title: Evolution and functional impact of rare coding variation from deep sequencing of human exomes.
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.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Tennessen
authors.forename: Abigail W
authors.initials: AW
authors.lastname: Bigham
authors.forename: Timothy D
authors.initials: TD
authors.lastname: O'Connor
authors.forename: Wenqing
authors.initials: W
authors.lastname: Fu
authors.forename: Eimear E
authors.initials: EE
authors.lastname: Kenny
authors.forename: Simon
authors.initials: S
authors.lastname: Gravel
authors.forename: Sean
authors.initials: S
authors.lastname: McGee
authors.forename: Ron
authors.initials: R
authors.lastname: Do
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Liu
authors.forename: Goo
authors.initials: G
authors.lastname: Jun
authors.forename: Hyun Min
authors.initials: HM
authors.lastname: Kang
authors.forename: Daniel
authors.initials: D
authors.lastname: Jordan
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: Goncalo
authors.initials: G
authors.lastname: Abecasis
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Shamil
authors.initials: S
authors.lastname: Sunyaev
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Bustamante
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Akey
mesh_terms: D001741:Black or African American / Q000235:genetics*; D004194:Disease / Q000235:genetics; D019143:Evolution, Molecular; D059472:Exome; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011158:Population Growth; D012641:Selection, Genetic; D044465:White People / Q000235:genetics*