Differential base-sharing between humans and Neanderthals: inter-breeding or greater mutability in heterozygotes?

Abstract

The idea that humans interbred with other Hominins, most notably Neanderthals, is now accepted as fact. The finding of hybrid skeletons shows that fertile matings did occur. However, inferences about the size of the resulting legacy assume that back-mutations are rare enough to be ignored and that mutation rate does not vary. In reality, back-mutations are common, mutation rate does vary between populations and there is mounting evidence that heterozygosity and mutation rate covary. If so, the large loss of heterozygosity that occurred when humans migrated out of Africa would have reduced the mutation rate, leaving Africans to diverge faster from our common ancestor and from related lineages like Neanderthals. To test whether this idea impacts estimates of introgressed fraction, I calculated D, a measure of relative base-sharing with Neanderthals, and heterozygosity difference between all pairwise combinations of populations in the 1000 genomes Phase 3 data. D and heterozygosity difference are ubiquitously negatively correlated across all comparisons, between all regions and even between populations within each major region including Africa. In addition, the larger sample of populations in the Simons Genome Diversity project reveals a pan-Eurasian correlation between Neanderthal and Denisovan fraction. These correlations challenge a simple hybridisation model but do seem consistent with a model where more heterozygous human populations tend to diverge faster from Neanderthals than populations with lower heterozygosity. Indeed, the strongest correlation between Neanderthal content and geography indicates and origin where humans likely left Africa, exactly mimicking the pattern seen for loss of heterozygosity. Such a model explains why evidence for inter-breeding is found more or less wherever archaic and human populations are compared. How much of variation in D is due to introgression and how much is due to heterozygosity-mediated variation in mutation rate remains to be determined.\n\nAuthor summaryThe idea that humans inter-bred with related lineages such as Neanderthals, leaving an appreciable legacy in modern genomes, has rapidly progressed from shocking revelation to accepted dogma. My analysis explores an alternative model in which mutation rate slowed when diversity was lost in a population bottleneck as humans moved out of Africa to colonise the world. I find that, across Eurasia, the size of inferred legacy closely matches the pattern of diversity loss but shows no relationship to where human and Neanderthal populations likely overlapped. My results do not challenge the idea that some inter-breeding occurred, but they do indicate that some, much or even most of the signal that has be attributed entirely to archaic legacies, arises from unexpected variation in mutation rate. More generally, my analysis helps explain why inter-breeding is inferred almost wherever tests are conducted even though most species avoid hybridisation.