title: Homozygous loss-of-function variants in European cosmopolitan and isolate populations.
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.
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine and vera.kaiser@igmm.ed.ac.uk.
authors.forename: Vera B
authors.initials: VB
authors.lastname: Kaiser
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine and.
authors.forename: Victoria
authors.initials: V
authors.lastname: Svinti
authors.affiliation: The Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK.
authors.forename: James G
authors.initials: JG
authors.lastname: Prendergast
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine and.
authors.forename: You-Ying
authors.initials: YY
authors.lastname: Chau
authors.affiliation: Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
authors.forename: Archie
authors.initials: A
authors.lastname: Campbell
authors.affiliation: Medical School, University of Split, Soltanska 2, Split 21000, Croatia.
authors.forename: Inga
authors.initials: I
authors.lastname: Patarcic
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.affiliation: Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Joshi
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine and.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Hastie
authors.affiliation: Medical School, University of Split, Soltanska 2, Split 21000, Croatia.
authors.forename: Ana
authors.initials: A
authors.lastname: Miljkovic
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine and.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Taylor
authors.affiliation: Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, Uppsala SE-75108, Sweden and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Enroth
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Yasin
authors.initials: Y
authors.lastname: Memari
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Anja
authors.initials: A
authors.lastname: Kolb-Kokocinski
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine and.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.affiliation: Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, Uppsala SE-75108, Sweden and.
authors.forename: Ulf
authors.initials: U
authors.lastname: Gyllensten
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Durbin
authors.affiliation: Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK.
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
authors.affiliation: Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK.
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.affiliation: 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.
authors.forename: Ozren
authors.initials: O
authors.lastname: Polašek
authors.affiliation: Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, Uppsala SE-75108, Sweden and.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Johansson
authors.affiliation: Max-Planck-Institute for Molecular Genetics, Otto-Warburg-Laboratory, Berlin, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Sauer
authors.affiliation: Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.affiliation: Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK.
authors.forename: Ross M
authors.initials: RM
authors.lastname: Fraser
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine and.
authors.forename: Camilla
authors.initials: C
authors.lastname: Drake
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine and.
authors.forename: Veronique
authors.initials: V
authors.lastname: Vitart
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine and.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine and.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Semple
authors.affiliation: 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.
authors.forename: James F
authors.initials: JF
authors.lastname: Wilson
mesh_terms: D059472:Exome; D005787:Gene Frequency; D006720:Homozygote; D006801:Humans; D009154:Mutation; D010641:Phenotype; D012641:Selection, Genetic; D044465:White People / Q000235:genetics*