title: Health and population effects of rare gene knockouts in adult humans with related parents.
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.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Vagheesh M
authors.initials: VM
authors.lastname: Narasimhan
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Hunt
authors.affiliation: Bradford Institute for Health Research, Bradford Teaching Hospitals National Health Service (NHS) Foundation Trust, Bradford BD9 6RJ, UK.
authors.forename: Dan
authors.initials: D
authors.lastname: Mason
authors.affiliation: Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Baker
authors.affiliation: 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.
authors.forename: Konrad J
authors.initials: KJ
authors.lastname: Karczewski
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Barnes
authors.affiliation: Diabetes and Endocrine Centre, Heart of England NHS Foundation Trust and University of Birmingham, Birmingham B9 5SS, UK.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Barnett
authors.affiliation: TPP, Mill House, Troy Road, Leeds LS18 5TN, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Bates
authors.affiliation: Aston Research Centre for Healthy Ageing, Aston University, Birmingham B4 7ET, UK.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Bellary
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Bockett
authors.affiliation: 10X Genomics, 7068 Koll Center Parkway, Suite 415, Pleasanton, CA 94566, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Giorda
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Griffiths
authors.affiliation: Farr Institute of Health Informatics Research, London NW1 2DA, UK. Institute of Health Informatics, University College London, London NW1 2DA, UK.
authors.forename: Harry
authors.initials: H
authors.lastname: Hemingway
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Zhilong
authors.initials: Z
authors.lastname: Jia
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: M Ann
authors.initials: MA
authors.lastname: Kelly
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Hajrah A
authors.initials: HA
authors.lastname: Khawaja
authors.affiliation: 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.
authors.forename: Monkol
authors.initials: M
authors.lastname: Lek
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Shane
authors.initials: S
authors.lastname: McCarthy
authors.affiliation: Bradford Institute for Health Research, Bradford Teaching Hospitals National Health Service (NHS) Foundation Trust, Bradford BD9 6RJ, UK.
authors.forename: Rosie
authors.initials: R
authors.lastname: McEachan
authors.affiliation: 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.
authors.forename: Anne
authors.initials: A
authors.lastname: O'Donnell-Luria
authors.affiliation: Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Paigen
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Constantinos A
authors.initials: CA
authors.lastname: Parisinos
authors.affiliation: Bradford Institute for Health Research, Bradford Teaching Hospitals National Health Service (NHS) Foundation Trust, Bradford BD9 6RJ, UK.
authors.forename: Eamonn
authors.initials: E
authors.lastname: Sheridan
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Southgate
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Tee
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Yali
authors.initials: Y
authors.lastname: Xue
authors.affiliation: 10X Genomics, 7068 Koll Center Parkway, Suite 415, Pleasanton, CA 94566, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Schnall-Levin
authors.affiliation: Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Petko M
authors.initials: PM
authors.lastname: Petkov
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Tyler-Smith
authors.affiliation: 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.
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.affiliation: 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.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.affiliation: 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.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.affiliation: Bradford Institute for Health Research, Bradford Teaching Hospitals National Health Service (NHS) Foundation Trust, Bradford BD9 6RJ, UK.
authors.forename: John
authors.initials: J
authors.lastname: Wright
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. rd@sanger.ac.uk d.vanheel@qmul.ac.uk.
authors.forename: Richard
authors.initials: R
authors.lastname: Durbin
authors.affiliation: 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.
authors.forename: David A
authors.initials: DA
authors.lastname: van Heel
mesh_terms: D000328:Adult; D003241:Consanguinity; D004252:DNA Mutational Analysis; D011307:Drug Prescriptions; D059472:Exome / Q000235:genetics; D005260:Female; D005298:Fertility; D055786:Gene Knockout Techniques; D005804:Genes, Lethal; D056426:Genetic Loci; D015894:Genome, Human; D006262:Health; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D059765:Homologous Recombination; D006720:Homozygote; D006801:Humans; D008297:Male; D009035:Mothers; D010154:Pakistan / Q000208:ethnology; D010641:Phenotype; D006113:United Kingdom
chemical_list: D011495:Histone-Lysine N-Methyltransferase; C544431:PRDM9 protein, human