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

A genetic mechanism for Tibetan high-altitude adaptation.

Author information

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].

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.

PMID:
25129147
PMCID:
PMC4473257
DOI:
10.1038/ng.3067
[Indexed for MEDLINE]
Free PMC Article

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