A cross-disorder dosage sensitivity map of the human genome.

DNA Copy Number Variations / genetics Gene Dosage Genome, Human Haploinsufficiency / genetics Humans
copy-number variation developmental disorders disease association dosage sensitivity genomics haploinsufficiency statistical genetics structural variation triplosensitivity

Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
04 08 2022
Historique:
received: 22 12 2020
revised: 17 03 2022
accepted: 20 06 2022
pubmed: 3 8 2022
medline: 10 8 2022
entrez: 2 8 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.cell.2022.06.036 PMID: 35917817 PMC: PMC9742861
pubmed: 35917817
pii: S0092-8674(22)00788-7
doi: 10.1016/j.cell.2022.06.036
pmc: PMC9742861
mid: NIHMS1819123
pii:
doi:

Types de publication

Journal Article Research Support, U.S. Gov't, Non-P.H.S. Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

3041-3055.e25

Subventions

Organisme : NICHD NIH HHS
ID : R03 HD099547
Pays : United States
Organisme : NINDS NIH HHS
ID : L30 NS093200
Pays : United States
Organisme : NIDCR NIH HHS
ID : R00 DE026824
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG002295
Pays : United States
Organisme : NINDS NIH HHS
ID : K08 NS117891
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD081256
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE031261
Pays : United States
Organisme : NIMH NIH HHS
ID : R56 MH115957
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS093200
Pays : United States
Organisme : NICHD NIH HHS
ID : P50 HD104224
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH115957
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH106826
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD096326
Pays : United States

Investigateurs

Andres Metspalu (A)
Reedik Mägi (R)
Mari Nelis (M)
Lili Milani (L)
Tõnu Esko (T)

Commentaires et corrections

Type : CommentIn
Type : CommentIn

Informations de copyright

Copyright © 2022 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests M.E.T. receives research funding and/or reagents from Levo Therapeutics, Microsoft Inc., and Illumina Inc. R.B., C. Lauricella, A.J., L.M., S.W., and J.M. are employees of GeneDx, Inc. S.A. is an employee of Invitae Corp.

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Auteurs

Ryan L 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 School, Boston, MA 02115, USA. Electronic address: rlcollins@g.harvard.edu.

Joseph T 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.

Eleonora Porcu (E)

Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.

Maarja 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.

Rhonda Brandon (R)

GeneDx, Gaithersburg, MD 20877, USA.

Christopher Lauricella (C)

GeneDx, Gaithersburg, MD 20877, USA.

Lide Han (L)

Division of Genetic Medicine, Department of Medicine, and Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

Theodore Morley (T)

Division of Genetic Medicine, Department of Medicine, and Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

Lisa-Marie Niestroj (LM)

Cologne Center for Genomics, University of Cologne, 51149 Cologne, Germany.

Jacob 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 General Hospital, Boston, MA 02114, USA.

Selin 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.

Daniel P 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, Boston, MA 02114, USA.

Philip M 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 School, Boston, MA 02114, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.

Jack 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 School, Boston, MA 02114, USA.

Konrad J 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, Boston, MA 02114, USA.

Georgios 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.

Chelsea 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 School, Boston, MA 02114, USA.

Diane Lucente (D)

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

Kiana 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 School, Boston, MA 02115, USA.

Margit 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.

Xander 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 School, Boston, MA 02114, USA.

Kaitlin E 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 School, Boston, MA 02115, USA; Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10, UK.

Mi Trinh (M)

Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10, UK.

Farid 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.

Urmo Võsa (U)

Estonian Genome Centre, Institute of Genomics, University of Tartu, 51010 Tartu, Estonia.

Matthew E Hurles (ME)

Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10, UK.

Swaroop Aradhya (S)

GeneDx, Gaithersburg, MD 20877, USA.

Erica E 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.

Hilary 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, Boston, MA 02114, USA.

James F 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.

Aura Janze (A)

GeneDx, Gaithersburg, MD 20877, USA.

Nicholas 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.

Ludmila Matyakhina (L)

GeneDx, Gaithersburg, MD 20877, USA.

Benjamin M 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, Boston, MA 02114, USA.

David Sanders (D)

Avenue 80, Inc., Fort Wayne, IN 46802, USA.

Stephanie Warren (S)

GeneDx, Gaithersburg, MD 20877, USA.

Jennelle C Hodge (JC)

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Dennis 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.

Douglas M 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 Medical Center, Nashville, TN 37232, USA.

Jeanne Meck (J)

GeneDx, Gaithersburg, MD 20877, USA.

Reedik Mägi (R)

Estonian Genome Centre, Institute of Genomics, University of Tartu, 51010 Tartu, Estonia.

Tõnu Esko (T)

Estonian Genome Centre, Institute of Genomics, University of Tartu, 51010 Tartu, Estonia.

Alexandre Reymond (A)

Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.

Zoltán 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.

Hakon 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.

Shamil 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, Boston, MA 02115, USA.

Harrison 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 School, Boston, MA 02114, USA; Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: hbrand@broadinstitute.org.

Michael E 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, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: talkowsk@broadinstitute.org.

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Classifications MeSH

questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Variation structurale du génome › Variations de nombre de copies de segment d'ADN › A cross-disorder dosage sensitivity map of the...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Dosage génique › A cross-disorder dosage sensitivity map of the...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Génome humain › A cross-disorder dosage sensitivity map of the...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Dosage génique › Haploinsuffisance › A cross-disorder dosage sensitivity map of the...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › A cross-disorder dosage sensitivity map of the...