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

Details

Serval ID
serval:BIB_2170895E98F2
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A cross-disorder dosage sensitivity map of the human genome.
Journal
Cell
Author(s)
Collins R.L., Glessner J.T., Porcu E., Lepamets M., Brandon R., Lauricella C., Han L., Morley T., Niestroj L.M., Ulirsch J., Everett S., Howrigan D.P., Boone P.M., Fu J., Karczewski K.J., Kellaris G., Lowther C., Lucente D., Mohajeri K., Nõukas M., Nuttle X., Samocha K.E., Trinh M., Ullah F., Võsa U., Hurles M.E., Aradhya S., Davis E.E., Finucane H., Gusella J.F., Janze A., Katsanis N., Matyakhina L., Neale B.M., Sanders D., Warren S., Hodge J.C., Lal D., Ruderfer D.M., Meck J., Mägi R., Esko T., Reymond A., Kutalik Z., Hakonarson H., Sunyaev S., Brand H., Talkowski M.E.
Working group(s)
Epi25 Consortium, Estonian Biobank Research Team
Contributor(s)
Metspalu A., Mägi R., Nelis M., Milani L., Esko T.
ISSN
1097-4172 (Electronic)
ISSN-L
0092-8674
Publication state
Published
Issued date
04/08/2022
Peer-reviewed
Oui
Volume
185
Number
16
Pages
3041-3055.e25
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
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 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.
Keywords
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
Pubmed
Web of science
Open Access
Yes
Create date
24/08/2022 8:22
Last modification date
02/09/2022 5:40
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