Efficient discovery of single-nucleotide polymorphisms in coding regions of human genes

• Published in: The pharmacogenomics journal Vol. 2; no. 4; pp. 236 - 242
• Main Authors: HU, G, MODREK, B, RIISE STENSLAND, H. M. F, SAARELA, J, PAJUKANTA, P, KUSTANOVICH, V, PELTONEN, L, NELSON, S. F, LEE, C
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 2002; Nature Publishing Group
• Subjects: Amino acids; Biological and medical sciences; Chromosome Mapping; Classical genetics, quantitative genetics, hybrids; Databases, Nucleic Acid; Expressed Sequence Tags; Fundamental and applied biological sciences. Psychology; Gene mapping; Genetic screening; Genetic susceptibility; Genetics of eukaryotes. Biological and molecular evolution; Health aspects; Heterozygote; Humans; Methods, theories and miscellaneous; Multigene Family; Natural selection; Nucleotide sequence; Open Reading Frames - genetics; Phenotypes; Physiological aspects; Polymorphism, Single Nucleotide - genetics; Protein Conformation; Protein structure; Proteins; Proteins - chemistry; Proteins - genetics; Reproducibility of Results; Single nucleotide polymorphisms; Single-nucleotide polymorphism; United States; Genetic mapping; Human; Gene; Nucleotide sequence; Identification; Single nucleotide polymorphism; Molecular biology; Data mining; Bioinformatics; Protein
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/sj.tpj.6500109

Single nucleotide polymorphisms in protein coding regions (cSNPs) are of great interest for their effects on phenotype and potential for mapping disease genes. We have identified 5,400 novel exonic SNPs from alignments of public EST data to the draft human genome sequence, and approximately 12,000 more novel exonic SNPs from EST cluster alignments. We found 82% of the genomic-aligned SNPs and 63% of the EST-only SNPs to be detectably polymorphic in 20 Finnish DNA samples. 37% of the SNPs mapped to known protein coding regions, yielding 6,500 distinct, novel cSNPs from the two datasets. These data reveal selection against mutations that alter protein structure, and distinct classes of genes under strongly positive vs. negative pressure from natural selection for amino acid replacement (detected by K(A)/K(S)ratio). We have searched these cSNPs for compatibility with the amino acid profile at each site and structural impact on protein core stability.