Post by Admin on Jan 2, 2022 22:44:16 GMT
The Sherpa in Tibet have the highest amount of Denisovan ancestry (0.106%) in Asia. Due to Han-like admixture associated with hg O (33.13%), it subsequently dropped to 0.082% in the modern Tibetan population. Four ancient samples from Upper_YR_LN were assigned to O2a2b1a by Ning et al. (2020) and the Tibetans' generic link to the Yellow River (YR) Basin was established by 3,000 BP through later migrations to Tibet. The Sherpa are native to the most mountainous regions of the Tibet Autonomous Region, where modern humans and the Denisovans coexisted. After the recent discovery that the Denisovan introgression event into the ancestral population of Tibetans took place around 48,700 (16,000–59,500) years ago in Tibet (Zhang et al. 2021), Tibet should be considered a homeland of Haplogroup D1a1 ancestral to Japanese (D1a2a) and Onge (D1a2b) branches, which originated in Tibet 40,000-50,000 years before present. The ancient Tibetans were a ghost Basal East Asian population, which was distinct from the Han Chinese and basal to the Onge and Jomon. Indigenous high-altitude populations of the Tibetan plateau provide an example of East Asian populations that do not fit into the simple one migration hypothesis.
Haplogroup D1a1, which is ancestral to the Japanese and Onge branches, originated in Tibet 40,000-50,000 years before present and subsequently migrated to Siberia and Japan (D1a2a) 35,000-40,000 years before present. The Denisovan introgression event into the ancestral population of Tibetans is estimated around 43,000 years ago, which is prior to the split. The D1a2b group migrated to the Andaman Islands is an outlier as D1 is entirely absent in Australia and Oceania, while D1a2a occurs at a very low frequency among the Han people to the east with a spike in Korea. Alternatively, the Jomon (D1a2a) would have gone straight to Taiwan after the split and taken a northward coastal route to Siberia as present-day Taiwan aborigines as well as populations from the Okhotsk-Primorye region (i.e. Ulchi and Nivhk) also showed a significant excess of allele sharing with the Jomon.
The Sherpa in Tibet have the highest amount of Denisovan ancestry (0.106%) in Asia. Due to Han-like admixture associated with hg O (33.13%), it subsequently dropped to 0.082% in the modern Tibetan population. Four ancient samples from Upper_YR_LN were assigned to O2a2b1a by Ning et al. (2020) and the Tibetans' generic link to the Yellow River (YR) Basin was established by 3,000 BP through later migrations to Tibet. The Sherpa are native to the most mountainous regions of the Tibet Autonomous Region, where modern humans and the Denisovans coexisted.
After the recent discovery that the Denisovan introgression event into the ancestral population of Tibetans took place around 48,700 (16,000–59,500) years ago in Tibet (Zhang et al. 2021), Tibet should be considered a homeland of Haplogroup D1a1 ancestral to Japanese (D1a2a) and Onge (D1a2b) branches, which originated in Tibet 40,000-50,000 years before present. The ancient Tibetans were a ghost Basal East Asian population, which was distinct from the Han Chinese and basal to the Onge and Jomon. Indigenous high-altitude populations of the Tibetan plateau provide an example of East Asian populations that do not fit into the simple one migration hypothesis. Tibetans and Sherpa show a divergent history from lowland East Asian populations such as Han Chinese (Jeong et al. 2014), and their adaptive haplotype spanning the EPAS1 gene shares its ancestry with that of an archaic hominin (Huerta-Sánchez et al. 2014).
D0 is tentatively dated approximately 10 kya by Jacobs et al. (2019) because D0 introgression was ongoing more recently than the divergence of American and East Asian populations, suggesting secondary Denisovan introgression to East Asian and Native American populations from the said source populations. The timing estimate of the East Asian-specific Denisovan introgression (D0) at around 48 kya by Zhang et al. (2021) is specific to the Tibetans, which is not the same introgression event as D0 defined by Jacobs et al. (2019).
The history and evolution of the Denisovan-EPAS1 haplotype in Tibetans
Significance
The discovery of the archaic Denisovan hominins is one of the most significant findings in human evolutionary biology in the last decade. However, as of today, we have more questions than answers regarding this mysterious hominin group. This study leverages the information from the well-known example of adaptive introgression on the EPAS1 gene in Tibetans, to gain insight on the history of our species’ interaction with Denisovans. We show that the Tibetan-EPAS1 haplotype came from the East Asian-specific Denisovan introgression event, and it remained selectively neutral for a long time in the population before positive selection occurred, which may be concurrent with the permanent inhabitation of the Tibetan Plateau after the Last Glacial Maximum (LGM).
Abstract
Recent studies suggest that admixture with archaic hominins played an important role in facilitating biological adaptations to new environments. For example, interbreeding with Denisovans facilitated the adaptation to high-altitude environments on the Tibetan Plateau. Specifically, the EPAS1 gene, a transcription factor that regulates the response to hypoxia, exhibits strong signatures of both positive selection and introgression from Denisovans in Tibetan individuals. Interestingly, despite being geographically closer to the Denisova Cave, East Asian populations do not harbor as much Denisovan ancestry as populations from Melanesia. Recently, two studies have suggested two independent waves of Denisovan admixture into East Asians, one of which is shared with South Asians and Oceanians. Here, we leverage data from EPAS1 in 78 Tibetan individuals to interrogate which of these two introgression events introduced the EPAS1 beneficial sequence into the ancestral population of Tibetans, and we use the distribution of introgressed segment lengths at this locus to infer the timing of the introgression and selection event. We find that the introgression event unique to East Asians most likely introduced the beneficial haplotype into the ancestral population of Tibetans around 48,700 (16,000–59,500) y ago, and selection started around 9,000 (2,500–42,000) y ago. Our estimates suggest that one of the most convincing examples of adaptive introgression is in fact selection acting on standing archaic variation.
The identification of the Denisovan genome using DNA recovered from a phalanx bone is one of the most stunning discoveries in human evolution in the past decade (1, 2). However, many questions remain unanswered regarding the Denisovans. For example: What did they look like? What was their geographical range? What is their genetic legacy to modern humans? Much of the ongoing research investigating the Denisovans focuses on studying the morphological features from dental and cranial samples (3), dating the age of remains from the Denisova Cave (4), and learning about the admixture events that involved Denisovans, Neanderthals, and other unknown archaic populations (1, 5⇓–7). We now know that Denisovans diverged from Neanderthals ∼390 thousand years ago (ka) (8, 9), and both groups inhabited Eurasia until up to 40 ka (4, 10) based on radiocarbon dating of materials from Neanderthal or Denisovan archeological sites.
Although the fossil remains of Denisovans found so far are limited in number and highly fragmented in nature (1, 11, 12), certain aspects of this hominin group have been revealed through studying a single high-coverage genome (2). The occurrence of admixture between archaic hominins and modern humans is undisputed, as it left varying amounts of archaic DNA in our genomes at detectable levels (1, 8, 13). Notably, Papuans and Indigenous Australians harbor the largest genome-wide amount of Denisovan introgression [∼1–5% (1, 6, 14⇓–16)], followed by East and South Asians [∼0.06–0.5% (1, 6, 14)], and Indigenous Americans [∼0.05–0.4% (1, 6, 14)]. Thus, one approach to study the Denisovans is through the surviving Denisovan DNA segments in modern humans.
Examination of Denisovan-like DNA in modern humans revealed a number of candidate genes with robust signatures of adaptive introgression (16⇓⇓⇓⇓–21), among which the most well-known example is found in the Endothelial Pas Domain Protein 1 gene (EPAS1) in modern Tibetans (22⇓–24) that facilitated local adaptation to their high altitude and hypoxic environment. The discovery of adaptive introgression in Tibetans is particularly striking, as they do not carry high amounts of Denisovan ancestry genome-wide, compared to other South Asian and Oceanian populations (6). Conversely, the Oceanian populations—including the Papuans—do not carry the Denisovan EPAS1 haplotype, perhaps because Denisovan populations that introgressed into ancestral Papuan populations did not harbor the EPAS1 adaptive haplotype, or the variant got lost through genetic drift due to the absence of selective pressure outside of the high-altitude environment. The Tibetan Plateau, with an average altitude above 3,500 m and oxygen concentration considerably lower than at sea level, creates a strong physiological stress for most humans. One common acclimatization to the hypoxic environment is an increase in hemoglobin concentration (25), which increases blood viscosity and is associated with increased risk of pregnancy complications and cardiovascular disease (26, 27). Remarkably, Tibetans have a severely blunted acclimatization response compared to lowlanders at high altitudes and tend not to suffer from clinically elevated hemoglobin concentration (28). This presumed adaptive response is directly associated with variants in the EPAS1 gene, which encodes a transcription factor in the hypoxia response pathway.
The remarkable Denisovan connection to Tibetans’ high-altitude adaptation has led to more questions regarding this already mysterious hominin group. For example, why are populations with Denisovan ancestry, including the Tibetans and Oceanians, located far away from the Denisova Cave in Siberia? One explanation for these seemingly puzzling findings is a large Denisovan geographical range. Multiple introgression events or a higher initial proportion of introgression may explain why some human populations exhibit higher levels of Denisovan introgression despite being located far away from the Altai Mountains in Siberia. Indeed, Browning et al. (7) proposed two Denisovan introgressions into modern East Asians, one of which is shared with Papuans and South Asians. More recently, Jacobs et al. (29) proposed an additional introgression event into the ancestral population of Papuans, making a total of three Denisovan introgression pulses in Asia. Their estimates of split times between the Denisovan groups that admixed with modern humans are large enough (∼280–360 ka) to suggest that there were multiple Denisovan-like hominin groups inhabiting diverse locations in Asia.
In this study, we investigate the surviving Denisovan introgressed segments in Tibetans to address the following questions: Do Tibetans exhibit signatures of more than one Denisovan introgression? If so, which introgression event introduced the beneficial EPAS1 haplotype, and when? Did selection act immediately after introgression, or plausibly later when modern humans began inhabiting the Tibetan Plateau? To address these questions, we examined the EPAS1 gene sequences from a combined dataset of 78 Tibetan individuals from two previously published studies (23, 30), among which 38 are high-coverage whole-genome sequences (30). We leveraged information from the introgressed tracts in Tibetans to infer the key time points related to the Denisovan introgression, as well as the onset of selection. We also employed the whole genomes in the combined dataset to demonstrate that the ancestors of modern Tibetans, similar to other East Asian populations (7), experienced two Denisovan introgression events. Our results provide resolution to the East Asian-specific Denisovan admixture event that led to one of the most fascinating stories of human adaptation, and shed light on the effects of different evolutionary processes that shape patterns of adaptive introgression in humans.
Haplogroup D1a1, which is ancestral to the Japanese and Onge branches, originated in Tibet 40,000-50,000 years before present and subsequently migrated to Siberia and Japan (D1a2a) 35,000-40,000 years before present. The Denisovan introgression event into the ancestral population of Tibetans is estimated around 43,000 years ago, which is prior to the split. The D1a2b group migrated to the Andaman Islands is an outlier as D1 is entirely absent in Australia and Oceania, while D1a2a occurs at a very low frequency among the Han people to the east with a spike in Korea. Alternatively, the Jomon (D1a2a) would have gone straight to Taiwan after the split and taken a northward coastal route to Siberia as present-day Taiwan aborigines as well as populations from the Okhotsk-Primorye region (i.e. Ulchi and Nivhk) also showed a significant excess of allele sharing with the Jomon.
The Sherpa in Tibet have the highest amount of Denisovan ancestry (0.106%) in Asia. Due to Han-like admixture associated with hg O (33.13%), it subsequently dropped to 0.082% in the modern Tibetan population. Four ancient samples from Upper_YR_LN were assigned to O2a2b1a by Ning et al. (2020) and the Tibetans' generic link to the Yellow River (YR) Basin was established by 3,000 BP through later migrations to Tibet. The Sherpa are native to the most mountainous regions of the Tibet Autonomous Region, where modern humans and the Denisovans coexisted.
Populations Neanderthal ancestry A X (%)
Denisovan ancestry A X (%)
Sherpa 1.395 0.250 0.106 0.000
Tibetan 1.389 0.169 0.082 0.010
Onge 1.325 0.533 0.057 0.000
Japanese 1.308 0.444 0.058 0.000
Han 1.495 0.144 0.062 0.005
Hungarian 1.122 0.057 0.019 0.000
Estonian 1.076 0.167 0.021 0.000
Polish 1.086 0.240 0.036 0.000
Ulchi 1.508 0.177 0.064 0.000
Atayal 1.531 0.785 0.062 0.000
She 1.468 0.224 0.077 0.000
Papuan 1.596 0.366 1.123 0.269
Table S2: Summary of proportion of the genome confidently inferred to be archaic in ancestry (related to Table 1). A and X refer to estimates across the autosomes and X chromosome respectively.
After the recent discovery that the Denisovan introgression event into the ancestral population of Tibetans took place around 48,700 (16,000–59,500) years ago in Tibet (Zhang et al. 2021), Tibet should be considered a homeland of Haplogroup D1a1 ancestral to Japanese (D1a2a) and Onge (D1a2b) branches, which originated in Tibet 40,000-50,000 years before present. The ancient Tibetans were a ghost Basal East Asian population, which was distinct from the Han Chinese and basal to the Onge and Jomon. Indigenous high-altitude populations of the Tibetan plateau provide an example of East Asian populations that do not fit into the simple one migration hypothesis. Tibetans and Sherpa show a divergent history from lowland East Asian populations such as Han Chinese (Jeong et al. 2014), and their adaptive haplotype spanning the EPAS1 gene shares its ancestry with that of an archaic hominin (Huerta-Sánchez et al. 2014).
D0 is tentatively dated approximately 10 kya by Jacobs et al. (2019) because D0 introgression was ongoing more recently than the divergence of American and East Asian populations, suggesting secondary Denisovan introgression to East Asian and Native American populations from the said source populations. The timing estimate of the East Asian-specific Denisovan introgression (D0) at around 48 kya by Zhang et al. (2021) is specific to the Tibetans, which is not the same introgression event as D0 defined by Jacobs et al. (2019).
The history and evolution of the Denisovan-EPAS1 haplotype in Tibetans
Significance
The discovery of the archaic Denisovan hominins is one of the most significant findings in human evolutionary biology in the last decade. However, as of today, we have more questions than answers regarding this mysterious hominin group. This study leverages the information from the well-known example of adaptive introgression on the EPAS1 gene in Tibetans, to gain insight on the history of our species’ interaction with Denisovans. We show that the Tibetan-EPAS1 haplotype came from the East Asian-specific Denisovan introgression event, and it remained selectively neutral for a long time in the population before positive selection occurred, which may be concurrent with the permanent inhabitation of the Tibetan Plateau after the Last Glacial Maximum (LGM).
Abstract
Recent studies suggest that admixture with archaic hominins played an important role in facilitating biological adaptations to new environments. For example, interbreeding with Denisovans facilitated the adaptation to high-altitude environments on the Tibetan Plateau. Specifically, the EPAS1 gene, a transcription factor that regulates the response to hypoxia, exhibits strong signatures of both positive selection and introgression from Denisovans in Tibetan individuals. Interestingly, despite being geographically closer to the Denisova Cave, East Asian populations do not harbor as much Denisovan ancestry as populations from Melanesia. Recently, two studies have suggested two independent waves of Denisovan admixture into East Asians, one of which is shared with South Asians and Oceanians. Here, we leverage data from EPAS1 in 78 Tibetan individuals to interrogate which of these two introgression events introduced the EPAS1 beneficial sequence into the ancestral population of Tibetans, and we use the distribution of introgressed segment lengths at this locus to infer the timing of the introgression and selection event. We find that the introgression event unique to East Asians most likely introduced the beneficial haplotype into the ancestral population of Tibetans around 48,700 (16,000–59,500) y ago, and selection started around 9,000 (2,500–42,000) y ago. Our estimates suggest that one of the most convincing examples of adaptive introgression is in fact selection acting on standing archaic variation.
The identification of the Denisovan genome using DNA recovered from a phalanx bone is one of the most stunning discoveries in human evolution in the past decade (1, 2). However, many questions remain unanswered regarding the Denisovans. For example: What did they look like? What was their geographical range? What is their genetic legacy to modern humans? Much of the ongoing research investigating the Denisovans focuses on studying the morphological features from dental and cranial samples (3), dating the age of remains from the Denisova Cave (4), and learning about the admixture events that involved Denisovans, Neanderthals, and other unknown archaic populations (1, 5⇓–7). We now know that Denisovans diverged from Neanderthals ∼390 thousand years ago (ka) (8, 9), and both groups inhabited Eurasia until up to 40 ka (4, 10) based on radiocarbon dating of materials from Neanderthal or Denisovan archeological sites.
Although the fossil remains of Denisovans found so far are limited in number and highly fragmented in nature (1, 11, 12), certain aspects of this hominin group have been revealed through studying a single high-coverage genome (2). The occurrence of admixture between archaic hominins and modern humans is undisputed, as it left varying amounts of archaic DNA in our genomes at detectable levels (1, 8, 13). Notably, Papuans and Indigenous Australians harbor the largest genome-wide amount of Denisovan introgression [∼1–5% (1, 6, 14⇓–16)], followed by East and South Asians [∼0.06–0.5% (1, 6, 14)], and Indigenous Americans [∼0.05–0.4% (1, 6, 14)]. Thus, one approach to study the Denisovans is through the surviving Denisovan DNA segments in modern humans.
Examination of Denisovan-like DNA in modern humans revealed a number of candidate genes with robust signatures of adaptive introgression (16⇓⇓⇓⇓–21), among which the most well-known example is found in the Endothelial Pas Domain Protein 1 gene (EPAS1) in modern Tibetans (22⇓–24) that facilitated local adaptation to their high altitude and hypoxic environment. The discovery of adaptive introgression in Tibetans is particularly striking, as they do not carry high amounts of Denisovan ancestry genome-wide, compared to other South Asian and Oceanian populations (6). Conversely, the Oceanian populations—including the Papuans—do not carry the Denisovan EPAS1 haplotype, perhaps because Denisovan populations that introgressed into ancestral Papuan populations did not harbor the EPAS1 adaptive haplotype, or the variant got lost through genetic drift due to the absence of selective pressure outside of the high-altitude environment. The Tibetan Plateau, with an average altitude above 3,500 m and oxygen concentration considerably lower than at sea level, creates a strong physiological stress for most humans. One common acclimatization to the hypoxic environment is an increase in hemoglobin concentration (25), which increases blood viscosity and is associated with increased risk of pregnancy complications and cardiovascular disease (26, 27). Remarkably, Tibetans have a severely blunted acclimatization response compared to lowlanders at high altitudes and tend not to suffer from clinically elevated hemoglobin concentration (28). This presumed adaptive response is directly associated with variants in the EPAS1 gene, which encodes a transcription factor in the hypoxia response pathway.
The remarkable Denisovan connection to Tibetans’ high-altitude adaptation has led to more questions regarding this already mysterious hominin group. For example, why are populations with Denisovan ancestry, including the Tibetans and Oceanians, located far away from the Denisova Cave in Siberia? One explanation for these seemingly puzzling findings is a large Denisovan geographical range. Multiple introgression events or a higher initial proportion of introgression may explain why some human populations exhibit higher levels of Denisovan introgression despite being located far away from the Altai Mountains in Siberia. Indeed, Browning et al. (7) proposed two Denisovan introgressions into modern East Asians, one of which is shared with Papuans and South Asians. More recently, Jacobs et al. (29) proposed an additional introgression event into the ancestral population of Papuans, making a total of three Denisovan introgression pulses in Asia. Their estimates of split times between the Denisovan groups that admixed with modern humans are large enough (∼280–360 ka) to suggest that there were multiple Denisovan-like hominin groups inhabiting diverse locations in Asia.
In this study, we investigate the surviving Denisovan introgressed segments in Tibetans to address the following questions: Do Tibetans exhibit signatures of more than one Denisovan introgression? If so, which introgression event introduced the beneficial EPAS1 haplotype, and when? Did selection act immediately after introgression, or plausibly later when modern humans began inhabiting the Tibetan Plateau? To address these questions, we examined the EPAS1 gene sequences from a combined dataset of 78 Tibetan individuals from two previously published studies (23, 30), among which 38 are high-coverage whole-genome sequences (30). We leveraged information from the introgressed tracts in Tibetans to infer the key time points related to the Denisovan introgression, as well as the onset of selection. We also employed the whole genomes in the combined dataset to demonstrate that the ancestors of modern Tibetans, similar to other East Asian populations (7), experienced two Denisovan introgression events. Our results provide resolution to the East Asian-specific Denisovan admixture event that led to one of the most fascinating stories of human adaptation, and shed light on the effects of different evolutionary processes that shape patterns of adaptive introgression in humans.
