mammalian
<400> 341
tggaaagctg agatggaggg cggcatggc 29
<210> 342
<211> 28
<212> DNA
<213> mammalian
86
CA 02330022 2001-11-27
<400> 342
tggaaagctg agatggaggg cggcatgg 28
<210> 343
<211> 27
<212> DNA
<213> mammalian
<400> 343
tggaaagctg agatggaggg cggcatg 27
<210> 344
<211> 26
<212> DNA
<213> mammalian
<400> 344
tggaaagctg agatggaggg cggcat 26
<210> 345
<211> 25
<212> DNA
<213> mammalian
<400> 345
tggaaagctg agatggaggg cggca 25
<210> 346
<211> 24
<212> DNA
<213> mammalian
87
CA 02330022 2001-11-27
<400> 346
tggaaagctg agatggaggg cggc 24
<210> 347
<211> 23
<212> DNA
<213> mammalian
<400> 347
tggaaagctg agatggaggg cgg 23
<210> 348
<211> 22
<212> DNA
<213> mammalian
<400> 348
tggaaagctg agatggaggg cg 22
<210> 349
<211> 21
<212> DNA
<213> mammalian
<400> 349
tggaaagctg agatggaggg c 21
<210> 350
<211> 20
<212> DNA
<213> mammalian
88
CA 02330022 2001-11-27
<400> 350
tggaaagctg agatggaggg 20
<210> 351
<211> 19
<212> DNA
<213> mammalian
<400> 351
tggaaagctg agatggagg 19
<210> 352
<211> 18
<212> DNA
<213> mammalian
<400> 352
tggaaagctg agatggag 18
<210> 353
<211> 17
<212> DNA
<213> mammalian
<400> 353
tggaaagctg agatgga 17
<210> 354
<211> 16
<212> DNA
<213> mammalian
89
CA 02330022 2001-11-27
<400> 354
tggaaagctg agatgg 16
<210> 355
<211> 15
<212> DNA
<213> mammalian
<400> 355
tggaaagctg agatg 15
<210> 356
<211> 14
<212> DNA
<213> mammalian
<400> 356
tggaaagctg agat 14
<210> 357
<211> 13
<212> DNA
<213> mammalian
<400> 357
tggaaagctg aga 13
<210> 358
<211> 12
<212> DNA
<213> mammalian
CA 02330022 2001-11-27
<400> 358
tggaaagctg ag 12
<210> 359
<211> 11
<212> DNA
<213> mammalian
<400> 359
tggaaagctg a 11
<210> 360
<211> 10
<212> DNA
<213> mammalian
<400> 360
tggaaagctg 10
<210> 361
<211> 43
<212> DNA
<213> mammalian
<400> 361
ggaaagctga gatggagggc ggcatggcgg gcacaggctg ggc 43
<210> 362
<211> 42
<212> DNA
<213> mammalian
91
CA 02330022 2001-11-27
<400> 362
ggaaagctga gatggagggc ggcatggcgg gcacaggctg gg 42
<210> 363
<211> 41
<212> DNA
<213> mammalian
<400> 363
ggaaagctga gatggagggc ggcatggcgg gcacaggctg g 41
<210> 364
<211> 40
<212> DNA
<213> mammalian
<400> 364
ggaaagctga gatggagggc ggcatggcgg gcacaggctg 40
<210> 365
<211> 39
<212> DNA
<213> mammalian
<400> 365
ggaaagctga gatggagggc ggcatggcgg gcacaggct 39
<210> 366
<211> 38
<212> DNA
<213> mammalian
92
CA 02330022 2001-11-27
<400> 366
ggaaagctga gatggagggc ggcatggcgg gcacaggc 38
<210> 367
<211> 37
<212> DNA
<213> mammalian
<400> 367
ggaaagctga gatggagggc ggcatggcgg gcacagg 37
<210> 368
<211> 36
<212> DNA
<213> mammalian
<400> 368
ggaaagctga gatggagggc ggcatggcgg gcacag 36
<210> 369
<211> 35
<212> DNA
<213> mammalian
<400> 369
ggaaagctga gatggagggc ggcatggcgg gcaca 35
<210> 370
<211> 34
<212> DNA
<213> mammalian
93
CA 02330022 2001-11-27
<400> 370
ggaaagctga gatggagggc ggcatggcgg gcac 34
<210> 371
<211> 33
<212> DNA
<213> mammalian
<400> 371
ggaaagctga gatggagggc ggcatggcgg gca 33
<210> 372
<211> 32
<212> DNA
<213> mammalian
<400> 372
ggaaagctga gatggagggc ggcatggcgg gc 32
<210> 373
<211> 31
<212> DNA
<213> mammalian
<400> 373
ggaaagctga gatggagggc ggcatggcgg g 31
<210> 374
<211> 30
<212> DNA
<213> mammalian
94
CA 02330022 2001-11-27
<400> 374
ggaaagctga gatggagggc ggcatggcgg 30
<210> 375
<211> 29
<212> DNA
<213> mammalian
<400> 375
ggaaagctga gatggagggc ggcatggcg 29
<210> 376
<211> 28
<212> DNA
<213> mammalian
<400> 376
ggaaagctga gatggagggc ggcatggc 2g
<210> 377
<211> 27
<212> DNA
<213> mammalian
<400> 377
ggaaagctga gatggagggc ggcatgg 27
<210> 378
<211> 26
<212> DNA
<213> mammalian
CA 02330022 2001-11-27
<400> 378
ggaaagctga gatggagggc ggcatg 26
<210> 379
<211> 25
<212> DNA
<213> mammalian
<400> 379
ggaaagctga gatggagggc ggcat 25
<210> 380
<211> 24
<212> DNA
<213> mammalian
<400> 380
ggaaagctga gatggagggc ggca 24
<210> 381
<211> 23
<212> DNA
<213> mammalian
<400> 381
ggaaagctga gatggagggc ggc 23
<210> 382
<211> 22
<212> DNA
<213> mammalian
96
CA 02330022 2001-11-27
<400> 382
ggaaagctga gatggagggc gg 22
<210> 383
<211> 21
<212> DNA
<213> mammalian
<400> 383
ggaaagctga gatggagggc g 21
<210> 384
<211> 20
<212> DNA
<213> mammalian
<400> 384
ggaaagctga gatggagggc 20
<210> 385
<211> 19
<212> DNA
<213> mammalian
<400> 385
ggaaagctga gatggaggg 19
<210> 386
<211> 18
<212> DNA
<213> mammalian
97
CA 02330022 2001-11-27
<400> 386
ggaaagctga gatggagg 18
<210> 387
<211> 17
<212> DNA
<213> mammalian
<400> 387
ggaaagctga gatggag 17
<210> 388
<211> 16
<212> DNA
<213> mammalian
<400> 388
ggaaagctga gatgga 16
<210> 389
<211> 15
<212> DNA
<213> mammalian
<400> 389
ggaaagctga gatgg 15
<210> 390
<211> 14
<212> DNA
<213> mammalian
98
CA 02330022 2001-11-27
<400> 390
ggaaagctga gatg 14
<210> 391
<211> 13
<212> DNA
<213> mammalian
<400> 391
ggaaagctga gat 13
<210> 392
<211> 12
<212> DNA
<213> mammalian
<400> 392
ggaaagctga ga 12
<210> 393
<211> 11
<212> DNA
<213> mammalian
<400> 393
ggaaagctga g 11
<210> 394
<211> 10
<212> DNA
<213> mammalian
99
CA 02330022 2001-11-27
<400> 394
ggaaagctga 10
<210> 395
<211> 42
<212> DNA
<213> mammalian
<400> 395
gaaagctgag atggagggcg gcatggcggg cacaggctgg gc 42
<210> 396
<211> 41
<212> DNA
<213> mammalian
<400> 396
gaaagctgag atggagggcg gcatggcggg cacaggctgg g 41
<210> 397
<211> 40
<212> DNA
<213> mammalian
<400> 397
gaaagctgag atggagggcg gcatggcggg cacaggctgg 40
<210> 398
<211> 39
<212> DNA
<213> mammalian
100
CA 02330022 2001-11-27
<400> 398
gaaagctgag atggagggcg gcatggcggg cacaggctg
39
<210> 399
<211> 38
<212> DNA
<213> mammalian
<400> 399
gaaagctgag atggagggcg gcatggcggg cacaggct 3g
<210> 400
<211> 37
<212> DNA
<213> mammalian
<400> 400
gaaagctgag atggagggcg gcatggcggg cacaggc 37
<210> 401
<211> 36
<212> DNA
<213> mammalian
<400> 401
gaaagctgag atggagggcg gcatggcggg cacagg 36
<210> 402
<211> 35
<212> DNA
<213> mammalian
101
CA 02330022 2001-11-27
<400> 402
gaaagctgag atggagggcg gcatggcggg cacag 35
<210> 403
<211> 34
<212> DNA
<213> mammalian
<400> 403
gaaagctgag atggagggcg gcatggcggg caca 34
<210> 404
<211> 33
<212> DNA
<213> mammalian
<400> 404
gaaagctgag atggagggcg gcatggcggg cac 33
<210> 405
<211> 32
<212> DNA
<213> mammalian
<400> 405
gaaagctgag atggagggcg gcatggcggg ca 32
<210> 406
<211> 31
<212> DNA
<213> mammalian
102
CA 02330022 2001-11-27
<400> 406
gaaagctgag atggagggcg gcatggcggg c 31
<210> 407
<211> 30
<212> DNA
<213> mammalian
<400> 407
gaaagctgag atggagggcg gcatggcggg 30
<210> 408
<211> 29
<212> DNA
<213> mammalian
<400> 408
gaaagctgag atggagggcg gcatggcgg 29
<210> 409
<211> 28
<212> DNA
<213> mammalian
<400> 409
gaaagctgag atggagggcg gcatggcg 28
<210> 410
<211> 27
<212> DNA
<213> mammalian
103
CA 02330022 2001-11-27
<400> 410
gaaagctgag atggagggcg gcatggc 27
<210> 411
<211> 26
<212> DNA
<213> mammalian
<400> 411
gaaagctgag atggagggcg gcatgg 26
<210> 412
<211> 25
<212> DNA
<213> mammalian
<400> 412
gaaagctgag atggagggcg gcatg 25
<210> 413
<211> 24
<212> DNA
<213> mammalian
<400> 413
gaaagctgag atggagggcg gcat 24
<210> 414
<211> 23
<212> DNA
<213> mammalian
104
CA 02330022 2001-11-27
<400> 414
gaaagctgag atggagggcg gca 23
<210> 415
<211> 22
<212> DNA
<213> mammalian
<400> 415
gaaagctgag atggagggcg gc 22
<210> 416
<211> 21
<212> DNA
<213> mammalian
<400> 416
gaaagctgag atggagggcg g 21
<210> 417
<211> 20
<212> DNA
<213> mammalian
<400> 417
gaaagctgag atggagggcg 20
<210> 418
<211> 19
<212> DNA
<213> mammalian
105
CA 02330022 2001-11-27
<400> 418
gaaagctgag atggagggc 1g
<210> 419
<211> 18
<212> DNA
<213> mammalian
<400> 419
gaaagctgag atggaggg 1g
<210> 420
<211> 17
<212> DNA
<213> mammalian
<400> 420
gaaagctgag atggagg 17
<210> 421
<211> 16
<212> DNA
<213> mammalian
<400> 421
gaaagctgag atggag 16
<210> 422
<211> 15
<212> DNA
<213> mammalian
106
CA 02330022 2001-11-27
<400> 422
gaaagctgag atgga 15
<210> 423
<211> 14
<212> DNA
<213> mammalian
<400> 423
gaaagctgag atgg 14
<210> 424
<211> 13
<212> DNA
<213> mammalian
<400> 424
gaaagctgag atg 13
<210> 425
<211> 12
<212> DNA
<213> mammalian
<400> 425
gaaagctgag at 12
<210> 426
<211> 11
<212> DNA
<213>- mammalian
107
CA 02330022 2001-11-27
<400> 426
gaaagctgag a 11
<210> 427
<211> 10
<212> DNA
<213> mammalian
<400> 427
gaaagctgag 10
<210> 428
<211> 41
<212> DNA
<213> mammalian
<400> 428
aaagctgaga tggagggcgg catggcgggc acaggctggg c 41
<210> 429
<211> 40
<212> DNA
<213> mammalian
<400> 429
aaagctgaga tggagggcgg catggcgggc acaggctggg 40
<210> 430
<211> 39
<212> DNA
<213> mammalian
108
CA 02330022 2001-11-27
<400> 430
aaagctgaga tggagggcgg catggcgggc acaggctgg 39
<210> 431
<211> 38
<212> DNA
<213> mammalian
<400> 431
aaagctgaga tggagggcgg catggcgggc acaggctg 38
<210> 432
<211> 37
<212> DNA
<213> mammalian
<400> 432
aaagctgaga tggagggcgg catggcgggc acaggct 37
<210> 433
<211> 36
<212> DNA
<213> mammalian
<400> 433
aaagctgaga tggagggcgg catggcgggc acaggc 36
<210> 434
<211> 35
<212> DNA
<213> mammalian
109
CA 02330022 2001-11-27
<400> 434
aaagctgaga tggagggcgg catggcgggc acagg 35
<210> 435
<211> 34
<212> DNA
<213> mammalian
<400> 435
aaagctgaga tggagggcgg catggcgggc acag 34
<210> 436
<211> 33
<212> DNA
<213> mammalian
<400> 436
aaagctgaga tggagggcgg catggcgggc aca 33
<210> 437
<211> 32
<212> DNA
<213> mammalian
<400> 437
aaagctgaga tggagggcgg catggcgggc ac 32
<210> 438
<211> 31
<212> DNA
<213> mammalian
110
CA 02330022 2001-11-27
<400> 438
aaagctgaga tggagggcgg catggcgggc a 31
<210> 439
<211> 30
<212> DNA
<213> mammalian
<400> 439
aaagctgaga tggagggcgg catggcgggc 30
<210> 440
<211> 29
<212> DNA
<213> mammalian
<400> 440
aaagctgaga tggagggcgg catggcggg 29
<210> 441
<211> 28
<212> DNA
<213> mammalian
<400> 441
aaagctgaga tggagggcgg catggcgg 2g
<210> 442
<211> 27
<212> DNA
<213> mammalian
111
CA 02330022 2001-11-27
<400> 442
aaagctgaga tggagggcgg catggcg 27
<210> 443
<211> 26
<212> DNA
<213> mammalian
<400> 443
aaagctgaga tggagggcgg catggc 26
<210> 444
<211> 25
<212> DNA
<213> mammalian
<400> 444
aaagctgaga tggagggcgg catgg 25
<210> 445
<211> 24
<212> DNA
<213> mammalian
<400> 445
aaagctgaga tggagggcgg catg 24
<210> 446
<211> 23
<212> DNA
<213> mammalian
112
CA 02330022 2001-11-27
<400> 446
aaagctgaga tggagggcgg cat 23
<210> 447
<211> 22
<212> DNA
<213> mammalian
<400> 447
aaagctgaga tggagggcgg ca 22
<210> 448
<211> 21
<212> DNA
<213> mammalian
<400> 448
aaagctgaga tggagggcgg c 21
<210> 449
<211> 20
<212> DNA
<213> mammalian
<400> 449
aaagctgaga tggagggcgg 20
<210> 450
<211> 19
<212> DNA
<213> mammalian
113
CA 02330022 2001-11-27
<400> 450
aaagctgaga tggagggcg 19
<210> 451
<211> 18
<212> DNA
<213> mammalian
<400> 451
aaagctgaga tggagggc 18
<210> 452
<211> 17
<212> DNA
<213> mammalian
<400> 452
aaagctgaga tggaggg 17
<210> 453
<211> 16
<212> DNA
<213> mammalian
<400> 453
aaagctgaga tggagg 16
<210> 454
<211> 15
<212> DNA
<213> mammalian
114
CA 02330022 2001-11-27
<400> 454
aaagctgaga tggag 15
<210> 455
<211> 14
<212> DNA
<213> mammalian
<400> 455
aaagctgaga tgga 14
<210> 456
<211> 13
<212> DNA
<213> mammalian
<400> 456
aaagctgaga tgg 13
<210> 457
<211> 12
<212> DNA
<213> mammalian
<400> 457
aaagctgaga tg 12
<210> 458
<211> 11
<212> DNA
<213> mammalian
115
CA 02330022 2001-11-27
<400> 458
aaagctgaga t 11
<210> 459
<211> 10
<212> DNA
<213> mammalian
<400> 459
aaagctgaga 10
<210> 460
<211> 40
<212> DNA
<213> mammalian
<400> 460
aagctgagat ggagggcggc atggcgggca caggctgggc 40
<210> 461
<211> 39
<212> DNA
<213> mammalian
<400> 461
aagctgagat ggagggcggc atggcgggca caggctggg 39
<210> 462
<211> 38
<212> DNA
<213> mammalian
116
CA 02330022 2001-11-27
<400> 462
aagctgagat ggagggcggc atggcgggca caggctgg 38
<210> 463
<211> 37
<212> DNA
<213> mammalian
<400> 463
aagctgagat ggagggcggc atggcgggca caggctg 37
<210> 464
<211> 36
<212> DNA
<213> mammalian
<400> 464
aagctgagat ggagggcggc atggcgggca caggct 36
<210> 465
<211> 35
<212> DNA
<213> mammalian
<400> 465
aagctgagat ggagggcggc atggcgggca caggc 35
<210> 466
<211> 34
<212> DNA
<213> mammalian
117
CA 02330022 2001-11-27
<400> 466
aagctgagat ggagggcggc atggcgggca cagg 34
<210> 467
<211> 33
<212> DNA
<213> mammalian
<400> 467
aagctgagat ggagggcggc atggcgggca cag 33
<210> 468
<211> 32
<212> DNA
<213> mammalian
<400> 468
aagctgagat ggagggcggc atggcgggca ca 32
<210> 469
<211> 31
<212> DNA
<213> mammalian
<400> 469
aagctgagat ggagggcggc atggcgggca c 31
<210> 470
<211> 30
<212> DNA
<213> mammalian
118
CA 02330022 2001-11-27
<400> 470
aagctgagat ggagggcggc atggcgggca 30
<210> 471
<211> 29
<212> DNA
<213> mammalian
<400> 471
aagctgagat ggagggcggc atggcgggc 29
<210> 472
<211> 28
<212> DNA
<213> mammalian
<400> 472
aagctgagat ggagggcggc atggcggg 2g
<210> 473
<211> 27
<212> DNA
<213> mammalian
<400> 473
aagctgagat ggagggcggc atggcgg 27
<210> 474
<211> 26
<212> DNA
<213> mammalian
119
CA 02330022 2001-11-27
<400> 474
aagctgagat ggagggcggc atggcg 26
<210> 475
<211> 25
<212> DNA
<213> mammalian
<400> 475
aagctgagat ggagggcggc atggc 25
<210> 476
<211> 24
<212> DNA
<213> mammalian
<400> 476
aagctgagat ggagggcggc atgg 24
<210> 477
<211> 23
<212> DNA
<213> mammalian
<400> 477
aagctgagat ggagggcggc atg 23
<210> 478
<211> 22
<212> DNA
<213> mammalian
120
CA 02330022 2001-11-27
<400> 478
aagctgagat ggagggcggc at 22
<210> 479
<211> 21
<212> DNA
<213> mammalian
<400> 479
aagctgagat ggagggcggc a 21
<210> 480
<211> 20
<212> DNA
<213> mammalian
<400> 480
aagctgagat ggagggcggc 20
<210> 481
<211> 19
<212> DNA
<213> mammalian
<400> 481
aagctgagat ggagggcgg 19
<210> 482
<211> 18
<212> DNA
<213> mammalian
121
CA 02330022 2001-11-27
<400> 482
aagctgagat ggagggcg 1g
<210> 483
<211> 17
<212> DNA
<213> mammalian
<400> 483
aagctgagat ggagggc 17
<210> 484
<211> 16
<212> DNA
<213> mammalian
<400> 484
aagctgagat ggaggg 16
<210> 485
<211> 15
<212> DNA
<213> mammalian
<400> 485
aagctgagat ggagg 15
<210> 486
<211> 14
<212> DNA
<213> mammalian
122
CA 02330022 2001-11-27
<400> 486
aagctgagat ggag 14
<210> 487
<211> 13
<212> DNA
<213> mammalian
<400> 487
aagctgagat gga 13
<210> 488
<211> 12
<212> DNA
<213> mammalian
<400> 488
aagctgagat gg 12
<210> 489
<211> 11
<212> DNA
<213> mammalian
<400> 489
aagctgagat g 11
<210> 490
<211> 10
<212> DNA
<213> mammalian
123
CA 02330022 2001-11-27
<400> 490
aagctgagat 10
<210> 491
<211> 39
<212> DNA
<213> mammalian
<400> 491
agctgagatg gagggcggca tggcgggcac aggctgggc 39
<210>492
<211>38
<212>DNA
<213>mammalian
<400> 492
agctgagatg gagggcggca tggcgggcac aggctggg 38
<210> 493
<211> 37
<212> DNA
<213> mammalian
<400> 493
agctgagatg gagggcggca tggcgggcac aggctgg 37
<210>494
<211>36
<212>DNA
<213>mammalian
124
CA 02330022 2001-11-27
<400> 494
agctgagatg gagggcggca tggcgggcac aggctg 36
<210> 495
<211> 35
<212> DNA
<213> mammalian
<400> 495
agctgagatg gagggcggca tggcgggcac aggct 35
<210> 496
<211> 34
<212> DNA
<213> mammalian
<400> 496
agctgagatg gagggcggca tggcgggcac aggc 34
<210> 497
<211> 33
<212> DNA
<213> mammalian
<400> 497
agctgagatg gagggcggca tggcgggcac agg 33
<210> 498
<211> 32
<212> DNA
<213> mammalian
125
CA 02330022 2001-11-27
<400> 498
agctgagatg gagggcggca tggcgggcac ag 32
<210> 499
<211> 31
<212> DNA
<213> mammalian
<400> 499
agctgagatg gagggcggca tggcgggcac a 31
<210> 500
<211> 30
<212> DNA
<213> mammalian
<400> 500
agctgagatg gagggcggca tggcgggcac 30
<210> 501
<211> 29
<212> DNA
<213> mammalian
<400> 501
agctgagatg gagggcggca tggcgggca 29
<210> 502
<211> 28
<212> DNA
<213> mammalian
126
CA 02330022 2001-11-27
<400> 502
agctgagatg gagggcggca tggcgggc 28
<210> 503
<211> 27
<212> DNA
<213> mammalian
<400> 503
agctgagatg gagggcggca tggcggg 27
<210> 504
<211> 26
<212> DNA
<213> mammalian
<400> 504
agctgagatg gagggcggca tggcgg 26
<210> 505
<211> 25
<212> DNA
<213> mammalian
<400> 505
agctgagatg gagggcggca tggcg 25
<210> 506
<211> 24
<212> DNA
<213> mammalian
127
CA 02330022 2001-11-27
<400> 506
agctgagatg gagggcggca tggc 24
<210> 507
<211> 23
<212> DNA
<213> mammalian
<400> 507
agctgagatg gagggcggca tgg 23
<210> 508
<211> 22
<212> DNA
<213> mammalian
<400> 508
agctgagatg gagggcggca tg 22
<210> 509
<211> 21
<212> DNA
<213> mammalian
<400> 509
agctgagatg gagggcggca t 21
<210> 510
<211> 20
<212> DNA
<213> mammalian
128
CA 02330022 2001-11-27
<400> 510
agctgagatg gagggcggca 20
<210> 511
<211> 19
<212> DNA
<213> mammalian
<400> 511
agctgagatg gagggcggc 19
<210> 512
<211> 18
<212> DNA
<213> mammalian
<400> 512
agctgagatg gagggcgg 18
<210> 513
<211> 17
<212> DNA
<213> mammalian
<400> 513
agctgagatg gagggcg 17
<210> 514
<211> 16
<212> DNA
<213> mammalian
129
CA 02330022 2001-11-27
<400> 514
agctgagatg gagggc 16
<210> 515
<211> 15
<212> DNA
<213> mammalian
<400> 515
agctgagatg gaggg 15
<210> 516
<211> 14
<212> DNA
<213> mammalian
<400> 516
agctgagatg gagg 14
<210> 517
<211> 13
<212> DNA
<213> mammalian
<400> 517
agctgagatg gag 13
<210> 518
<211> 12
<212> DNA
<213> mammalian
130
CA 02330022 2001-11-27
<400> 518
agctgagatg ga 12
<210> 519
<211> 11
<212> DNA
<213> mammalian
<400> 519
agctgagatg g 11
<210> 520
<211> 10
<212> DNA
<213> mammalian
<400> 520
agctgagatg 10
<210> 521
<211> 38
<212> DNA
<213> mammalian
<400> 521
gctgagatgg agggcggcat ggcgggcaca ggctgggc 38
<210> 522
<211> 37
<212> DNA
<213> mammalian
131
CA 02330022 2001-11-27
<400> 522
gctgagatgg agggcggcat ggcgggcaca ggctggg 37
<210> 523
<211> 36
<212> DNA
<213> mammalian
<400> 523
gctgagatgg agggcggcat ggcgggcaca ggctgg 36
<210> 524
<211> 35
<212> DNA
<213> mammalian
<400> 524
gctgagatgg agggcggcat ggcgggcaca ggctg 35
<210> 525
<211> 34
<212> DNA
<213> mammalian
<400> 525
gctgagatgg agggcggcat ggcgggcaca ggct 34
<210> 526
<211> 33
<212> DNA
<213> mammalian
132
CA 02330022 2001-11-27
<400> 526
gctgagatgg agggcggcat ggcgggcaca ggc 33
<210> 527
<211> 32
<212> DNA
<213> mammalian
<400> 527
gctgagatgg agggcggcat ggcgggcaca gg 32
<210> 528
<211> 31
<212> DNA
<213> mammalian
<400> 528
gctgagatgg agggcggcat ggcgggcaca g 31
<210> 529
<211> 30
<212> DNA
<213> mammalian
<400> 529
gctgagatgg agggcggcat ggcgggcaca 30
<210> 530
<211> 29
<212> DNA
<213> mammalian
133
CA 02330022 2001-11-27
<400> 530
gctgagatgg agggcggcat ggcgggcac 29
<210> 531
<211> 28
<212> DNA
<213> mammalian
<400> 531
gctgagatgg agggcggcat ggcgggca 28
<210> 532
<211> 27
<212> DNA
<213> mammalian
<400> 532
gctgagatgg agggcggcat ggcgggc 27
<210> 533
<211> 26
<212> DNA
<213> mammalian
<400> 533
gctgagatgg agggcggcat ggcggg 26
<210> 534
<211> 25
<212> DNA
<213> mammalian
134
CA 02330022 2001-11-27
<400> 534
gctgagatgg agggcggcat ggcgg 25
<210> 535
<211> 24
<212> DNA
<213> mammalian
<400> 535
gctgagatgg agggcggcat ggcg 24
<210> 536
<211> 23
<212> DNA
<213> mammalian
<400> 536
gctgagatgg agggcggcat ggc 23
<210> 537
<211> 22
<212> DNA
<213> mammalian
<400> 537
gctgagatgg agggcggcat gg 22
<210> 538
<211> 21
<212> DNA
<213> mammalian
135
CA 02330022 2001-11-27
<400> 538
gctgagatgg agggcggcat g 21
<210> 539
<211> 20
<212> DNA
<213> mammalian
<400> 539
gctgagatgg agggcggcat 20
<210> 540
<211> 19
<212> DNA
<213> mammalian
<400> 540
gctgagatgg agggcggca 19
<210> 541
<211> 18
<212> DNA
<213> mammalian
<400> 541
gctgagatgg agggcggc 18
<210> 542
<211> 17
<212> DNA
<213> mammalian
136
CA 02330022 2001-11-27
<400> 542
gctgagatgg agggcgg 1~
<210> 543
<211> 16
<212> DNA
<213> mammalian
<400> 543
gctgagatgg agggcg 16
<210> 544
<211> 15
<212> DNA
<213> mammalian
<400> 544
gctgagatgg agggc 15
<210> 545
<211> 14
<212> DNA
<213> mammalian
<400> 545
gctgagatgg aggg 14
<210> 546
<211> 13
<212> DNA
<213> mammalian
137
CA 02330022 2001-11-27
<400> 546
gctgagatgg agg 13
<210> 547
<211> 12
<212> DNA
<213> mammalian
<400> 547
gctgagatgg ag 12
<210> 548
<211> 11
<212> DNA
<213> mammalian
<400> 548
gctgagatgg a 11
<210> 549
<211> 10
<212> DNA
<213> mammalian
<400> 549
gctgagatgg 10
<210> 550
<211> 37
<212> DNA
<213> mammalian
138
CA 02330022 2001-11-27
<400> 550
ctgagatgga gggcggcatg gcgggcacag gctgggc 37
<210> 551
<211> 36
<212> DNA
<213> mammalian
<400> 551
ctgagatgga gggcggcatg gcgggcacag gctggg 36
<210> 552
<211> 35
<212> DNA
<213> mammalian
<400> 552
ctgagatgga gggcggcatg gcgggcacag gctgg 35
<210> 553
<211> 34
<212> DNA
<213> mammalian
<400> 553
ctgagatgga gggcggcatg gcgggcacag gctg 34
<210> 554
<211> 33
<212> DNA
<213> mammalian
139
CA 02330022 2001-11-27
<400> 554
ctgagatgga gggcggcatg gcgggcacag get 33
<210> 555
<211> 32
<212> DNA
<213> mammalian
<400> 555
ctgagatgga gggcggcatg gcgggcacag gc 32
<210> 556
<211> 31
<212> DNA
<213> mammalian
<400> 556
ctgagatgga gggcggcatg gcgggcacag g 31
<210> 557
<211> 30
<212> DNA
<213> mammalian
<400> 557
ctgagatgga gggcggcatg gcgggcacag 30
<210> 558
<211> 29
<212> DNA
<213> mammalian
140
CA 02330022 2001-11-27
<400> 558
ctgagatgga gggcggcatg gcgggcaca 29
<210> 559
<211> 28
<212> DNA
<213> mammalian
<400> 559
ctgagatgga gggcggcatg gcgggcac 28
<210> 560
<211> 27
<212> DNA
<213> mammalian
<400> 560
ctgagatgga gggcggcatg gcgggca 27
<210> 561
<211> 26
<212> DNA
<213> mammalian
<400> 561
ctgagatgga gggcggcatg gcgggc 26
<210> 562
<211> 25
<212> DNA
<213> mammalian
141
CA 02330022 2001-11-27
<400> 562
ctgagatgga gggcggcatg gcggg 25
<210> 563
<211> 24
<212> DNA
<213> mammalian
<400> 563
ctgagatgga gggcggcatg gcgg 24
<210> 564
<211> 23
<212> DNA
<213> mammalian
<400> 564
ctgagatgga gggcggcatg gcg 23
<210> 565
<211> 22
<212> DNA
<213> mammalian
<400> 565
ctgagatgga gggcggcatg gc 22
<210> 566
<211> 21
<212> DNA
<213> mammalian
142
CA 02330022 2001-11-27
<400> 566
ctgagatgga gggcggcatg g 21
<210> 567
<211> 20
<212> DNA
<213> mammalian
<400> 567
ctgagatgga gggcggcatg 20
<210> 568
<211> 19
<212> DNA
<213> mammalian
<400> 568
ctgagatgga gggcggcat 19
<210> 569
<211> 18
<212> DNA
<213> mammalian
<400> 569
ctgagatgga gggcggca 18
<210> 570
<211> 17
<212> DNA
<213> mammalian
143
CA 02330022 2001-11-27
<400> 570
ctgagatgga gggcggc 17
<210> 571
<211> 16
<212> DNA
<213> mammalian
<400> 571
ctgagatgga gggcgg 16
<210> 572
<211> 15
<212> DNA
<213> mammalian
<400> 572
ctgagatgga gggcg 15
<210> 573
<211> 14
<212> DNA
<213> mammalian
<400> 573
ctgagatgga gggc 14
<210> 574
<211> 13
<212> DNA
<213> mammalian
144
CA 02330022 2001-11-27
<400> 574
ctgagatgga ggg 13
<210> 575
<211> 12
<212> DNA
<213> mammalian
<400> 575
ctgagatgga gg 12
<210> 576
<211> 11
<212> DNA
<213> mammalian
<400> 576
ctgagatgga g 11
<210> 577
<211> 10
<212> DNA
<213> mammalian
<400> 577
ctgagatgga 10
<210> 578
<211> 36
<212> DNA
<213> mammalian
145
CA 02330022 2001-11-27
<400> 578
tgagatggag ggcggcatgg cgggcacagg ctgggc 36
<210> 579
<211> 35
<212> DNA
<213> mammalian
<400> 579
tgagatggag ggcggcatgg cgggcacagg ctggg 35
<210> 580
<211> 34
<212> DNA
<213> mammalian
<400> 580
tgagatggag ggcggcatgg cgggcacagg ctgg 34
<210> 581
<211> 33
<212> DNA
<213> mammalian
<400> 581
tgagatggag ggcggcatgg cgggcacagg ctg 33
<210> 582
<211> 32
<212> DNA
<213> mammalian
146
CA 02330022 2001-11-27
<400> 582
tgagatggag ggcggcatgg cgggcacagg ct 32
<210> 583
<211> 31
<212> DNA
<213> mammalian
<400> 583
tgagatggag ggcggcatgg cgggcacagg c 31
<210> 584
<211> 30
<212> DNA
<213> mammalian
<400> 584
tgagatggag ggcggcatgg cgggcacagg 30
<210> 585
<211> 29
<212> DNA
<213> mammalian
<400> 585
tgagatggag ggcggcatgg cgggcacag 29
<210> 586
<211> 28
<212> DNA
<213> mammalian
147
CA 02330022 2001-11-27
<400> 586
tgagatggag ggcggcatgg cgggcaca 2g
<210> 587
<211> 27
<212> DNA
<213> mammalian
<400> 587 .
tgagatggag ggcggcatgg cgggcac 27
<210> 588
<211> 26
<212> DNA
<213> mammalian
<400> 588
tgagatggag ggcggcatgg cgggca 26
<210> 589
<211> 25
<212> DNA
<213> mammalian
<400> 589
tgagatggag ggcggcatgg cgggc 25
<210> 590
<211> 24
<212> DNA
<213> mammalian
148
CA 02330022 2001-11-27
<400> 590
tgagatggag ggcggcatgg cggg 24
<210> 591
<211> 23
<212> DNA
<213> mammalian
<400> 591
tgagatggag ggcggcatgg cgg 23
<210> 592
<211> 22
<212> DNA
<213> mammalian
<400> 592
tgagatggag ggcggcatgg cg 22
<210> 593
<211> 21
<212> DNA
<213> mammalian
<400> 593
tgagatggag ggcggcatgg c 21
<210> 594
<211> 20
<212> DNA
<213> mammalian
149
CA 02330022 2001-11-27
<400> 594
tgagatggag ggcggcatgg 20
<210> 595
<211> 19
<212> DNA
<213> mammalian
<400> 595
tgagatggag ggcggcatg 19
<210> 596
<211> 18
<212> DNA
<213> mammalian
<400> 596
tgagatggag ggcggcat 18
<210> 597
<211> 17
<212> DNA
<213> mammalian
<400> 597
tgagatggag ggcggca 17
<210> 598
<211> 16
<212> DNA
<213> mammalian
150
CA 02330022 2001-11-27
<400> 598
tgagatggag ggcggc 16
<210> 599
<211> 15
<212> DNA
<213> mammalian
<400> 599
tgagatggag ggcgg 15
<210> 600
<211> 14
<212> DNA
<213> mammalian
<400> 600
tgagatggag ggcg 14
<210> 601
<211> 13
<212> DNA
<213> mammalian
<400> 601
tgagatggag ggc 13
<210> 602
<211> 12
<212> DNA
<213> mammalian
151
CA 02330022 2001-11-27
<400> 602
tgagatggag gg 12
<210> 603
<211> 11
<212> DNA
<213> mammalian
<400> 603
tgagatggag g 11
<210> 604
<211> 10
<212> DNA
<213> mammalian
<400> 604
tgagatggag 10
<210> 605
<211> 35
<212> DNA
<213> mammalian
<400> 605
gagatggagg gcggcatggc gggcacaggc tgggc 35
<210> 606
<211> 34
<212> DNA
<213> mammalian
152
CA 02330022 2001-11-27
<400> 606
gagatggagg gcggcatggc gggcacaggc tggg 34
<210> 607
<211> 33
<212> DNA
<213> mammalian
<400> 607
gagatggagg gcggcatggc gggcacaggc tgg 33
<210> 608
<211> 32
<212> DNA
<213> mammalian
<400> 608
gagatggagg gcggcatggc gggcacaggc tg 32
<210> 609
<211> 31
<212> DNA
<213> mammalian
<400> 609
gagatggagg gcggcatggc gggcacaggc t 31
<210> 610
<211> 30
<212> DNA
<213> mammalian
153
CA 02330022 2001-11-27
<400> 610
gagatggagg gcggcatggc gggcacaggc 30
<210> 611
<211> 29
<212> DNA
<213> mammalian
<400> 611
gagatggagg gcggcatggc gggcacagg 29
<210> 612
<211> 28
<212> DNA
<213> mammalian
<400> 612
gagatggagg gcggcatggc gggcacag 28
<210> 613
<211> 27
<212> DNA
<213> mammalian
<400> 613
gagatggagg gcggcatggc gggcaca 27
<210> 614
<211> 26
<212> DNA
<213> mammalian
154
CA 02330022 2001-11-27
<400> 614
gagatggagg gcggcatggc gggcac 26
<210> 615
<211> 25
<212> DNA
<213> mammalian
<400> 615
gagatggagg gcggcatggc gggca 25
<210> 616
<211> 24
<212> DNA
<213> mammalian
<400> 616
gagatggagg gcggcatggc gggc 24
<210> 617
<211> 23
<212> DNA
<213> mammalian
<400> 617
gagatggagg gcggcatggc ggg 23
<210> 618
<211> 22
<212> DNA
<213> mammalian
155
CA 02330022 2001-11-27
<400> 618
gagatggagg gcggcatggc gg 22
<210> 619
<211> 21
<212> DNA
<213> mammalian
<400> 619
gagatggagg gcggcatggc g 21
<210> 620
<211> 20
<212> DNA
<213> mammalian
<400> 620
gagatggagg gcggcatggc 20
<210> 621
<211> 19
<212> DNA
<213> mammalian
<400> 621
gagatggagg gcggcatgg 19
<210> 622
<211> 18
<212> DNA
<213> mammalian
156
CA 02330022 2001-11-27
<400> 622
gagatggagg gcggcatg 18
<210> 623
<211> 17
<212> DNA
<213> mammalian
<400> 623
gagatggagg gcggcat 17
<210> 624
<211> 16
<212> DNA
<213> mammalian
<400> 624
gagatggagg gcggca 16
<210> 625
<211> 15
<212> DNA
<213> mammalian
<400> 625
gagatggagg gcggc 15
<210> 626
<211> 14
<212> DNA
<213> mammalian
157
CA 02330022 2001-11-27
<400> 626
gagatggagg gcgg 14
<210> 627
<211> 13
<212> DNA
<213> mammalian
<400> 627
gagatggagg gcg 13
<210> 628
<211> 12
<212> DNA
<213> mammalian
<400> 628
gagatggagg gc 12
<210> 629
<211> 11
<212> DNA
<213> mammalian
<400> 629
gagatggagg g 11
<210> 630
<211> 10
<212> DNA
<213> mammalian
158
CA 02330022 2001-11-27
<400> 630
gagatggagg 10
<210> 631
<211> 34
<212> DNA
<213> mammalian
<400> 631
agatggaggg cggcatggcg ggcacaggct gggc 34
<210> 632
<211> 33
<212> DNA
<213> mammalian
<400> 632
agatggaggg cggcatggcg ggcacaggct ggg 33
<210> 633
<211> 32
<212> DNA
<213> mammalian
<400> 633
agatggaggg cggcatggcg ggcacaggct gg 32
<210> 634
<211> 31
<212> DNA
<213> mammalian
159
CA 02330022 2001-11-27
<400> 634
agatggaggg cggcatggcg ggcacaggct g 31
<210> 635
<211> 30
<212> DNA
<213> mammalian
<400> 635
agatggaggg cggcatggcg ggcacaggct 30
<210> 636
<211> 29
<212> DNA
<213> mammalian
<400> 636
agatggaggg cggcatggcg ggcacaggc 29
<210> 637
<211> 28
<212> DNA
<213> mammalian
<400> 637
agatggaggg cggcatggcg ggcacagg 28
<210> 638
<211> 27
<212> DNA
<213> mammalian
160
CA 02330022 2001-11-27
<400> 638
agatggaggg cggcatggcg ggcacag 2~
<210> 639
<211> 26
<212> DNA
<213> mammalian
<400> 639
agatggaggg cggcatggcg ggcaca 26
<210> 640
<211> 25
<212> DNA
<213> mammalian
<400> 640
agatggaggg cggcatggcg ggcac 25
<210> 641
<211> 24
<212> DNA
<213> mammalian
<400> 641
agatggaggg cggcatggcg ggca 24
<210> 642
<211> 23
<212> DNA
<213> mammalian
<400> 642
161
CA 02330022 2001-11-27
agatggaggg cggcatggcg ggc 23
<210> 643
<211> 22
<212> DNA
<213> mammalian
<400> 643
agatggaggg cggcatggcg gg 22
<210> 644
<211> 21
<212> DNA
<213> mammalian
<400> 644
agatggaggg cggcatggcg g 21
<210> 645
<211> 20
<212> DNA
<213> mammalian
<400> 645
agatggaggg cggcatggcg 20
<210> 646
<211> 19
<212> DNA
<213> mammalian
<400> 646
162
CA 02330022 2001-11-27
agatggaggg cggcatggc 1g
<210> 647
<211> 18
<212> DNA
<213> mammalian
<400> 647
agatggaggg cggcatgg 1g
<210> 648
<211> 17
<212> DNA
<213> mammalian
<400> 648
agatggaggg cggcatg 17
<210> 649
<211> 16
<212> DNA
<213> mammalian
<400> 649
agatggaggg cggcat 16
<210> 650
<211> 15
<212> DNA
<213> mammalian
<400> 650
163
CA 02330022 2001-11-27
agatggaggg cggca 15
<210> 651
<211> 14
<212> DNA
<213> mammalian
<400> 651
agatggaggg cggc 14
<210> 652
<211> 13
<212> DNA
<213> mammalian
<400> 652
agatggaggg cgg 13
<210> 653
<211> 12
<212> DNA
<213> mammalian
<400> 653
agatggaggg cg 12
<210> 654
<211> 11
<212> DNA
<213> mammalian
<400> 654
164
CA 02330022 2001-11-27
agatggaggg c 11
<210> 655
<211> 10
<212> DNA
<213> mammalian
<400> 655
agatggaggg 10
<210> 656
<211> 33
<212> DNA
<213> mammalian
<400> 656
gatggagggc ggcatggcgg gcacaggctg ggc 33
<210> 657
<211> 32
<212> DNA
<213> mammalian
<400> 657
gatggagggc ggcatggcgg gcacaggctg gg 32
<210> 658
<211> 31
<212> DNA
<213> mammalian
<400> 658
165
CA 02330022 2001-11-27
gatggagggc ggcatggcgg gcacaggctg g 31
<210> 659
<211> 30
<212> DNA
<213> mammalian
<400> 659
gatggagggc ggcatggcgg gcacaggctg 30
<210> 660
<211> 29
<212> DNA
<213> mammalian
<400> 660
gatggagggc ggcatggcgg gcacaggct 29
<210> 661
<211> 28
<212> DNA
<213> mammalian
<400> 661
gatggagggc ggcatggcgg gcacaggc 28
<210> 662
<211> 27
<212> DNA
<213> mammalian
<400> 662
166
CA 02330022 2001-11-27
gatggagggc ggcatggcgg gcacagg 27
<210> 663
<211> 26
<212> DNA
<213> mammalian
<400> 663
gatggagggc ggcatggcgg gcacag 26
<210> 664
<211> 25
<212> DNA
<213> mammalian
<400> 664
gatggagggc ggcatggcgg gcaca 25
<210> 665
<211> 24
<212> DNA
<213> mammalian
<400> 665
gatggagggc ggcatggcgg gcac 24
<210> 666
<211> 23
<212> DNA
<213> mammalian
<400> 666
167
CA 02330022 2001-11-27
gatggagggc ggcatggcgg gca 23
<210> 667
<211> 22
<212> DNA
<213> mammalian
<400> 667
gatggagggc ggcatggcgg gc 22
<210> 668
<211> 21
<212> DNA
<213> mammalian
<400> 668
gatggagggc ggcatggcgg g 21
<210> 669
<211> 20
<212> DNA
<213> mammalian
<400> 669
gatggagggc ggcatggcgg 20
<210> 670
<211> 19
<212> DNA
<213> mammalian
<400> 670
168
CA 02330022 2001-11-27
gatggagggc ggcatggcg 19
<210> 671
<211> 18
<212> DNA
<213> mammalian
<400> 671
gatggagggc ggcatggc 18
<210> 672
<211> 17
<212> DNA
<213> mammalian
<400> 672
gatggagggc ggcatgg 17
<210> 673
<211> 16
<212> DNA
<213> mammalian
<400> 673
gatggagggc ggcatg 16
<210> 674
<211> 15
<212> DNA
<213> mammalian
<400> 674
169
CA 02330022 2001-11-27
gatggagggc ggcat 15
<210> 675
<211> 14
<212> DNA
<213> mammalian
<400> 675
gatggagggc ggca 14
<210> 676
<211> 13
<212> DNA
<213> mammalian
<400> 676
gatggagggc ggc 13
<210> 677
<211> 12
<212> DNA
<213> mammalian
<400> 677
gatggagggc gg 12
<210> 678
<211> 11
<212> DNA
<213> mammalian
<400> 678
170
CA 02330022 2001-11-27
gatggagggc g 11
<210> 679
<211> 10
<212> DNA
<213> mammalian
<400> 679
gatggagggc
<210> 680
<211> 32
<212> DNA
<213> mammalian
<400> 680
atggagggcg gcatggcggg cacaggctgg gc 32
<210> 681
<211> 31
<212> DNA
<213> mammalian
<400> 681
atggagggcg gcatggcggg cacaggctgg g 31
<210> 682
<211> 30
<212> DNA
<213> mammalian
<400> 682
171
CA 02330022 2001-11-27
atggagggcg gcatggcggg cacaggctgg 30
<210> 683
<211> 29
<212> DNA
<213> mammalian
<400> 683
atggagggcg gcatggcggg cacaggctg 29
<210> 684
<211> 28
<212> DNA
<213> mammalian
<400> 684
atggagggcg gcatggcggg cacaggct 2g
<210> 685
<211> 27
<212> DNA
<213> mammalian
<400> 685
atggagggcg gcatggcggg cacaggc 27
<210> 686
<211> 26
<212> DNA
<213> mammalian
<400> 686
172
CA 02330022 2001-11-27
atggagggcg gcatggcggg cacagg 26
<210> 687
<211> 25
<212> DNA
<213> mammalian
<400> 687
atggagggcg gcatggcggg cacag 25
<210> 688
<211> 24
<212> DNA
<213> mammalian
<400> 688
atggagggcg gcatggcggg caca 24
<210> 689
<211> 23
<212> DNA
<213> mammalian
<400> 689
atggagggcg gcatggcggg cac 23
<210> 690
<211> 22
<212> DNA
<213> mammalian
<400> 690
173
CA 02330022 2001-11-27
atggagggcg gcatggcggg ca 22
<210> 691
<211> 21
<212> DNA
<213> mammalian
<400> 691
atggagggcg gcatggcggg c 21
<210> 692
<211> 20
<212> DNA
<213> mammalian
<400> 692
atggagggcg gcatggcggg 20
<210> 693
<211> 19
<212> DNA
<213> mammalian
<400> 693
atggagggcg gcatggcgg 19
<210> 694
<211> 18
<212> DNA
<213> mammalian
<400> 694
174
CA 02330022 2001-11-27
atggagggcg gcatggcg 18
<210> 695
<211> 17
<212> DNA
<213> mammalian
<400> 695
atggagggcg gcatggc 17
<210> 696
<211> 16
<212> DNA
<213> mammalian
<400> 696
atggagggcg gcatgg 16
<210> 697
<211> 15
<212> DNA
<213> mammalian
<400> 697
atggagggcg gcatg 15
<210> 698
<211> 14
<212> DNA
<213> mammalian
<400> 698
175
CA 02330022 2001-11-27
atggagggcg gcat 14
<210> 699
<211> 13
<212> DNA
<213> mammalian
<400> 699
atggagggcg gca 13
<210> 700
<211> 12
<212> DNA
<213> mammalian
<400> 700
atggagggcg gc 12
<210> 701
<211> 11
<212> DNA
<213> mammalian
<400> 701
atggagggcg g 11
<210> 702
<211> 10
<212> DNA
<213> mammalian
<400> 702
176
CA 02330022 2001-11-27
atggagggcg 10
<210> 703
<211> 31
<212> DNA
<213> mammalian
<400> 703
tggagggcgg catggcgggc acaggctggg c 31
<210> 704
<211> 30
<212> DNA
<213> mammalian
<400> 704
tggagggcgg catggcgggc acaggctggg 30
<210> 705
<211> 29
<212> DNA
<213> mammalian
<400> 705
tggagggcgg catggcgggc acaggctgg 29
<210> 706
<211> 28
<212> DNA
<213> mammalian
<400> 706
177
CA 02330022 2001-11-27
tggagggcgg catggcgggc acaggctg 2g
<210> 707
<211> 27
<212> DNA
<213> mammalian
<400> 707
tggagggcgg catggcgggc acaggct 27
<210> 708
<211> 26
<212> DNA
<213> mammalian
<400> 708
tggagggcgg catggcgggc acaggc 26
<210> 709
<211> 25
<212> DNA
<213> mammalian
<400> 709
tggagggcgg catggcgggc acagg 25
<210> 710
<211> 24
<212> DNA
<213> mammalian
<400> 710
178
CA 02330022 2001-11-27
tggagggcgg catggcgggc acag 24
<210> 711
<211> 23
<212> DNA
<213> mammalian
<400> 711
tggagggcgg catggcgggc aca 23
<210> 712
<211> 22
<212> DNA
<213> mammalian
<400> 712
tggagggcgg catggcgggc ac 22
<210> 713
<211> 21
<212> DNA
<213> mammalian
<400> 713
tggagggcgg catggcgggc a 21
<210> 714
<211> 20
<212> DNA
<213> mammalian
<400> 714
179
CA 02330022 2001-11-27
tggagggcgg catggcgggc 20
<210> 715
<211> 19
<212> DNA
<213> mammalian
<400> 715
tggagggcgg catggcggg 1g
<210> 716
<211> 18
<212> DNA
<213> mammalian
<400> 716
tggagggcgg catggcgg 1g
<210> 717
<211> 17
<212> DNA
<213> mammalian
<400> 717
tggagggcgg catggcg 17
<210> 718
<211> 16
<212> DNA
<213> mammalian
<400> 718
180
CA 02330022 2001-11-27
tggagggcgg catggc 16
<210> 719
<211> 15
<212> DNA
<213> mammalian
<400> 719
tggagggcgg catgg
<210> 720
<211> 14
<212> DNA
<213> mammalian
<400> 720
tggagggcgg catg 14
<210> 721
<211> 13
<212> DNA
<213> mammalian
<400> 721
tggagggcgg cat
13
<210> 722
<211> 12
<212> DNA
<213> mammalian
<400> 722
tggagggcgg ca
12
181
CA 02330022 2001-11-27
<210> 723
<211> 11
<212> DNA
<213> mammalian
<400> 723
tggagggcgg c 11
<210> 724
<211> 10
<212> DNA
<213> mammalian
<400> 724
tggagggcgg 10
<210> 725
<211> 30
<212> DNA
<213> mammalian
<400> 725
ggagggcggc atggcgggca caggctgggc 30
<210> 726
<211> 29
<212> DNA
<213> mammalian
<400> 726
ggagggcggc atggcgggca caggctggg 29
182
CA 02330022 2001-11-27
<210> 727
<211> 28
<212> DNA
<213> mammalian
<400> 727
ggagggcggc atggcgggca caggctgg 2g
<210> 728
<211> 27
<212> DNA
<213> mammalian
<400> 728
ggagggcggc atggcgggca caggctg 27
<210> 729
<211> 26
<212> DNA
<213> mammalian
<400> 729
ggagggcggc atggcgggca caggct 26
<210> 730
<211> 25
<212> DNA
<213> mammalian
<400> 730
ggagggcggc atggcgggca caggc 25
183
CA 02330022 2001-11-27
<210> 731
<211> 24
<212> DNA
<213> mammalian
<400> 731
ggagggcggc atggcgggca cagg 24
<210> 732
<211> 23
<212> DNA
<213> mammalian
<400> 732
ggagggcggc atggcgggca cag 23
<210> 733
<211> 22
<212> DNA
<213> mammalian
<400> 733
ggagggcggc atggcgggca ca 22
<210> 734
<211> 21
<212> DNA
<213> mammalian
<400> 734
ggagggcggc atggcgggca c 21
184
CA 02330022 2001-11-27
<210> 735
<211> 20
<212> DNA
<213> mammalian
<400> 735
ggagggcggc atggcgggca 20
<210> 736
<211> 19
<212> DNA
<213> mammalian
<400> 736
ggagggcggc atggcgggc 1g
<210> 737
<211> 18
<212> DNA
<213> mammalian
<400> 737
ggagggcggc atggcggg 1g
<210> 738
<211> 17
<212> DNA
<213> mammalian
<400> 738
ggagggcggc atggcgg 17
185
CA 02330022 2001-11-27
<210> 739
<211> 16
<212> DNA
<213> mammalian
<400> 739
ggagggcggc atggcg 16
<210> 740
<211> 15
<212> DNA
<213> mammalian
<400> 740
ggagggcggc atggc 15
<210> 741
<211> 14
<212> DNA
<213> mammalian
<400> 741
ggagggcggc atgg 14
<210> 742
<211> 13
<212> DNA
<213> mammalian
<400> 742
ggagggcggc atg 13
186
CA 02330022 2001-11-27
<210> 743
<211> 12
<212> DNA
<213> mammalian
<400> 743
ggagggcggc at 12
<210> 744
<211> 11
<212> DNA
<213> mammalian
<400> 744
ggagggcggc a 11
<210> 745
<211> 10
<212> DNA
<213> mammalian
<400> 745
ggagggcggc 10
<210> 746
<211> 29
<212> DNA
<213> mammalian
<400> 746
gagggcggca tggcgggcac aggctgggc 29
187
CA 02330022 2001-11-27
<210> 747
<211> 28
<212> DNA
<213> mammalian
<400> 747
gagggcggca tggcgggcac aggctggg 28
<210> 748
<211> 27
<212> DNA
<213> mammalian
<400> 748
gagggcggca tggcgggcac aggctgg 27
<210> 749
<211> 26
<212> DNA
<213> mammalian
<400> 749
gagggcggca tggcgggcac aggctg 26
<210> 750
<211> 25
<212> DNA
<213> mammalian
<400> 750
gagggcggca tggcgggcac aggct 25
188
CA 02330022 2001-11-27
<210> 751
<211> 24
<212> DNA
<213> mammalian
<400> 751
gagggcggca tggcgggcac aggc 24
<210> 752
<211> 23
<212> DNA
<213> mammalian
<400> 752
gagggcggca tggcgggcac agg 23
<210> 753
<211> 22
<212> DNA
<213> mammalian
<400> 753
gagggcggca tggcgggcac ag 22
<210> 754
<211> 21
<212> DNA
<213> mammalian
<400> 754
gagggcggca tggcgggcac a 21
189
CA 02330022 2001-11-27
<210> 755
<211> 20
<212> DNA
<213> mammalian
<400> 755
gagggcggca tggcgggcac 20
<210> 756
<211> 19
<212> DNA
<213> mammalian
<400> 756
gagggcggca tggcgggca 19
<210> 757
<211> 18
<212> DNA
<213> mammalian
<400> 757
gagggcggca tggcgggc 1g
<210> 758
<211> 17
<212> DNA
<213> mammalian
<400> 758
gagggcggca tggcggg 17
190
CA 02330022 2001-11-27
<210> 759
<211> 16
<212> DNA
<213> mammalian
<400> 759
gagggcggca tggcgg 16
<210> 760
<211> 15
<212> DNA
<213> mammalian
<400> 760
gagggcggca tggcg 15
<210> 761
<211> 14
<212> DNA
<213> mammalian
<400> 761
gagggcggca tggc 14
<210> 762
<211> 13
<212> DNA
<213> mammalian
<400> 762
gagggcggca tgg 13
191
CA 02330022 2001-11-27
<210> 763
<211> 12
<212> DNA
<213> mammalian
<400> 763
gagggcggca tg 12
<210> 764
<211> 11
<212> DNA
<213> mammalian
<400> 764
gagggcggca t 11
<210> 765
<211> 10
<212> DNA
<213> mammalian
<400> 765
gagggcggca 10
<210> 766
<211> 28
<212> DNA
<213> mammalian
<400> 766
agggcggcat ggcgggcaca ggctgggc 28
192
CA 02330022 2001-11-27
<210> 767
<211> 27
<212> DNA
<213> mammalian
<400> 767
agggcggcat ggcgggcaca ggctggg 27
<210> 768
<211> 26
<212> DNA
<213> mammalian
<400> 768
agggcggcat ggcgggcaca ggctgg 26
<210> 769
<211> 25
<212> DNA
<213> mammalian
<400> 769
agggcggcat ggcgggcaca ggctg 25
<210> 770
<211> 24
<212> DNA
<213> mammalian
<400> 770
agggcggcat ggcgggcaca ggct 24
193
CA 02330022 2001-11-27
<210> 771
<211> 23
<212> DNA
<213> mammalian
<400> 771
agggcggcat ggcgggcaca ggc 23
<210> 772
<211> 22
<212> DNA
<213> mammalian
<400> 772
agggcggcat ggcgggcaca gg 22
<210> 773
<211> 21
<212> DNA
<213> mammalian
<400> 773
agggcggcat ggcgggcaca g 21
<210> 774
<211> 20
<212> DNA
<213> mammalian
<400> 774
agggcggcat ggcgggcaca 20
194
CA 02330022 2001-11-27
<210> 775
<211> 19
<212> DNA
<213> mammalian
<400> 775
agggcggcat ggcgggcac 19
<210> 776
<211> 18
<212> DNA
<213> mammalian
<400> 776
agggcggcat ggcgggca 1g
<210> 777
<211> 17
<212> DNA
<213> mammalian
<400> 777
agggcggcat ggcgggc 17
<210> 778
<211> 16
<212> DNA
<213> mammalian
<400> 778
agggcggcat ggcggg 16
195
CA 02330022 2001-11-27
<210> 779
<211> 15
<212> DNA
<213> mammalian
<400> 779
agggcggcat ggcgg 15
<210> 780
<211> 14
<212> DNA
<213> mammalian
<400> 780
agggcggcat ggcg 14
<210> 781
<211> 13
<212> DNA
<213> mammalian
<400> 781
agggcggcat ggc 13
<210> 782
<211> 12
<212> DNA
<213> mammalian
<400> 782
agggcggcat gg 12
196
CA 02330022 2001-11-27
<210> 783
<211> 11
<212> DNA
<213> mammalian
<400> 783
agggcggcat g 11
<210> 784
<211> 10
<212> DNA
<213> mammalian
<400> 784
agggcggcat 10
<210> 785
<211> 27
<212> DNA
<213> mammalian
<400> 785
gggcggcatg gcgggcacag gctgggc 27
<210> 786
<211> 26
<212> DNA
<213> mammalian
<400> 786
gggcggcatg gcgggcacag gctggg 26
197
CA 02330022 2001-11-27
<210> 787
<211> 25
<212> DNA
<213> mammalian
<400> 787
gggcggcatg gcgggcacag gctgg 25
<210> 788
<211> 24
<212> DNA
<213> mammalian
<400> 788
gggcggcatg gcgggcacag gctg 24
<210> 789
<211> 23
<212> DNA
<213> mammalian
<400> 789
gggcggcatg gcgggcacag get 23
<210> 790
<211> 22
<212> DNA
<213> mammalian
<400> 790
gggcggcatg gcgggcacag gc 22
198
CA 02330022 2001-11-27
<210> 791
<211> 21
<212> DNA
<213> mammalian
<400> 791
gggcggcatg gcgggcacag g 21
<210> 792
<211> 20
<212> DNA
<213> mammalian
<400> 792
gggcggcatg gcgggcacag 20
<210> 793
<211> 19
<212> DNA
<213> mammalian
<400> 793
gggcggcatg gcgggcaca 19
<210> 794
<211> 18
<212> DNA
<213> mammalian
<400> 794
gggcggcatg gcgggcac 18
199
CA 02330022 2001-11-27
<210> 795
<211> 17
<212> DNA
<213> mammalian
<400> 795
gggcggcatg gcgggca 17
<210> 796
<211> 16
<212> DNA
<213> mammalian
<400> 796
gggcggcatg gcgggc 16
<210> 797
<211> 15
<212> DNA
<213> mammalian
<400> 797
gggcggcatg gcggg 15
<210> 798
<211> 14
<212> DNA
<213> mammalian
<400> 798
gggcggcatg gcgg 14
200
CA 02330022 2001-11-27
<210> 799
<211> 13
<212> DNA
<213> mammalian
<400> 799
gggcggcatg gcg 13
<210> 800
<211> 12
<212> DNA
<213> mammalian
<400> 800
gggcggcatg gc 12
<210> 801
<211> 11
<212> DNA
<213> mammalian
<400> 801
gggcggcatg g 11
<210> 802
<211> 10
<212> DNA
<213> mammalian
<400> 802
gggcggcatg 10
201
CA 02330022 2001-11-27
<210> 803
<211> 26
<212> DNA
<213> mammalian
<400> 803
ggcggcatgg cgggcacagg ctgggc 26
<210> 804
<211> 25
<212> DNA
<213> mammalian
<400> 804
ggcggcatgg cgggcacagg ctggg 25
<210> 805
<211> 24
<212> DNA
<213> mammalian
<400> 805
ggcggcatgg cgggcacagg ctgg 24
<210> 806
<211> 23
<212> DNA
<213> mammalian
<400> 806
ggcggcatgg cgggcacagg ctg 23
202
CA 02330022 2001-11-27
<210> 807
<211> 22
<212> DNA
<213> mammalian
<400> 807
ggcggcatgg cgggcacagg ct 22
<210> 808
<211> 21
<212> DNA
<213> mammalian
<400> 808
ggcggcatgg cgggcacagg c 21
<210> 809
<211> 20
<212> DNA
<213> mammalian
<400> 809
ggcggcatgg cgggcacagg 20
<210> 810
<211> 19
<212> DNA
<213> mammalian
<400> 810
ggcggcatgg cgggcacag 19
203
CA 02330022 2001-11-27
<210> 811
<211> 18
<212> DNA
<213> mammalian
<400> 811
ggcggcatgg cgggcaca 18
<210> 812
<211> 17
<212> DNA
<213> mammalian
<400> 812
ggcggcatgg cgggcac 17
<210> 813
<211> 16
<212> DNA
<213> mammalian
<400> 813
ggcggcatgg cgggca 16
<210> 814
<211> 15
<212> DNA
<213> mammalian
<400> 814
ggcggcatgg cgggc 15
204
CA 02330022 2001-11-27
<210> 815
<211> 14
<212> DNA
<213> mammalian
<400> 815
ggcggcatgg cggg 14
<210> 816
<211> 13
<212> DNA
<213> mammalian
<400> 816
ggcggcatgg cgg 13
<210> 817
<211> 12
<212> DNA
<213> mammalian
<400> 817
ggcggcatgg cg 12
<210> 818
<211> 11
<212> DNA
<213> mammalian
<400> 818
ggcggcatgg c 11
205
CA 02330022 2001-11-27
<210> 819
<211> 10
<212> DNA
<213> mammalian
<400> 819
ggcggcatgg 10
<210> 820
<211> 25
<212> DNA
<213> mammalian
<400> 820
gcggcatggc gggcacaggc tgggc 25
<210> 821
<211> 24
<212> DNA
<213> mammalian
<400> 821
gcggcatggc gggcacaggc tggg 24
<210> 822
<211> 23
<212> DNA
<213> mammalian
<400> 822
gcggcatggc gggcacaggc tgg 23
206
CA 02330022 2001-11-27
<210> 823
<211> 22
<212> DNA
<213> mammalian
<400> 823
gcggcatggc gggcacaggc tg 22
<210> 824
<211> 21
<212> DNA
<213> mammalian
<400> 824
gcggcatggc gggcacaggc t 21
<210> 825
<211> 20
<212> DNA
<213> mammalian
<400> 825
gcggcatggc gggcacaggc 20
<210> 826
<211> 19
<212> DNA
<213> mammalian
<400> 826
gcggcatggc gggcacagg 19
207
CA 02330022 2001-11-27
<210> 827
<211> 18
<212> DNA
<213> mammalian
<400> 827
gcggcatggc gggcacag 18
<210> 828
<211> 17
<212> DNA
<213> mammalian
<400> 828
gcggcatggc gggcaca 17
<210> 829
<211> 16
<212> DNA
<213> mammalian
<400> 829
gcggcatggc gggcac 16
<210> 830
<211> 15
<212> DNA
<213> mammalian
<400> 830
gcggcatggc gggca 15
208
CA 02330022 2001-11-27
<210> 831
<211> 14
<212> DNA
<213> mammalian
<400> 831
gcggcatggc gggc 14
<210> 832
<211> 13
<212> DNA
<213> mammalian
<400> 832
gcggcatggc ggg 13
<210> 833
<211> 12
<212> DNA
<213> mammalian
<400> 833
gcggcatggc gg 12
<210> 834
<211> 11
<212> DNA
<213> mammalian
<400> 834
gcggcatggc g 11
209
CA 02330022 2001-11-27
<210> 835
<211> 10
<212> DNA
<213> mammalian
<400> 835
gcggcatggc 10
<210> 836
<211> 24
<212> DNA
<213> mammalian
<400> 836
cggcatggcg ggcacaggct gggc 24
<210> 837
<211> 23
<212> DNA
<213> mammalian
<400> 837
cggcatggcg ggcacaggct ggg 23
<210> 838
<211> 22
<212> DNA
<213> mammalian
<400> 838
cggcatggcg ggcacaggct gg 22
210
CA 02330022 2001-11-27
<210> 839
<211> 21
<212> DNA
<213> mammalian
<400> 839
cggcatggcg ggcacaggct g 21
<210> 840
<211> 20
<212> DNA
<213> mammalian
<400> 840
cggcatggcg ggcacaggct 20
<210> 841
<211> 19
<212> DNA
<213> mammalian
<400> 841
cggcatggcg ggcacaggc 19
<210> 842
<211> 18
<212> DNA
<213> mammalian
<400> 842
cggcatggcg ggcacagg 18
211
CA 02330022 2001-11-27
<210> 843
<211> 17
<212> DNA
<213> mammalian
<400> 843
cggcatggcg ggcacag 17
<210> 844
<211> 16
<212> DNA
<213> mammalian
<400> 844
cggcatggcg ggcaca 16
<210> 845
<211> 15
<212> DNA
<213> mammalian
<400> 845
cggcatggcg ggcac 15
<210> 846
<211> 14
<212> DNA
<213> mammalian
<400> 846
cggcatggcg ggca 14
212
CA 02330022 2001-11-27
<210> 847
<211> 13
<212> DNA
<213> mammalian
<400> 847
cggcatggcg ggc 13
<210> 848
<211> 12
<212> DNA
<213> mammalian
<400> 848
cggcatggcg gg 12
<210> 849
<211> 11
<212> DNA
<213> mammalian
<400> 849
cggcatggcg g 11
<210> 850
<211> 10
<212> DNA
<213> mammalian
<400> 850
cggcatggcg 10
213
CA 02330022 2001-11-27
<210> 851
<211> 23
<212> DNA
<213> mammalian
<400> 851
ggcatggcgg gcacaggctg ggc 23
<210> 852
<211> 22
<212> DNA
<213> mammalian
<400> 852
ggcatggcgg gcacaggctg gg 22
<210> 853
<211> 21
<212> DNA
<213> mammalian
<400> 853
ggcatggcgg gcacaggctg g 21
<210> 854
<211> 20
<212> DNA
<213> mammalian
<400> 854
ggcatggcgg gcacaggctg 20
214
CA 02330022 2001-11-27
<210> 855
<211> 19
<212> DNA
<213> mammalian
<400> 855
ggcatggcgg gcacaggct 19
<210> 856
<211> 18
<212> DNA
<213> mammalian
<400> 856
ggcatggcgg gcacaggc 18
<210> 857
<211> 17
<212> DNA
<213> mammalian
<400> 857
ggcatggcgg gcacagg 17
<210> 858
<211> 16
<212> DNA
<213> mammalian
<400> 858
ggcatggcgg gcacag 16
215
CA 02330022 2001-11-27
<210> 859
<211> 15
<212> DNA
<213> mammalian
<400> 859
ggcatggcgg gcaca 15
<210> 860
<211> 14
<212> DNA
<213> mammalian
<400> 860
ggcatggcgg gcac 14
<210> 861
<211> 13
<212> DNA
<213> mammalian
<400> 861
ggcatggcgg gca 13
<210> 862
<211> 12
<212> DNA
<213> mammalian
<400> 862
ggcatggcgg gc 12
216
CA 02330022 2001-11-27
<210> 863
<211> 11
<212> DNA
<213> mammalian
<400> 863
ggcatggcgg g 11
<210> 864
<211> 10
<212> DNA
<213> mammalian
<400> 864
ggcatggcgg 10
<210> 865
<211> 22
<212> DNA
<213> mammalian
<400> 865
gcatggcggg cacaggctgg gc 22
<210> 866
<211> 21
<212> DNA
<213> mammalian
<400> 866
gcatggcggg cacaggctgg g 21
217
CA 02330022 2001-11-27
<210> 867
<211> 20
<212> DNA
<213> mammalian
<400> 867
gcatggcggg cacaggctgg 20
<210> 868
<211> 19
<212> DNA
<213> mammalian
<400> 868
gcatggcggg cacaggctg 19
<210> 869
<211> 18
<212> DNA
<213> mammalian
<400> 869
gcatggcggg cacaggct 1g
<210> 870
<211> 17
<212> DNA
<213> mammalian
<400> 870
gcatggcggg cacaggc 17
218
CA 02330022 2001-11-27
<210> 871
<211> 16
<212> DNA
<213> mammalian
<400> 871
gcatggcggg cacagg 16
<210> 872
<211> 15
<212> DNA
<213> mammalian
<400> 872
gcatggcggg cacag 15
<210> 873
<211> 14
<212> DNA
<213> mammalian
<400> 873
gcatggcggg caca 14
<210> 874
<211> 13
<212> DNA
<213> mammalian
<400> 874
gcatggcggg cac 13
219
CA 02330022 2001-11-27
<210> 875
<211> 12
<212> DNA
<213> mammalian
<400> 875
gcatggcggg ca 12
<210> 876
<211> 11
<212> DNA
<213> mammalian
<400> 876
gcatggcggg c 11
<210> 877
<211> 10
<212> DNA
<213> mammalian
<400> 877
gcatggcggg 10
<210> 878
<211> 21
<212> DNA
<213> mammalian
<400> 878
catggcgggc acaggctggg c 21
220
CA 02330022 2001-11-27
<210> 879
<211> 20
<212> DNA
<213> mammalian
<400> 879
catggcgggc acaggctggg 20
<210> 880
<211> 19
<212> DNA
<213> mammalian
<400> 880
catggcgggc acaggctgg 19
<210> 881
<211> 18
<212> DNA
<213> mammalian
<400> 881
catggcgggc acaggctg 18
<210> 882
<211> 17
<212> DNA
<213> mammalian
<400> 882
catggcgggc acaggct 17
221
CA 02330022 2001-11-27
<210> 883
<211> 16
<212> DNA
<213> mammalian
<400> 883
catggcgggc acaggc 16
<210> 884
<211> 15
<212> DNA
<213> mammalian
<400> 884
catggcgggc acagg 15
<210> 885
<211> 14
<212> DNA
<213> mammalian
<400> 885
catggcgggc acag 14
<210> 886
<211> 13
<212> DNA
<213> mammalian
<400> 886
catggcgggc aca 13
222
CA 02330022 2001-11-27
<210> 887
<211> 12
<212> DNA
<213> mammalian
<400> 887
catggcgggc ac 12
<210> 888
<211> 11
<212> DNA
<213> mammalian
<400> 888
catggcgggc a 11
<210> 889
<211> 10
<212> DNA
<213> mammalian
<400> 889
catggcgggc 10
<210> 890
<211> 20
<212> DNA
<213> mammalian
<400> 890
atggcgggca caggctgggc 20
223
CA 02330022 2001-11-27
<210> 891
<211> 19
<212> DNA
<213> mammalian
<400> 891
atggcgggca caggctggg 19
<210> 892
<211> 18
<212> DNA
<213> mammalian
<400> 892
atggcgggca caggctgg 1g
<210> 893
<211> 17
<212> DNA
<213> mammalian
<400> 893
atggcgggca caggctg 17
<210> 894
<211> 16
<212> DNA
<213> mammalian
<400> 894
atggcgggca caggct 16
224
CA 02330022 2001-11-27
<210> 895
<211> 15
<212> DNA
<213> mammalian
<400> 895
atggcgggca caggc 15
<210> 896
<211> 14
<212> DNA
<213> mammalian
<400> 896
atggcgggca cagg 14
<210> 897
<211> 13
<212> DNA
<213> mammalian
<400> 897
atggcgggca cag 13
<210> 898
<211> 12
<212> DNA
<213> mammalian
<400> 898
atggcgggca ca 12
225
CA 02330022 2001-11-27
<210> 899
<211> 11
<212> DNA
<213> mammalian
<400> 899
atggcgggca c
11
<210> 900
<211> 10
<212> DNA
<213> mammalian
<400> 900
atggcgggca 10
<210> 901
<211> 19
<212> DNA
<213> mammalian
<400> 901
tggcgggcac aggctgggc 19
<210> 902
<211> 18
<212> DNA
<213> mammalian
<400> 902
tggcgggcac aggctggg 1g
226
CA 02330022 2001-11-27
<210> 903
<211> 17
<212> DNA
<213> mammalian
<400> 903
tggcgggcac aggctgg 17
<210> 904
<211> 16
<212> DNA
<213> mammalian
<400> 904
tggcgggcac aggctg 16
<210> 905
<211> 15
<212> DNA
<213> mammalian
<400> 905
tggcgggcac aggct 15
<210> 906
<211> 14
<212> DNA
<213> mammalian
<400> 906
tggcgggcac aggc 14
227
CA 02330022 2001-11-27
<210> 907
<211> 13
<212> DNA
<213> mammalian
<400> 907
tggcgggcac agg 13
<210> 908
<211> 12
<212> DNA
<213> mammalian
<400> 908
tggcgggcac ag 12
<210> 909
<211> 11
<212> DNA
<213> mammalian
<400> 909
tggcgggcac a
11
<210> 910
<211> 10
<212> DNA
<213> mammalian
<400> 910
tggcgggcac
228
CA 02330022 2001-11-27
<210> 911
<211> 18
<212> DNA
<213> mammalian
<400> 911
ggcgggcaca ggctgggc 18
<210> 912
<211> 17
<212> DNA
<213> mammalian
<400> 912
ggcgggcaca ggctggg 17
<210> 913
<211> 16
<212> DNA
<213> mammalian
<400> 913
ggcgggcaca ggctgg 16
<210> 914
<211> 15
<212> DNA
<213> mammalian
<400> 914
ggcgggcaca ggctg
229
CA 02330022 2001-11-27
<210> 915
<211> 14
<212> DNA
<213> mammalian
<400> 915
ggcgggcaca ggct 14
<210> 916
<211> 13
<212> DNA
<213> mammalian
<400> 916
ggcgggcaca ggc 13
<210> 917
<211> 12
<212> DNA
<213> mammalian
<400> 917
ggcgggcaca gg 12
<210> 918
<211> 11
<212> DNA
<213> mammalian
<400> 918
ggcgggcaca g 11
230
DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.
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Brevets.
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