Ancient epidemics can be detected through the lens of abundant host genomic adaptation

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.

Introduction

Harris and Nielsen (2016) Harris K.

Nielsen R. The genetic cost of Neanderthal introgression. Fu et al., 2015 Fu Q.

Hajdinjak M.

Moldovan O.T.

Constantin S.

Mallick S.

Skoglund P.

Patterson N.

Rohland N.

Lazaridis I.

Nickel B.

et al. An early modern human from Romania with a recent Neanderthal ancestor. Juric et al., 2016 Juric I.

Aeschbacher S.

Coop G. The strength of selection against Neanderthal introgression. Recent advances in the detection of introgression have led to the discovery that the majority of genomic segments initially introgressed from Neanderthals to modern humans were rapidly removed by purifying selection.estimated that the proportion of Neanderthal ancestry in modern human genomes rapidly fell from ∼10% to the current levels of 2%–3% in modern Asians and Europeans ().

This history of interbreeding and purifying selection against IS raises several important questions. First, among the introgressed sequences that were ultimately retained, can we detect which sequences persisted by chance because they were not as deleterious or not deleterious at all to the recipient species, and which persisted not despite natural selection but because of it—that is, which IS increased in frequency due to positive selection? If any of the introgressed sequences were indeed driven into the recipient species due to positive selection, can we determine which pressures in the environment drove this adaptation?

Here, we test this hypothesis by assessing whether VIPs are enriched in IS overall and, more specifically, in longer and more frequent IS that are more likely to have been driven into the recipient genome by positive directional selection. Because purifying selection strongly affects the probability of introgressed sequences being retained by chance, we test introgression enrichments at VIPs after controlling for the stronger purifying selection at VIPs as well as many other potentially confounding factors.

Sankararaman et al. (2014) Sankararaman S.

Mallick S.

Dannemann M.

Prüfer K.

Kelso J.

Pääbo S.

Patterson N.

Reich D. The genomic landscape of Neanderthal ancestry in present-day humans. Figure 1 Higher Frequency and Longer Adaptive Introgressed Segments Compared to Neutral Ones Show full caption Sankararaman et al. (2014) Sankararaman S.

Mallick S.

Dannemann M.

Prüfer K.

Kelso J.

Pääbo S.

Patterson N.

Reich D. The genomic landscape of Neanderthal ancestry in present-day humans. 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 byusing 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. See also Figure S1 Figure S1 Definition of Introgressed Segments, Related to Figure 1 Show full caption (A) Green areas depict regions that were inherited from Neanderthals in different individuals from the same population. The population-wide posterior probability of an allele being inherited from Neanderthals (y axis) is depicted by the blue curve on the graph. The introgressed segment in the figure (blue rectangle) is defined as a genomic region where the posterior probabilities at SNPs exceed the fixed threshold of 0.2. We tolerated that the posterior probability falls transiently below the fixed threshold for no more than ten consecutive SNPs (small dent below 0.2 in the figure). (B) Allele-specific estimates of probabilities of Neanderthal ancestry in a genomic window. Light orange. Low probability. Orange: moderate probability. Dark orange: high probability. Each round represents a specific allele and the corresponding probability of Neanderthal ancestry estimated by the CRF. The basic logic of the analysis is as follows. If positive directional selection occurs soon after interbreeding, adaptive Neanderthal introgressed haplotypes are expected to rapidly increase in frequency before being fragmented by recombination and thus should lead to the presence of long and frequent IS as a result ( Figure 1 ). Over time, recombination is expected to break up IS while purifying selection should remove deleterious alleles that hitchhiked together with the adaptive variant(s). As a result, the signal should erode over time. However, because IS scattered across multiple individuals by recombination can be identified and aggregated into single contiguous genomic regions, as was done byand shown schematically in Figure 1 , the originally adaptive introgressed segment of Neanderthal ancestry might still be identifiable as aggregated segments of Neanderthal ancestry. Furthermore, the frequency and length of such retained regions of Neanderthal ancestry can be assessed ( Figure S1 STAR Methods ).

Here, we gathered a large dataset of thousands of VIPs and showed that they are strongly enriched within longer and more frequent IS of Neanderthal origin in modern human genomes, as well as in the longer IS of modern human origin in the Neanderthal genome. Furthermore, we found that VIPs that specifically interact with RNA viruses are particularly enriched in Neanderthal IS in modern European genomes compared to VIPs that interact with DNA viruses. We provide a number of arguments suggesting that it is specifically adaptation in response to viruses that drove these enrichments. We next identify several viruses as likely agents of selection, as well as a number of specific VIPs as likely targets of adaptation. Finally, we estimate that adaptation overall, and specifically adaptation in response to viruses, was an important force in the history of those Neanderthal IS that were ultimately retained in modern human genomes.