Cell. 2022 Aug 4;185(16):3041-3055.e25. doi: 10.1016/j.cell.2022.06.036. Epub 2022 Aug 1.

A cross-disorder dosage sensitivity map of the human genome

Ryan L Collins ¹, Joseph T Glessner ², Eleonora Porcu ³, Maarja Lepamets ⁴, Rhonda Brandon ⁵, Christopher Lauricella ⁵, Lide Han ⁶, Theodore Morley ⁶, Lisa-Marie Niestroj ⁷, Jacob Ulirsch ⁸, Selin Everett ⁹, Daniel P Howrigan ¹⁰, Philip M Boone ¹¹, Jack Fu ¹², Konrad J Karczewski ¹⁰, Georgios Kellaris ¹³, Chelsea Lowther ¹², Diane Lucente ¹⁴, Kiana Mohajeri ¹⁵, Margit Nõukas ⁴, Xander Nuttle ¹², Kaitlin E Samocha ¹⁶, Mi Trinh ¹⁷, Farid Ullah ¹³, Urmo Võsa ¹⁸, Epi25 Consortium; Estonian Biobank Research Team; Matthew E Hurles ¹⁷, Swaroop Aradhya ⁵, Erica E Davis ¹³, Hilary Finucane ¹⁰, James F Gusella ⁹, Aura Janze ⁵, Nicholas Katsanis ¹³, Ludmila Matyakhina ⁵, Benjamin M Neale ¹⁰, David Sanders ¹⁹, Stephanie Warren ⁵, Jennelle C Hodge ²⁰, Dennis Lal ²¹, Douglas M Ruderfer ²², Jeanne Meck ⁵, Reedik Mägi ¹⁸, Tõnu Esko ¹⁸, Alexandre Reymond ²³, Zoltán Kutalik ²⁴, Hakon Hakonarson ², Shamil Sunyaev ²⁵, Harrison Brand ²⁶, Michael E Talkowski ²⁷Collaborators, Affiliations expand

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.

• PMID: 35917817
• DOI: 10.1016/j.cell.2022.06.036