An unusual suspect: an uncommon human-specific synonymous coding variant within the?UGT1A6?gene explains a GWAS signal and protects against bladder cancer

摘要

Deep exome resequencing is a powerful approach for delineating patternsof protein-coding variation among genes, pathways, individuals andpopulations. We analyzed exome data from 2,440 individuals of Europeanand African ancestry as part of the National Heart, Lung, and BloodInstitute's Exome Project, the aim of which is to discover novel genes andmechanisms that contribute to heart, lung and blood disorders. Each exomewas sequenced to a mean coverage of 116×, allowing detailed inferencesabout the population genomic patterns of both common variation andrare coding variation. We identified more than 500,000 single nucleotidevariations, the majority of which were novel and rare (76% of variants hada minor allele frequency of less than 0.1%), reflecting the recent dramaticincrease in the size of the human population. The unprecedented magnitudeof this dataset allowed us to rigorously characterize the large variationin nucleotide diversity among genes (ranging from 0 to 1.32%), as well asthe role of positive and purifying selection in shaping patterns of proteincoding variation and the diff erential signatures of population structure fromrare and common variation. This dataset provides a framework for personagenomics and is an important resource that will allow inferences of broadimportance to human evolution and health.