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BIALLELIC MARKERS
RELATED APPLICTIONS
This application claims priority to U.S.
Application No. 09/057,871 filed April 9, 1998, the
contents of which are incorporated herein by reference
in their entirety.
BACKGROUND OF THE INVENTION
The genomes of all organisms undergo spontaneous
mutation in the course of their continuing evolution,
generating variant forms of progenitor sequences
(Gusella, Ann. Rev. Biochem. 55, 831-854 (1986)). The
variant form may confer an evolutionary advantage or
disadvantage relative to a progenitor form or may be
neutral. In some instances, a variant form confers a
lethal disadvantage and is not transmitted to subsequent
generations of the organism. In other instances, a
variant form confers an evolutionary advantage to the
species and is eventually incorporated into the DNA of
many or most members of the species and effectively
becomes the progenitor form. In many instances, both
progenitor and variant forms) survive and co-exist in a
species population. The coexistence of multiple forms
of a sequence gives rise to polymorphisms.
Several different types of polymorphism have been
reported. A restriction fragment length polymorphism
(RFLP) Is a variation in DNA sequence that alters the
length of a restriction fragment (Botstein et al., Am.
J. Hum. Genet. 32, 314-331 (1980)). The restriction
fragment length polymorphism may create or delete a
restriction site, thus changing the length of the
restriction fragment. RFLPs have been widely used in
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human and animal genetic analyses (see WO 90/13668;
W090/11369; Donis-Keller, Cell 51, 319-337 (1987);
Lander et al., Genetics 121, 85-99 (1989)). L~hen a
heritable trait can be linked to a particular RFLP, the
presence of the RFLP in an individual can be used to
predict the likelihood that the animal will also exhibit
the trait.
Other polymorphisms take the form of short tandem
repeats (STRs) that include tandem di-, tri- and tetra-
nucleotide repeated motifs. These tandem repeats are
also referred to as variable number tandem repeat (VNTR)
polymorphisms. VNTRs have been used in identity and
paternity analysis (US 5,075,217; Armour et al., FEBS
Lett. 307, 113-115 (1992); Horn et al., WO 91/14003;
Jeffreys, EP 370,719), and in a large number of genetic
mapping studies.
Other polymorphisms take the form of single
nucleotide variations between individuals of the same
species. Such polymorphisms are far more frequent than
RFLPs, STRs and VNTRs. Some single nucleotide
polymorphisms occur in protein-coding sequences, in
which case, one of the polymorphic forms may give rise
to the expression of a defective or other variant
protein and, potentially, a genetic disease. Examples
of genes, in which polymorphisms within coding sequences
give rise to genetic disease include (3-globin (sickle
cell anemia) and CFTR (cystic fibrosis). Other single
nucleotide polymorphisms occur in noncoding regions.
Some of these polymorphisms may also result in defective
protein expression (e. g., as a result of defective
splicing). Other single nucleotide polymorphisms have
no phenotypic effects.
Single nucleotide polymorphisms can be used in the
same manner as RFLPs and VNTRs, but offer several
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advantages. Single nucleotide polymorphisms occur with
greater frequency and are spaced more uniformly
throughout the genome than other forms of polymorphism.
The greater frequency and uniformity of single
nucleotide polymorphisms means that there is a greater
probability that such a polymorphism will be found in
close proximity to a genetic locus of interest than
would be the case for other polymorphisms. The
different forms of characterized single nucleotide
polymorphisms are often easier to distinguish than other
types of polymorphism (e. g., by use of assays employing
allele-specific hybridization probes or primers).
Only a small percentage of the total repository of
polymorphisms in humans and other organisms has been
identified. The limited number of polymorphisms
identified to date is due to the large amount of work
required for their detection by conventional methods.
For example, a conventional approach to identifying
polymorphisms might be to sequence the same stretch of
DNA in a population of individuals by dideoxy
sequencing. In this type of approach, the amount of
work increases in proportion to both the length of
sequence and the number of individuals in a population
and becomes impractical for large stretches of DNA or
large numbers of persons.
SUMMARY OF THE INVENTION
The invention provides nucleic acid sequences
comprising nucleic acid segments of from about 10 to
about 200 bases as shown in the Table, column 7,
including a polymorphic site. Complements of these
segments are also included. The segments can be DNA or
RNA, and can be double- or single-stranded. Segments
can be, for example, 10-20, 10-50 or 10-100 bases long.
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Preferred segments include a biallelic polymorphic site.
The base occupying the polymorphic site in the segments
can be the reference (Table, column 3) or an alternative
base (Table, column 4).
The invention further provides allele-specific
oligonucleotides that hybridize to a segment of a
fragment shown in the Table, column 7, or its
complement. These oligonucleotides can be probes or
primers. Also provided are isolated nucleic acids
comprising a sequence shown in the Table, column 7, or
the complement thereto, in which the polymorphic site
within the sequence is occupied by a base other than the
reference base shown in the Table, column 3.
The invention further provides a method of analyzing
a nucleic acid from an individual. The method
determines which base is present at any one of the
polymorphic sites shown in the Table. Optionally, a set
of bases occupying a set of the polymorphic sites shown
in the Table is determined. This type of analysis can
be performed on a number of individuals, who are tested
for the presence of a disease phenotype. The presence
or absence of disease phenotype is then correlated with
a base or set of bases present at the polymorphic sites
in the individuals tested.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
An oligonucleotide can be DNA or RNA, and single- or
double-stranded. Oligonucleotides can be naturally
occurring or synthetic, but are typically prepared by
synthetic means. The oligonucleotides of the present
invention can comprise all of an oligonucleotide
sequence presented in column 7 of the Table or a segment
of such an oligonucleotide which includes a polymorphic
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site. Oligonucleotides can be all of a nucleic acid
segment as represented in column 7 of the Table; a
nucleic acid sequence which comprises a nucleic acid
segment represented in column 7 of the Table and
additional nucleic acids (present at either or both ends
of a nucleic acid segment of column 7); or a portion
(fragment) of a nucleic acid segment represented in
column 7 of the Table which includes a polymorphic site.
Preferred oligonucleotides of the invention include
segments of DNA, or their complements, which include any
one of the polymorphic sites shown in the Table. The
segments can be between 5 and 250 bases, and, in
specific embodiments, are between 5-10, 5-20, 10-20, 10-
50, 20-50 or 10-100 bases. For example, segments of the
invention can be 5, 6, 8, 10, 12, 14, 16, 18, 20, 22,
24, 25, 26, 28 or 30 nucleotides in length. The
polymorphic site can occur within any position of the
segment. The segments can be from any of the allelic
forms of DNA shown in the Table. In a particular
embodiment, the nucleotide at the polymorphic site is
different from the nucleotide in a corresponding
reference or wild-type allele.
Hybridization probes are oligonucleotides which bind
in a base-specific manner to a complementary strand of
nucleic acid. Such probes include peptide nucleic
acids, as described in Nielsen et al., Science 254,
2497-1500 (1991).
As used herein, the term primer refers to a single-
stranded oligonucleotide which acts as a point of
initiation of template-directed DNA synthesis under
appropriate conditions (e. g., in the presence of four
different nucleoside triphosphates and an agent for
polymerization, such as, DNA or RNA polymerase or
reverse transcriptase) in an appropriate buffer and at a
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suitable temperature. The appropriate length of a
primer depends on the intended use of the primer, but
typically ranges from 15 to 30 nucleotides. Short
primer molecules generally require cooler temperatures
to form sufficiently stable hybrid complexes with the
template. A primer need not reflect the exact sequence
of the template, but must be sufficiently complementary
to hybridize with a template. The term primer site
refers to the area of the target DNA to which a primer
hybridizes. The term primer pair refers to a set of
primers including a 5' (upstream) primer that hybridizes
with the 5' end of the DNA sequence to be amplified and
a 3' (downstream) primer that hybridizes with the
complement of the 3' end of the sequence to be
amplified.
As used herein, linkage describes the tendency of
genes, alleles, loci or genetic markers to be inherited
together as a result of their location on the same
chromosome. It can be measured by percent recombination
between the two genes, alleles, loci or genetic markers.
As used herein, polymorphism refers to the
occurrence of two or more genetically determined
alternative sequences or alleles in a population. A
polymorphic marker or site is the locus at which
divergence occurs. Preferred markers have at least two
alleles, each occurring at frequency of greater than 1~,
and more preferably greater than 10~ or 20$ of a
selected population. A polymorphic locus may be as
small as one base pair. Polymorphic markers include
restriction fragment length polymorphisms, variable
number of tandem repeats (VNTR's), hypervariable
regions, minisatellites, dinucleotide repeats,
trinucleotide repeats, tetranucleotide repeats, simple
sequence repeats, and insertion elements such as Alu.
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The first identified allelic form is arbitrarily
designated as the reference form and other allelic forms
are designated as alternative or variant alleles. The
allelic form occurring most frequently in a selected
population is sometimes referred to as the wildtype
form. Diploid organisms may be homozygous or
heterozygous for allelic forms. A diallelic or
biallelic polymorphism has two forms. A triallelic
polymorphism has three forms.
A single nucleotide polymorphism occurs at a
polymorphic site occupied by a single nucleotide, which
is the site of variation between allelic sequences. The
site is usually preceded by and followed by highly
conserved sequences of the allele (e. g., sequences that
vary in less than 1/100 or 1/1000 members of the
populations).
A single nucleotide polymorphism usually arises due
to substitution of one nucleotide for another at the
polymorphic site. A transition is the replacement of
one purine by another purine or one pyrimidine by
another pyrimidine. A transversion is the replacement
of a purine by a pyrimidine or vice versa. Single
nucleotide polymorphisms can also arise from a deletion
of a nucleotide or an insertion of a nucleotide relative
to a reference allele. Typically the polymorphic site
is occupied by a base other than the reference base.
For example, where the reference allele contains the
base "T" at the polymorphic site, the altered allele can
contain a "C", "G" or "A" at the polymorphic site.
Hybridizations are usually performed under stringent
conditions, for example, at a salt concentration of no
more than 1 M and a temperature of at least 25°C. For
example, conditions of 5X SSPE (750 mM NaCl, 50 mM
NaPhosphate', 5 mM EDTA, pH 7.4) and a temperature of 25-
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30°C, or equivalent conditions, are suitable for allele-
specific probe hybridizations. Equivalent conditions
can be determined by varying one or more of the
parameters given as an example, as known in the art,
while maintaining a similar degree of identity or
similarity between the target nucleotide sequence and
the primer or probe used.
The term "isolated" is used herein to indicate that
the material in question exists in a physical milieu
distinct from that in which it occurs in nature. For
example, an isolated nucleic acid of the invention may
be substantially isolated with respect to the complex
cellular milieu in which it naturally occurs. In some
instances, the isolated material will form part of a
composition (for example, a crude extract containing
other substances), buffer system or reagent mix. In
other circumstance, the material may be purified to
essential homogeneity, for example as determined by PAGE
or column chromatography such as HPLC. Preferably, an
isolated nucleic acid comprises at least about 50, 80 or
90 percent (on a molar basis) of all macromolecular
species present.
I. Novel Polymorphisms of the Invention
The novel polymorphisms of the invention are listed
in the Table. The first column of the Table lists the
names assigned to the fragments in which the
polymorphisms occur. The fragments are all human
genomic fragments. The sequence of one allelic form of
each of the fragments (arbitrarily referred to as the
prototypical or reference form) has been previously
published. These sequences are listed at
http://www-genome.wi.mit.edu/ (all STS's (sequence tag
sites)); http://shgc.stanford.edu (Stanford STS's); and
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http://ww.tigr.org/ (TIGR STS's). The Web sites also
list primers for amplification of the fragments, and the
genomic location of fragments. Some fragments are
expressed sequence tags, and some are random genomic
fragments. All information in the websites concerning
the fragments listed in the Table is incorporated by
reference in its entirety for all purposes.
The second column lists the position in the fragment
in which a polymorphic site has been found. Positions
are numbered consecutively with the first base of the
fragment sequence as listed in one of the above
databases being assigned the number one: The third
column lists the base occupying the polymorphic site in
the sequence in the data base. This base is arbitrarily
designated the reference or prototypical form, but it is
not necessarily the most frequently occurring form. The
fourth column in the Table lists the alternative bases)
at the polymorphic site. The fifth column of the Table
lists a 5' (upstream or forward) primer that hybridizes
with the 5' end of the DNA sequence to be amplified.
The sixth column of the Table lists a 3' (downstream or
reverse) primer that hybridizes with the complement of
the 3' end of the sequence to be amplified. The seventh
column of the Table lists a number of bases of sequence
on either side of the polymorphic site in each fragment.
The indicated sequences can be either DNA or RNA. In
the latter, the T's shown in the Table are replaced by
U's. The base occupying the polymorphic site is
indicated in EUPAC-IUB ambiguity code.
II. Analysis of Polymorphisms
A. Preparation of Samples
Polymorphisms are detected in a target nucleic acid
from an individual being analyzed. For assay of genomic
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DNA, virtually any biological sample (other than pure
red blood cells) is suitable. For example, convenient
tissue samples include whole blood, semen, saliva,
tears, urine, fecal material, sweat, buccal, skin and
hair. For assay of cDNA or mRNA, the tissue sample must
be obtained from an organ in which the target nucleic
acid is expressed. For example, if the target nucleic
acid is a cytochrome P450, the liver is a suitable
source.
Many of the methods described below require
amplification of DNA from target samples. This can be
accomplished by e.g., PCR. See generally PCR
Technology: Principles and Applications for DNA
Amplification (ed. H.A. Erlich, Freeman Press, NY, NY,
1992); PCR Protocols: A Guide to Methods and
Applications (eds. Innis, et al., Academic Press, San
Diego, CA, 1990); Mattila et al., Nucleic Acids Res. 19,
4967 (1991); Eckert et al., PCR Methods and Applications
1, 17 (1991); PCR (eds. McPherson et al., IRL Press,
Oxford); and U.S. Patent 4,683,202.
Other suitable amplification methods include the
ligase chain reaction (LCR) (see Wu and Wallace,
Genomics 4, 560 (1989), Landegren et al., Science 241,
1077 (1988), transcription amplification (Kwoh et al.,
Proc. Natl. Acad. Sci. USA 86, 1173 (1989) ) , and
self-sustained sequence replication (Guatelli et al.,
Proc. Nat. Acad. Sci. USA, 87, 1874 (1990)) and nucleic
acid based sequence amplification (NASBA). The latter
two amplification methods involve isothermal reactions
based on isothermal transcription, which produce both
single stranded RNA (ssRNA) and double stranded DNA
(dsDNA) as the amplification products in a ratio of
about 30 or 100 to 1, respectively.
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B. Detection of Polymorphisms in Target DNA
There are two distinct types of analysis of target
DNA for detecting polymorphisms. The first type of
analysis, sometimes referred to as de novo
characterization, is carried out to identify polymorphic
sites not previously characterized (i.e., to identify
new polymorphisms). This analysis compares target
sequences in different individuals to identify points of
variation, i.e., polymorphic sites. By analyzing groups
of individuals representing the greatest ethnic
diversity among humans and greatest breed and species
variety in plants and animals, patterns characteristic
of the most common alleles/haplotypes of the locus can
be identified, and the frequencies of such
alleles/haplotypes in the population can be determined.
Additional allelic frequencies can be determined for
subpopulations characterized by criteria such as
geography, race, or gender. The de novo identification
of polymorphisms of the invention is described in the
Examples section. The second type of analysis
determines which forms) of a characterized (known)
polymorphism are present in individuals under test.
There are a variety of suitable procedures, which are
discussed in turn.
1. Allele-Specific Probes
The design and use of allele-specific probes for
analyzing polymorphisms is described by e.g., Saiki et
al., Nature 324, 163-166 (1986); Dattagupta, EP 235,726,
Saiki, WO 89/11548. Allele-specific probes can be
designed that hybridize to a segment of target DNA from
one individual but do not hybridize to the corresponding
segment from another individual due to the presence of
different polymorphic forms in the respective segments
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from the two individuals. Hybridization conditions
should be sufficiently stringent that there is a
significant difference in hybridization intensity
between alleles, and preferably an essentially binary
response, whereby a probe hybridizes to only one of the
alleles. Some probes are designed to hybridize to a
segment of target DNA such that the polymorphic site
aligns with a central position {e.g., in a 15-mer at the
7 position; in a 16-mer, at either the 8 or 9 position)
of the probe. This design of probe achieves good
discrimination in hybridization between different
allelic forms.
Allele-specific probes are often used in pairs, one
member of a pair showing a perfect match to a reference
form of a target sequence and the other member showing a
perfect match to a variant form. Several pairs of
probes can then be immobilized on the same support for
simultaneous analysis of multiple polymorphisms within
the same target sequence.
2. Tiling Arrays
The polymorphisms can also be identified by
hybridization to nucleic acid arrays, some examples of
which are described in WO 95/11995. One form of such
arrays is described in the Examples section in
connection with de novo identification of polymorphisms.
The same array or a different array can be used for
analysis of characterized polymorphisms. WO 95/11995
also describes subarrays that are optimized for
detection of a variant form of a precharacterized
polymorphism. Such a subarray contains probes designed
to be complementary to a second reference sequence,
which is an allelic variant of the first reference
sequence. The second group of probes is designed by the
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same principles as described in the Examples, except
that the probes exhibit complementarity to the second
reference sequence. The inclusion of a second group (or
further groups) can be particularly useful for analyzing
short subsequences of the primary reference sequence in
which multiple mutations are expected to occur within a
short distance commensurate with the length of the
probes (e.g., two or more mutations within 9 to 21
bases).
3. Allele-Specific Primers
An allele-specific primer hybridizes to a site on
target DATA overlapping a polymorphism and only primes
amplification of an allelic form to which the primer
exhibits perfect complementarity. See Gibbs, Nucleic
Acid Res. 17, 2427-2448 (1989). This primer is used in
conjunction with a second primer which hybridizes at a
distal site. Amplification proceeds from the two
primers, resulting in a detectable product which
indicates the particular allelic form is present. A
control is usually performed with a second pair of
primers, one of which shows a single base mismatch at
the polymorphic site and the other of which exhibits
perfect complementarity to a distal site. The single-
base mismatch prevents amplification and no detectable
product is formed. The method works best when the
mismatch is included in the 3'-most position of the
oligonucleotide aligned with the polymorphism because
this position is most destabilizing to elongation from
the primer (see, e.g., WO 93/22456).
4. Direct-Sequencing
The direct analysis of the sequence of polymorphisms
of the present invention can be accomplished using
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either the dideoxy chain termination method or the Maxam
Gilbert method (see Sambrook et al., Molecular Cloning,
A Laboratory Manual (2nd Ed., CSHP, New York 1989);
Zyskind et al., Recombinant DNA Laboratory Manual,
(Acad. Press, 1988)).
5. Denaturing Gradient Gel Electrophoresis
Amplification products generated using the
polymerase chain reaction can be analyzed by the use of
denaturing gradient gel electrophoresis. Different
alleles can be identified based on the different
sequence-dependent melting properties and
electrophoretic migration of DNA in solution. Erlich,
ed., PCR Technology, Principles and Applications for DNA
Amplification, (W. H. Freeman and Co, New York, 1992),
Chapter 7.
6. Single-Strand Conformation Polymorphism Analysis
Alleles of target sequences can be differentiated
using single-strand conformation polymorphism analysis,
which identifies base differences by alteration in
electrophoretic migration of single stranded PCR
products, as described in Orita et al., Proc. Nat. Acad.
Sci. 86, 2766-2770 (1989). Amplified PCR products can
be generated as described above, and heated or otherwise
denatured, to form single stranded amplification
products. Single-stranded nucleic acids may refold or
form secondary structures which are partially dependent
on the base sequence. The different electrophoretic
mobilities of single-stranded amplification products can
be related to base-sequence differences between alleles
of target sequences.
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III. Methods of Use
After determining polymorphic forms) present in an
individual at one or more polymorphic sites, this
information can be used in a number of methods.
A. Forensics
Determination of which polymorphic forms occupy a
set of polymorphic sites in an individual identifies a
set of polymorphic forms that distinguishes the
individual. See generally National Research Council,
The Evaluation of Forensic DNA Evidence (Eds. Pollard et
al., National Academy Press, DC, 1996). The more sites
that are analyzed, the lower the probability that the
set of polymorphic forms in one individual is the same
as that in an unrelated individual. Preferably, if
multiple sites are analyzed, the sites are unlinked.
Thus, polymorphisms of the invention are often used in
conjunction with polymorphisms in distal genes.
Preferred polymorphisms for use in forensics are
biallelic because the population frequencies of two
polymorphic forms can usually be determined with greater
accuracy than those of multiple polymorphic forms at
multi-allelic loci.
The capacity to identify a distinguishing or unique
set of forensic markers in an individual is useful for
forensic analysis. For example, one can determine
whether a blood sample from a suspect matches a blood or
other tissue sample from a crime scene by determining
whether the set of polymorphic forms occupying selected
polymorphic sites is the same in the suspect and the
sample. If the set of polymorphic markers does not
match between a suspect and a sample, it can be
concluded (barring experimental error) that the suspect
was not the source of the sample. If the set of markers
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does match, one can conclude that the DNA from the
suspect is consistent with that found at the crime
scene. If frequencies of the polymorphic forms at the
loci tested have been determined (e.g., by analysis of a
suitable population of individuals), one can perform a
statistical analysis to determine the probability that a
match of suspect and crime scene sample would occur by
chance.
p(ID) is the probability that two random individuals
have the same polymorphic or allelic form at a given
polymorphic site. In biallelic loci, four genotypes are
possible: AA, AB, BA, and BB. If alleles A and B occur
in a haploid genome of the organism with frequencies x
and y, the probability of each genotype in a diploid
organism is (see WO 95/12607):
Homozygote: p(AA)= x2
Homozygote: p(BB)= y2 - (1-x)2
Single Heterozygote: p(AB)= p(BA)= xy = x(1-x)
Both Heterozygotes: p(AB+BA)= 2xy = 2x(1-x)
The probability of identity at one locus (i.e, the
probability that two individuals, picked at random from
a population will have identical polymorphic forms at a
given locus) is given by the equation:
P(ID) - (xz)Z + (2xy)2 + (YZ)2.
These calculations can be extended for any number of
polymorphic forms at a given locus. For example, the
probability of identity p(ID) for a 3-allele system
where the alleles have the frequencies in the population
of x, y and z, respectively, is equal to the sum of the
squares of the genotype frequencies:
P(ID) - x4 + (2xy)2 + (2Yz)2 + (2xz)2 + z4 + y4
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In a locus of n alleles, the appropriate binomial
expansion is used to calculate p(ID) and p(exc).
The cumulative probability of identity (cum p(ID))
for each of multiple unlinked loci is determined by
multiplying the probabilities provided by each locus.
cum p(ID) - p(ID1)p(ID2)p(ID3).... p(IDn)
The cumulative probability of non-identity for n
loci (i.e. the probability that two random individuals
will be different at 1 or more loci) is given by the
equation:
cum p(nonID) - 1-cum p(ID).
If several polymorphic loci are tested, the
cumulative probability of non-identity for random
individuals becomes very high (e.g., one billion to
one). Such probabilities can be taken into account
together with other evidence in determining the guilt or
innocence of the suspect.
B. Paternity Testing
The object of paternity testing is usually to
determine whether a male is the father of a child. In
most cases, the mother of the child is known and thus,
the mother's contribution to the child's genotype can be
traced. Paternity testing investigates whether the part
of the child's genotype not attributable to the mother
is consistent with that of the putative father.
Paternity testing can be performed by analyzing sets of
polymorphisms in the putative father and the child.
If the set of polymorphisms in the child
attributable to the father does not match the set of
polymorphisms of the putative father, it can be
concluded, barring experimental error, that the putative
father is not the real father. If the set of
polymorphisms in the child attributable to the father
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does match the set of polymorphisms of the putative
father, a statistical calculation can be performed to
determine the probability of coincidental match.
The probability of parentage exclusion (representing
the probability that a random male will have a
polymorphic form at a given polymorphic site that makes
him incompatible as the father) is given by the equation
(see WO 95/12607):
p(exc) - xy(1-xy)
where x and y are the population frequencies of alleles
A and B of a biallelic polymorphic site.
(At a triallelic site p(exc) - xy(1-xy) + yz(1- yz)
+ xz(1-xz)+ 3xyz(1-xyz))), where x, y and z and the
respective population frequencies of alleles A, B and
C) .
The probability of non-exclusion is
p(non-exc) - 1-p(exc)
The cumulative probability of non-exclusion
(representing the value obtained when n loci are used)
is thus:
cum p(non-exc) - p(non-excl)p(non-exc2)p(non-
exc3).... p(non-excn)
The cumulative probability of exclusion for n loci
(representing the probability that a random male will be
excluded)
cum p(exc) - 1 - cum p(non-exc).
If several polymorphic loci are included in the
analysis, the cumulative probability of exclusion of a
random male is very high. This probability can be taken
into account in assessing the liability of a putative
father whose polymorphic marker set matches the child's
polymorphic marker set attributable to his/her father.
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C. Correlation of Polymorphisms with Phenotypic
Traits
The polymorphisms of the invention may contribute to
the phenotype of an organism in different ways. Some
polymorphisms occur within a protein coding sequence and
contribute to phenotype by affecting protein structure.
The effect may be neutral, beneficial or detrimental, or
both beneficial and detrimental, depending on the
circumstances. For example, a heterozygous sickle cell
mutation confers resistance to malaria, but a homozygous
sickle cell mutation is usually lethal. Other
polymorphisms occur in noncoding regions but may exert
phenotypic effects indirectly via influence on
replication, transcription, and translation. A single
polymorphism may affect more than one phenotypic trait.
Likewise, a single phenotypic trait may be affected by
polymorphisms in different genes. Further, some
polymorphisms predispose an individual to a distinct
mutation that is causally related to a certain
phenotype.
Phenotypic traits include diseases that have known
but hitherto unmapped genetic components (e. g.,
agammaglobulimenia, diabetes insipidus, Lesch-Nyhan
syndrome, muscular dystrophy, Wiskott-Aldrich syndrome,
Fabry's disease, familial hypercholesterolemia,
polycystic kidney disease, hereditary spherocytosis, von
Willebrand's disease, tuberous sclerosis, hereditary
hemorrhagic telangiectasia, familial colonic polyposis,
Ehlers-Danlos syndrome, osteogenesis imperfecta, and
acute intermittent porphyria). Phenotypic traits also
include symptoms of, or susceptibility to,
multifactorial diseases of which a component is or may
be genetic, such as autoimmune diseases, inflammation,
cancer, diseases of the nervous system, and infection by
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pathogenic microorganisms. Some examples of autoimmune
diseases include rheumatoid arthritis, multiple
sclerosis, diabetes (insulin-dependent and non-
independent), systemic lupus erythematosus and Graves
disease. Some examples of cancers include cancers of
the bladder, brain, breast, colon, esophagus, kidney,
leukemia, liver, lung, oral cavity, ovary, pancreas,
prostate, skin, stomach and uterus. Phenotypic traits
also include characteristics such as longevity,
appearance (e. g., baldness, obesity), strength, speed,
endurance, fertility, and susceptibility or receptivity
to particular drugs or therapeutic treatments.
Correlation is performed for a population of
individuals who have been tested for the presence or
absence of a phenotypic trait of interest and for
polymorphic markers sets. To perform such analysis, the
presence or absence of a set of polymorphisms (i.e. a
polymorphic set) is determined for a set of the
individuals, some of whom exhibit a particular trait,
and some of which exhibit lack of the trait. The
alleles of each polymorphism of the set are then
reviewed to determine whether the presence or absence of
a particular allele is associated with the trait of
interest. Correlation can be performed by standard
statistical methods such as a x-squared test and
statistically significant correlations between
polymorphic forms) and phenotypic characteristics are
noted. For example, it might be found that the presence
of allele A1 at polymorphism A correlates with heart
disease. As a further example, it might be found that
the combined presence of allele A1 at polymorphism A and
allele B1 at polymorphism B correlates with increased
milk production of a farm animal.
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Such correlations can be exploited in several ways.
In the case of a strong correlation between a set of one
or more polymorphic forms and a disease for which
treatment is available, detection of the polymorphic
form set in a human or animal patient may justify
immediate administration of treatment, or at least the
institution of regular monitoring of the patient.
Detection of a polymorphic form correlated with serious
disease in a couple contemplating a family may also be
valuable to the couple in their reproductive decisions.
For example, the female partner might elect to undergo
in vitro fertilization to avoid the possibility of
transmitting such a polymorphism from her husband to her
offspring. In the case of a weaker, but still
statistically significant correlation between a
polymorphic set and human disease, immediate therapeutic
intervention or monitoring may not be justified.
Nevertheless, the patient can be motivated to begin
simple life-style changes (e. g., diet, exercise) that
can be accomplished at little cost to the patient but
confer potential benefits in reducing the risk of
conditions to which the patient may have increased
susceptibility by virtue of variant alleles.
Identification of a polymorphic set in a patient
correlated with enhanced receptiveness to one of several
treatment regimes for a disease indicates that this
treatment regime should be followed.
For animals and plants, correlations between
characteristics and phenotype are useful for breeding
for desired characteristics. For example, Beitz et al.,
US 5,292,639 discuss use of bovine mitochondrial
polymorphisms in a breeding program to improve milk
production in cows. To evaluate the effect of mtDNA D-
loop sequence polymorphism on milk production, each cow
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was assigned a value of 1 if variant or 0 if wildtype
with respect to a prototypical mitochondrial DNA
sequence at each of 17 locations considered. Each
production trait was analyzed individually with the
following animal model:
Yii~n= a + YSi + P~ + Xk + ail + . . . (31~ + PEn + an +ep
where Yi~~p is the milk, fat, fat percentage, SNF, SNF
percentage, energy concentration, or lactation energy
record; ,u is an overall mean; YS; is the effect common to
all cows calving in year-season; Xk is the effect common
to cows in either the high or average selection line; (31
to ~31~ are the binomial regressions of production record
on mtDNA D-loop sequence polymorphisms; PEn is permanent
environmental effect common to all records of cow n; an
is effect of animal n and is composed of the additive
genetic contribution of sire and dam breeding values and
a Mendelian sampling effect; and ep is a random residual.
It was found that eleven of seventeen polymorphisms
tested influenced at least one production trait.
Bovines having the best polymorphic forms for milk
production at these eleven loci are used as parents for
breeding the next generation of the herd.
D. Genetic Mapping of Phenotypic Traits
The previous section concerns identifying
correlations between phenotypic traits and polymorphisms
that directly or indirectly contribute to those traits.
The present section describes identification of a
physical linkage between a genetic locus associated with
a trait of interest and polymorphic markers that are not
associated with the trait, but are in physical proximity
with the genetic locus responsible for the trait and co-
segregate with it. Such analysis is useful for mapping
a genetic locus associated with a phenotypic trait to a
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chromosomal position, and thereby cloning genes)
responsible for the trait. See Lander et al., Proc.
Natl. Acad. Sci.. (USA) 83, 7353-7357 (1986); Lander et
al., Proc. Natl. Acad. Sci. (USA) 84, 2363-2367 (1987);
Donis-Keller et al., Cell 51, 319-337 (1987); Lander et
al., Genetics 121, 185-199 (1989)). Genes localized by
linkage can be cloned by a process known as directional
cloning. See Wainwright, Med. J. Australia 159, 170-174
(1993); Collins, Nature Genetics 1, 3-6 (1992).
Linkage studies are typically performed on members
of a family. Available members of the family are
characterized for the presence or absence of a
phenotypic trait and for a set of polymorphic markers.
The distribution of polymorphic markers in an
informative meiosis is then analyzed to determine which
polymorphic markers co-segregate with a phenotypic
trait. See, e.g., Kerem et al., Science 245, 2073-1080
(1989); Monaco et al., Nature 316, 842 (1985); Yamoka et
al., Neurology 40, 222-226 (1990); Rossiter et al.,
FASEB Journal 5, 21-27 (1992).
Linkage is analyzed by calculation of LOD (log of
the odds) values. A lod value is the relative
likelihood of obtaining observed segregation data for a
marker and a genetic locus when the two are located at a
recombination fraction 8, versus the situation in which
the two are not linked, and thus segregating
independently (Thompson & Thompson, Genetics in
Medicine (5th ed, W.B. Saunders Company, Philadelphia,
1991); Strachan, "Mapping the human genome" in The Human
Genome (BIOS Scientific Publishers Ltd, Oxford), Chapter
4). A series of likelihood ratios are calculated at
various recombination fractions (8), ranging from 8 =
0.0 (coincident loci) to 8 = 0.50 (unlinked). Thus, the
likelihood at a given value of 8 is: probability of
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data if loci linked at 8 to probability of data if loci
unlinked. The computed likelihoods are usually
expressed as the loglo of this ratio (i.e., a lod score).
For example, a lod score of 3 indicates 1000:1 odds
against an apparent observed linkage being a
coincidence. The use of logarithms allows data
collected from different families to be combined by
simple addition. Computer programs are available for
the calculation of lod scores for differing values of 8
(e. g., LIPED, MLINK (Lathrop, Proc. Nat. Acad. Sci.
(USA) 81, 3443-3446 (1984)). For any particular lod
score, a recombination fraction may be determined from
mathematical tables. See Smith et al., Mathematical
tables for research workers in human genetics
(Churchill, London, 1961); Smith, Ann. Hum. Genet. 32,
127-150 (1968). The value of 8 at which the lod score
is the highest is considered to be the best estimate of
the recombination fraction.
Positive lod score values suggest that the two loci
are linked, whereas negative values suggest that linkage
is less likely (at that value of 8) than the possibility
that the two loci are unlinked. By convention, a
combined lod score of +3 or greater (equivalent to
greater than 1000:1 odds in favor of linkage) is
considered definitive evidence that two loci are linked.
Similarly, by convention, a negative lod score of -2 or
less is taken as definitive evidence against linkage of
the two loci being compared. Negative linkage data are
useful in excluding a chromosome or a segment thereof
from consideration. The search focuses on the remaining
non-excluded chromosomal locations.
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IV. Modified Polypeptides and Gene Sequences
The invention further provides variant forms of
nucleic acids and corresponding proteins. The nucleic
acids comprise one of the sequences described in the
Table, column 8, in which the polymorphic position is
occupied by one of the alternative bases for that
position. Some nucleic acids encode full-length variant
forms of proteins. Similarly, variant proteins have the
prototypical amino acid sequences encoded by nucleic
acid sequences shown in the Table, column 8, (read so as
to be in-frame with the full-length coding sequence of
which it is a component) except at an amino acid encoded
by a codon including one of the polymorphic positions
shown in the Table. That position is occupied by the
amino acid coded by the corresponding codon in any of
the alternative forms shown in the Table.
Variant genes can be expressed in an expression
vector in which a variant gene is operably linked to a
native or other promoter. Usually, the promoter is a
eukaryotic promoter for expression in a mammalian cell.
The transcription regulation sequences typically include
a heterologous promoter and optionally an enhancer which
is recognized by the host. The selection of an
appropriate promoter, for example trp, lac, phage
promoters, glycolytic enzyme promoters and tRNA
promoters, depends on the host selected. Commercially
available expression vectors can be used. Vectors can
include host-recognized replication systems, amplifiable
genes, selectable markers, host sequences useful for
insertion into the host genome, and the like.
The means of introducing the expression construct
into a host cell varies depending upon the particular
construction and the target host. Suitable means
include fusion, conjugation, transfection, transduction,
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electroporation or injection, as described in Sambrook,
supra. A wide variety of host cells can be employed for
expression of the variant gene, both prokaryotic and
eukaryotic. Suitable host cells include bacteria such
as E. coli, yeast, filamentous fungi, insect cells,
mammalian cells, typically immortalized, e.g., mouse,
CHO, human and monkey cell lines and derivatives
thereof. Preferred host cells are able to process the
variant gene product to produce an appropriate mature
polypeptide. Processing includes glycosylation,
ubiquitination, disulfide bond formation, general post-
translational modification, and the like.
The protein may be isolated by conventional means of
protein biochemistry and purification to obtain a
substantially pure product, i.e., 80, 95 or 99~ free of
cell component contaminants, as described in Jacoby,
Methods in Enzymology Volume 104, Academic Press, New
York (1984); Scopes, Protein Purification, Principles
and Practice, 2nd Edition, Springer-Verlag, New York
(1987); and Deutscher (ed), Guide to Protein
Purification, Methods in Enzymology, Vol. 182 (1990).
If the protein is secreted, it can be isolated from the
supernatant in which the host cell is grown. If not
secreted, the protein can be isolated from a lysate of
the host cells.
The invention further provides transgenic nonhuman
animals capable of expressing an exogenous variant gene
and/or having one or both alleles of an endogenous
variant gene inactivated. Expression of an exogenous
variant gene is usually achieved by operably linking the
gene to a promoter and optionally an enhancer, and
microinjecting the construct into a zygote. See Hogan
et al., "Manipulating the Mouse Embryo, A Laboratory
Manual," Cold Spring Harbor Laboratory. Inactivation of
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endogenous variant genes can be achieved by forming a
transgene in which a cloned variant gene is inactivated
by insertion of a positive selection marker. See
Capecchi, Science 244, 1288-1292 (1989). The transgene
is then introduced into an embryonic stem cell, where it
undergoes homologous recombination with an endogenous
variant gene. Mice and other rodents are preferred
animals. Such animals provide useful drug screening
systems.
In addition to substantially full-length
polypeptides expressed by variant genes, the present
invention includes biologically active fragments of the
polypeptides, or analogs thereof, including organic
molecules which simulate the interactions of the
peptides. Biologically active fragments include any
portion of the full-length polypeptide which confers a
biological function on the variant gene product,
including ligand binding, and antibody binding. Ligand
binding includes binding by nucleic acids, proteins or
polypeptides, small biologically active molecules, or
large cellular structures.
Polyclonal and/or monoclonal antibodies that
specifically bind to variant gene products but not to
corresponding prototypical gene products are also
provided. Antibodies can be made by.injecting mice or
other animals with the variant gene product or synthetic
peptide fragments thereof. Monoclonal antibodies are
screened as are described, for example, in Harlow &
Lane, Antibodies, A Laboratory Manual, Cold Spring
Harbor Press, New York (1988); Goding, Monoclonal
antibodies, Principles and Practice (2d ed.) Academic
Press, New York (1986). Monoclonal antibodies are
tested for specific immunoreactivity with a variant gene
product and lack of imznunoreactivity to the
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corresponding prototypical gene product. These
antibodies are useful in diagnostic assays for detection
of the variant form, or as an active ingredient in a
pharmaceutical composition.
V. Kits
The invention further provides kits comprising at
least one allele-specific oligonucleotide as described
above. Often, the kits contain one or more pairs of
allele-specific oligonucleotides hybridizing to
different forms of a polymorphism. In some kits, the
allele-specific oligonucleotides are provided
immobilized to a substrate. For example, the same
substrate can comprise allele-specific oligonucleotide
probes for detecting at least 10, 100 or all of the
polymorphisms shown in the Table. Optional additional
components of the kit include, for example, restriction
enzymes, reverse-transcriptase or polymerase, the
substrate nucleoside triphosphates, means used to label
(for example, an avidin-enzyme conjugate and enzyme
substrate and chromogen if the label is biotin), and the
appropriate buffers for reverse transcription, PCR, or
hybridization reactions. Usually, the kit also contains
instructions for carrying out the methods.
The following Examples are offered for the purpose
of illustrating the present invention and are not to be
construed to limit the scope of this invention. The
teachings of all references cited herein are hereby
incorporated herein by reference.
EXAMPLES
The polymorphisms shown in the Table were identified
by resequencing of target sequences from three to ten
unrelated individuals of diverse ethnic and geographic
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backgrounds by hybridization to probes immobilized to
microfabricated arrays or conventional sequencing. The
strategy and principles for design and use of such
arrays are generally described in WO 95/11995. The
strategy provides arrays of probes for analysis of
target sequences showing a high degree of sequence
identity to the reference sequences of the fragments
shown in the Table, column 1. The reference sequences
were sequence-tagged sites (STSs) developed in the
course of the Human Genome Project (see, e.g., Science
270, 1945-1954 (1995); Nature 380, 152-154 (1996)).
Most STS's ranged from 100 by to 300 by in size.
A typical probe array used in this analysis has two
groups of four sets of probes that respectively tile
both strands of a reference sequence. A first probe set
comprises a plurality of probes exhibiting perfect
complementarily with one of the reference sequences.
Each probe in the first probe set has an interrogation
position that corresponds to a nucleotide in the
reference sequence. That is, the interrogation position
is aligned with the corresponding nucleotide in the
reference sequence, when the probe and reference
sequence are aligned to maximize complementarily between
the two. For each probe in the first set, there are
three corresponding probes from three additional probe
sets. Thus, there are four probes corresponding to each
nucleotide in the reference sequence. The probes from
the three additional probe sets are identical to the
corresponding probe from the first probe set except at
the interrogation position, which occurs in the same
position in each of the four corresponding probes from
the four probe sets, and is occupied by a different
nucleotide in the four probe sets. In the present
analysis, probes were 25 nucleotides long. Arrays tiled
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for multiple different references sequences were
included on the same substrate.
Multiple target sequences from an individual were
amplified from human genomic DNA using primers for the
fragments indicated in the listed Web sites. The
amplified target sequences were fluorescently labelled
during or after PCR. The labelled target sequences were
hybridized with a substrate bearing immobilized arrays
of probes. The amount of lable bound to probes was
measured. Analysis of the pattern of label revealed the
nature and position of differences between the target
and reference sequence. For example, comparison of the
intensities of four corresponding probes reveals the
identity of a corresponding nucleotide in the target
sequences aligned with the interrogation position of the
probes. The corresponding nucleotide is the complement
of the nucleotide occupying the interrogation position
of the probe showing the highest intensity (see WO
95/11995). The existence of a polymorphism is also
manifested by differences in normalized hybridization
intensities of probes flanking the polymorphism when the
probes hybridized to corresponding targets from
different individuals. For example, relative loss of
hybridization intensity in a "footprint" of probes
flanking a polymorphism signals a difference between the
target and reference (i.e., a polymorphism) (see EP
717,113). Additionally, hybridization intensities for
corresponding targets from different individuals can be
classified into groups or clusters suggested by the
data, not defined a priori, such that isolates in a give
cluster tend to be similar and isolates in different
clusters tend to be dissimilar. Hybridizations to
samples from different individuals were performed
separately. The Table summarizes the data obtained for
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target sequences in comparison with a reference sequence
for the individuals tested.
From the foregoing, it is apparent that the
invention includes a number of general uses that can be
expressed concisely as follows. The invention provides
for the use of any of the nucleic acid segments
described above in the diagnosis or monitoring of
diseases, such as cancer, inflammation, heart disease,
diseases of the CNS, and susceptibility to infection by
microorganisms. The invention further provides for the
use of any of the nucleic acid segments in the
manufacture of a medicament for the treatment or
prophylaxis of such diseases. The invention further
provides for the use of any of the DNA segments as a
pharmaceutical.
All publications and patent applications cited above
are incorporated by reference in their entirety for all
purposes to the same extent as if each individual
publication or patent application were specifically and
individually indicated to be so incorporated by
reference .
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32
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