Tibetans have lived at high altitude for generations and are thought to be genetically adapted to hypoxic environments. Most are protected from hypoxia-induced polycythemia, and a haplotype of EPAS1, encoding hypoxia-inducible factor (HIF-2α), has been associated with lower hemoglobin levels. We earlier reported a Tibetan-specific EGLN1 haplotype encoding PHD2 which abrogates HIF augmentation in hypoxia. We genotyped 347 Tibetan individuals from varying altitudes for both the Tibetan-specific EGLN1 haplotype and 10 candidate SNPs in the EPAS1 haplotype and correlated their association with hemoglobin levels. The effect of the EGLN1 haplotype on hemoglobin exhibited age dependency at low altitude, while at higher altitudes, it showed a trend to lower hemoglobin levels in the presence of the Tibetan-selected EPAS1 rs142764723 C/C allele. The observed gene-environment and gene-gene interactions and the moderate effect of the EGLN1 and EPAS1 haplotypes on hemoglobin indicate that other modifiers exist. It remains to be determined whether a blunting of erythropoiesis or other physiological consequences of HIF downregulation are the primary drivers of these genetic adaptations among Tibetans.
Most Tibetans are protected from polycythemia while living in high altitude.
An EGLN1 co-adapted haplotype, EGLN1 c.12C>G, c.380G>C is uniquely Tibetan.
The Tibetan EPAS1 haplotype has introgressed from the Denisovan genome.
While EGLN1 and EPAS1 genotypes lower Hb, this study indicates additional Hb modifiers.
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West JB (1996) Prediction of barometric pressures at high altitude with the use of model atmospheres. J Appl Physiol (1985) 81(4):1850–1854
Beall CM, Blangero J, Williams-Blangero S, Goldstein MC (1994) Major gene for percent of oxygen saturation of arterial hemoglobin in Tibetan highlanders. Am J Phys Anthropol 95(3):271–276
Moore LG, Niermeyer S, Zamudio S (1998) Human adaptation to high altitude: regional and life-cycle perspectives. Am J Phys Anthropol Suppl 27:25–64
Wu T, Wang X, Wei C, Cheng H, Wang X, Li Y, Ge D, Zhao H, Young P, Li G et al (2005) Hemoglobin levels in Qinghai-Tibet: different effects of gender for Tibetans vs. Han. J Appl Physiol (1985) 98(2):598–604
Beall CM, Brittenham GM, Strohl KP, Blangero J, Williams-Blangero S, Goldstein MC, Decker MJ, Vargas E, Villena M, Soria R et al (1998) Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara. Am J Phys Anthropol 106(3):385–400
Winslow RM, Chapman KW, Gibson CC, Samaja M, Monge CC, Goldwasser E, Sherpa M, Blume FD, Santolaya R (1989) Different hematologic responses to hypoxia in Sherpas and Quechua Indians. J Appl Physiol (1985) 66 (4):1561–1569
Simonson TS, McClain DA, Jorde LB, Prchal JT (2012) Genetic determinants of Tibetan high-altitude adaptation. Hum Genet 131(4):527–533
Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo ZX, Pool JE, Xu X, Jiang H, Vinckenbosch N, Korneliussen TS et al (2010) Sequencing of 50 human exomes reveals adaptation to high altitude. Science 329(5987):75–78
Beall CM, Cavalleri GL, Deng L, Elston RC, Gao Y, Knight J, Li C, Li JC, Liang Y, McCormack M et al (2010) Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders. Proc Natl Acad Sci U S A 107(25):11459–11464
Bigham A, Bauchet M, Pinto D, Mao X, Akey JM, Mei R, Scherer SW, Julian CG, Wilson MJ, Lopez Herraez D et al (2010) Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. PLoS Genet 6(9):e1001116
Huerta-Sanchez E, Jin X, Asan, Bianba Z, Peter BM, Vinckenbosch N, Liang Y, Yi X, He M, Somel M et al (2014) Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. Nature 512(7513):194–197
Semenza GL (2014) Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol 9:47–71
Kaelin WG Jr, Ratcliffe PJ (2008) Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30(4):393–402
Lorenzo FR, Simonson TS, Yang Y, Ge RL, Prchal JT (2012) A novel PHD2 mutation associated with tibetan genetic adaptation to high altitude hypoxia. In: American Society of Hematology, Orlando, FL
Lorenzo FR, Huff C, Myllymaki M, Olenchock B, Swierczek S, Tashi T, Gordeuk V, Wuren T, Ri-Li G, McClain DA et al (2014) A genetic mechanism for Tibetan high-altitude adaptation. Nat Genet 46(9):951–956
Liew M, Pryor R, Palais R, Meadows C, Erali M, Lyon E, Wittwer C (2004) Genotyping of single-nucleotide polymorphisms by high-resolution melting of small amplicons. Clin Chem 50(7):1156–1164
Moore LG, Young D, McCullough RE, Droma T, Zamudio S (2001) Tibetan protection from intrauterine growth restriction (IUGR) and reproductive loss at high altitude. Am J Hum Biol 13(5):635–644
Torroni A, Miller JA, Moore LG, Zamudio S, Zhuang J, Droma T, Wallace DC (1994) Mitochondrial DNA analysis in Tibet: implications for the origin of the Tibetan population and its adaptation to high altitude. Am J Phys Anthropol 93(2):189–199
Hu H ST, Glusman G, Roach JC, Cavalleri G, Brunkow ME, McCormack M, Petousi N, Lorenzo FL, Gelinas R, Jorde LB et al. (2013) Insights on the evolutionary history of Tibetans from whole-genome sequence data. In: Annual Cold Spring Harbor Biology of Genomes Meeting, Cold Spring Harbor, NY
Grossman S, Shlyakhter I, Karlsson E, Byrne E, Morales S et al (2010) A composite of multiple signals distinguishes causal variants in regions of positive selection. Science 327(5967):883–886
Cox DR (2006) Principles of statistical inference. Cambridge University Press, Cambridge
R Development Core Team (2013) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna
Ravasi G, Pelucchi S, Greni F, Mariani R, Giuliano A, Parati G, Silvestri L, Piperno A (2014) Circulating factors are involved in hypoxia-induced hepcidin suppression. Blood Cells Mol Dis 53(4):204–210
Talbot NP, Lakhal S, Smith TG, Privat C, Nickol AH, Rivera-Ch M, Leon-Velarde F, Dorrington KL, Mole DR, Robbins PA (2012) Regulation of hepcidin expression at high altitude. Blood 119(3):857–860
Leon-Velarde F, Maggiorini M, Reeves JT, Aldashev A, Asmus I, Bernardi L, Ge RL, Hackett P, Kobayashi T, Moore LG et al (2005) Consensus statement on chronic and subacute high altitude diseases. High Alt Med Biol 6(2):147–157
Niermeyer S, Tobin A, Schoen E, Carter T, Klein JD (2015) A new commitment to newborn survival. Pediatrics. doi:10.1542/peds.2014-3185
Gonzales GF, Steenland K, Tapia V (2009) Maternal hemoglobin level and fetal outcome at low and high altitudes. Am J Physiol Regul Integr Comp Physiol 297(5):R1477–R1485
The authors gratefully acknowledge the use of laboratory facilities of the Research Center for High Altitude Medicine at Qinghai University, Xining, China; the Regional Center for Biotechnology, Government of India, Gurgaon, India; and the Tibet Institute of Medical Sciences, Lhasa, Tibet Autonomous Region, China.
TB was supported by project “Increasing Opportunities for Career Growth in Research and Development in the Field of Medical Sciences,” ITMS: 26110230067. Ge RiLi is supported by National Basic Research Program (NBRP# 2012CB518200, PIS&T # 0S2012GR0195) and National Natural Science Foundation of China (# 30393133). JP is supported by NIH-P01CA108671, VA Merit Review Award and University of Utah Seed Grant Program for studies of hypoxic adaptation. The Colorado cohort study materials were made possible by NSF BNS-8919645 and DAMD 17-87-C-7202 grants to Lorna G. Moore.
We thank Robert Pryor for developing the double-layer capillary tube method used to genotype EGLN1 c.12C>G.
Written informed consent was obtained from all participants and institutional review board approval by each collaborating group was also obtained.
Conflict of interest
The authors declare that they have no conflict of interest to declare.
Victor R. Gordeuk, Josef T. Prchal, and RiLi Ge contributed equally to this work.
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Tashi, T., Scott Reading, N., Wuren, T. et al. Gain-of-function EGLN1 prolyl hydroxylase (PHD2 D4E:C127S) in combination with EPAS1 (HIF-2α) polymorphism lowers hemoglobin concentration in Tibetan highlanders. J Mol Med 95, 665–670 (2017). https://doi.org/10.1007/s00109-017-1519-3
- High altitude
- Genetic adaptation
- High-resolution melting assay