Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis

Sequence variation in human genes is largely confined to single-nucleotide polymorphisms (SNPs) and is valuable in tests of association with common di seases and pharmacogenetic traits. We performed a systematic and comprehens ive survey of molecular variation to assess the nature, pattern and frequen cy of SNPs in 75 candidate human genes for blood-pressure homeostasis and h ypertension. We assayed 28 Mb(190 kb in 148 alleles) of genomic sequence, c omprising the 5' and 3' untranslated regions (UTRs), introns and coding seq uence of these genes, for sequence differences in individuals of African an d Northern European descent using high-density variant detection arrays (VD As). We identified 874 candidate human SNPs, of which 22% were confirmed by DNA sequencing to reveal a discordancy rate of 21% for VDA detection. The SNPs detected have an average minor allele frequency of 11%, and 387 are wi thin the coding sequence (cSNPs). Of all cSNPs, 54% lead to a predicted cha nge in the protein sequence, implying a high level of human protein diversi ty. These protein-altering SNPs are 38% of the total number of such SNPs ex pected, are more likely to be population-specific and are rarer in the huma n population, directly demonstrating the effects of natural selection on hu man genes. Overall, the degree of nucleotide polymorphism across these huma n genes, and orthologous great ape sequences, is highly variable and is cor related with the effects of functional conservation on gene sequences.