A systematic survey of loss-of-function variants in human protein-coding genes.

TitleA systematic survey of loss-of-function variants in human protein-coding genes.
Publication TypeJournal Article
Year of Publication2012
AuthorsMacArthur, DG, Balasubramanian, S, Frankish, A, Huang, N, Morris, J, Walter, K, Jostins, L, Habegger, L, Pickrell, JK, Montgomery, SB, Albers, CA, Zhang, ZD, Conrad, DF, Lunter, G, Zheng, H, Ayub, Q, DePristo, MA, Banks, E, Hu, M, Handsaker, RE, Rosenfeld, JA, Fromer, M, Jin, M, Mu, XJasmine, Khurana, E, Ye, K, Kay, M, Saunders, GIan, Suner, M-M, Hunt, T, Barnes, IHA, Amid, C, Carvalho-Silva, DR, Bignell, AH, Snow, C, Yngvadottir, B, Bumpstead, S, Cooper, DN, Xue, Y, Romero, IGallego, Wang, J, Li, Y, Gibbs, RA, McCarroll, SA, Dermitzakis, ET, Pritchard, JK, Barrett, JC, Harrow, J, Hurles, ME, Gerstein, MB, Tyler-Smith, C
Corporate Authors1000 Genomes Project Consortium
Date Published2012 Feb 17
KeywordsDisease, Gene Expression, Gene Frequency, Genetic Variation, Genome, Human, Humans, Phenotype, Polymorphism, Single Nucleotide, Proteins, Selection, Genetic

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.

Alternate JournalScience
PubMed ID22344438
PubMed Central IDPMC3299548
Grant ListRG/09/012/28096 / BHF_ / British Heart Foundation / United Kingdom
U54 HG003273 / HG / NHGRI NIH HHS / United States
090532 / WT_ / Wellcome Trust / United Kingdom
090532/Z/09/Z / WT_ / Wellcome Trust / United Kingdom
/ WT_ / Wellcome Trust / United Kingdom
085532 / WT_ / Wellcome Trust / United Kingdom
R21 AA022707 / AA / NIAAA NIH HHS / United States
BB/I02593X/1 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom
098051 / WT_ / Wellcome Trust / United Kingdom

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