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

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.