title: A systematic survey of loss-of-function variants in human protein-coding genes.
abstract: Genome-sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome. Here we apply stringent filters to 2951 putative LoF variants obtained from 185 human genomes to determine their true prevalence and properties. We estimate that human genomes typically contain ~100 genuine LoF variants with ~20 genes completely inactivated. We identify rare and likely deleterious LoF alleles, including 26 known and 21 predicted severe disease-causing variants, as well as common LoF variants in nonessential genes. We describe functional and evolutionary differences between LoF-tolerant and recessive disease genes and a method for using these differences to prioritize candidate genes found in clinical sequencing studies.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK. macarthur@atgu.mgh.harvard.edu
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.forename: Suganthi
authors.initials: S
authors.lastname: Balasubramanian
authors.forename: Adam
authors.initials: A
authors.lastname: Frankish
authors.forename: Ni
authors.initials: N
authors.lastname: Huang
authors.forename: James
authors.initials: J
authors.lastname: Morris
authors.forename: Klaudia
authors.initials: K
authors.lastname: Walter
authors.forename: Luke
authors.initials: L
authors.lastname: Jostins
authors.forename: Lukas
authors.initials: L
authors.lastname: Habegger
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Pickrell
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Montgomery
authors.forename: Cornelis A
authors.initials: CA
authors.lastname: Albers
authors.forename: Zhengdong D
authors.initials: ZD
authors.lastname: Zhang
authors.forename: Donald F
authors.initials: DF
authors.lastname: Conrad
authors.forename: Gerton
authors.initials: G
authors.lastname: Lunter
authors.forename: Hancheng
authors.initials: H
authors.lastname: Zheng
authors.forename: Qasim
authors.initials: Q
authors.lastname: Ayub
authors.forename: Mark A
authors.initials: MA
authors.lastname: DePristo
authors.forename: Eric
authors.initials: E
authors.lastname: Banks
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.forename: Robert E
authors.initials: RE
authors.lastname: Handsaker
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Rosenfeld
authors.forename: Menachem
authors.initials: M
authors.lastname: Fromer
authors.forename: Mike
authors.initials: M
authors.lastname: Jin
authors.forename: Xinmeng Jasmine
authors.initials: XJ
authors.lastname: Mu
authors.forename: Ekta
authors.initials: E
authors.lastname: Khurana
authors.forename: Kai
authors.initials: K
authors.lastname: Ye
authors.forename: Mike
authors.initials: M
authors.lastname: Kay
authors.forename: Gary Ian
authors.initials: GI
authors.lastname: Saunders
authors.forename: Marie-Marthe
authors.initials: MM
authors.lastname: Suner
authors.forename: Toby
authors.initials: T
authors.lastname: Hunt
authors.forename: If H A
authors.initials: IH
authors.lastname: Barnes
authors.forename: Clara
authors.initials: C
authors.lastname: Amid
authors.forename: Denise R
authors.initials: DR
authors.lastname: Carvalho-Silva
authors.forename: Alexandra H
authors.initials: AH
authors.lastname: Bignell
authors.forename: Catherine
authors.initials: C
authors.lastname: Snow
authors.forename: Bryndis
authors.initials: B
authors.lastname: Yngvadottir
authors.forename: Suzannah
authors.initials: S
authors.lastname: Bumpstead
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.forename: Yali
authors.initials: Y
authors.lastname: Xue
authors.forename: Irene Gallego
authors.initials: IG
authors.lastname: Romero
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Yingrui
authors.initials: Y
authors.lastname: Li
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: Steven A
authors.initials: SA
authors.lastname: McCarroll
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Pritchard
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Barrett
authors.forename: Jennifer
authors.initials: J
authors.lastname: Harrow
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.forename: Mark B
authors.initials: MB
authors.lastname: Gerstein
authors.forename: Chris
authors.initials: C
authors.lastname: Tyler-Smith
mesh_terms: D004194:Disease / Q000235:genetics; D015870:Gene Expression; D005787:Gene Frequency; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D012641:Selection, Genetic
chemical_list: D011506:Proteins