Health and population effects of rare gene knockouts in adult humans with related parents | Zendy

Vagheesh M. Narasimhan | Zendy; Karen A. Hunt | Zendy; Dan Mason | Zendy; Christopher L. Baker | Zendy; Konrad J. Karczewski | Zendy; Michael R. Barnes | Zendy; Anthony Barnett | Zendy; Chris Bates | Zendy; Srikanth Bellary | Zendy; Nicholas Bockett | Zendy; Kristina Giorda | Zendy; Chris Griffiths | Zendy; Harry Hemingway | Zendy; Zhilong Jia | Zendy; M. A. Kelly | Zendy; Hajrah Khawaja | Zendy; Monkol Lek | Zendy; Shane McCarthy | Zendy; Rosemary McEachan | Zendy; Anne O’DonnellLuria | Zendy; Kenneth Paigen | Zendy; Constantinos A. Parisinos | Zendy; Eamonn Sheridan | Zendy; Laura Southgate | Zendy; Louise Tee | Zendy; Mark Thomas | Zendy; Yali Xue | Zendy; Michael Schnall-Levin | Zendy; Petko M. Petkov | Zendy; Chris TylerSmith | Zendy; Eamonn R. Maher | Zendy; Richard C. Trembath | Zendy; Daniel G. MacArthur | Zendy; John Wright | Zendy; Richard Durbin | Zendy; David A. van Heel | Zendy

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Health and population effects of rare gene knockouts in adult humans with related parents

Author(s) -

Vagheesh M. Narasimhan,

Karen A. Hunt,

Dan Mason,

Christopher L. Baker,

Konrad J. Karczewski,

Michael R. Barnes,

Anthony Barnett,

Chris Bates,

Srikanth Bellary,

Nicholas Bockett,

Kristina Giorda,

Chris Griffiths,

Harry Hemingway,

Zhilong Jia,

M. A. Kelly,

Hajrah Khawaja,

Monkol Lek,

Shane McCarthy,

Rosemary McEachan,

Anne O’DonnellLuria,

Kenneth Paigen,

Constantinos A. Parisinos,

Eamonn Sheridan,

Laura Southgate,

Louise Tee,

Mark Thomas,

Yali Xue,

Michael Schnall-Levin,

Petko M. Petkov,

Chris TylerSmith,

Eamonn R. Maher,

Richard C. Trembath,

Daniel G. MacArthur,

John Wright,

Richard Durbin,

David A. van Heel

Publication year - 2016

Publication title -

science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 12.556

H-Index - 1186

eISSN - 1095-9203

pISSN - 0036-8075

DOI - 10.1126/science.aac8624

Subject(s) - genetics , allele , gene knockout , biology , gene , phenotype , loss function , consanguinity , population , heterozygote advantage , medicine , environmental health

Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on essential genetic loci and demonstrate PRDM9 redundancy in humans.

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