Abstract
Approximately 2-4% of the human genome is in non-Africans comprised of DNA intro- gressed from Neanderthals. Recent studies have shown that there is a paucity of introgressed DNA around functional regions, presumably caused by selection after introgression. This observation has been suggested to be a possible consequence of the accumulation of a large amount of Dobzhansky-Muller incompatibilities, i.e. epistatic effects between human and Neanderthal specific mutations, since the divergence of humans and Neanderthals approx. 400-600 kya. However, using previously published estimates of inbreeding in Neanderthals, and of the distribution of fitness effects from human protein coding genes, we show that the average Neanderthal would have had at least 40% lower fitness than the average human due to higher levels of inbreeding and an increased mutational load, regardless of the dominance coefficients of new mutations. Using simulations, we show that under the assumption of additive dominance effects, early Neanderthal/human hybrids would have experienced strong negative selection, though not so strong that it would prevent Neanderthal DNA from entering the human population. In fact, the increased mutational load in Neanderthals predicts the observed reduction in Neanderthal introgressed segments around protein coding genes, without any need to invoke epistasis. The simulations also predict that there is a residual Neanderthal derived mutational load in non-African humans, leading to an average fitness reduction of at least 0.5%. Although there has been much previous debate about the effects of the out-of-Africa bottleneck on mutational loads in non-Africans, the significant deleterious effects of Neanderthal introgression have hitherto been left out of this discussion, but might be just as important for understanding fitness differences among human populations. We also show that if deleterious mutations are recessive, the Neanderthal admixture fraction would gradually increase over time due to selection for Neanderthal haplotypes that mask human deleterious mutations in the heterozygous state. This effect of dominance heterosis might partially explain why adaptive introgression appears to be widespread in nature.
