The distribution of highly deleterious variants across human ancestry groups

Abstract

A major focus of human genetics is to map severe disease mutations. Increasingly that goal is understood as requiring huge numbers of people to be sequenced from every broadly-defined genetic ancestry group, so as not to miss "ancestry-specific variants." Here, we argue that this focus is unwarranted. We start with first principles considerations, based on models of mutation-drift-selection balance, which suggest highly pathogenic mutations should be at similarly low frequencies across ancestry groups. Severe disease mutations tend to be strongly deleterious, and thus evolutionarily young, and are kept at relatively constant frequency through recurrent mutation. Therefore, highly pathogenic alleles are shared identical by descent within extended families, not broad ancestry groups, and sequencing more people should yield similar numbers regardless of ancestry. We illustrate these points using gnomAD genetic ancestry groupings, and show that the classes of variants most likely to be highly pathogenic, notably sets of loss of function alleles at strongly constrained genes, conform well to these predictions. While there are many important reasons to diversify genomic research, strongly deleterious alleles will be found at comparable rates in people of all ancestries, and the information they provide about human biology is shared across ancestries.