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Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants.

TitleAnalysis of 6,515 exomes reveals the recent origin of most human protein-coding variants.
Publication TypeJournal Article
Year of Publication2013
AuthorsFu W, O'Connor TD, Jun G, Kang HMin, Abecasis G, Leal SM, Gabriel S, Rieder MJ, Altshuler D, Shendure J, Nickerson DA, Bamshad MJ
Secondary AuthorsAkey JM
Corporate AuthorsNHLBI Exome Sequencing Project
JournalNature
Volume493
Issue7431
Pagination216-20
Date Published2013 Jan 10
ISSN1476-4687
KeywordsAfrica, African Continental Ancestry Group, Alleles, Europe, European Continental Ancestry Group, Evolution, Molecular, Exome, Exons, Genetic Variation, Humans, Open Reading Frames, Polymorphism, Single Nucleotide, United States
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.

DOI10.1038/nature11690
Alternate JournalNature
PubMed ID23201682
PubMed Central IDPMC3676746
Grant ListRC2 HL102923 / HL / NHLBI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
RC2 HL-102926 / HL / NHLBI NIH HHS / United States
U01 HG006513 / HG / NHGRI NIH HHS / United States
RC2 HL-102923 / HL / NHLBI NIH HHS / United States
RC2 HL-102924 / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
090532 / / Wellcome Trust / United Kingdom
RC2 HL103010 / HL / NHLBI NIH HHS / United States
RC2HL-102925 / HL / NHLBI NIH HHS / United States
RC2 HL-103010 / HL / NHLBI NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States