Zoological Research ›› 2017, Vol. 38 ›› Issue (3): 155-162.doi: 10.24272/j.issn.2095-8137.2017.037

• Articles • Previous Articles     Next Articles

GCH1 plays a role in the high-altitude adaptation of Tibetans

Yong-Bo Guo1,2, Yao-Xi He2,4, Chao-Ying Cui3, Ouzhuluobu3, Baimakangzhuo3, Duojizhuoma3, Dejiquzong3, Bianba3, Yi Peng2, Cai-juan Bai3, Gonggalanzi3, Yong-Yue Pan3, Qula3, Kangmin3, Cirenyangji3, Baimayangji3, Wei Guo3, Yangla3, Hui Zhang2, Xiao-Ming Zhang2, Wang-Shan Zheng1,2, Shu-Hua Xu5,8,9, Hua Chen6, Sheng-Guo Zhao1, Yuan Cai1, Shi-Ming Liu7, Tian-Yi Wu7, Xue-Bin Qi2, Bing Su2   

  1. 1 College of Animal Science and Technology, Gansu Agricultural University, Lanzhou Gansu 730070, China;
    2 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming Yunnan 650223, China;
    3 High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa Tibet 850000, China;
    4 Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming Yunnan 650204, China;
    5 Chinese Academy of Sciences 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, Chinese Academy of Sciences, Shanghai 200031, China;
    6 Center for Computational Genomics, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China;
    7 National Key Laboratory of High Altitude Medicine, High Altitude Medical Research Institute, Xining Qinghai 810012, China;
    8 School of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China;
    9 Collaborative Innovation Center of Genetics and Development, Shanghai 200438, China
  • Received:2017-03-24 Revised:2017-04-27 Online:2017-05-18 Published:2017-05-18
  • Contact: Bing Su,E-mail:sub@mail.kiz.ac.cn;Xue-Bin Qi,E-mail:qixuebin@mail.kiz.ac.cn E-mail:sub@mail.kiz.ac.cn;qixuebin@mail.kiz.ac.cn
  • Supported by:

    This study was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB13010000), the National Natural Science Foundation of China (91631306 to BS, 31671329 to XQ, 31460287 to Ou., 31501013 to HZ and 31360032 to CC), the National 973 program (2012CB518202 to TW), the State Key Laboratory of Genetic Resources and Evolution (GREKF15-05, GREKF16-04), and the Zhufeng Scholar Program of Tibetan University


Tibetans are well adapted to high-altitude hypoxia. Previous genome-wide scans have reported many candidate genes for this adaptation, but only a few have been studied. Here we report on a hypoxia gene (GCH1, GTP-cyclohydrolase I), involved in maintaining nitric oxide synthetase (NOS) function and normal blood pressure, that harbors many potentially adaptive variants in Tibetans. We resequenced an 80.8 kb fragment covering the entire gene region of GCH1 in 50 unrelated Tibetans. Combined with previously published data, we demonstrated many GCH1 variants showing deep divergence between highlander Tibetans and lowlander Han Chinese. Neutrality tests confirmed a signal of positive Darwinian selection on GCH1 in Tibetans. Moreover, association analysis indicated that the Tibetan version of GCH1 was significantly associated with multiple physiological traits in Tibetans, including blood nitric oxide concentration, blood oxygen saturation, and hemoglobin concentration. Taken together, we propose that GCH1 plays a role in the genetic adaptation of Tibetans to high altitude hypoxia.

Antoniades C, Shirodaria C, Warrick N, Cai SJ, de Bono J, Lee J, Leeson P, Neubauer S, Ratnatunga C, Pillai R, Refsum H, Channon KM. 2006. 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels:effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation, 114(11):1193-1201.
Beall CM, Strohl KP, Blangero J, Williams-Blangero S, Almasy LA, Decker MJ, Worthman CM, Goldstein MC, Vargas E, Villena M, Soria R, Alarcon AM, Gonzales C. 1997. Ventilation and hypoxic ventilatory response of Tibetan and Aymara high altitude natives. American Journal of Physical Anthropology, 104(4):427-447.
Beall CM. 2006. Andean, Tibetan, and Ethiopian patterns of adaptation to high-altitude hypoxia. Integrative and Comparative Biology, 46(1):18-24.
Beall CM, Cavalleri GL, Deng LB, Elston RC, Gao Y, Knight J, Li CH, Li JC, Liang Y, McCormack M, Montgomery HE, Pan H, Robbins PA, Shianna KV, Tam SC, Tsering N, Veeramah KR, Wang W, Wangdui P, Weale ME, Xu YM, Xu Z, Yang L, Zaman MJ, Zeng CQ, Zhang L, Zhang XL, Zhaxi P, Zheng YT. 2010. Natural selection on EPAS1(HIF2α) associated with low hemoglobin concentration in Tibetan highlanders. Proceedings of the National Academy of Sciences of the United States of America, 107(25):11459-11464.
Bigham A, Bauchet M, Pinto D, Mao XY, Akey JM, Mei R, Scherer SW, Julian CG, Wilson MJ, Herráez DL, Brutsaert T, Parra EJ, Moore LG, Shriver MD. 2010. Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. PLoS Genetics, 6(9):e1001116.
Davydov EV, Goode DL, Sirota M, Cooper GM, Sidow A, Batzoglou S. 2010. Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Computational Biology, 6(12):e1001025.
Ernst J, Kellis M. 2012. ChromHMM:automating chromatin-state discovery and characterization. Nature Methods, 9(3):215-216.
Erzurum SC, Ghosh S, Janocha AJ, Xu W, Bauer S, Bryan NS, Tejero J, Hemann C, Hille R, Stuehr DJ, Feelisch M, Beall CM. 2007. Higher blood flow and circulating NO products offset high-altitude hypoxia among Tibetans. Proceedings of the National Academy of Sciences of the United States of America, 104(45):17593-17598.
Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Noordegraaf AV, Beghetti M, Ghofrani A, Sanchez MAG, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M, Aboyans V, Vaz Carneiro A, Achenbach S, Agewall S, Allanore Y, Asteggiano R, Badano LP, Barberà JA, Bouvaist H, Bueno H, Byrne RA, Carerj S, Castro G, Erol C, Falk V, FunckBrentano C, Gorenflo M, Granton J, Iung B, Kiely DG, Kirchhof P, Kjellstrom B, Landmesser U, Lekakis J, Lionis C, Lip GY, Orfanos SE, Park MH, Piepoli MF, Ponikowski P, Revel MP, Rigau D, Rosenkranz S, Völler H, Zamorano JL. 2016. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension:the joint task force for the diagnosis and treatment of pulmonary hypertension of the european society of cardiology (ESC) and the european respiratory society (ERS):endorsed by:association for european paediatric and congenital cardiology (AEPC), international society for heart and lung transplantation (ISHLT). European Heart Journal, 37(1):67-119.
Hackett PH, Roach RC. 2001. High-altitude illness. The New England Journal of Medicine, 345(2):107-114.
Khoo JP, Zhao L, Alp NJ, Bendall JK, Nicoli T, Rockett K, Wilkins MR, Channon KM. 2005. Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension. Circulation, 111(16):2126-2133.
Lorenzo FR, Huff C, Myllymäki M, Olenchock B, Swierczek S, Tashi T, Gordeuk V, Wuren T, Ri-Li G, McClain DA, Khan TM, Koul PA, Guchhait P, Salama ME, Xing JC, Semenza GL, Liberzon E, Wilson A, Simonson TS, Jorde LB, Kaelin WG, Jr., Koivunen P, Prchal JT. 2014. A genetic mechanism for Tibetan high-altitude adaptation. Nature Genetics, 46(9):951-956.
Lu DS, Lou HY, Yuan K, Wang XJ, Wang YC, Zhang C, Lu Y, Yang X, Deng L, Zhou Y, Feng QD, Hu Y, Ding QL, Yang YJ, Li SL, Jin L, Guan YQ, Su B, Kang LL, Xu SH. 2016. Ancestral origins and genetic history of tibetan highlanders. The American Journal of Human Genetics, 99(3):580-594.
Macinnis MJ, Koehle MS, Rupert JL. 2010. Evidence for a genetic basis for altitude illness:2010 update. High Altitude Medicine & Biology, 11(4):349-368.
McLaughlin VV, McGoon MD. 2006. Pulmonary arterial hypertension. Circulation, 114(13):1417-1431.
Peng Y, Yang ZH, Zhang H, Cui CY, Qi XB, Luo XJ, Tao X, Wu TY, Ouzhuluobu, Basang, Ciwangsangbu, Danzengduojie, Chen H, Shi H, Su B. 2011. Genetic variations in tibetan populations and high-altitude adaptation at the himalayas. Molecular Biology and Evolution, 28(2):1075-1081.
Peng Y, Cui CY, He YX, Ouzhuluobu, Zhang H, Yang DY, Zhang Q, Bianbazhuoma, Yang LX, He YB, Xiang K, Zhang XM, Bhandari S, Shi P, Yangla, Dejiquzong, Baimakangzhuo, Duojizhuoma, Pan YY, Cirenyangji, Baimayangji, Gonggalanzi, Bai CJ, Bianba, Basang, Ciwangsangbu, Xu SH, Chen H, Liu SM, Wu TY, Qi XB, Su B. 2017. Down-regulation of EPAS1 transcription and genetic adaptation of tibetans to high-altitude hypoxia. Molecular Biology and Evolution, 34(4):818-830.
Petousi N, Croft QPP, Cavalleri GL, Cheng HY, Formenti F, Ishida K, Lunn D, McCormack M, Shianna KV, Talbot NP, Ratcliffe PJ, Robbins PA. 2014. Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia. Journal of Applied Physiology, 116(7):893-904.
Pickert G, Lim HY, Weigert A, Häussler A, Myrczek T, Waldner M, Labocha S, Ferreirós N, Geisslinger G, Lötsch J, Becker C, Brüne B, Tegeder I. 2013. Inhibition of GTP cyclohydrolase attenuates tumor growth by reducing angiogenesis and M2-like polarization of tumor associated macrophages. International Journal of Cancer, 132(3):591-604.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, Sham PC. 2007. PLINK:a tool set for whole-genome association and population-based linkage analyses. The American Journal of Human Genetics, 81(3):559-575.
Qi XB, Cui CY, Peng Y, Zhang XM, Yang ZH, Zhong H, Zhang H, Xiang K, Cao XY, Wang Y, Ouzhuluobu, Basang, Ciwangsangbu, Bianba, Gonggalanzi, Wu TY, Chen H, Shi H, Su B. 2013. Genetic evidence of paleolithic colonization and neolithic expansion of modern humans on the tibetan plateau. Molecular Biology and Evolution, 30(8):1761-1778.
Sabeti PC, Reich DE, Higgins JM, Levine HZP, Richter DJ, Schaffner SF, Gabriel SB, Platko JV, Patterson NJ, McDonald GJ, Ackerman HC, Campbell SJ, Altshuler D, Cooper R, Kwiatkowski D, Ward R, Lander ES. 2002. Detecting recent positive selection in the human genome from haplotype structure. Nature, 419(6909):832-837.
Sabeti PC, Varilly P, Fry B, Lohmueller J, Hostetter E, Cotsapas C, Xie XH, Byrne EH, McCarroll SA, Gaudet R, Schaffner SF, Lander ES, The International HapMap Consortium. 2007. Genome-wide detection and characterization of positive selection in human populations. Nature, 449(7164):913-918.
Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. 2011. Mechanisms of disease:pulmonary arterial hypertension. Nature Reviews Cardiology, 8(8):443-455.
Simonson TS, Yang YZ, Huff CD, Yun HX, Qin G, Witherspoon DJ, Bai ZZ, Lorenzo FR, Xing JC, Jorde LB, Prchal JT, Ge RL. 2010. Genetic evidence for high-altitude adaptation in Tibet. Science, 329(5987):72-75.
Szpiech ZA, Hernandez RD. 2014. Selscan:an efficient multithreaded program to perform EHH-based scans for positive selection. Molecular Biology and Evolution, 31(10):2824-2827.
Tajima F. 1989. Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics, 123(3):585-595.
Voight BF, Kudaravalli S, Wen XQ, Pritchard JK. 2006. A map of recent positive selection in the human genome. PLoS Biology, 4(3):e72.
Weir BS, Cockerham CC. 1984. Estimating F-statistics for the analysis of population structure. Evolution, 38(6):1358-1370.
Wilkins MR, Ghofrani HA, Weissmann N, Aldashev A, Zhao L. 2015. Pathophysiology and treatment of high-altitude pulmonary vascular disease. Circulation, 131(6):582-590.
Wu TY, Kayser B. 2006. High altitude adaptation in Tibetans. High Altitude Medicine & Biology, 7(3):193-208.
Xiang K, Ouzhuluobu, Peng Y, Yang ZH, Zhang XM, Cui CY, Zhang H, Li M, Zhang YF, Bianba, Gonggalanzi, Basang, Ciwangsangbu, Wu TY, Chen H, Shi H, Qi XB, Su B. 2013. Identification of a Tibetan-specific mutation in the hypoxic gene EGLN1 and its contribution to high-altitude adaptation. Molecular Biology and Evolution, 30(8):1889-1898.
Xu SH, Li SL, Yang YJ, Tan JZ, Lou HY, Jin WF, Yang L, Pan XD, Wang JC, Shen YP, Wu BL, Wang HY, Jin L. 2011. A genome-wide search for signals of high-altitude adaptation in Tibetans. Molecular Biology and Evolution, 28(2):1003-1011.
Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo ZXP, Pool JE, Xu X, Jiang H, Vinckenbosch N, Korneliussen TS, Zheng HC, Liu T, He WM, Li K, Luo RB, Nie XF, Wu HL, Zhao MR, Cao HZ, Zou J, Shan Y, Li SZ, Yang Q, Asan, Ni PX, Tian G, Xu JM, Liu X, Jiang T, Wu RH, Zhou GY, Tang MF, Qin JJ, Wang T, Feng SJ, Li GH, Huasang, Luosang JB, Wang W, Chen F, Wang YD, Zheng XG, Li Z, Bianba Z, Yang G, Wang XP, Tang SH, Gao GY, Chen Y, Luo Z, Gusang L, Cao Z, Zhang QH, Ouyang WH, Ren XL, Liang HQ, Zheng HS, Huang YB, Li JX, Bolund L, Kristiansen K, Li YR, Zhang Y, Zhang XQ, Li RQ, Li SG, Yang HM, Nielsen R, Wang J, Wang J. 2010. Sequencing of 50 human exomes reveals adaptation to high altitude. Science, 329(5987):75-78.
Zhang L, Chen WZ, Liu YJ, Hu X, Zhou K, Chen L, Peng S, Zhu H, Zou HL, Bai J, Wang ZB. 2010. Feasibility of magnetic resonance imaging-guided high intensity focused ultrasound therapy for ablating uterine fibroids in patients with bowel lies anterior to uterus. European Journal of Radiology, 73(2):396-403.

No related articles found!
Full text



[1] LIAO Wen-bo,LI Cao ,*,HU Jin-chu ,*,LU Xin. Vocal Behaviour of Sichuan Hill Partridge (Arborophila rufipectus) in Breeding Season[J]. Zoological Research, 2007, 28(1): 56 -62 .
[2] XIONG Yu-liang,WANG Wan-yu,YANG Chang-jin,TIEN Yun-fen. Inhibitory Effects of The Elapidae Venoms in The Mice's Sarcoma 180 Ehrilich Ascititers Carcenoma[J]. Zoological Research, 1989, 10(1): 31 -35 .
[3] YU Bo,KUANG Rong-ping,SHAN Fang,TANG Ye-zhong,ZHONG Ning. Effect of Temperature on The Development of Woolly Apple Aphip,Eriosoma Lanigerum (Hausm.)[J]. Zoological Research, 1989, 10(1): 51 -56 .
[4] ZHU Shi-mo,HUANG Fi-sheng. Effect of Geological Vicissitude on Orignation of Termite from Yunnan,China[J]. Zoological Research, 1989, 10(1): 1 -8 .
[5] HOU Yi-di,PENG Yan-zhang. A Description of New Species of Trichocephalus (Trichocephalidae,Trichocephalata) From The Golden Monkey,Rhinopithecus Bieti[J]. Zoological Research, 1989, 10(1): 45 -50 .
[6] YANG Da-tong,LI Si-min. A New Species of the Genus Rana From Yunnan[J]. Zoological Research, 1980, 1(2): 261 -264 .
[7] LI Fan,ZHONG Jun-sheng. A NEW SPECIES OF RHINOGOBIUS FROM ZHEJIANG PROVINCE, CHINA (Teleostei: Gobiidae)[J]. Zoological Research, 2007, 28(5): 539 -544 .
[8] . Phylogentic Relationships of Butterflies in the Subfamily Elymninae (Lepidoptera: Satyridae) Based on Mitochondrial ND1 and COI Gene Sequences[J]. Zoological Research, 2007, 28(5): 477 -484 .
[9] DING Fang,ZHOU Hong-lin,LIU Yang,MA Lan,SU Ying,DU Ling. Effects of Glucose on Development of ICR Mouse Embryosin vitro[J]. Zoological Research, 2007, 28(5): 501 -506 .
[10] ZHAO Hua-fu,LIU Jia,HU Jian. An Improved Method on Encapsulation Assays by Larval Hemocytes from Ostrinia furnacalis in vitro[J]. Zoological Research, 2007, 28(6): 675 -680 .