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Hum Mol Genet. 2015 Oct 1;24(19):5464-74. doi: 10.1093/hmg/ddv272. Epub 2015 Jul 14.

Homozygous loss-of-function variants in European cosmopolitan and isolate populations.

Author information

1
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine and vera.kaiser@igmm.ed.ac.uk.
2
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine and.
3
The Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK.
4
Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
5
Medical School, University of Split, Soltanska 2, Split 21000, Croatia.
6
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
7
Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK.
8
Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, Uppsala SE-75108, Sweden and.
9
Medical School, University of Split, Soltanska 2, Split 21000, Croatia, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK.
10
Max-Planck-Institute for Molecular Genetics, Otto-Warburg-Laboratory, Berlin, Germany.
11
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine and Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK.

Abstract

Homozygous loss of function (HLOF) variants provide a valuable window on gene function in humans, as well as an inventory of the human genes that are not essential for survival and reproduction. All humans carry at least a few HLOF variants, but the exact number of inactivated genes that can be tolerated is currently unknown—as are the phenotypic effects of losing function for most human genes. Here, we make use of 1432 whole exome sequences from five European populations to expand the catalogue of known human HLOF mutations; after stringent filtering of variants in our dataset, we identify a total of 173 HLOF mutations, 76 (44%) of which have not been observed previously. We find that population isolates are particularly well suited to surveys of novel HLOF genes because individuals in such populations carry extensive runs of homozygosity, which we show are enriched for novel, rare HLOF variants. Further, we make use of extensive phenotypic data to show that most HLOFs, ascertained in population-based samples, appear to have little detectable effect on the phenotype. On the contrary, we document several genes directly implicated in disease that seem to tolerate HLOF variants. Overall HLOF genes are enriched for olfactory receptor function and are expressed in testes more often than expected, consistent with reduced purifying selection and incipient pseudogenisation.

PMID:
26173456
PMCID:
PMC4572071
DOI:
10.1093/hmg/ddv272
[Indexed for MEDLINE]
Free PMC Article

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