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Evolution and functional impact of rare coding variation from deep sequencing of human exomes.

TitleEvolution and functional impact of rare coding variation from deep sequencing of human exomes.
Publication TypeJournal Article
Year of Publication2012
AuthorsTennessen JA, Bigham AW, O'Connor TD, Fu W, Kenny EE, Gravel S, McGee S, Do R, Liu X, Jun G, Kang HMin, Jordan D, Leal SM, Gabriel S, Rieder MJ, Abecasis G, Altshuler D, Nickerson DA, Boerwinkle E, Sunyaev S, Bustamante CD, Bamshad MJ
Secondary AuthorsAkey JM
Corporate AuthorsBroad GO, Seattle GO, NHLBI Exome Sequencing Project
JournalScience
Volume337
Issue6090
Pagination64-9
Date Published2012 Jul 06
ISSN1095-9203
KeywordsAfrican Americans, Disease, European Continental Ancestry Group, Evolution, Molecular, Exome, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Male, Polymorphism, Single Nucleotide, Population Growth, Selection, Genetic
Abstract

As a first step toward understanding how rare variants contribute to risk for complex diseases, we sequenced 15,585 human protein-coding genes to an average median depth of 111× in 2440 individuals of European (n = 1351) and African (n = 1088) ancestry. We identified over 500,000 single-nucleotide variants (SNVs), the majority of which were rare (86% with a minor allele frequency less than 0.5%), previously unknown (82%), and population-specific (82%). On average, 2.3% of the 13,595 SNVs each person carried were predicted to affect protein function of ~313 genes per genome, and ~95.7% of SNVs predicted to be functionally important were rare. This excess of rare functional variants is due to the combined effects of explosive, recent accelerated population growth and weak purifying selection. Furthermore, we show that large sample sizes will be required to associate rare variants with complex traits.

DOI10.1126/science.1219240
Alternate JournalScience
PubMed ID22604720
PubMed Central IDPMC3708544
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
R01 HG003229 / HG / NHGRI NIH HHS / United States
RC2 HL-102924 / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
RC2 HL-102925 / HL / NHLBI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
RC2 HL-103010 / HL / NHLBI NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States