Tibetan University

Lhasa, China

Tibetan University

Lhasa, China

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PubMed | Peoples Hospital of Dangxiong County, Tibetan University, High Altitude Medical Research Institute, CAS Kunming Institute of Zoology and 4 more.
Type: | Journal: Molecular biology and evolution | Year: 2017

Tibetans are well adapted to the hypoxic environments at high altitude, yet the molecular mechanism of this adaptation remains elusive. We reported comprehensive genetic and functional analyses of EPAS1, a gene encoding hypoxia inducible factor 2 (HIF-2) with the strongest signal of selection in previous genome-wide scans of Tibetans. We showed that the Tibetan-enriched EPAS1 variants down-regulate expression in human umbilical endothelial cells and placentas. Heterozygous EPAS1 knockout mice display blunted physiological responses to chronic hypoxia, mirroring the situation in Tibetans. Furthermore, we found that the Tibetan version of EPAS1 is not only associated with the relatively low hemoglobin level as a polycythemia protectant, but also is associated with a low pulmonary vasoconstriction response in Tibetans. We propose that the down-regulation of EPAS1 contributes to the molecular basis of Tibetans adaption to high-altitude hypoxia.

PubMed | CAS Beijing Institute of Genomics, High Altitude Medical Research Institute, CAS Kunming Institute of Zoology, The Municipal Peoples Hospital of Lhasa and Tibetan University
Type: Journal Article | Journal: Human mutation | Year: 2016

Tibetans are well adapted to high-altitude environments. Among the adaptive traits in Tibetans, the relatively low hemoglobin level is considered a blunted erythropoietic response to hypoxic challenge. Previously, EPAS1 and EGLN1, the major upstream regulators in the hypoxic pathway, were reportedly involved in the hemoglobin regulation in Tibetans. In this study, we report a downstream gene (HMOX2) involved in heme catabolism, which harbors potentially adaptive variants in Tibetans. We first resequenced the entire genomic region (45.6 kb) of HMOX2 in Tibetans, which confirmed the previously suspected signal of positive selection on HMOX2 in Tibetans. Subsequent association analyses of hemoglobin levels in two independent Tibetan populations (a total of 1,250 individuals) showed a male-specific association between the HMOX2 variants and hemoglobin levels. Tibetan males with the derived C allele at rs4786504:T>C displayed lower hemoglobin level as compared with the T allele carriers. Furthermore, our in vitro experiments indicated that the C allele of rs4786504 could increase the expression of HMOX2, presumably leading to a more efficient breakdown of heme that may help maintain a relatively low hemoglobin level at high altitude. Collectively, we propose that HMOX2 contributes to high-altitude adaptation in Tibetans by functioning as a modifier in the regulation of hemoglobin metabolism.

Qi X.,CAS Kunming Institute of Zoology | Cui C.,Tibetan University | Peng Y.,CAS Kunming Institute of Zoology | Peng Y.,University of Chinese Academy of Sciences | And 22 more authors.
Molecular Biology and Evolution | Year: 2013

Tibetans live on the highest plateau in the world, their current population size is approximately 5 million, and most of them live at an altitude exceeding 3,500 m. Therefore, the Tibetan Plateau is a remarkable area for cultural and biological studies of human population history. However, the chronological profile of the Tibetan Plateau's colonization remains an unsolved question of human prehistory. To reconstruct the prehistoric colonization and demographic history of modern humans on the Tibetan Plateau, we systematically sampled 6,109 Tibetan individuals from 41 geographic populations across the entire region of the Tibetan Plateau and analyzed the phylogeographic patterns of both paternal (n= 2,354) and maternal (n= 6,109) lineages as well as genome-wide single nucleotide polymorphism markers (n = 50) in Tibetan populations. We found that there have been two distinct, major prehistoric migrations of modern humans into the Tibetan Plateau. The first migration was marked by ancient Tibetan genetic signatures dated to approximately 30,000 years ago, indicating that the initial peopling of the Tibetan Plateau by modern humans occurred during the Upper Paleolithic rather than Neolithic. We also found evidences for relatively young (only 7-10 thousand years old) shared Y chromosome and mitochondrial DNA haplotypes between Tibetans and Han Chinese, suggesting a second wave of migration during the early Neolithic. Collectively, the genetic data indicate that Tibetans have been adapted to a high altitude environment since initial colonization of the Tibetan Plateau in the early Upper Paleolithic, before the last glacial maximum, followed by a rapid population expansion that coincided with the establishment of farming and yak pastoralism on the Plateau in the early Neolithic. © The Author 2013.

Peng Y.,CAS Kunming Institute of Zoology | Peng Y.,University of Chinese Academy of Sciences | Yang Z.,CAS Kunming Institute of Zoology | Yang Z.,University of Chinese Academy of Sciences | And 13 more authors.
Molecular Biology and Evolution | Year: 2011

Modern humans have occupied almost all possible environments globally since exiting Africa about 100,000 years ago. Both behavioral and biological adaptations have contributed to their success in surviving the rigors of climatic extremes, including cold, strong ultraviolet radiation, and high altitude. Among these environmental stresses, high-altitude hypoxia is the only condition in which traditional technology is incapable of mediating its effects. Inhabiting at >3,000-m high plateau, the Tibetan population provides a widely studied example of high-altitude adaptation. Yet, the genetic mechanisms underpinning long-term survival in this environmental extreme remain unknown. We performed an analysis of genome-wide sequence variations in Tibetans. In combination with the reported data, we identified strong signals of selective sweep in two hypoxia-related genes, EPAS1 and EGLN1. For these two genes, Tibetans show unusually high divergence from the non-Tibetan lowlanders (Han Chinese and Japanese) and possess high frequencies of many linked sequence variations as reflected by the Tibetan-specific haplotypes. Further analysis in seven Tibetan populations (1,334 individuals) indicates the prevalence of selective sweep across the Himalayan region. The observed indicators of natural selection on EPAS1 and EGLN1 suggest that during the long-term occupation of high-altitude areas, the functional sequence variations for acquiring biological adaptation to high-altitude hypoxia have been enriched in Tibetan populations. © 2010 The Author.

Xiang K.,CAS Kunming Institute of Zoology | Xiang K.,University of Chinese Academy of Sciences | Ouzhuluobu,Tibetan University | Peng Y.,CAS Kunming Institute of Zoology | And 18 more authors.
Molecular Biology and Evolution | Year: 2013

Tibetans are well adapted to high-altitude hypoxic conditions, and in recent genome-wide scans, many candidate genes have been reported involved in the physiological response to hypoxic conditions. However, the limited sequence variations analyzed in previous studies would not be sufficient to identify causal mutations. Here we conducted resequencing of the entire genomic region (59.4 kb) of the hypoxic gene EGLN1 (one of the top candidates from the genome-wide scans) in Tibetans and identified 185 sequence variations, including 13 novel variations (12 substitutions and 1 insertion or deletion). There is a nonsynonymous mutation (rs186996510, D4E) showing surprisingly deep divergence between Tibetans and lowlander populations (FST = 0.709 between Tibetans and Han Chinese). It is highly prevalent in Tibetans (70.9% on average) but extremely rare in Han Chinese, Japanese, Europeans, and Africans (0.56-2.27%), suggesting that it might be the causal mutation of EGLN1 contributing to high-altitude hypoxic adaptation. Neutrality test confirmed the signal of Darwinian positive selection on EGLN1 in Tibetans. Haplotype network analysis revealed a Tibetan-specific haplotype, which is absent in other world populations. The estimated selective intensity (0.029 for the C allele of rs186996510) puts EGLN1 among the known genes that have undergone the strongest selection in human populations, and the onset of selection was estimated to have started at the early Neolithic (∼8,400 years ago). Finally, we detected a significant association between rs186996510 and hemoglobin levels in Tibetans, suggesting that EGLN1 contributes to the adaptively low hemoglobin level of Tibetans compared with acclimatized lowlanders at high altitude. © The Author 2013.

PubMed | High Altitude Medical Research Institute, CAS Kunming Institute of Zoology and Tibetan University
Type: | Journal: Scientific reports | Year: 2015

Sherpas living around the Himalayas are renowned as high-altitude mountain climbers but when and where the Sherpa people originated from remains contentious. In this study, we collected DNA samples from 582 Sherpas living in Nepal and Tibet Autonomous Region of China to study the genetic diversity of both their maternal (mitochondrial DNA) and paternal (Y chromosome) lineages. Analysis showed that Sherpas share most of their paternal and maternal lineages with indigenous Tibetans, representing a recently derived sub-lineage. The estimated ages of two Sherpa-specific mtDNA sub-haplogroups (C4a3b1 and A15c1) indicate a shallow genetic divergence between Sherpas and Tibetans less than 1,500 years ago. These findings reject the previous theory that Sherpa and Han Chinese served as dual ancestral populations of Tibetans, and conversely suggest that Tibetans are the ancestral populations of the Sherpas, whose adaptive traits for high altitude were recently inherited from their ancestors in Tibet.

Wunnemann B.,Nanjing University | Wunnemann B.,Free University of Berlin | Yan D.,Nanjing University | Yan D.,Free University of Berlin | Ci R.,Tibetan University
Geomorphology | Year: 2015

Proxy records from lakes on the Tibetan Plateau are commonly used to infer monsoon-related climatic changes during the late Quaternary. Specific influences of catchment processes and their interaction with the lake basin are seldom utilized. Based on morphological field investigations, supported by remote sensing analyses in combination with radiocarbon-dated sediment data from lacustrine sequences along paleoshorelines and terraces, we can demonstrate that close relationships exist between glacier dynamics, fluvial-alluvial fan/terrace formation and lake level and lake area changes of Paiku Co, southern Tibet. Our results show that the formation of large-scale, fluvial-alluvial fans (F1) predates the maximum advance of the Xixiabangma glaciers. The latter formed a distinct terminal moraine complex north of the present glaciers during the local LGM (LLGM) at 42-21. cal. ky BP. A younger fan generation (F2) developed from the LLGM to the late Holocene, which was accompanied by lake level fluctuations with a generally decreasing trend. The highest morphologically traceable lake level at 4665. m. asl existed prior to 25. cal. ky BP and induced a potential overflow to the neighboring Langqiang Co and Pengqu River. A high level also existed during the LLGM, followed by a minor decline until ca. 15. cal. ky BP, owing to reduced meltwater discharge under cold and dry climatic conditions. A return to the previous level during the late-glacial/early Holocene period between 11.9 and 9.5. cal. ky BP is likely caused by climate warming, increased meltwater discharge, and enhanced Indian Summer Monsoon (ISM) moisture supply. Afterwards, Paiku Co shrank gradually toward its present level, while the youngest fan (F3) generation evolved as individual small-sized bodies under ephemeral discharge conditions from the mid-Holocene to the present. The formation of four terrace levels (T4-1) is likely the result of sequential incision into the fan generations with a mean erosion rate of 50. cm/ky, caused by lake level lowering. Tectonic impact cannot be completely ruled out. Since 1976, the glaciers lost ca. 15% in area, accompanied by lake area loss of ~. 3.7% between 1972 and June 2014. Seasonal lake level variations of about 1-2. m in height occur in response to summer monsoon rainfall.Our data show a close interaction between glacial dynamics, fluvial processes, terrace formation, and water budget changes throughout the last 25. cal. ky BP in response to the well-known, insolation-driven, ISM-effective moisture supply during the late-glacial and Holocene period. Temperature-driven meltwater dynamics were the controlling factors for variations in water balance of Paiku Co. © 2015 Elsevier B.V.

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