Post by Admin on Jan 4, 2022 0:02:23 GMT
Discussion
Previous studies have shown that archaic introgression contributed to a range of phenotypic variation in modern humans (5, 57, 58), and that a number of introgressed genes were plausibly subject to positive selection (17, 18). Here, we used sequencing data of the most convincing example of adaptive introgression, EPAS1 in Tibetans, to address a series of questions regarding the origin and the timing of Denisovan introgression in East Asia. Our work supports the two-pulse Denisovan admixture model proposed by Browning et al., and our analysis suggests that the beneficial haplotype of EPAS1 in Tibetans originated from the East Asian-specific Denisovan introgression, involving a Denisovan group that is more closely related to the Altai Denisovan individual from the Denisova Cave. Besides EPAS1, archaic introgression has left segments in various genes across the genome, and affected multiple biological pathways including hypoxia.
This work provides a timing estimate of the East Asian-specific Denisovan introgression, which we inferred at around 48 ka, and is consistent with archaeological evidence showing Denisovan ancestry in modern human individuals from 34 to 40 ka (59, 60). Our point estimate suggests that the East Asian-specific admixture event is more ancient (48 ka) than the Papuan-specific pulse (30 ka), and closer to the first Denisovan introgression that is shared by Asian and Oceanian lineages (45 ka, Fig. 4) (29). Interestingly, the low mismatch observed in Jacobs et al. between Altai Denisovan and East Asian-specific Denisovan introgressed segments suggests that the Denisovan population that introgressed uniquely into East Asians (D0 in Fig. 4) was more closely related to the Altai population (that the sequenced Altai Denisovan belonged to) compared to the other two Denisovan populations (D1 and D2 in Fig. 4) that introgressed into humans.
Fig. 4.
Timeline of three Denisovan introgression events in Asia, and the selection of the adaptive EPAS1 allele. This figure is inspired by figure 4 in Jacobs et al. (29) that portrays three distinct Denisovan lineages (D0, D1, and D2), their inferred introgression times, and the split times (measured from the present) between them. Time estimates for D1 and D2 are from Jacobs et al. (29) using Papuan data, and the estimate for the East Asian-specific (D0) introgression time and the selection time in Tibetans come from this study.
The timing of human settlement in the Tibetan Plateau, including archaic hominins, remains under investigation. The discovery of a partial mandible from the Middle Pleistocene (Xiahe Denisovan) in Baishiya Karst Cave (BKC), located at 3,280-m altitude in the Tibetan Plateau suggests that Denisovan-like archaic hominins may have been present at high altitude at least 160 ka (61). More recently, analysis of mtDNA recovered from sediment excavated in this cave (inferred to be from ∼100 to ∼60 ka and maybe as recently as 45 ka) revealed that it grouped most closely with Denisovan mtDNA (62), suggesting that Denisovan-like populations may have inhabited this region for a long period of time. In contrast, evidence for modern human activity has been found on the interior of the Tibetan plateau as early as 40 ka from the Nwya Devu site (63), although long-term human settlements on the high-altitude plateau are believed to be rare at that time. Currently, existing archaeological evidence generally supports two settlement scenarios. The archaeological sites from middle to late Holocene (62⇓⇓–65) indicate that year-round large-scale settlements of people on the plateau started after 3.6 ka facilitated by the advent of agriculture, while analyses on the mobility of hunter-gatherers (66⇓–68) suggest that permanent inhabitation (most likely on a smaller scale) may have occurred more distantly in the past. Our estimate of the Denisovan East Asian-specific admixture time (48 ka) from tract lengths surrounding the EPAS1 gene is larger than most estimates of when modern humans permanently settled in the Tibetan Plateau, suggesting that the admixture most likely occurred outside of this region.
Furthermore, our estimate of the onset time of positive selection on EPAS1 (∼8.9 ka) suggests that selection did not target the Denisovan introgressed alleles immediately after introgression, and possibly coincides with the time of permanent hunter-gatherer Tibetan settlements of populations from lowland East Asia during the Late Pleistocene or early Holocene (64). While evidence of even earlier arrivers exists (e.g., Denisovan from BKC and modern humans at the Nwya Devu site, 40 ka or earlier), it is unclear how long they survived in the Tibetan Plateau, whether they were genetically adapted to the hypoxic environment, or if modern Tibetans are their direct descendants. Only one study has reported ancient DNA from the Himalayas (the Nepalese side) where the oldest samples date to 3.15 ka (65). Interestingly, only the more recent samples (dated to 1.75–1.25 ka) exhibit the EPAS1 alleles present in modern Tibetans. Future studies of ancient humans in this region will help provide additional context and finer resolution to the population history on the Tibetan Plateau.
Previous studies have estimated the time of Denisovan introgression in Asia (SI Appendix, Table S7), but there are multiple differences between our analyses and theirs. The first relates to the underlying assumption of a single introgression event into East Asia (1, 6). Those studies used all of the surviving Denisovan segments (in Papuans or Tibetans), and it is unclear whether that estimate is an average of the two Denisovan introgression events (7, 29) into East Asians, or if the estimate is closer to one of the introgression events. By contrast, we are using the data of a single gene that clearly has been the target of selection, having the advantage that, because it is a small local region of the genome, it is highly likely that the fragments are the remnants of archaic DNA introduced by a single admixture event. The second difference is that we account for positive selection in our inference since we show that selection affects the tract length. The other estimates assume neutrality, and it is unclear whether adaptively introgressed loci could change or bias estimates from genome-wide summary statistics of introgression (e.g., the distribution of introgressed tract lengths, linkage disequilibrium decay pattern). Finally, we use an ABC framework for parameter estimation, while the estimation methods used by others (30, 32, 52) could also lead to some differences in the inferences.
We acknowledge that we have made several assumptions and choices in our work. First, we rely on the sequencing data of only a single gene, which is reflected in our large credible intervals. One way to reduce uncertainty might be to use all the putative introgressed segments introduced via the East Asian Denisovan introgression event, but doing so would require making a different set of assumptions regarding how selection is acting on each of those regions. Second, we have assumed a demographic model for Tibetans from estimates of population size changes from PSMC curves. Our conclusion that selection of EPAS1 acted on standing archaic variation also stands true under all scenarios. We also do not know what the real distribution of tract lengths looks like in Tibetans, and we have inferred that using an HMM. How accurately the HMM infers the true tract lengths in Tibetans is unknown, but other methods [e.g., ArchaicSeeker 2.0 (30)] yield similar results (SI Appendix, Methods and Fig. S15). Even if the HMM does not capture the true Tibetan tract lengths, by applying the HMM to both the real data and the simulated data, we hope that the same bias occurs in both, reducing the likelihood of distorting the parameter estimates.
During the last decade, we have begun to appreciate that gene flow between archaic and modern humans played a major role in shaping human evolution as well as our genetic diversity. The introduction of archaic variants evidently facilitated adaptations to local environments in multiple populations. Our results for EPAS1 demonstrate the importance of selection on standing archaic variation, which other studies suggest is widespread (69, 70). However, recent work infers that selection immediately after introgression explains most examples of adaptive introgression from Neanderthals in Europeans (71). More analysis of other adaptively introgressed loci in multiple populations will further elucidate whether and under what conditions selection on standing archaic variation is the primary mode for adaptation. As we continue to sequence the remains of other archaic and modern humans, a high-resolution picture of archaic introgression in modern humans is expected to be revealed.
Previous studies have shown that archaic introgression contributed to a range of phenotypic variation in modern humans (5, 57, 58), and that a number of introgressed genes were plausibly subject to positive selection (17, 18). Here, we used sequencing data of the most convincing example of adaptive introgression, EPAS1 in Tibetans, to address a series of questions regarding the origin and the timing of Denisovan introgression in East Asia. Our work supports the two-pulse Denisovan admixture model proposed by Browning et al., and our analysis suggests that the beneficial haplotype of EPAS1 in Tibetans originated from the East Asian-specific Denisovan introgression, involving a Denisovan group that is more closely related to the Altai Denisovan individual from the Denisova Cave. Besides EPAS1, archaic introgression has left segments in various genes across the genome, and affected multiple biological pathways including hypoxia.
This work provides a timing estimate of the East Asian-specific Denisovan introgression, which we inferred at around 48 ka, and is consistent with archaeological evidence showing Denisovan ancestry in modern human individuals from 34 to 40 ka (59, 60). Our point estimate suggests that the East Asian-specific admixture event is more ancient (48 ka) than the Papuan-specific pulse (30 ka), and closer to the first Denisovan introgression that is shared by Asian and Oceanian lineages (45 ka, Fig. 4) (29). Interestingly, the low mismatch observed in Jacobs et al. between Altai Denisovan and East Asian-specific Denisovan introgressed segments suggests that the Denisovan population that introgressed uniquely into East Asians (D0 in Fig. 4) was more closely related to the Altai population (that the sequenced Altai Denisovan belonged to) compared to the other two Denisovan populations (D1 and D2 in Fig. 4) that introgressed into humans.
Fig. 4.
Timeline of three Denisovan introgression events in Asia, and the selection of the adaptive EPAS1 allele. This figure is inspired by figure 4 in Jacobs et al. (29) that portrays three distinct Denisovan lineages (D0, D1, and D2), their inferred introgression times, and the split times (measured from the present) between them. Time estimates for D1 and D2 are from Jacobs et al. (29) using Papuan data, and the estimate for the East Asian-specific (D0) introgression time and the selection time in Tibetans come from this study.
The timing of human settlement in the Tibetan Plateau, including archaic hominins, remains under investigation. The discovery of a partial mandible from the Middle Pleistocene (Xiahe Denisovan) in Baishiya Karst Cave (BKC), located at 3,280-m altitude in the Tibetan Plateau suggests that Denisovan-like archaic hominins may have been present at high altitude at least 160 ka (61). More recently, analysis of mtDNA recovered from sediment excavated in this cave (inferred to be from ∼100 to ∼60 ka and maybe as recently as 45 ka) revealed that it grouped most closely with Denisovan mtDNA (62), suggesting that Denisovan-like populations may have inhabited this region for a long period of time. In contrast, evidence for modern human activity has been found on the interior of the Tibetan plateau as early as 40 ka from the Nwya Devu site (63), although long-term human settlements on the high-altitude plateau are believed to be rare at that time. Currently, existing archaeological evidence generally supports two settlement scenarios. The archaeological sites from middle to late Holocene (62⇓⇓–65) indicate that year-round large-scale settlements of people on the plateau started after 3.6 ka facilitated by the advent of agriculture, while analyses on the mobility of hunter-gatherers (66⇓–68) suggest that permanent inhabitation (most likely on a smaller scale) may have occurred more distantly in the past. Our estimate of the Denisovan East Asian-specific admixture time (48 ka) from tract lengths surrounding the EPAS1 gene is larger than most estimates of when modern humans permanently settled in the Tibetan Plateau, suggesting that the admixture most likely occurred outside of this region.
Furthermore, our estimate of the onset time of positive selection on EPAS1 (∼8.9 ka) suggests that selection did not target the Denisovan introgressed alleles immediately after introgression, and possibly coincides with the time of permanent hunter-gatherer Tibetan settlements of populations from lowland East Asia during the Late Pleistocene or early Holocene (64). While evidence of even earlier arrivers exists (e.g., Denisovan from BKC and modern humans at the Nwya Devu site, 40 ka or earlier), it is unclear how long they survived in the Tibetan Plateau, whether they were genetically adapted to the hypoxic environment, or if modern Tibetans are their direct descendants. Only one study has reported ancient DNA from the Himalayas (the Nepalese side) where the oldest samples date to 3.15 ka (65). Interestingly, only the more recent samples (dated to 1.75–1.25 ka) exhibit the EPAS1 alleles present in modern Tibetans. Future studies of ancient humans in this region will help provide additional context and finer resolution to the population history on the Tibetan Plateau.
Previous studies have estimated the time of Denisovan introgression in Asia (SI Appendix, Table S7), but there are multiple differences between our analyses and theirs. The first relates to the underlying assumption of a single introgression event into East Asia (1, 6). Those studies used all of the surviving Denisovan segments (in Papuans or Tibetans), and it is unclear whether that estimate is an average of the two Denisovan introgression events (7, 29) into East Asians, or if the estimate is closer to one of the introgression events. By contrast, we are using the data of a single gene that clearly has been the target of selection, having the advantage that, because it is a small local region of the genome, it is highly likely that the fragments are the remnants of archaic DNA introduced by a single admixture event. The second difference is that we account for positive selection in our inference since we show that selection affects the tract length. The other estimates assume neutrality, and it is unclear whether adaptively introgressed loci could change or bias estimates from genome-wide summary statistics of introgression (e.g., the distribution of introgressed tract lengths, linkage disequilibrium decay pattern). Finally, we use an ABC framework for parameter estimation, while the estimation methods used by others (30, 32, 52) could also lead to some differences in the inferences.
We acknowledge that we have made several assumptions and choices in our work. First, we rely on the sequencing data of only a single gene, which is reflected in our large credible intervals. One way to reduce uncertainty might be to use all the putative introgressed segments introduced via the East Asian Denisovan introgression event, but doing so would require making a different set of assumptions regarding how selection is acting on each of those regions. Second, we have assumed a demographic model for Tibetans from estimates of population size changes from PSMC curves. Our conclusion that selection of EPAS1 acted on standing archaic variation also stands true under all scenarios. We also do not know what the real distribution of tract lengths looks like in Tibetans, and we have inferred that using an HMM. How accurately the HMM infers the true tract lengths in Tibetans is unknown, but other methods [e.g., ArchaicSeeker 2.0 (30)] yield similar results (SI Appendix, Methods and Fig. S15). Even if the HMM does not capture the true Tibetan tract lengths, by applying the HMM to both the real data and the simulated data, we hope that the same bias occurs in both, reducing the likelihood of distorting the parameter estimates.
During the last decade, we have begun to appreciate that gene flow between archaic and modern humans played a major role in shaping human evolution as well as our genetic diversity. The introduction of archaic variants evidently facilitated adaptations to local environments in multiple populations. Our results for EPAS1 demonstrate the importance of selection on standing archaic variation, which other studies suggest is widespread (69, 70). However, recent work infers that selection immediately after introgression explains most examples of adaptive introgression from Neanderthals in Europeans (71). More analysis of other adaptively introgressed loci in multiple populations will further elucidate whether and under what conditions selection on standing archaic variation is the primary mode for adaptation. As we continue to sequence the remains of other archaic and modern humans, a high-resolution picture of archaic introgression in modern humans is expected to be revealed.
