The Strength of Selection Against Neanderthal Introgression

Abstract

Hybridization between humans and Neanderthals has resulted in a low level of Neanderthal ancestry scattered across the genomes of many modern-day humans. After hybridization, on average, selection appears to have removed Neanderthal alleles from the human population. Quantifying the strength and causes of this selection against Neanderthal ancestry is key to understanding our relationship to Neanderthals and, more broadly, how populations remain distinct after secondary contact. Here, we develop a novel method for estimating the genome-wide average strength of selection and the density of selected sites using estimates of Neanderthal allele frequency along the genomes of modern-day humans. We confirm that East Asians had somewhat higher initial levels of Neanderthal ancestry than Europeans even after accounting for selection. We find that the bulk of purifying selection against Neanderthal ancestry is best understood as acting on many weakly deleterious alleles. We propose that the majority of these alleles were effectively neutral-and segregating at high frequency-in Neanderthals, but became selected against after entering human populations of much larger effective size. While individually of small effect, these alleles potentially imposed a heavy genetic load on the early-generation human-Neanderthal hybrids. This work suggests that differences in effective population size may play a far more important role in shaping levels of introgression than previously thought.A small percentage of Neanderthal DNA is present in the genomes of many contemporary human populations due to hybridization tens of thousands of years ago. Much of this Neanderthal DNA appears to be deleterious in humans, and natural selection is acting to remove it. One hypothesis is that the underlying alleles were not deleterious in Neanderthals, but rather represent genetic incompatibilities that became deleterious only once they were introduced to the human population. If so, reproductive barriers must have evolved rapidly between Neanderthals and humans after their split. Here, we show that oberved patterns of Neanderthal ancestry in modern humans can be explained simply as a consequence of the difference in effective population size between Neanderthals and humans. Specifically, we find that on average, selection against individual Neanderthal alleles is very weak. This is consistent with the idea that Neanderthals over time accumulated many unconditionally weakly deleterious alleles 1 that in their small population were effectively neutral. However, after introgressing into larger human populations, those alleles became exposed to purifying selection. Thus, rather than being the result of hybrid incompatibilities, differences between human and Neanderthal effective population sizes appear to have played a key role in shaping our present-day shared ancestry.

The genetic history of Ice Age Europe

“…Because all the European samples we analyzed dating to between 37,000 and 14,000 years ago are consistent with descent from a single founding population, admixture with populations with lower Neanderthal ancestry cannot explain the steady decrease in Neanderthal-derived DNA that we detect during this period, showing that natural selection against Neanderthal DNA must have driven this phenomenon (Figure 2). We also obtain an independent line of evidence for selection from our observation that the decrease in Neanderthal-derived alleles is more marked near genes than in less constrained regions of the genome (P=0.010) (Supplementary Information section 3; Extended Data Table 3) 22–25 .…”

The Combined Landscape of Denisovan and Neanderthal Ancestry in Present-Day Humans

“…It has been suggested that the empirically observed reduction in Neanderthal ancestry in Europeans and East Asians near functionally important regions could be explained by a greater load of weakly deleterious alleles in Neanderthals due to the smaller population size of Neanderthals since separation, followed by purging of deleterious Neanderthal alleles in the mixed population [17, 18]. Since we have shown that similar patterns are associated with the Denisovan introgression event, it seems plleausib that similar evolutionary forces operated to remove Denisovan ancestry segments.…”

A genetic method for dating ancient genomes provides a direct estimate of human generation interval in the last 45,000 years

“…Another concern is that previous studies have shown that Neanderthal ancestry proportion varies across chromosomes, with unexpectedly large regions devoid of any Neanderthal ancestry and correlation in Neanderthal ancestry proportion to B-statistic (a measure of linked selection) (12,35), implying a role for natural selection in removing Neanderthal-derived alleles from the modern human gene pool (36). The B-statistic or B-score measures the reduction in diversity levels at a site due to linked selection, with smaller values implying higher selective constraint in the region (37).…”