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Homozygous loss-of-function variants in european cosmopolitan and isolate populations

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Item Type:Article
Title:Homozygous loss-of-function variants in european cosmopolitan and isolate populations
Creators Name:Kaiser, V.B. and Svinti, V. and Prendergast, J.G. and Chau, Y.Y. and Campbell, A. and Patarcic, I. and Barroso, I. and Joshi, P.K. and Hastie, N.D. and Miljkovic, A. and Taylor, M.S. and Enroth, S. and Memari, Y. and Kolb-Kokocinski, A. and Wright, A.F. and Gyllensten, U. and Durbin, R. and Rudan, I. and Campbell, H. and Polašek, O. and Johansson, A. and Sauer, S. and Porteous, D.J. and Fraser, R.M. and Drake, C. and Vitart, V. and Hayward, C. and Semple, C.A. and Wilson, J.F.
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.
Keywords:European Continental Ancestry Group, Exome, Gene Frequency, Genetic Selection, Homozygote, Mutation, Phenotype
Source:Human Molecular Genetics
ISSN:0964-6906
Publisher:Oxford University Press (U.K.)
Volume:24
Number:19
Page Range:5464-5474
Date:1 October 2015
Official Publication:https://doi.org/10.1093/hmg/ddv272
PubMed:View item in PubMed

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