title: Down-Regulation of EPAS1 Transcription and Genetic Adaptation of Tibetans to High-Altitude Hypoxia.
abstract: 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 2α (HIF-2α) 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.
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Peng
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, China.
authors.forename: Chaoying
authors.initials: C
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.|Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Yaoxi
authors.initials: Y
authors.lastname: He
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, China.
authors.lastname: Ouzhuluobu
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.|High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
authors.forename: Deying
authors.initials: D
authors.lastname: Yang
authors.affiliation: Perspective Sciences, Chongqing, China.
authors.forename: Qu
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: The Municipal People's Hospital of Lhasa, Lhasa, China.
authors.lastname: Bianbazhuoma
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.|Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Yibo
authors.initials: Y
authors.lastname: He
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Xiang
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
authors.forename: Sushil
authors.initials: S
authors.lastname: Bhandari
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Shi
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, China.
authors.lastname: Yangla
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, China.
authors.lastname: Dejiquzong
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, China.
authors.lastname: Baimakangzhuo
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, China.
authors.lastname: Duojizhuoma
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, China.
authors.forename: Yongyue
authors.initials: Y
authors.lastname: Pan
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, China.
authors.lastname: Cirenyangji
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, China.
authors.lastname: Baimayangji
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, China.
authors.lastname: Gonggalanzi
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, China.
authors.forename: Caijuan
authors.initials: C
authors.lastname: Bai
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, China.
authors.lastname: Bianba
authors.affiliation: People's Hospital of Dangxiong County, Dangxiong, China.
authors.lastname: Basang
authors.affiliation: People's Hospital of Dangxiong County, Dangxiong, China.
authors.lastname: Ciwangsangbu
authors.affiliation: Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for Computational Biology (PICB), Shanghai Institutes for Biological Sciences, CAS, Shanghai, China.|School of Life Science and Technology, ShanghaiTech University, Shanghai, China.|Collaborative Innovation Center of Genetics and Development, Shanghai, China.
authors.forename: Shuhua
authors.initials: S
authors.lastname: Xu
authors.affiliation: Center for Computational Genomics, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Chen
authors.affiliation: National Key Laboratory of High Altitude Medicine, High Altitude Medical Research Institute, Xining, China.
authors.forename: Shiming
authors.initials: S
authors.lastname: Liu
authors.affiliation: National Key Laboratory of High Altitude Medicine, High Altitude Medical Research Institute, Xining, China.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
authors.forename: Xuebin
authors.initials: X
authors.lastname: Qi
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.|High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Su
mesh_terms: D000064:Acclimatization / Q000235:genetics; D000220:Adaptation, Biological / Q000235:genetics; D000222:Adaptation, Physiological / Q000235:genetics; D000328:Adult; D000531:Altitude; D000532:Altitude Sickness / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation; D005006:Ethnicity / Q000235:genetics; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006454:Hemoglobins; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic; D018609:Tibet; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D006454:Hemoglobins; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: EPAS1; Tibetans; genetic adaptation; high altitude; hypoxia; transgenic mice