An Abundance of Rare Functional Variants in 202 Drug Target Genes Sequenced in 14,002 People

TLDR

Rare genetic variants contribute to complex disease risk, but their abundance in human populations is largely unknown. The study sequenced 202 drug‑target genes in 14,002 individuals to map the spectrum of rare variation. The authors sequenced these genes and analyzed the resulting variation patterns to estimate population growth, deleterious variant proportions, and gene‑specific mutation rates. Rare variants are abundant—about one every 17 bases—and geographically localized, and rapid population growth plus weak purifying selection results in many deleterious variants relevant to disease risk.

Abstract

Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (1 every 17 bases) and geographically localized, so that even with large sample sizes, rare variant catalogs will be largely incomplete. We used the observed patterns of variation to estimate population growth parameters, the proportion of variants in a given frequency class that are putatively deleterious, and mutation rates for each gene. We conclude that because of rapid population growth and weak purifying selection, human populations harbor an abundance of rare variants, many of which are deleterious and have relevance to understanding disease risk.