A genetic mechanism for Tibetan high-altitude adaptation

Felipe R. Lorenzo, Chad Huff, Mikko Myllymäki, Benjamin Olenchock, Sabina Swierczek, Tsewang Tashi, Victor Gordeuk, Tana Wuren, Ri Li Ge, Donald A. McClain, Tahsin M. Khan, Parvaiz A. Koul, Prasenjit Guchhait, Mohamed E. Salama, Jinchuan Xing, Gregg L. Semenza, Ella Liberzon, Andrew Wilson, Tatum S. Simonson, Lynn B. JordeWilliam G. Kaelin, Peppi Koivunen, Josef T. Prchal

Research output: Contribution to journalArticlepeer-review

210 Scopus citations


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 K m 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.

Original languageEnglish (US)
Pages (from-to)951-956
Number of pages6
JournalNature Genetics
Issue number9
StatePublished - 2014

ASJC Scopus subject areas

  • Genetics


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