Lorenzo, Felipe R and Huff, Chad and Myllymäki, Mikko and Olenchock, Benjamin and Swierczek, Sabina and Tashi, Tsewang and Gordeuk, Victor and Wuren, Tana and Ri-Li, Ge and McClain, Donald A and Khan, Tahsin M and Koul, Parvaiz A and Guchhait, Prasenjit and Salama, Mohamed E and Xing, Jinchuan and Semenza, Gregg L and Liberzon, Ella and Wilson, Andrew and Simonson, Tatum S and Jorde, Lynn B and Kaelin, William G and Koivunen, Peppi and Prchal, Josef T (2014) A genetic mechanism for Tibetan high-altitude adaptation. Nature Genetics, 46 (9). pp. 951-956. ISSN 1061-4036

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Abstract

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.

Item Type:	Article
Subjects:	Biomedical Science Biochemical and Biophysical Sciences
Depositing User:	RCB Library
Date Deposited:	06 Nov 2017 11:49
Last Modified:	06 Nov 2017 11:49
URI:	http://rcb.sciencecentral.in/id/eprint/106

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