Estimating the selective effects of heterozygous protein-truncating variants from human exome data

被引：97

作者：

Cassa, Christopher A. ^{[1
]}

Weghorn, Donate ^{[1
]}

Balick, Daniel J. ^{[1
]}

Jordan, Daniel M. ^{[3
]}

Nusinow, David ^{[1
]}

Samocha, Kaitlin E. ^{[4
,5
]}

O'Donnell-Luria, Anne ^{[4
,6
]}

MacArthur, Daniel G. ^{[2
,4
]}

Daly, Mark J. ^{[2
,4
]}

Beier, David R. ^{[7
,8
]}

Sunyaev, Shamil R. ^{[1
,2
]}

机构：

[1] Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA

[2] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[3] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[4] Harvard Med Sch, Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA USA

[5] Harvard Med Sch, Program Biol & Biomed Sci, Boston, MA USA

[6] Boston Childrens Hosp, Div Genet & Genom, Boston, MA USA

[7] Seattle Childrens Res Inst, Ctr Dev Biol & Regenerat Med, Seattle, WA 98101 USA

[8] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA

来源：

NATURE GENETICS | 2017年 / 49卷 / 05期

基金：

美国国家卫生研究院;

关键词：

DELETERIOUS-MUTATION; GENETIC-VARIATION; CODING VARIATION; MUTANT-GENE; EVOLUTION; AGE; IDENTIFICATION; INDIVIDUALS; PATTERNS; DISEASE;

D O I：

10.1038/ng.3831

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

The evolutionary cost of gene loss is a central question in genetics and has been investigated in model organisms and human cell lines(1-3). In humans, tolerance of the loss of one or both functional copies of a gene is related to the gene's causal role in disease. However, estimates of the selection and dominance coefficients in humans have been elusive. Here we analyze exome sequence data from 60,706 individuals(4) to make genome-wide estimates of selection against heterozygous loss of gene function. Using this distribution of selection coefficients for heterozygous protein-truncating variants (PTVs), we provide corresponding Bayesian estimates for individual genes. We find that genes under the strongest selection are enriched in embryonic lethal mouse knockouts, Mendelian disease-associated genes, and regulators of transcription. Screening by essentiality, we find a large set of genes under strong selection that are likely to have crucial functions but have not yet been thoroughly characterized.

引用

页码：806 / +

页数：8

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