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Science. 2016 Apr 22;352(6284):474-7. doi: 10.1126/science.aac8624. Epub 2016 Mar 3.

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

Author information

1
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
2
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
3
Bradford Institute for Health Research, Bradford Teaching Hospitals National Health Service (NHS) Foundation Trust, Bradford BD9 6RJ, UK.
4
Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, ME 04609, USA.
5
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
6
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
7
Diabetes and Endocrine Centre, Heart of England NHS Foundation Trust and University of Birmingham, Birmingham B9 5SS, UK.
8
TPP, Mill House, Troy Road, Leeds LS18 5TN, UK.
9
Aston Research Centre for Healthy Ageing, Aston University, Birmingham B4 7ET, UK.
10
10X Genomics, 7068 Koll Center Parkway, Suite 415, Pleasanton, CA 94566, USA.
11
Farr Institute of Health Informatics Research, London NW1 2DA, UK. Institute of Health Informatics, University College London, London NW1 2DA, UK.
12
School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
13
Department of Medical Genetics, University of Cambridge and National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Box 238, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
14
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK. Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, UK.
15
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. rd@sanger.ac.uk d.vanheel@qmul.ac.uk.
16
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK. rd@sanger.ac.uk d.vanheel@qmul.ac.uk.

Abstract

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.

PMID:
26940866
PMCID:
PMC4985238
DOI:
10.1126/science.aac8624
[Indexed for MEDLINE]
Free PMC Article

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