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Neanderthals and modern humans have crossed at least twice in the last 100,000 years. There is evidence that most of the introgressed DNA segments of Neanderthals in modern humans have been purified by selection, but less is known about the adaptive nature of retained introgressed sequences. We hypothesized that Neanderthals mingling with modern humans led to (1) the exposure of each species to new viruses and (2) the exchange of adaptive alleles offering resistance to these viruses. Here we find that in modern humans, long, frequent – and more likely adaptive – segments of Neanderthal ancestry are enriched in proteins that interact with viruses (VIP). We found that VIPs that specifically interact with RNA viruses were more likely to belong to introgressed segments in modern Europeans. Our results show that conserved segments of Neanderthal ancestry can be used to detect old epidemics.
After their divergence 500,000 to 800,000 years ago, modern humans and Neanderthals met at least twice: the first time 100,000 years ago (Kuhlwilm et al., 2016) and the second one 50,000 years ago (Fu et al., 2015, Green et al., 2010, Pääbo, 2015, Sankararaman et al., 2012, Sankararaman et al., 2014). The first episode of miscegenation left introgressed segments (IS) of modern human ancestry within Neanderthal genomes (Kuhlwilm et al., 2016), revealed by the analysis of ancient DNA from Only one Neanderthalian Altai individual sequenced by Prüfer et al. (2014). This first miscegenation event seems to have left no detectable segment of Neanderthal ancestry in existing modern human genomes (Kuhlwilm et al., 2016). In contrast, the second episode of miscegenation left a detectable IS of Neanderthal ancestry in the genomes of modern non-African humans (Fu et al., 2015, Green et al., 2010, Prüfer et al., 2014, Sankararaman et al., 2014, Vernot and Akey, 2014).
Recent advances in introgression detection have found that the majority of genomic segments initially introgressed from Neanderthal humans to modern humans have been rapidly cleared by purification from humans. selection. Harris and Nielsen (2016) have estimated that the proportion of Neanderthal ancestry in modern human genomes has declined rapidly from about 10% at current levels of 2% to 3% among Asians and modern Europeans (Fu and al., 2015, Juric et al., 2016).
This history of hybridization selection and purification against IS raises several important questions. First, among the introgressed sequences that were finally retained, can we detect which sequences persisted by chance because they were not as harmful or not harmful to the recipient species, and which persisted not despite natural selection but because of that – that is, what frequency has increased because of positive selection? If one of the introgressed sequences was actually introduced into the recipient species because of positive selection, can we determine what pressures in the environment led to this adaptation?
We have recently discovered that proteins that interact with viruses (proteins interacting with viruses) [VIPs]) evolve under both a stricter purification selection and tend to adapt to much higher speeds compared to similar proteins that do not interact with viruses (Enard et al., 2016).
We estimated that virus interactions accounted for about 30% of protein adaptation in the human lineage (Enard et al., 2016). Because viruses seem to have led so many adaptations in the human lineage, and because it is plausible that, when Neanderthals and modern humans came across, they also exchanged viruses directly through contact or via their shared environment, we hypothesized that some introgressed sequences might have been protective against the viruses being exchanged and introduced into the recipient species by positive directional selection. According to this model, several cases of probable adaptive introgression (Gittelman et al., 2016, Racimo et al., 2015, Racimo et al., 2017) from Neanderthals to modern humans involve specialized immune genes. in the treatment of pathogens, including viruses. (Abi-Rached et al., 2011, Dannemann et al., 2016, Deschamps et al., 2016, Houldcroft and Underdown, 2016, Mendez et al., 2012, Mendez et al., 2013, Nedelec et al., 2016 , Quach et al., 2016, Sams et al., 2016).
Here, we test this hypothesis by determining whether VIPs are enriched in global SIs and, more specifically, in longer, more frequent SIs, which are more likely to be introduced into the recipient's genome by positive directional selection. Since purification selection strongly affects the likelihood that introgressed sequences will be retained by chance, we test the introgression enrichment of VIPs after control of the stronger VIP purification selection as well as many other confounding factors. potential.
The basic logic of the analysis is as follows. If positive directional selection occurs shortly after miscegenation, the adaptive Neanderthal haplotypes introgressed should increase rapidly in frequency before being fragmented by recombination, which should result in the presence of long and frequent AEs. Over time, recombination is expected to break the SI, while purification of the selection should eliminate harmful alleles that have hitched with the adaptive variant (s). As a result, the signal should erode over time.
In summary, we have confirmed that 4,534 VIPs in our ensemble are better preserved and have more deleterious separating variants than non-VIPs (Enard et al., 2016). The higher levels of preservation and selection of VIP purification, as well as the higher rate of loss of more limited sequences of Neanderthal ancestry derived from the modern human genome, imply that IEs containing VIPs are more likely to 39, have been removed by purification. It is therefore essential to control the different levels of purification selection to increase the detection power of VIP enrichment in IS. An imperfect control of the purification of the selection may indeed make the test of enrichment of the VIPs in the introgressed regions too conservative, because, in the null hypothesis that no adaptation is aimed at the VIPs. preferably, we would expect that VIPs are less present in the Neanderthal IS compared to non-VIP.
Although we have combined VIP and HT VIPs into a single VIP category, we have systematically confirmed throughout the document that the main results achieved when combining all VIPs were also valid when using only VIPs. VIP LT organized by hand.
Control confusing factors between VIPs and non-VIPs
To determine whether VIPs are enriched in introgressed segments between modern humans and Neanderthals, it is first important to define what other factors, in addition to stress levels, affect the onset of EI along the genome regardless of interactions with viruses. In the genome, the factors that influence the onset of an SI must differ from inside to outside the IS. We must therefore match VIPs and non-VIPs for genomic factors that (1) differ within the IS outside of, and (2) also differ between VIPs and non-VIPs.
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