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A genetic mechanism for Tibetan high-altitude adaptation.
Nat. Genet..08 17, 2014;46(9):951-6.
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 J, Semenza GL, Liberzon E, Wilson A, Simonson TS, Jorde LB, Kaelin WG, Koivunen P, Prchal JT.
1] Department of Medicine, University of Utah School of Medicine and George E. Wahlin Veterans Administration Medical Center, Salt Lake City, Utah, USA.  Eccles Institute of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA. .
Tibetans do not exhibit increased hemoglobin concentration at high altitude. We describe a high-frequency missense mutation in the EGLN1 gene, which encodes prolyl hydroxylase 2 (PHD2), that contributes to this adaptive response. We show that a variant in EGLN1, c.[12C>G; 380G>C], contributes functionally to the Tibetan high-altitude phenotype. PHD2 triggers the degradation of hypoxia-inducible factors (HIFs), which mediate many physiological responses to hypoxia, including erythropoiesis. The PHD2 p.[Asp4Glu; Cys127Ser] variant exhibits a lower Km value for oxygen, suggesting that it promotes increased HIF degradation under hypoxic conditions. Whereas hypoxia stimulates the proliferation of wild-type erythroid progenitors, the proliferation of progenitors with the c.[12C>G; 380G>C] mutation in EGLN1 is significantly impaired under hypoxic culture conditions. We show that the c.[12C>G; 380G>C] mutation originated ∼8,000 years ago on the same haplotype previously associated with adaptation to high altitude. The c.[12C>G; 380G>C] mutation abrogates hypoxia-induced and HIF-mediated augmentation of erythropoiesis, which provides a molecular mechanism for the observed protection of Tibetans from polycythemia at high altitude.