title: HMOX2 Functions as a Modifier Gene for High-Altitude Adaptation in Tibetans.
abstract: 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.
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.|Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, China.
authors.forename: Deying
authors.initials: D
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Peng
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, 850000, China.
authors.lastname: Ouzhuluobu
authors.affiliation: The Municipal People's Hospital of Lhasa, Lhasa, 850000, Tibet, China.
authors.lastname: Bianbazhuoma
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, 850000, China.
authors.forename: Chaoying
authors.initials: C
authors.lastname: Cui
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, 850000, China.
authors.lastname: Bianba
authors.affiliation: National Key Laboratory of High Altitude Medicine, High Altitude Medical Research Institute, Xining, 810012, China.
authors.forename: Liangbang
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, 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, 650223, China.|Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, China.
authors.forename: Yaoxi
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, 650223, 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, 650223, 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, 650223, China.|Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, China.
authors.forename: Jiewei
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.|Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Shi
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, 850000, China.
authors.forename: Yongyue
authors.initials: Y
authors.lastname: Pan
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, 850000, China.
authors.lastname: Duojizhuoma
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, 850000, China.
authors.lastname: Dejiquzong
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, 850000, China.
authors.lastname: Cirenyangji
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, 850000, China.
authors.lastname: Baimakangzhuo
authors.affiliation: High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, 850000, China.
authors.lastname: Gonggalanzi
authors.affiliation: National Key Laboratory of High Altitude Medicine, High Altitude Medical Research Institute, Xining, 810012, China.
authors.forename: Shimin
authors.initials: S
authors.lastname: Liu
authors.affiliation: National Key Laboratory of High Altitude Medicine, High Altitude Medical Research Institute, Xining, 810012, China.
authors.lastname: Gengdeng
authors.affiliation: National Key Laboratory of High Altitude Medicine, High Altitude Medical Research Institute, Xining, 810012, China.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Wu
authors.affiliation: Center for Computational Genomics, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, 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, 650223, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Su
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D000328:Adult; D000483:Alleles; D000531:Altitude; D005006:Ethnicity; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency; D006418:Heme / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000378:metabolism; D006454:Hemoglobins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D012737:Sex Factors; D015398:Signal Transduction; D018609:Tibet
chemical_list: D006454:Hemoglobins; D006418:Heme; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2
keywords: HMOX2; Tibetans; genetic adaptation; hemoglobin; high altitude