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Cell DOI:10.1016/j.cell.2022.06.036

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

Publication TypeJournal Article
Year of Publication2022
AuthorsCollins, RL, Glessner, JT, Porcu, E, Lepamets, M, Brandon, R, Lauricella, C, Han, L, Morley, T, Niestroj, L-M, Ulirsch, J, Everett, S, Howrigan, DP, Boone, PM, Fu, J, Karczewski, KJ, Kellaris, G, Lowther, C, Lucente, D, Mohajeri, K, Nõukas, M, Nuttle, X, Samocha, KE, Trinh, M, Ullah, F, Võsa, U, Hurles, ME, Aradhya, S, Davis, EE, Finucane, H, Gusella, JF, Janze, A, Katsanis, N, Matyakhina, L, Neale, BM, Sanders, D, Warren, S, Hodge, JC, Lal, D, Ruderfer, DM, Meck, J, Mägi, R, Esko, T, Reymond, A, Kutalik, Z, Hakonarson, H, Sunyaev, S, Brand, H, Talkowski, ME
Corporate AuthorsEpi25 Consortium, Estonian Biobank Research Team
JournalCell
Volume185
Issue16
Pages3041-3055.e25
Date Published2022 Aug 04
ISSN1097-4172
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.

DOI10.1016/j.cell.2022.06.036
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/35917817?dopt=Abstract

Alternate JournalCell
PubMed ID35917817