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Homozygous loss-of-function variants in European cosmopolitan and isolate populations
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2015 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 19, 5464-5475 p.Article in journal (Refereed) Published
Abstract [en]

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 1,432 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.

Place, publisher, year, edition, pages
2015. Vol. 24, no 19, 5464-5475 p.
National Category
Medical Genetics
URN: urn:nbn:se:uu:diva-258903DOI: 10.1093/hmg/ddv272ISI: 000363018100007PubMedID: 26173456OAI: oai:DiVA.org:uu-258903DiVA: diva2:842602
Swedish Research Council, K2007-66X-20270-01-3Swedish Research Council, 2011-2354Swedish Society for Medical Research (SSMF)EU, FP7, Seventh Framework Programme, 262055Swedish Research Council, 80576801Swedish Research Council, 70374401Wellcome trust, WT091310EU, European Research Council, LSHG-CT-2006-018947
Available from: 2015-07-21 Created: 2015-07-21 Last updated: 2016-08-29Bibliographically approved

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Enroth, StefanGyllensten, UlfJohansson, Åsa
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Medicinsk genetik och genomikScience for Life Laboratory, SciLifeLab
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