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Nat Genet. 2015 May;47(5):448-52. doi: 10.1038/ng.3243. Epub 2015 Mar 25.

Identification of a large set of rare complete human knockouts.

Author information

1
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
2
1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
3
1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] Department of Anthropology, University of Iceland, Reykjavik, Iceland.
4
1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] Department of Internal Medicine, Landspitali The National University Hospital of Iceland, Reykjavik, Iceland.
5
1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

Abstract

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-of-function 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).

PMID:
25807282
DOI:
10.1038/ng.3243
[Indexed for MEDLINE]

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