2. Academic Validation
  3. A genetic mechanism for Tibetan high-altitude adaptation

A genetic mechanism for Tibetan high-altitude adaptation

  • Nat Genet. 2014 Sep;46(9):951-6. doi: 10.1038/ng.3067.
Felipe R Lorenzo 1,  Chad Huff 2,  Mikko Myllymäki 3,  Benjamin Olenchock 4,  Sabina Swierczek 5,  Tsewang Tashi 5,  Victor Gordeuk 6,  Tana Wuren 7,  Ge Ri-Li 7,  Donald A McClain 5,  Tahsin M Khan 8,  Parvaiz A Koul 9,  Prasenjit Guchhait 10,  Mohamed E Salama 11,  Jinchuan Xing 12,  Gregg L Semenza 13,  Ella Liberzon 14,  Andrew Wilson 15,  Tatum S Simonson 16,  Lynn B Jorde 17,  William G Kaelin Jr 14,  Peppi Koivunen 3,  Josef T Prchal 18
Affiliations

Affiliations

  • 1 1] Department of Medicine, University of Utah School of Medicine and George E. Wahlin Veterans Administration Medical Center, Salt Lake City, Utah, USA. [2].
  • 2 1] Eccles Institute of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA. [2] Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. [3].
  • 3 1] Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland. [2].
  • 4 Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 5 Department of Medicine, University of Utah School of Medicine and George E. Wahlin Veterans Administration Medical Center, Salt Lake City, Utah, USA.
  • 6 Sickle Cell Center, University of Illinois, Chicago, Illinois, USA.
  • 7 Research Center for High-Altitude Medicine, Qinghai University, Xining, People's Republic of China.
  • 8 Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 9 Sher-i-Kashmir Institute of Medical Sciences, Srinagar, India.
  • 10 Regional Centre for Biotechnology, Gurgaon, India.
  • 11 1] Department of Pathology, University of Utah, Salt Lake City, Utah, USA. [2] ARUP Laboratories, Hematopathology, Salt Lake City, Utah, USA.
  • 12 1] Eccles Institute of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA. [2] Department of Genetics, Rutgers, State University of New Jersey, Piscataway, New Jersey, USA.
  • 13 Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • 14 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
  • 15 Departmant of Family and Preventive Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.
  • 16 1] Eccles Institute of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA. [2] Division of Physiology, University of California San Diego School of Medicine, La Jolla, California, USA.
  • 17 Eccles Institute of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA.
  • 18 1] Department of Medicine, University of Utah School of Medicine and George E. Wahlin Veterans Administration Medical Center, Salt Lake City, Utah, USA. [2] Eccles Institute of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA. [3].
PMID: 25129147 DOI: 10.1038/ng.3067
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.

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