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Health and population effects of rare gene knockouts in adult humans with related parents.
Narasimhan, Vagheesh M; Hunt, Karen A; Mason, Dan; Baker, Christopher L; Karczewski, Konrad J; Barnes, Michael R; Barnett, Anthony H; Bates, Chris; Bellary, Srikanth; Bockett, Nicholas A; Giorda, Kristina; Griffiths, Christopher J; Hemingway, Harry; Jia, Zhilong; Kelly, M Ann; Khawaja, Hajrah A; Lek, Monkol; McCarthy, Shane; McEachan, Rosie; O'Donnell-Luria, Anne; Paigen, Kenneth; Parisinos, Constantinos A; Sheridan, Eamonn; Southgate, Laura; Tee, Louise; Thomas, Mark; Xue, Yali; Schnall-Levin, Michael; Petkov, Petko M; Tyler-Smith, Chris; Maher, Eamonn R; Trembath, Richard C; MacArthur, Daniel G; Wright, John; Durbin, Richard; van Heel, David A.
Afiliación
  • Narasimhan VM; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  • Hunt KA; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
  • Mason D; Bradford Institute for Health Research, Bradford Teaching Hospitals National Health Service (NHS) Foundation Trust, Bradford BD9 6RJ, UK.
  • Baker CL; Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, ME 04609, USA.
  • Karczewski KJ; 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.
  • Barnes MR; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
  • Barnett AH; Diabetes and Endocrine Centre, Heart of England NHS Foundation Trust and University of Birmingham, Birmingham B9 5SS, UK.
  • Bates C; TPP, Mill House, Troy Road, Leeds LS18 5TN, UK.
  • Bellary S; Aston Research Centre for Healthy Ageing, Aston University, Birmingham B4 7ET, UK.
  • Bockett NA; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
  • Giorda K; 10X Genomics, 7068 Koll Center Parkway, Suite 415, Pleasanton, CA 94566, USA.
  • Griffiths CJ; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
  • Hemingway H; Farr Institute of Health Informatics Research, London NW1 2DA, UK. Institute of Health Informatics, University College London, London NW1 2DA, UK.
  • Jia Z; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
  • Kelly MA; School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
  • Khawaja HA; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
  • Lek M; 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.
  • McCarthy S; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  • McEachan R; Bradford Institute for Health Research, Bradford Teaching Hospitals National Health Service (NHS) Foundation Trust, Bradford BD9 6RJ, UK.
  • O'Donnell-Luria A; 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.
  • Paigen K; Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, ME 04609, USA.
  • Parisinos CA; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
  • Sheridan E; Bradford Institute for Health Research, Bradford Teaching Hospitals National Health Service (NHS) Foundation Trust, Bradford BD9 6RJ, UK.
  • Southgate L; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
  • Tee L; School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
  • Thomas M; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  • Xue Y; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  • Schnall-Levin M; 10X Genomics, 7068 Koll Center Parkway, Suite 415, Pleasanton, CA 94566, USA.
  • Petkov PM; Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, ME 04609, USA.
  • Tyler-Smith C; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  • Maher ER; 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
  • Trembath RC; 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.
  • MacArthur DG; 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.
  • Wright J; Bradford Institute for Health Research, Bradford Teaching Hospitals National Health Service (NHS) Foundation Trust, Bradford BD9 6RJ, UK.
  • Durbin R; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. rd@sanger.ac.uk d.vanheel@qmul.ac.uk.
  • van Heel DA; 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.
Science ; 352(6284): 474-7, 2016 Apr 22.
Article en En | MEDLINE | ID: mdl-26940866
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Salud / N-Metiltransferasa de Histona-Lisina / Consanguinidad Límite: Adult / Female / Humans / Male País/Región como asunto: Asia / Europa Idioma: En Revista: Science Año: 2016 Tipo del documento: Article País de afiliación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Salud / N-Metiltransferasa de Histona-Lisina / Consanguinidad Límite: Adult / Female / Humans / Male País/Región como asunto: Asia / Europa Idioma: En Revista: Science Año: 2016 Tipo del documento: Article País de afiliación: Reino Unido