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A cross-disorder dosage sensitivity map of the human genome.
Collins, Ryan L; Glessner, Joseph T; Porcu, Eleonora; Lepamets, Maarja; Brandon, Rhonda; Lauricella, Christopher; Han, Lide; Morley, Theodore; Niestroj, Lisa-Marie; Ulirsch, Jacob; Everett, Selin; Howrigan, Daniel P; Boone, Philip M; Fu, Jack; Karczewski, Konrad J; Kellaris, Georgios; Lowther, Chelsea; Lucente, Diane; Mohajeri, Kiana; Nõukas, Margit; Nuttle, Xander; Samocha, Kaitlin E; Trinh, Mi; Ullah, Farid; Võsa, Urmo; Hurles, Matthew E; Aradhya, Swaroop; Davis, Erica E; Finucane, Hilary; Gusella, James F; Janze, Aura; Katsanis, Nicholas; Matyakhina, Ludmila; Neale, Benjamin M; Sanders, David; Warren, Stephanie; Hodge, Jennelle C; Lal, Dennis; Ruderfer, Douglas M; Meck, Jeanne; Mägi, Reedik; Esko, Tõnu; Reymond, Alexandre; Kutalik, Zoltán; Hakonarson, Hakon; Sunyaev, Shamil; Brand, Harrison; Talkowski, Michael E.
Afiliação
  • Collins RL; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Division of Medical Sciences and Department of Medicine, Harvard Medical Sch
  • Glessner JT; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Division of Human Genetics, Perelman School of Medicine, Philadelphia, PA 19104, USA.
  • Porcu E; Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
  • Lepamets M; Estonian Genome Centre, Institute of Genomics, University of Tartu, 51010 Tartu, Estonia; Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia.
  • Brandon R; GeneDx, Gaithersburg, MD 20877, USA.
  • Lauricella C; GeneDx, Gaithersburg, MD 20877, USA.
  • Han L; Division of Genetic Medicine, Department of Medicine, and Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Morley T; Division of Genetic Medicine, Department of Medicine, and Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Niestroj LM; Cologne Center for Genomics, University of Cologne, 51149 Cologne, Germany.
  • Ulirsch J; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Division of Medical Sciences and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Analytic and Translational Genetics Unit, Massachusetts
  • Everett S; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
  • Howrigan DP; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Bo
  • Boone PM; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical
  • Fu J; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical
  • Karczewski KJ; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Bo
  • Kellaris G; Advanced Center for Translational and Genetic Medicine, Stanley Manne Children's Research Institute, Lurie Children's Hospital, Chicago, IL 60611, USA; Departments of Pediatrics and Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • Lowther C; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical
  • Lucente D; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Mohajeri K; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Division of Medical Sciences and Department of Medicine, Harvard Medical Sch
  • Nõukas M; Estonian Genome Centre, Institute of Genomics, University of Tartu, 51010 Tartu, Estonia; Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia.
  • Nuttle X; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical
  • Samocha KE; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Division of Medical Sciences and Department of Medicine, Harvard Medical Sch
  • Trinh M; Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10, UK.
  • Ullah F; Advanced Center for Translational and Genetic Medicine, Stanley Manne Children's Research Institute, Lurie Children's Hospital, Chicago, IL 60611, USA; Departments of Pediatrics and Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • Võsa U; Estonian Genome Centre, Institute of Genomics, University of Tartu, 51010 Tartu, Estonia.
  • Hurles ME; Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10, UK.
  • Aradhya S; GeneDx, Gaithersburg, MD 20877, USA.
  • Davis EE; Advanced Center for Translational and Genetic Medicine, Stanley Manne Children's Research Institute, Lurie Children's Hospital, Chicago, IL 60611, USA; Departments of Pediatrics and Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • Finucane H; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Bo
  • Gusella JF; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
  • Janze A; GeneDx, Gaithersburg, MD 20877, USA.
  • Katsanis N; Advanced Center for Translational and Genetic Medicine, Stanley Manne Children's Research Institute, Lurie Children's Hospital, Chicago, IL 60611, USA; Departments of Pediatrics and Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • Matyakhina L; GeneDx, Gaithersburg, MD 20877, USA.
  • Neale BM; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Bo
  • Sanders D; Avenue 80, Inc., Fort Wayne, IN 46802, USA.
  • Warren S; GeneDx, Gaithersburg, MD 20877, USA.
  • Hodge JC; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • Lal D; Cologne Center for Genomics, University of Cologne, 51149 Cologne, Germany; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • Ruderfer DM; Division of Genetic Medicine, Department of Medicine, and Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Center for Precision Medicine, Department of Biomedical Informatics, and Department of Psychiatry and Behavioral Sciences, Vanderbilt University Me
  • Meck J; GeneDx, Gaithersburg, MD 20877, USA.
  • Mägi R; Estonian Genome Centre, Institute of Genomics, University of Tartu, 51010 Tartu, Estonia.
  • Esko T; Estonian Genome Centre, Institute of Genomics, University of Tartu, 51010 Tartu, Estonia.
  • Reymond A; Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
  • Kutalik Z; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Center for Primary Care and Public Health, University of Lausanne, 1015 Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland.
  • Hakonarson H; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Division of Human Genetics, Perelman School of Medicine, Philadelphia, PA 19104, USA.
  • Sunyaev S; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Division of Medical Sciences and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Bost
  • Brand H; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical
  • Talkowski ME; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Bo
Cell ; 185(16): 3041-3055.e25, 2022 08 04.
Article em En | MEDLINE | ID: mdl-35917817
Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the properties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million individuals to construct a genome-wide catalog of dosage sensitivity across 54 disorders, which defined 163 dosage sensitive segments associated with at least one disorder. These segments were typically gene dense and often harbored dominant dosage sensitive driver genes, which we were able to prioritize using statistical fine-mapping. Finally, we designed an ensemble machine-learning model to predict probabilities of dosage sensitivity (pHaplo & pTriplo) for all autosomal genes, which identified 2,987 haploinsufficient and 1,559 triplosensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will provide broad utility for human disease research and clinical genetics.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Genoma Humano / Variações do Número de Cópias de DNA Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Humans Idioma: En Revista: Cell Ano de publicação: 2022 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Genoma Humano / Variações do Número de Cópias de DNA Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Humans Idioma: En Revista: Cell Ano de publicação: 2022 Tipo de documento: Article