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
  • 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.