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. 2018 Oct 4;175(2):360-371.e13.
doi: 10.1016/j.cell.2018.08.034.

Evidence That RNA Viruses Drove Adaptive Introgression Between Neanderthals and Modern Humans

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Free PMC article

Evidence That RNA Viruses Drove Adaptive Introgression Between Neanderthals and Modern Humans

David Enard et al. Cell. .
Free PMC article

Abstract

Neanderthals and modern humans interbred at least twice in the past 100,000 years. While there is evidence that most introgressed DNA segments from Neanderthals to modern humans were removed by purifying selection, less is known about the adaptive nature of introgressed sequences that were retained. We hypothesized that interbreeding between Neanderthals and modern humans led to (1) the exposure of each species to novel viruses and (2) the exchange of adaptive alleles that provided resistance against these viruses. Here, we find that long, frequent-and more likely adaptive-segments of Neanderthal ancestry in modern humans are enriched for proteins that interact with viruses (VIPs). We found that VIPs that interact specifically with RNA viruses were more likely to belong to introgressed segments in modern Europeans. Our results show that retained segments of Neanderthal ancestry can be used to detect ancient epidemics.

Keywords: Neanderthals; RNA viruses; adaptive introgression.

Figures

Figure 1.
Figure 1.. Higher frequency and longer adaptive introgressed segments compared to neutral ones
Green: introgressed Neanderthal segment. Grey: genomic background of the receiving population. Contiguous fragments of IS result in a longer region with a higher probability/frequency of introgressed alleles. The frequencies of alleles inherited from Neanderthals were estimated by Sankararaman et al. (Sankararaman et al. 2014) using the Conditional Random Field approach. Note that Figure 1 is a schematization meant to highlight the differences between the neutral and the adaptive introgression scenario. The represented frequencies or length of IS are meant for illustration purpose only and do not represent actual cases present in our dataset.
Figure 2.
Figure 2.. Confounding factors included in the bootstrap test
A) Venn Diagram of the factors that could confound the comparison of VIPs with non-VIPs, that is those that differ both between VIPs and non-VIPs and also inside and outside introgressions. B) Bootstrap matching of potential confounding factors between VIPs and control non-VIPs for introgression from Neanderthals to East Asian modern humans. Boxplot intervals represent the discrepancy between confounding factors between VIPs and non-VIPs before bootstrap matching. The red dots represent the difference in confounding factors between VIPs and non-VIPs after bootstrap matching. Note that for the factor “regulatory density” the residual discrepancy is in the conservative direction. C) Same as B) but for introgression from Neanderthals to European modern humans.
Figure 3.
Figure 3.. Excess of introgression from Neanderthals to modern humans at VIPs
The graphs show the relative excess (y-axis) of IS of Neanderthal ancestry within Asian and European modern human genomes as a function of increasing lower segment size threshold (x-axis) and increasing lower segment frequency threshold (panels from left to right)..The black line is the observed excess. The grey area is the 95% confidence interval. For representation purposes, any excess greater than 10 is depicted as 10 in the graphs. Segment size thresholds for which the confidence interval is not represented correspond to thresholds beyond which there are no IS overlapping control non-VIPs. Orange dots: bootstrap test P<0.05. Red dots: bootstrap test P<0.001. The dashed line indicates an excess of 1. The lower segment size threshold was increased until there were fewer than three remaining IS overlapping VIPs or non-VIPs included in the matching. The points that have no confidence interval are points where VIPs still have several overlapping IS, but where control non-VIPs no longer have any overlapping introgressed segment. A) Excess in all VIPs. B) Excess in VIPs across high recombination regions (> 1.5 cM/Mb, the median recombination rate within IS).
Figure 4.
Figure 4.. Excess of introgression from modern humans to Neanderthals at VIPs
Legend as in Figure 3. A) All VIPs. B) High recombination VIPs.
Figure 5.
Figure 5.. Excess of introgression from Neanderthals to modern humans at RNA VIPs vs. DNA VIPs
Legend as in Figure 3, except that the y-axis represents the excess of introgressions at RNA VIPs vs. DNA VIPs, rather than VIPs vs. non-VIPs.
Figure 6.
Figure 6.. Excess of introgression from Neanderthals to modern humans at IAV-only, HIV-only, and HCV-only VIPs
Legend as in Figure 3.
Figure 7.
Figure 7.. Enrichments in adaptive introgression from Neanderthals to modern humans among Gene Ontology annotations over-represented or not over-represented in VIPs
We compared the enrichment in adaptive introgression of specific GO annotations. We estimated how much each GO function was enriched in introgressed segments by comparing the number of genes of the GO function within introgressed segments compared to the number of genes expected by chance (STAR Methods). The enrichment is then the ratio of the observed number of genes for a given function within introgressed segments divided by the average random expectation. All the enrichments were measured excluding VIPs since we want to specifically estimate the effect of internal host functions independently of interactions with viruses. Red: distributions of enrichments (x-axis) across GO functions found at more than 50 VIPs and that are significantly over-represented among VIPs. Blue: distributions of enrichments across GO functions found at more than 50 VIPs but not over-represented among VIPs. A. Mock example corresponding to the case where GO functions over-represented in VIPs are not enriched in adaptive introgression (the red and blue distributions overlap each other). B. Mock example corresponding to the case where GO functions over-represented in VIPs are enriched in adaptive introgression compared to other GO functions (the red distribution is shifted to the right). C. Enrichments in introgressed segments longer than 50kb and at frequencies higher than 5% in Europe. D. Enrichments in introgressed segments longer than 100kb and at frequencies higher than 15% in Europe. E. Enrichments in introgressed segments longer than 50kb and at frequencies higher than 5% in East Asia. F. Enrichments in introgressed segments longer than 100kb and at frequencies higher than 15% in East Asia.

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