A genetic mechanism for Tibetan high-altitude adaptation

Nat Genet. 2014 Sep;46(9):951-6. doi: 10.1038/ng.3067. Epub 2014 Aug 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acclimatization / genetics*
  • Adaptation, Physiological / genetics*
  • Adult
  • Altitude
  • Asian Continental Ancestry Group / genetics*
  • Erythropoiesis / genetics
  • Female
  • Humans
  • Hypoxia / genetics
  • Hypoxia-Inducible Factor-Proline Dioxygenases / genetics
  • Male
  • Middle Aged
  • Phenotype
  • Polycythemia / genetics
  • Polymorphism, Single Nucleotide
  • Young Adult

Substances

  • EGLN1 protein, human
  • Hypoxia-Inducible Factor-Proline Dioxygenases