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

V. Narasimhan, K.A. Hunt, D. Mason, C.L. Baker, K.J. Karczewski, M.R. Barnes, A.H. Barnett, C. Bates, S. Bellary, N.A. Bockett, K. Giorda, C.J. Griffiths, H. Hemingway, Z. Jia, M.A. Kelly, H.A. Khawaja, Monkol Lek, S. McCarthy, R. McEachan, K. Paigen, C. Parisinos, E. Sheridan, Laura Southgate, L. Tee, M. Thomas, Y. Xue, M. Schnall-Levin, P.M. Petkov, C. Tyler-Smith, E.R. Maher, R.C. Trembath, D.G. MacArthur, J. Wright, R. Durbin, D.A. van Heel
doi: https://doi.org/10.1101/031641
V. Narasimhan
1Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
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K.A. Hunt
2Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
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D. Mason
3Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford BD9 6RJ, UK.
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C.L. Baker
4Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, Maine, United States of America.
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K.J. Karczewski
5Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
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M.R. Barnes
6William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
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A.H. Barnett
7Diabetes and Endocrine Centre, Heart of England NHS Foundation Trust and University of Birmingham, Birmingham B9 5SS, UK.
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C. Bates
8TPP, Mill House, Troy Road, Leeds LS18 5TN, UK.
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S. Bellary
9Aston Research Centre For Healthy Ageing (ARCHA), Aston University, Birmingham B4 7ET, UK.
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N.A. Bockett
2Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
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K. Giorda
1010XGenomics Inc., 7068 Koll Center Parkway, Suite 415, Pleasanton, CA 94566, USA.
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C.J. Griffiths
2Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
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H. Hemingway
11Farr Institute of Health Informatics Research at London, London NW1 2DA, UK.
12Department of Epidemiology and Public Health, University College London, London WC1E 6BT, UK.
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Z. Jia
6William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
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M.A. Kelly
13School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
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H.A. Khawaja
6William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
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Monkol Lek
4Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, Maine, United States of America.
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S. McCarthy
1Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
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R. McEachan
14Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford BD9 6RJ, UK.
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K. Paigen
4Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, Maine, United States of America.
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C. Parisinos
2Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
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E. Sheridan
14Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford BD9 6RJ, UK.
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Laura Southgate
2Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
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L. Tee
13School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
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M. Thomas
1Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
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Y. Xue
1Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
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M. Schnall-Levin
1010XGenomics Inc., 7068 Koll Center Parkway, Suite 415, Pleasanton, CA 94566, USA.
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P.M. Petkov
4Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, Maine, United States of America.
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C. Tyler-Smith
1Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
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E.R. Maher
15Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Box 238, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
16Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
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R.C. Trembath
2Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
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D.G. MacArthur
4Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, Maine, United States of America.
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J. Wright
14Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford BD9 6RJ, UK.
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R. Durbin
1Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
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  • For correspondence: rd@sanaer.ac.uk d.vanheel@amul.ac.uk
D.A. van Heel
2Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
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  • For correspondence: rd@sanaer.ac.uk d.vanheel@amul.ac.uk
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Abstract:

Complete gene knockouts are highly informative about gene function. We exome sequenced 3,222 British Pakistani-heritage adults with high parental relatedness, discovering 1,111 rare-variant homozygous likely loss of function (rhLOF) genotypes predicted to disrupt (knockout) 781 genes. Based on depletion of rhLOF genotypes, we estimate that 13.6% of knockouts are incompatible with adult life, finding on average 1.6 heterozygous recessive lethal LOF variants per adult. Linking to lifelong health records, we observed no association of rhLOF genotypes with prescription- or doctor-consultation rate, and no disease-related phenotypes in 33 of 42 individuals with rhLOF genotypes in recessive Mendelian disease genes. Phased genome sequencing of a healthy PRDM9 knockout mother, her child and controls, showed meiotic recombination sites localised away from PRDM9-dependent hotspots, demonstrating PRDM9 redundancy in humans.

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Posted November 14, 2015.
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Health and population effects of rare gene knockouts in adult humans with related parents
V. Narasimhan, K.A. Hunt, D. Mason, C.L. Baker, K.J. Karczewski, M.R. Barnes, A.H. Barnett, C. Bates, S. Bellary, N.A. Bockett, K. Giorda, C.J. Griffiths, H. Hemingway, Z. Jia, M.A. Kelly, H.A. Khawaja, Monkol Lek, S. McCarthy, R. McEachan, K. Paigen, C. Parisinos, E. Sheridan, Laura Southgate, L. Tee, M. Thomas, Y. Xue, M. Schnall-Levin, P.M. Petkov, C. Tyler-Smith, E.R. Maher, R.C. Trembath, D.G. MacArthur, J. Wright, R. Durbin, D.A. van Heel
bioRxiv 031641; doi: https://doi.org/10.1101/031641
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Health and population effects of rare gene knockouts in adult humans with related parents
V. Narasimhan, K.A. Hunt, D. Mason, C.L. Baker, K.J. Karczewski, M.R. Barnes, A.H. Barnett, C. Bates, S. Bellary, N.A. Bockett, K. Giorda, C.J. Griffiths, H. Hemingway, Z. Jia, M.A. Kelly, H.A. Khawaja, Monkol Lek, S. McCarthy, R. McEachan, K. Paigen, C. Parisinos, E. Sheridan, Laura Southgate, L. Tee, M. Thomas, Y. Xue, M. Schnall-Levin, P.M. Petkov, C. Tyler-Smith, E.R. Maher, R.C. Trembath, D.G. MacArthur, J. Wright, R. Durbin, D.A. van Heel
bioRxiv 031641; doi: https://doi.org/10.1101/031641

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