A map of constrained coding regions in the human genome

Abstract

ABSTRACTDeep catalogs of genetic variation collected from many thousands of humans enable the detection of intraspecies constraint by revealing coding regions with a scarcity of variation. While existing techniques summarize constraint for entire genes, single metrics cannot capture the fine-scale variability in constraint within each protein-coding gene. To provide greater resolution, we have created a detailed map of constrained coding regions (CCRs) in the human genome by leveraging coding variation observed among 123,136 humans from the Genome Aggregation Database (gnomAD). The most constrained coding regions in our map are enriched for both pathogenic variants in ClinVar and de novo mutations underlying developmental disorders. CCRs also reveal protein domain families under high constraint, suggest unannotated or incomplete protein domains, and facilitate the prioritization of previously unseen variation in studies of disease. Finally, a subset of CCRs with the highest constraint likely exist within genes that cause yet unobserved human phenotypes owing to strong purifying selection.