AU3371199A - Biallelic markers - Google Patents

Biallelic markers Download PDF

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AU3371199A
AU3371199A AU33711/99A AU3371199A AU3371199A AU 3371199 A AU3371199 A AU 3371199A AU 33711/99 A AU33711/99 A AU 33711/99A AU 3371199 A AU3371199 A AU 3371199A AU 3371199 A AU3371199 A AU 3371199A
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polymorphic
segment
pctius99
allele
uue
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Thomas Hudson
Eric S. Lander
David Wang
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Whitehead Institute for Biomedical Research
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6827—Hybridisation assays for detection of mutation or polymorphism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Description

WO 99/53095 PCTIUS99/06893 BIALLELIC MARKERS RELATED APPLICATIONS This application claims priority to U.S. Application No. 09/057,871 filed April 9, 1998, the 5 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, 10 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 15 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 20 becomes the progenitor form. In many instances, both progenitor and variant form(s) 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 25 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 30 restriction site, thus changing the length of the restriction fragment. RFLPs have been widely used in WO 99/53095 PCT/US99/06893 -2 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)). When a heritable trait can be linked to a particular RFLP, the 5 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 10 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; 15 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 20 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 25 of genes, in which polymorphisms within coding sequences give rise to genetic disease include B-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 30 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 WO 99/53095 PCT/US99/06893 -3 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 5 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 10 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 15 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 20 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 25 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, 30 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.
WO 99/53095 PCTIUS99/06893 -4 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). 5 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 10 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 15 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 20 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. 25 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 30 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 WO 99/53095 PCTIUS99/06893 -5 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 5 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 10 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 15 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 20 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 25 nucleic acid. Such probes include peptide nucleic acids, as described in Nielsen et al., Science 254, 1497-1500 (1991). As used herein, the term primer refers to a single stranded oligonucleotide which acts as a point of 30 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 WO 99/53095 PCTIUS99/06893 -6 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 5 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 10 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 15 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 20 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 25 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 30 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.
WO 99/53095 PCT/US99/06893 -7 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 5 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. 10 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 15 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 20 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 25 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. 30 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 250C. For example, conditions of 5X SSPE (750 mM NaCl, 50 mM NaPhosphate, 5 mM EDTA, pH 7.4) and a temperature of 25- WO 99/53095 PCT/US99/06893 -8 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, 5 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 10 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 15 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 20 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 25 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 30 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 WO 99/53095 PCT/US99/06893 -9 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 5 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 10 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 15 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 base(s) at the polymorphic site. The fifth column of the Table lists a 5' (upstream or forward) primer that hybridizes 20 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 25 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. 30 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 WO 99/53095 PCT/US99/06893 -10 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 5 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. 10 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, 15 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, 20 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., 25 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 30 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.
WO 99/53095 PCT/US99/06893 -11 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 5 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 10 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 15 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 20 Examples section. The second type of analysis determines which form(s) of a characterized (known) polymorphism are present in individuals under test. There are a variety of suitable procedures, which are discussed in turn. 25 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 30 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 WO 99/53095 PCT/US99/06893 -12 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 5 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) 10 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 15 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. 20 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 25 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 30 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 WO 99/53095 PCTIUS99/06893 -13 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 5 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). 10 3. Allele-Specific Primers An allele-specific primer hybridizes to a site on target DNA overlapping a polymorphism and only primes amplification of an allelic form to which the primer exhibits perfect complementarity. See Gibbs, Nucleic 15 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 20 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 25 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). 30 4. Direct-Sequencing The direct analysis of the sequence of polymorphisms of the present invention can be accomplished using WO 99/53095 PCTIUS99/06893 -14 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, 5 (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 10 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), 15 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 20 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 25 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 30 of target sequences.
WO 99/53095 PCTIUS99/06893 -15 III. Methods of Use After determining polymorphic form(s) present in an individual at one or more polymorphic sites, this information can be used in a number of methods. 5 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, 10 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 15 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 20 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 25 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 30 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 WO 99/53095 PCT/US99/06893 -16 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 5 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 10 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 15 organism is (see WO 95/12607): Homozygote: p(AA)= x 2 Homozygote: p(BB)= y 2 (1_X) 2 Single Heterozygote: p(AB)= p(BA)= xy = x(1-x) Both Heterozygotes: p(AB+BA)= 2xy = 2x(1-x) 20 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) = (x 2
)
2 + (2xy) 2 + (y 2 ) 2. 25 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 30 squares of the genotype frequencies: p(ID) = x 4 + (2xy)2 + (2yz) 2 + (2xz) 2 + z 4 + y4 WO 99/53095 PCT/US99/06893 -17 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 5 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 10 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 15 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 20 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 25 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 30 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 WO 99/53095 PCT/US99/06893 -18 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 5 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(l-xy) 10 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(l-xy) + yz(1- yz) + xz(l-xz)+ 3xyz(l-xyz))), where x, y and z and the respective population frequencies of alleles A, B and 15 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) 20 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 25 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 30 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.
WO 99/53095 PCTIUS99/06893 -19 C. Correlation of Polymorphisms with Phenotypic Traits The polymorphisms of the invention may contribute to the phenotype of an organism in different ways. Some 5 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 10 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 15 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 20 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, 25 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 30 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 WO 99/53095 PCT/US99/06893 -20 pathogenic microorganisms. Some examples of autoimmune diseases include rheumatoid arthritis, multiple sclerosis, diabetes (insulin-dependent and non independent), systemic lupus erythematosus and Graves 5 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, 10 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 15 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, 20 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 25 statistical methods such as a K-squared test and statistically significant correlations between polymorphic form(s) and phenotypic characteristics are noted. For example, it might be found that the presence of allele Al at polymorphism A correlates with heart 30 disease. As a further example, it might be found that the combined presence of allele Al at polymorphism A and allele B1 at polymorphism B correlates with increased milk production of a farm animal.
WO 99/53095 PCTIUS99/06893 -21 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 5 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 10 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 15 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 20 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 25 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 30 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 WO 99/53095 PCT/US99/06893 -22 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 5 following animal model: Yijkpn 1' + YSi + Pi + Xk + + ... 17 + PEn + an +ep where Yijknp is the milk, fat, fat percentage, SNF, SNF percentage, energy concentration, or lactation energy record; , is an overall mean; YSj is the effect common to 10 all cows calving in year-season; Xk is the effect common to cows in either the high or average selection line; p, to B17 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 15 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. 20 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 25 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 30 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 WO 99/53095 PCTIUS99/06893 -23 chromosomal position, and thereby cloning gene(s) 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); 5 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). 10 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 15 informative meiosis is then analyzed to determine which polymorphic markers co-segregate with a phenotypic trait. See, e.g., Kerem et al., Science 245, 1073-1080 (1989); Monaco et al., Nature 316, 842 (1985); Yamoka et al., Neurology 40, 222-226 (1990); Rossiter et al., 20 FASEB Journal 5, 21-27 (1991). 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 25 recombination fraction e, 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 30 Genome (BIOS Scientific Publishers Ltd, Oxford), Chapter 4). A series of likelihood ratios are calculated at various recombination fractions (e), ranging from e = 0.0 (coincident loci) to e = 0.50 (unlinked). Thus, the likelihood at a given value of e is: probability of WO 99/53095 PCT/US99/06893 -24 data if loci linked at 6 to probability of data if loci unlinked. The computed likelihoods are usually expressed as the log,, of this ratio (i.e., a lod score). For example, a lod score of 3 indicates 1000:1 odds 5 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 e 10 (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 15 (Churchill, London, 1961); Smith, Ann. Hum. Genet. 32, 127-150 (1968). The value of e 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 20 are linked, whereas negative values suggest that linkage is less likely (at that value of 6) 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 25 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 30 from consideration. The search focuses on the remaining non-excluded chromosomal locations.
WO 99/53095 PCT/US99/06893 -25 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 5 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 10 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 15 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 20 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 25 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 30 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, WO 99/53095 PCT/US99/06893 -26 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 5 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 10 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 15 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 20 (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 25 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 30 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 WO 99/53095 PCTIUS99/06893 -27 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 5 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. 10 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 15 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 20 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 25 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 30 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 immunoreactivity to the WO 99/53095 PCT/US99/06893 -28 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. 5 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 10 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 15 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 20 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 25 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 30 The polymorphisms shown in the Table were identified by resequencing of target sequences from three to ten unrelated individuals of diverse ethnic and geographic WO 99/53095 PCT/US99/06893 -29 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 5 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 10 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 bp to 300 bp in size. A typical probe array used in this analysis has two groups of four sets of probes that respectively tile 15 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 20 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 25 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 30 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 WO 99/53095 PCT/US99/06893 -30 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 5 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 10 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 15 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 20 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 25 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 30 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 WO 99/53095 PCT/US99/06893 -31 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 5 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 10 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 15 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 20 individually indicated to be so incorporated by reference.
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U0E E0- U E- < p U pU UE U E 1 pCD0 < U 0PU :14 p U UE~ U0~ 0 E 0 E, 00 G- 0 p !EU E-. 0 0 CDU:C 1 DPE ~0E0< 0 -E - c ~0 E- 0 E o -,<0 CD- 0 - U <C 10 0D 0 0 0 p U U <0 U U p U 01< 0000 I E E l 0E- 4 0 EE 000 &E 0 P P U 0 < CE- 1 E- E-- 0 U *E 0 E o K < p p 4 :4 C) < U P 0 E, U 0'U00 U < E-0 <U0 1 :0< pU < U0 0 U E 0 U4 U 0 E E,0 E 0 < 0U:zl PU E E- 0 I<K pU9E- p 0 DE - E <U< E 0&,C 4E-<UUC U E--;0 E0~ 0 - I< U UE- E-P E- < 0 < pU 0E- U E U 00 < U p p 0 0 E -E- U U0 U P & E- E- <0 E DPUUU& ,04<& U <<E <0~:- E5I ~ 0 0 ~ -- E- CD U << P4 -- 5 U UE-CD E-U UE-E P PE-,< < i 0U U0 U - < 0 U 9U0 U -0 0&I < 0 U P< UU - 0 ~0;IE,0 U 0 5 U 0 < < E-I UE5- U U <-E, < (D U0-<U[ 0 0 U5D- DE K -<: U I40<, DE - E- I ,40P4U c IUE U H C.) < 1_ (<CDE Cx' 0 E -E C <4 0& ,E < N U0( u~ c)9i: DU E ), -<U<0UE -<U< : -<E 0 U000; ,< U i 0 CD <: E -D E _-<<C < C)<U I N . I(NtI(t I) H< N C CD ~ U.- U5-U WO 99/53095 PCTIUS99/06893 323 1-~~- C(fl 0 00 IU 0<00 0 1 P0 U 0< UP , P P<E E0 10< E,< U UE 00. , P~ E <E < P<< :4E- P < 0 <0 P~0E P-0- 000 000 U PP E-PP- I :CPU < E, < <:4 CPP 0<00< 0 << <) b u- f< P< U0 UE-< iE-0<P-P < 0E< 0 U U< PU I U S 0 P~ <00 < j< UE, U < P~0 0E0 <<0U 0~<~- 0oE~ P ~ < P ~< i<E4 c UC 1 0 1 <00U4 P PE 0 P !0 P -'P < P 0<E, U E- 000 P<00<0 9 1UP CD 0U P E- E,E 00 E,<~- <0 U IIU UU<EUU P u Fc P 9 C)!-- 0 U 0PPU 4 0 0<- 1- 4 CD E.4 0<00 U P << 1UU-U0 0<<E <- U< I < I U EU- <E-<P- 0 -< E-D-E E 0 <'00Z4lt <E0< C ,Pe - <<0 E, P<~ < ~ I E <P-E- UP U < ~ 0 E.. E-1,x4 0E UE < 0.0P 0 U E<~ I UU PC) C.)P PP I- PE~-~0 4 < < U <0PC- U < U0 U <0 U << PF U OF P ~ F u- g 3 UE, P PC-0E - U00 F 0<< <0- 0 <<010000 P 0 P<0UUPU c 3< ( It,<F F-0 P<F F- 0< F- 0 -~ <P 0iFU-F-FU-< P- U- E--P 0 E-'< 0 P- 0 P <E0 E, 0 C- <0 F-5U 0 U < E u P0< P<<<'E P0 U4 O0<F~F-F00I U P U F << 0 <P U P P U U P P U0PE10 <F-OF-OFPO< C- 0 < I U <CU-E-<0 E0<FP 0 0 F< F- 01 < <0 U-~C f<4< 0 0 C< '- 089 10 FP 0 P C- 0 U 0 P -0 <0 P EPPU 0U 4PP 1 < < ) I u I U *PP<PP9E- 0C- 1 4U X I U )UE P P E<9E ,1 ,: l PPu < P PK 0 C- < 0 U0 C- U < U P<'UC 0 Uc P 1< EU- ED, U 4U U < uU K fc U0 P U PP 4Pt40 PEC U PE-C U flU uI P C-4 (DC (: < <'U< 41:4U I HI (E : IU< E < <CCPP I PE <~ CH u1 PU0 0PP I 0< Z0 P< < fU 0U <~ I f<> UI~ PI~ <I-H PIH HI C < PE <<E- ,E <U<Q<0!P0Prh- WO 99/53095 PCTIUS99/06893 324 UCCE E, 10 -t E-~~- c4 0 CE U U E ~u O E-CD U CDC E, E.~C <D E-E- p ,:C E U0 <0U-: .E u 9 CD U 09E <-~ ~CEC <D ~ U -E E E-~ P < E-E-~ UE- II - iE - UE- E uE~D 0E-E-E- E-~( E-DCC E- <. uC E- <E- C E-CDC 0 PC~C U ~ DCC E- 0 - 0p 0 E- CUU U E uDDD. U E- P U PE-C U E- ED E- U <<E E,0 , <0 U < U U E- suE- &, JU U<E U U U u U E- UC U CE- 0 < 1D0C- CU CDE- - -) E- E- E-) E- ~ ~ - u-E <+ < < E- UE~- 4 E Ec-C EUU E -EU ~&- U~ u 0 U 0 U U E- E-I 9 UE- E ,+ ! E -UU ~ U 0E-E CD U E, C- , E. &U~ E-c1< ( U ~- <E E, E- i E- C) g: E- C <I E D U o CD c U DE E E :14 -E- <C CD U u -E ,U 0 U E- U E -U -E U E- z U EDL C E (UP <01 E <D~CC E- - ~ UE- 9 - IE- E 4<E U-E, CE,-,:4< E,~~~~ U i ,U - < - UUU 0 P U00 U I<~ p0 E,0E 'UUU<<<0< U~~~~UC U U :E-opE p9 u u -- 0<CD. UU,$ 1< < -i0C EU U UUE . ,P u U00 i,<-~ E- U 0 -E 000, -0 Eu <- U u <U P-'UUE< ECDUUE00Ec E-0 < ~u <o9UUUU9 U UUE &I UDCD 0- 1 CD UU :-L E Ux4CE, U CUC-)E, P f< E- U P E<E U 1 EU U- <IU< :4E-E-U CD< U -<U p E-~ < :4pE,< U p4u p< U < U 0 1 pu p 0E- E- UE U 0E4 - < -~ CUCD < E- Uz E- < PPE- P' UD- U < U U U < E-U E-.9 E- <~ 0 P &- < DEU U U D 0 p E u 0 up E < UE-4 E UT I- I U E1 ,0 U PU U E UUU U E-UPP E-UUE U UU0POx .E 4t -[ U KI C u L 0 UE- 0 C) CD1< E < E, , 4 , U U - U& 0 0U E E E U -~ E- E- U -E iU ,UE P ~ ~ ~ ( E-E -U<UE rur)x 4 -E ,I 4 U UU<U 0& U0<(_ C U( < U u E- I E-c U Ix !E-UU< C WO 99/53095 PCT/US99/06893 -325 While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made 5 therein without departing from the spirit and scope of the invention as defined by the appended claims. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the 10 invention described specifically herein. Such equivalents are intended to be encompassed in the scope of the claims.

Claims (20)

1. A nucleic acid segment shown in column 7 of the Table, or a portion thereof which includes a 5 polymorphic site, or the complement of the segment or portion thereof.
2. The nucleic acid segment of claim 1 that is DNA.
3. The nucleic acid segment of claim 1 that is RNA.
4. The segment of claim 1 that is less than 100 bases. 10
5. The segment of claim 1 that is less than 50 bases.
6. The segment of claim 1 that is less than 20 bases.
7. The segment of claim 1, wherein the polymorphic site is biallelic. 15
8. The segment of claim 1, wherein the polymorphic form occupying the polymorphic site is the reference base for the fragment listed in the Table, column 3.
9. The segment of claim 1, wherein the polymorphic form occupying the polymorphic site is an alternative 20 form for the fragment listed in the Table, column 4.
10. An allele-specific oligonucleotide that hybridizes to a segment of a fragment shown in the Table, column 7 or its complement. WO 99/53095 PCT/US99/06893 -327
11. The allele-specific oligonucleotide of claim 10 that is a probe.
12. The allele-specific oligonucleotide of claim 10, wherein a central position of the probe aligns with 5 the polymorphic site of the fragment.
13. The allele-specific oligonucleotide of claim 10 that is a primer.
14. The allele-specific oligonucleotide of claim 13, wherein the 3' end of the primer aligns with the 10 polymorphic site of the fragment.
15. The allele-specific oligonucleotide of Claim 10, which is selected from the group consisting of the nucleotide sequences of the Table, column 5.
16. The allele-specific oligonucleotide of Claim 10, 15 which is selected from the group consisting of the nucleotide sequences of the Table, column 6.
17. An isolated nucleic acid comprising a sequence of the Table, column 7 or the complement thereof, wherein the polymorphic site within the sequence or 20 complement is occupied by a base other than the reference base shown in the Table, column 3.
18. A method of analyzing a nucleic acid, comprising obtaining the nucleic acid from an individual; and determining a base occupying any one of the 25 polymorphic sites shown in the Table. WO 99/53095 PCTIUS99/06893 -328
19. The method of claim 18, wherein the determining comprises determining a set of bases occupying a set of the polymorphic sites shown in the Table.
20. The method of claim 18, wherein the nucleic acid is 5 obtained from a plurality of individuals, and a base occupying one of the polymorphic positions is determined in each of the individuals, and the method further comprising testing each individual for the presence of a disease phenotype, and 10 correlating the presence of the disease phenotype with the base.
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AU1477601A (en) * 1999-11-10 2001-06-06 Affymetrix, Inc. Genetic compositions and methods
US6756214B2 (en) 2000-11-09 2004-06-29 Zymogenetics, Inc. Protein zlmda33
AU2002258626B2 (en) 2001-04-10 2007-01-18 Agensys, Inc. Nucleid acid and corresponding protein entitled 158P3D2 useful in treatment and detection of cancer
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