Details

Autor(en) / Beteiligte

• 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
• Metspalu, Andres
• Mägi, Reedik
• Nelis, Mari
• Milani, Lili
• Esko, Tõnu
• 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
• Reymond, Alexandre
• Kutalik, Zoltán
• Hakonarson, Hakon
• Sunyaev, Shamil
• Brand, Harrison
• Talkowski, Michael E.

Titel

A cross-disorder dosage sensitivity map of the human genome

Ist Teil von

• Cell, 2022-08, Vol.185 (16), p.3041-3055.e25

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Meta-analysis of rare copy-number variants (rCNVs) in nearly one million humans•Discovered hundreds of rCNV-disease associations across 54 disorders•Convergence of rCNVs & damaging coding variants at dosage sensitive loci•Ensemble machine learning identified 3,635 highly dosage sensitive genes Harmonizing genomic data from nearly one million individuals yields insights into the properties of rare copy-number variants across disorders and dosage sensitivity predictions for all autosomal protein-coding genes.