title: Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants.
abstract: Establishing the age of each mutation segregating in contemporary human populations is important to fully understand our evolutionary history and will help to facilitate the development of new approaches for disease-gene discovery. Large-scale surveys of human genetic variation have reported signatures of recent explosive population growth, notable for an excess of rare genetic variants, suggesting that many mutations arose recently. To more quantitatively assess the distribution of mutation ages, we resequenced 15,336 genes in 6,515 individuals of European American and African American ancestry and inferred the age of 1,146,401 autosomal single nucleotide variants (SNVs). We estimate that approximately 73% of all protein-coding SNVs and approximately 86% of SNVs predicted to be deleterious arose in the past 5,000-10,000 years. The average age of deleterious SNVs varied significantly across molecular pathways, and disease genes contained a significantly higher proportion of recently arisen deleterious SNVs than other genes. Furthermore, European Americans had an excess of deleterious variants in essential and Mendelian disease genes compared to African Americans, consistent with weaker purifying selection due to the Out-of-Africa dispersal. Our results better delimit the historical details of human protein-coding variation, show the profound effect of recent human history on the burden of deleterious SNVs segregating in contemporary populations, and provide important practical information that can be used to prioritize variants in disease-gene discovery.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. wqfu@u.washington.edu
authors.forename: Wenqing
authors.initials: W
authors.lastname: Fu
authors.forename: Timothy D
authors.initials: TD
authors.lastname: O'Connor
authors.forename: Goo
authors.initials: G
authors.lastname: Jun
authors.forename: Hyun Min
authors.initials: HM
authors.lastname: Kang
authors.forename: Goncalo
authors.initials: G
authors.lastname: Abecasis
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Akey
mesh_terms: D000349:Africa / Q000208:ethnology; D000483:Alleles; D044383:Black People / Q000235:genetics; D005060:Europe / Q000208:ethnology; D019143:Evolution, Molecular; D059472:Exome / Q000235:genetics*; D005091:Exons / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D016366:Open Reading Frames / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014481:United States; D044465:White People / Q000235:genetics; D001741:Black or African American