The Characteristics of Heterozygous Protein Truncating Variants in the Human Genome

被引：24

作者：

Bartha, Istvan ^{[1
,2
,3
]}

Rausell, Antonio ^{[1
,2
,4
]}

McLaren, Paul J. ^{[1
,2
,3
]}

Mohammadi, Pejman ^{[1
,2
,5
]}

Tardaguila, Manuel ^{[1
,2
,4
]}

Chaturvedi, Nimisha ^{[1
,2
,3
]}

Fellay, Jacques ^{[1
,2
,3
]}

Telenti, Amalio ^{[6
]}

机构：

[1] SIB, Lausanne, Switzerland

[2] SIB, Basel, Switzerland

[3] Ecole Polytech Fed Lausanne, Sch Life Sci, Lausanne, Switzerland

[4] SIB, Vital IT Grp, Lausanne, Switzerland

[5] Swiss Fed Inst Technol, Computat Biol Grp, Zurich, Switzerland

[6] J Craig Venter Inst, La Jolla, CA USA

来源：

PLOS COMPUTATIONAL BIOLOGY | 2015年 / 11卷 / 12期

基金：

瑞士国家科学基金会;

关键词：

GENE-FUNCTION; SEQUENCE; MOUSE; GENERATION; IDENTIFICATION; FRAMEWORK; SET;

D O I：

10.1371/journal.pcbi.1004647

中图分类号：

Q5 [生物化学];

学科分类号：

070307 [化学生物学];

摘要：

Sequencing projects have identified large numbers of rare stop-gain and frameshift variants in the human genome. As most of these are observed in the heterozygous state, they test a gene's tolerance to haploinsufficiency and dominant loss of function. We analyzed the distribution of truncating variants across 16,260 autosomal protein coding genes in 11,546 individuals. We observed 39,893 truncating variants affecting 12,062 genes, which significantly differed from an expectation of 12,916 genes under a model of neutral de novo mutation (p<10(-4)). Extrapolating this to increasing numbers of sequenced individuals, we estimate that 10.8% of human genes do not tolerate heterozygous truncating variants. An additional 10 to 15% of truncated genes may be rescued by incomplete penetrance or compensatory mutations, or because the truncating variants are of limited functional impact. The study of protein truncating variants delineates the essential genome and, more generally, identifies rare heterozygous variants as an unexplored source of diversity of phenotypic traits and diseases.

引用

页数：14

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