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Post by Admin on Jun 27, 2018 18:51:29 GMT
Figure 4 Contour Density Plots of Match Proportion of Introgressed Segments to the Altai Neanderthal and Altai Denisovan Genomes In order to look more closely at the Neanderthal and Denisovan ancestry in present-day humans, we plot two-way densities of match rate to the Altai Neanderthal and Altai Denisovan genomes for segments with at least ten positions that can be compared to the Altai Neanderthal and at least ten positions that can be compared to the Altai Denisovan (Figure 4). In each population, we see a large cluster of segments with high matching to the Altai Neanderthal and low matching to the Altai Denisovan. This cluster corresponds to segments introgressed from Neanderthals. In each population the mode of matching to the Altai Neanderthal for this cluster is approximately 0.8, whereas the mode of matching to the Altai Denisovan genome is approximately 0.2. Thus approximately 20% of the archaic-specific variants introgressed from Neanderthals are also carried by the Altai Denisovan due to the relatedness of the Neanderthal and Denisovan populations, whereas 80% of the archaic-specific variants introgressed from Neanderthals are present in the Altai Neanderthal. In each population we also see a small cluster of segments with almost no matching to the Altai Neanderthal or to the Altai Denisovan; these are likely to be false-positive results that do not correspond to archaic introgression. In the Asian and Papuan populations we see a third cluster of segments. The segments in this third cluster have high matching to the Altai Denisovan and low matching to the Altai Neanderthal. This cluster corresponds to segments introgressed from Denisovans and confirms the previous finding of Denisovan admixture in Papuans and in Asians (Prüfer et al., 2014, Qin and Stoneking, 2015, Sankararaman et al., 2016, Skoglund and Jakobsson, 2011). Figures 4 and 5 also indicate that several other populations may carry a small proportion of segments introgressed from Denisovans. These include the Finns, who are estimated to have obtained around 7% of their ancestry from East Asia (Sikora et al., 2014), and admixed American populations whose Native American ancestors are related to East Asians (Gutenkunst et al., 2009). In the Japanese and Chinese (Dai, Beijing, and Southern Han) populations we see that the Denisovan cluster of segments has a wide and bimodal distribution of match rates to the Altai Denisovan genome (Figure 4). A test for two distinct components of Denisovan ancestry (see the STAR Methods) is statistically significant (p < 0.05 after adjusting for multiple testing) in each of these four populations (Table 2) but is not significant in the other 1000 Genomes populations. The fitted two-component mixture has approximately one-third of the Denisovan segments in the Japanese and Chinese populations coming from the component with higher affinity to the Altai Denisovan genome. The putative archaic-specific alleles in the high-affinity component have a match rate of around 80% to the Altai Denisovan genome, which is similar to the match rate of putative archaic-specific alleles in Neanderthal introgressed segments with the Altai Neanderthal, whereas the putative archaic-specific alleles in the other (moderate-affinity) component have a match rate of around 50% to the Altai Denisovan genome. Table 2 Two-Component Mixtures for Denisovan-Related Introgression Population Math Eq Math Eq Math Eq Math Eq Math Eq p value Southern Han Chinese 0.82 0.46 0.08 0.12 0.42 0.00002 Han Chinese (Beijing) 0.84 0.50 0.08 0.14 0.36 0.00021 Chinese Dai 0.86 0.52 0.04 0.18 0.20 0.00069 Japanese (Tokyo) 0.86 0.52 0.06 0.18 0.26 0.00143 Finnish 0.84 0.50 0.04 0.14 0.22 0.00348 Punjabi (Pakistan) 0.82 0.48 0.10 0.12 0.10 0.04589
Based on the mode of matching to the Denisovan genome, most of the Denisovan ancestry in the South Asian and Papuan populations is from the archaic component with moderate affinity to the Altai Denisovan (Figure 4). This is consistent with previous work that noted that the Altai Denisovan is significantly more distantly related to the introgressing Denisovans compared to the relationship between the Altai Neanderthal and the introgressing Neanderthals (Prüfer et al., 2014).
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Post by Admin on Jun 28, 2018 18:59:29 GMT
To facilitate further analyses, we extracted subsets of segments based on their affinity to the Altai Neanderthal and to the Altai Denisovan (see the STAR Methods). We performed several analyses to check for possible confounders of match rate to the Denisovan genome. We checked whether the divergence between the Altai Neanderthal and Altai Denisovan differs between regions covered by the moderate-affinity Denisovan introgression and the high-affinity Denisovan introgression in case such differences could account for the two components. In the East Asian data, the mean relative divergence (number of homozygous discordances between the Altai Neanderthal and Altai Denisovan divided by the number of 1000 Genomes variants) per segment was 1.65 (SE 0.26) for high-affinity Denisovan segments and 2.51 (SE 1.00) for moderate-affinity Denisovan segments. The difference is not statistically significant (p > 0.05). We also investigated the average density of putative archaic-specific variants in segments attributed to the different components. We adjusted for length of the detected segments, because the power to detect segments increases with both length and the density of archaic-specific variants. In the East Asian data, the adjusted mean inverse density (bp per archaic-specific variant) was 103 (SE 440) for the high-affinity Denisovan segments, 395 (SE 464) for the moderate-affinity Denisovan segments, and 1,164 (SE 72) for the Neanderthal segments. The difference is not statistically significant (p > 0.05). Thus we do not find confounding by divergence or by density of archaic-specific alleles. We investigated the lengths of haplotypes within segments attributed to the different components in order to investigate potential differences in admixture time between components. We analyzed haplotype lengths in units of centimorgans (cM) rather than base pairs because centimorgan distances reflect recombination and are thus less variable. We adjusted for frequency and overall segment length because high frequency and high segment length increase power to detect a segment and are correlated with haplotype length. In the East Asian data, the mean adjusted haplotype length was 0.066 (SE 0.014) cM for Neanderthal segments, 0.19 (SE 0.13) cM for high-affinity Denisovan segments, 0.072 (SE 0.13) cM for moderate-affinity Denisovan segments, and 0.13 (SE 0.06) cM for Denisovan segments overall. These are not significantly different. We also checked for differences in Europeans, in South Asians, in Asians overall (East and South), and in Papuans, again finding no significant differences. While it is probable that the Neanderthal admixture and the two waves of Denisovan admixture occurred at distinct times, there is insufficient information in the data to determine the ordering of these events. Overall, East Asians and South Asians carry similar amounts of detected Denisovan ancestry, while Papuans carry much more detected Denisovan ancestry (Figure 5). Approximately one-third of the Denisovan ancestry segments in the East Asians are from the high-affinity component (Table 2), whereas very little of the Denisovan ancestry in the South Asians and Papuans is from the high-affinity component (Figure 4). A possible scenario consistent with this pattern would have the high-affinity component introgressing into East Asia after the split between East and South Asia. Because the Papuans have a much higher frequency of the moderate-affinity Denisovan component than other populations, it may be that this component was primarily introgressed into the ancestors of Papuans after they split from Asia, and arrived in Asia via migration from the ancestors of Papuans; however, other scenarios are also possible (Prüfer et al., 2014, Sankararaman et al., 2016).
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Post by Admin on Jun 29, 2018 18:44:53 GMT
Figure 5 Mean Amounts of Detected Introgressed Material per Individual, Classified by Affinity to the Altai Neanderthal and Altai Denisovan Genomes The frequency of Neanderthal introgression is substantially higher (∼30%) in East Asians than in Europeans (Meyer et al., 2012, Wall et al., 2013). This difference cannot be explained by differential effects of selection, but could be due to an additional Neanderthal admixture event into the ancestors of East Asians after the Europe-Asia split (Kim and Lohmueller, 2015, Vernot and Akey, 2015). Another possible explanation would be dilution of Neanderthal admixture in Europe due to migration from a population without Neanderthal admixture (Meyer et al., 2012, Vernot and Akey, 2015). In our results, the Neanderthal-introgressed segments in East Asians and in Europeans show indistinguishable levels of similarity to the Altai Neanderthal (Figure 4). There is also no clear difference between East Asians and Europeans in the similarity of their Neanderthal-introgressed segments to the Vindija 33.19 Neanderthal (Figure S4). Thus, if the ancestors of East Asians received a large pulse of Neanderthal admixture after splitting from Europeans, then the original (shared Eurasian) and additional (East Asian-specific) admixing populations must have been closely related. We found evidence that Asians carry Denisovan introgression, confirming previous reports that used alternative methods (Prüfer et al., 2014, Qin and Stoneking, 2015, Sankararaman et al., 2016, Skoglund and Jakobsson, 2011). Further, we found evidence for two waves of Denisovan admixture, one from a population closely related to the Altai Denisovan individual, and one from a population more distantly related to the Altai Denisovan. The component closely related to the Altai Denisovan is primarily present in East Asians, whereas the component more distantly related to the Altai Denisovan forms the major part of the Denisovan ancestry in Papuans and South Asians. The East Asian populations are the only populations with relatively equal and non-negligible contributions from both components, and it is in these populations that the two waves of Denisovan admixture are most evident. In contrast, we did not find evidence for two or more waves of Neanderthal admixture from diverged Neanderthal populations. The higher rates of Neanderthal introgression in East Asians relative to Europeans may be due to dilution of Neanderthal admixture in Europeans as a result of migration from a population without Neanderthal admixture (Meyer et al., 2012, Vernot and Akey, 2015). If there was an additional pulse of Neanderthal admixture into East Asians after the Europe-Asia split, then it was from a population closely related to the primary admixing Neanderthals. We found a number of high-frequency introgressed haplotypes that appear to have been subject to positive selection. Two of these regions are involved in immunity, containing the immunoglobulin heavy locus and a cluster of chemokine receptors. These regions, in addition to previous reports of positively selected introgressed haplotypes in histocompatibility leukocyte antigen (HLA) genes (Abi-Rached et al., 2011), Toll-like receptors (Deschamps et al., 2016), and many other immunity genes (Abi-Rached et al., 2011, Deschamps et al., 2016, Quach et al., 2016, Racimo et al., 2015) underscore the crucial role that Neanderthal introgression played in adapting the human immune system to the pathogenic landscape of Eurasia. Publication stage: In Press Corrected Proof
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Post by Admin on Aug 5, 2018 18:24:51 GMT
Researchers at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, have sequenced the genomes of five Neandertals that lived between 39,000 and 47,000 years ago. These late Neandertals are all more closely related to the Neandertals that contributed DNA to modern human ancestors than an older Neandertal from the Altai Mountains that was previously sequenced. Their genomes also provide evidence for a turnover in the Neandertal population towards the end of Neandertal history. Due to the limited number of specimens and difficulties in obtaining endogenous DNA from such old material, the number of Neandertals for which nuclear genomes have been sequenced is still limited. Since 2010 whole genome sequences have been generated for four Neandertals from Croatia, Siberia and the Russian Caucasus. This study adds five new genomes representing Neandertals from a wider geographic range and from a later time period than what was previously obtained. New methods for the removal of contaminating DNA from microbes and present-day humans that were developed by the Leipzig group have now enabled the researchers to sequence the genomes of five Neandertals from Belgium, France, Croatia, and Russia that are between 39,000 and 47,000 years old. These therefore represent some the latest surviving Neandertals in Europe. Having genomes from multiple Neandertals allows the researchers to begin to reconstruct Neandertal population history. "We see that the genetic similarity between these Neandertals is well-correlated with their geographical location. By comparing these genomes to the genome of an older Neandertal from the Caucasus we show that Neandertal populations seem to have moved and replaced each other towards the end of their history", says first author, Mateja Hajdinjak. The team also compared these Neandertal genomes to the genomes of people living today, and showed that all of the late Neandertals were more similar to the Neandertals that contributed DNA to present-day people living outside Africa than an older Neandertal from Siberia. Intriguingly, even though four of the Neandertals lived at a time when modern humans had already arrived in Europe they do not carry detectable amounts of modern human DNA. "It may be that gene flow was mostly unidirectional, from Neandertals into modern humans", says Svante Pääbo, Director at the Max Planck Institute for Evolutionary Anthropology. "Our work demonstrates that the generation of genome sequences from a large number of archaic human individuals is now technically feasible, and opens the possibility to study Neandertal populations across their temporal and geographical range", says Janet Kelso, the senior author of the new study. Abstract Although it has previously been shown that Neanderthals contributed DNA to modern humans1,2, not much is known about the genetic diversity of Neanderthals or the relationship between late Neanderthal populations at the time at which their last interactions with early modern humans occurred and before they eventually disappeared. Our ability to retrieve DNA from a larger number of Neanderthal individuals has been limited by poor preservation of endogenous DNA3 and contamination of Neanderthal skeletal remains by large amounts of microbial and present-day human DNA3,4,5. Here we use hypochlorite treatment6 of as little as 9 mg of bone or tooth powder to generate between 1- and 2.7-fold genomic coverage of five Neanderthals who lived around 39,000 to 47,000 years ago (that is, late Neanderthals), thereby doubling the number of Neanderthals for which genome sequences are available. Genetic similarity among late Neanderthals is well predicted by their geographical location, and comparison to the genome of an older Neanderthal from the Caucasus2,7 indicates that a population turnover is likely to have occurred, either in the Caucasus or throughout Europe, towards the end of Neanderthal history. We find that the bulk of Neanderthal gene flow into early modern humans originated from one or more source populations that diverged from the Neanderthals that were studied here at least 70,000 years ago, but after they split from a previously sequenced Neanderthal from Siberia2 around 150,000 years ago. Although four of the Neanderthals studied here post-date the putative arrival of early modern humans into Europe, we do not detect any recent gene flow from early modern humans in their ancestry. Nature doi:10.1038/nature26151
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Post by Admin on Oct 11, 2018 18:22:06 GMT
After their divergence 500,000 to 800,000 years ago, modern humans and Neanderthals interbred at least twice: the first time ∼100,000 years ago (Kuhlwilm et al., 2016) and the second ∼50,000 years ago (Fu et al., 2015, Green et al., 2010, Pääbo, 2015, Sankararaman et al., 2012, Sankararaman et al., 2014). The first interbreeding episode left introgressed segments (IS) of modern human ancestry within Neanderthal genomes (Kuhlwilm et al., 2016), as revealed by the analysis of ancient DNA from a single Altai Neanderthal individual sequenced by Prüfer et al. (2014). This first interbreeding event appears not to have left any detectable segments of Neanderthal ancestry in extant modern human genomes (Kuhlwilm et al., 2016). In contrast, the second interbreeding episode left detectable IS of Neanderthal ancestry within the genomes of non-African modern humans (Fu et al., 2015, Green et al., 2010, Prüfer et al., 2014, Sankararaman et al., 2014, Vernot and Akey, 2014). 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. Harris and Nielsen (2016) 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 (Fu et al., 2015, Juric et al., 2016). 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? Recently we found that proteins that interact with viruses (virus-interacting proteins [VIPs]) evolve under both stronger purifying selection and tend to adapt at much higher rates compared to similar proteins that do not interact with viruses (Enard et al., 2016). We estimated that interactions with viruses accounted for ∼30% of protein adaptation in the human lineage (Enard et al., 2016). Because viruses appear to have driven so much adaptation in the human lineage, and because it is plausible that when Neanderthals and modern humans interbred they also exchanged viruses either directly by contact or via their shared environment, we hypothesized that some introgressed sequences might have provided a measure of protection against the exchanged viruses and were driven into the recipient species by positive directional selection. Consistent with this model, several cases of likely adaptive introgression (Gittelman et al., 2016, Racimo et al., 2015, Racimo et al., 2017) from Neanderthals to modern humans involve immune genes that are specialized to deal with 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). Figure 1 Higher Frequency and Longer Adaptive Introgressed Segments Compared to Neutral Ones 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. 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 by Sankararaman et al. (2014) and 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).
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