Characterization of single-nucleotide polymorphisms in coding regions of human genes

A major goal in human genetics is to understand the role of common genetic variants in susceptibility to common diseases. This will require characteri zing the nature of gene variation in human populations, assembling an exten sive catalogue of single-nucleotide polymorphisms (SNPs) in candidate genes and performing association studies for particular diseases. At present, ou r knowledge of human gene variation remains rudimentary. Here we describe a systematic survey of SNPs in the coding regions of human genes. We identif ied SNPs in 106 genes relevant to cardiovascular disease, endocrinology and neuropsychiatry by screening an average of 114 independent alleles using 2 independent screening methods. To ensure high accuracy, all reported SNPs were confirmed by DNA sequencing. We identified 560 SNPs, including 392 cod ing-region SNPs (cSNPs) divided roughly equally between those causing synon ymous and non-synonymous changes. We observed different rates of polymorphi sm among classes of sites within genes (non-coding, degenerate and non-dege nerate) as well as between genes. The cSNPs most likely to influence diseas e, those that alter the amino acid sequence of the encoded protein, are fou nd at a lower rate and with lower allele frequencies than silent substituti ons. This likely reflects selection acting against deleterious alleles duri ng human evolution. The lower allele frequency of missense cSNPs has implic ations for the compilation of a comprehensive catalogue, as well as for the subsequent application to disease association.