Ancestry adjustment improves genome-wide estimates of regional intolerance

Abstract

Genomic regions subject to purifying selection are more likely to carry disease causing mutations. Cross species conservation is often used to identify such regions but has limited resolution to detect selection on short evolutionary timescales such as that occurring in only one species. In contrast, intolerance looks for depletion of variation relative to expectation within a species, allowing species specific features to be identified. When estimating the intolerance of noncoding sequence methods strongly leverage variant frequency distributions. As the expected distributions depend on demography, if not properly controlled for, ancestral population source may obfuscate signals of selection. We demonstrate that properly incorporating demography in intolerance estimation greatly improved variant classification (13% increase in AUC relative to comparison constraint test, CDTS; and 9% relative to conservation). We provide a genome-wide intolerance map that is conditional on demographic history that is likely to be particularly valuable for variant prioritization.