title: Genome-wide analysis of single-nucleotide polymorphisms in human expressed sequences.
abstract: Single-nucleotide polymorphisms (SNPs) have been explored as a high-resolution marker set for accelerating the mapping of disease genes. Here we report 48,196 candidate SNPs detected by statistical analysis of human expressed sequence tags (ESTs), associated primarily with coding regions of genes. We used Bayesian inference to weigh evidence for true polymorphism versus sequencing error, misalignment or ambiguity, misclustering or chimaeric EST sequences, assessing data such as raw chromatogram height, sharpness, overlap and spacing, sequencing error rates, context-sensitivity and cDNA library origin. Three separate validations-comparison with 54 genes screened for SNPs independently, verification of HLA-A polymorphisms and restriction fragment length polymorphism (RFLP) testing-verified 70%, 89% and 71% of our predicted SNPs, respectively. Our method detects tenfold more true HLA-A SNPs than previous analyses of the EST data. We found SNPs in a large fraction of known disease genes, including some disease-causing mutations (for example, the HbS sickle-cell mutation). Our comprehensive analysis of human coding region polymorphism provides a public resource for mapping of disease genes (available at http://www.bioinformatics.ucla.edu/snp).
authors.affiliation: Department of Chemistry & Biochemistry, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: K
authors.initials: K
authors.lastname: Irizarry
authors.forename: V
authors.initials: V
authors.lastname: Kustanovich
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.forename: N
authors.initials: N
authors.lastname: Brown
authors.forename: S
authors.initials: S
authors.lastname: Nelson
authors.forename: W
authors.initials: W
authors.lastname: Wong
authors.forename: C J
authors.initials: CJ
authors.lastname: Lee
mesh_terms: D001483:Base Sequence; D002874:Chromosome Mapping; D002892:Chromosomes, Human, Pair 22; D003115:Colony-Stimulating Factors / Q000235:genetics; D020224:Expressed Sequence Tags; D058851:GPI-Linked Proteins; D015723:Gene Library; D030342:Genetic Diseases, Inborn / Q000235:genetics; D005819:Genetic Markers; D015894:Genome, Human; D015234:HLA-A Antigens / Q000235:genetics*; D006801:Humans; D008562:Membrane Glycoproteins; D000090204:Mesothelin; D008957:Models, Genetic; D015233:Models, Statistical; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D011506:Proteins / Q000235:genetics*; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid
chemical_list: D003115:Colony-Stimulating Factors; D058851:GPI-Linked Proteins; D005819:Genetic Markers; D015234:HLA-A Antigens; D008562:Membrane Glycoproteins; D011506:Proteins; D000090204:Mesothelin