A map of constrained coding regions in the human genome

Abstract

Deep catalogs of genetic variation from thousands of humans enable the detection of intraspecies constraint by identifying coding regions with a scarcity of variation. While existing techniques summarize constraint for entire genes, single gene-wide metrics conceal regional constraint variability within each gene. Therefore, we have created a detailed map of constrained coding regions (CCRs) by leveraging variation observed among 123,136 humans from the Genome Aggregation Database. The most constrained CCRs are enriched for pathogenic variants in ClinVar and mutations underlying developmental disorders. CCRs highlight protein domain families under high constraint and suggest unannotated or incomplete protein domains. The highest-percentile CCRs complement existing variant prioritization methods when evaluating de novo mutations in studies of autosomal dominant disease. Finally, we identify highly constrained CCRs within genes lacking known disease associations. This observation suggests that CCRs may identify regions under strong purifying selection that, when mutated, cause severe developmental phenotypes or embryonic lethality.

Population genetic models of GERP scores suggest pervasive turnover of constrained sites across mammalian evolution

“…Second, because GERP is less effective when there is functional turnover, and at distinguishing weak selection from strong selection, improvement can be made by using polymorphism-based measures of purifying selection (Lek et al 2016;Karczewski et al 2019;Huang, Gulko, and Siepel 2017;Lawrie and Petrov 2014;Schrider and Kern 2015) . These methods should only improve as the sample sizes of human genomes become greater (Havrilla et al 2019) . Lastly, methods that seek to combine comparative genomic information with functional data (Gulko and Siepel 2019;Rentzsch et al 2019;Huang, Gulko, and Siepel 2017;Gulko et al 2015;Kircher et al 2014) may also offer improved power to identify functionally important sites.…”

A catalog of homoplasmic and heteroplasmic mitochondrial DNA variants in humans

“…The analysis of genetic variation in the population has been an efficient tool to understand the role and essentiality of genes, functional domains, and to assess the pathogenicity of variants underlying rare disease. For example, scientists have recently drawn maps of constrained coding regions using the Genome Aggregation Database (gnomAD) 7 , which highlighted regions depleted of non-synonymous variants across a large adult population. These regions pointed to genes and functional domains (some of them without any known function) that may cause severe developmental phenotypes when mutated 7 .…”

“…For example, scientists have recently drawn maps of constrained coding regions using the Genome Aggregation Database (gnomAD) 7 , which highlighted regions depleted of non-synonymous variants across a large adult population. These regions pointed to genes and functional domains (some of them without any known function) that may cause severe developmental phenotypes when mutated 7 . Another example was the development of a framework using population allele frequency information to assess whether a variant is "too common" to be pathogenic for a specific disease given the prevalence of this disease in the population, and its assumed genetic architecture 8 .…”

Integrated evolutionary and structural analysis reveals xenobiotics and pathogens as the major drivers of mammalian adaptation

“…Functionally important regions are routinely identified by taking advantage of the fact that they are highly conserved in evolution 1,2 . Similarly, methods for detecting regions harbouring adaptive changes have been developed to take advantage of the fact that rapid fixation of new alleles is a hallmark of positive selection 3,4 .…”