A test of the hypothesis that variable mutation rates create signals that have previously been interpreted as evidence of archaic introgression into humans

Abstract

AbstractIt is widely accepted that non-African humans carry 1-2% Neanderthal DNA due to historical inter-breeding. However, inferences about introgression rely on a critical assumption that mutation rate is constant and that back-mutations are too rare to be important. Both these assumptions have been challenged, and recent evidence points towards an alternative model where signals interpreted as introgression are driven mainly by higher mutation rates in Africa. In this model, non-Africans appear closer to archaics not because they harbour introgressed fragments but because Africans have diverged more. Here I test this idea by using the density of rare, human-specific variants (RHSVs) as a proxy for recent mutation rate. I find that sites that contribute most to the signal interpreted as introgression tend to occur in tightly defined regions spanning only a few hundred bases in which mutation rate differs greatly between the two human populations being compared. Mutation rate is invariably higher in the population into which introgression isnotinferred. I confirmed that RHSV density reflects mutation rate by conducting a parallel analysis looking at the density of RHSVs around sites with three alleles, an independent class of site that also requires recurrent mutations to form. Near-identical peaks in RHSV density are found, suggesting a common cause. Similarly, coalescent simulations confirm that, with constant mutation rate, introgressed fragments do not occur preferentially in regions with a high density of rare, human-specific variants. Together, these observations are difficult to reconcile with a model where excess base-sharing is driven by archaic legacies but instead provide support for a higher mutation rate inside Africa driving increased divergence from the ancestral human state.