title: A genetic mechanism for Tibetan high-altitude adaptation.
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.
authors.affiliation: 1] Department of Medicine, University of Utah School of Medicine and George E. Wahlin Veterans Administration Medical Center, Salt Lake City, Utah, USA. [2].
authors.forename: Felipe R
authors.initials: FR
authors.lastname: Lorenzo
authors.affiliation: 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].
authors.forename: Chad
authors.initials: C
authors.lastname: Huff
authors.affiliation: 1] Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland. [2].
authors.forename: Mikko
authors.initials: M
authors.lastname: Myllymäki
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Olenchock
authors.affiliation: Department of Medicine, University of Utah School of Medicine and George E. Wahlin Veterans Administration Medical Center, Salt Lake City, Utah, USA.
authors.forename: Sabina
authors.initials: S
authors.lastname: Swierczek
authors.affiliation: Department of Medicine, University of Utah School of Medicine and George E. Wahlin Veterans Administration Medical Center, Salt Lake City, Utah, USA.
authors.forename: Tsewang
authors.initials: T
authors.lastname: Tashi
authors.affiliation: Sickle Cell Center, University of Illinois, Chicago, Illinois, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Gordeuk
authors.affiliation: Research Center for High-Altitude Medicine, Qinghai University, Xining, People's Republic of China.
authors.forename: Tana
authors.initials: T
authors.lastname: Wuren
authors.affiliation: Research Center for High-Altitude Medicine, Qinghai University, Xining, People's Republic of China.
authors.forename: Ge
authors.initials: G
authors.lastname: Ri-Li
authors.affiliation: Department of Medicine, University of Utah School of Medicine and George E. Wahlin Veterans Administration Medical Center, Salt Lake City, Utah, USA.
authors.forename: Donald A
authors.initials: DA
authors.lastname: McClain
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Tahsin M
authors.initials: TM
authors.lastname: Khan
authors.affiliation: Sher-i-Kashmir Institute of Medical Sciences, Srinagar, India.
authors.forename: Parvaiz A
authors.initials: PA
authors.lastname: Koul
authors.affiliation: Regional Centre for Biotechnology, Gurgaon, India.
authors.forename: Prasenjit
authors.initials: P
authors.lastname: Guchhait
authors.affiliation: 1] Department of Pathology, University of Utah, Salt Lake City, Utah, USA. [2] ARUP Laboratories, Hematopathology, Salt Lake City, Utah, USA.
authors.forename: Mohamed E
authors.initials: ME
authors.lastname: Salama
authors.affiliation: 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.
authors.forename: Jinchuan
authors.initials: J
authors.lastname: Xing
authors.affiliation: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Ella
authors.initials: E
authors.lastname: Liberzon
authors.affiliation: Departmant of Family and Preventive Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wilson
authors.affiliation: 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.
authors.forename: Tatum S
authors.initials: TS
authors.lastname: Simonson
authors.affiliation: Eccles Institute of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Jorde
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Kaelin
authors.affiliation: 1] Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland. [2].
authors.forename: Peppi
authors.initials: P
authors.lastname: Koivunen
authors.affiliation: 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].
authors.forename: Josef T
authors.initials: JT
authors.lastname: Prchal
mesh_terms: D000064:Acclimatization / Q000235:genetics*; D000222:Adaptation, Physiological / Q000235:genetics*; D000328:Adult; D000531:Altitude; D044466:Asian People / Q000235:genetics*; D004920:Erythropoiesis / Q000235:genetics; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000235:genetics; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011086:Polycythemia / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C490190:EGLN1 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases