Identification of a large set of rare complete human knockouts

被引：173

作者：

Sulem, Patrick ^{[1
]}

Helgason, Hannes ^{[1
,2
]}

Oddson, Asmundur ^{[1
]}

Stefansson, Hreinn ^{[1
]}

Gudjonsson, Sigurjon A. ^{[1
]}

Zink, Florian ^{[1
]}

Hjartarson, Eirikur ^{[1
]}

Sigurdsson, Gunnar Th ^{[1
]}

Jonasdottir, Adalbjorg ^{[1
]}

Jonasdottir, Aslaug ^{[1
]}

Sigurdsson, Asgeir ^{[1
]}

Magnusson, Olafur Th ^{[1
]}

Kong, Augustine ^{[1
,2
]}

Helgason, Agnar ^{[1
,3
]}

Holm, Hilma ^{[1
,4
]}

Thorsteinsdottir, Unnur ^{[1
,5
]}

Masson, Gisli ^{[1
]}

Gudbjartsson, Daniel F. ^{[1
,2
]}

Stefansson, Kari ^{[1
,5
]}

机构：

[1] Amgen Inc, DeCODE Genet, Reykjavik, Iceland

[2] Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland

[3] Univ Iceland, Dept Anthropol, Reykjavik, Iceland

[4] Landspitali Natl Univ Hosp Iceland, Dept Internal Med, Reykjavik, Iceland

[5] Univ Iceland, Fac Med, Reykjavik, Iceland

来源：

NATURE GENETICS | 2015年 / 47卷 / 05期

关键词：

FUNCTIONAL IMPACT; VARIANTS; DISEASE; MOUSE; EVOLUTION; ONTOLOGY; GENETICS; MUTATION; DATABASE; ORIGIN;

D O I：

10.1038/ng.3243

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Loss-of-function mutations cause many mendelian diseases. Here we aimed to create a catalog of autosomal genes that are completely knocked out in humans by rare loss-of-function mutations. We sequenced the whole genomes of 2,636 Icelanders and imputed the sequence variants identified in this set into 101,584 additional chip-genotyped and phased Icelanders. We found a total of 6,795 autosomal loss-of-function SNPs and indels in 4,924 genes. Of the genotyped Icelanders, 7.7% are homozygotes or compound heterozygotes for loss-offunction mutations with a minor allele frequency (MAF) below 2% in 1,171 genes (complete knockouts). Genes that are highly expressed in the brain are less often completely knocked out than other genes. Homozygous loss-of-function offspring of two heterozygous parents occurred less frequently than expected (deficit of 136 per 10,000 transmissions for variants with MAF <2%, 95% confidence interval (CI) = 10-261).

引用

页码：448 / U30

页数：6

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