Collins, Ryan L., Glessner, Joseph T., Porcu, Eleonora, Lepamets, Maarja, Brandon, Rhonda, Lauricella, Christopher, Han, Lide, Morley, Theodore, Niestroj, Lisa-Marie, Ulirsch, Jacob ORCID: 0000-0002-7947-0827, Everett, Selin, Howrigan, Daniel P., Boone, Philip M., Fu, Jack ORCID: 0000-0003-4152-5471, Karczewski, Konrad J., Kellaris, Georgios, Lowther, Chelsea, Lucente, Diane, Mohajeri, Kiana, Noukas, Margit, Nuttle, Xander, Samocha, Kaitlin E., Trinh, Mi ORCID: 0000-0003-4185-0071, Ullah, Farid, Vosa, 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, Magi, Reedik, Esko, Tonu, Reymond, Alexandre, Kutalik, Zoltan ORCID: 0000-0001-8285-7523, Hakonarson, Hakon, Sunyaev, Shamil, Brand, Harrison and Talkowski, Michael E. (2022). A cross-disorder dosage sensitivity map of the human genome. Cell, 185 (16). S. 3041 - 3082. CAMBRIDGE: CELL PRESS. ISSN 1097-4172

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Abstract

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 prop-erties 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 trip-losensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will pro-vide broad utility for human disease research and clinical genetics.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Collins, Ryan L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Glessner, Joseph T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Porcu, EleonoraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lepamets, MaarjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brandon, RhondaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lauricella, ChristopherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Han, LideUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morley, TheodoreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niestroj, Lisa-MarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ulirsch, JacobUNSPECIFIEDorcid.org/0000-0002-7947-0827UNSPECIFIED
Everett, SelinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Howrigan, Daniel P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boone, Philip M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fu, JackUNSPECIFIEDorcid.org/0000-0003-4152-5471UNSPECIFIED
Karczewski, Konrad J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kellaris, GeorgiosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lowther, ChelseaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lucente, DianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mohajeri, KianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noukas, MargitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuttle, XanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Samocha, Kaitlin E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trinh, MiUNSPECIFIEDorcid.org/0000-0003-4185-0071UNSPECIFIED
Ullah, FaridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vosa, UrmoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hurles, Matthew E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aradhya, SwaroopUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Davis, Erica E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Finucane, HilaryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gusella, James F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Janze, AuraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Katsanis, NicholasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Matyakhina, LudmilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neale, Benjamin M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanders, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Warren, StephanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hodge, Jennelle C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lal, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruderfer, Douglas M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meck, JeanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Magi, ReedikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Esko, TonuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reymond, AlexandreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kutalik, ZoltanUNSPECIFIEDorcid.org/0000-0001-8285-7523UNSPECIFIED
Hakonarson, HakonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sunyaev, ShamilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brand, HarrisonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Talkowski, Michael E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-696381
DOI: 10.1016/j.cell.2022.06.036
Journal or Publication Title: Cell
Volume: 185
Number: 16
Page Range: S. 3041 - 3082
Date: 2022
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1097-4172
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
COPY-NUMBER VARIATION; STRUCTURAL VARIATION; DE-NOVO; PHENOTYPES; VARIANTS; RISK; VERTEBRATE; 16P11.2; HETEROGENEITY; DUPLICATIONSMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69638

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