Journal article
A genetic mechanism for Tibetan high-altitude adaptation
Nature genetics, Vol.46(9), pp.951-956
09/01/2014
DOI: 10.1038/ng.3067
PMCID: PMC4473257
PMID: 25129147
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.
Details
- Title: Subtitle
- A genetic mechanism for Tibetan high-altitude adaptation
- Creators
- Felipe R Lorenzo - University of UtahChad Huff - The University of Texas MD Anderson Cancer CenterMikko Myllymäki - University of OuluBenjamin Olenchock - Brigham and Women's HospitalSabina Swierczek - University of UtahTsewang Tashi - University of UtahVictor Gordeuk - University of Illinois ChicagoTana Wuren - Qinghai UniversityGe Ri-Li - Qinghai UniversityDonald A McClain - University of UtahTahsin M Khan - Icahn School of Medicine at Mount SinaiParvaiz A Koul - Sher-i-Kashmir Institute of Medical SciencesPrasenjit Guchhait - Regional Centre for BiotechnologyMohamed E Salama - University of UtahJinchuan Xing - Rutgers, The State University of New JerseyGregg L Semenza - Johns Hopkins UniversityElla Liberzon - Harvard UniversityAndrew Wilson - University of UtahTatum S Simonson - University of UtahLynn B Jorde - University of UtahWilliam G Kaelin Jr - Dana-Farber Cancer InstitutePeppi Koivunen - University of OuluJosef T Prchal - University of Utah
- Resource Type
- Journal article
- Publication Details
- Nature genetics, Vol.46(9), pp.951-956
- DOI
- 10.1038/ng.3067
- PMID
- 25129147
- PMCID
- PMC4473257
- NLM abbreviation
- Nat Genet
- ISSN
- 1061-4036
- eISSN
- 1546-1718
- Grant note
- P01CA108671 / NCI NIH HHS HL119355-01 / NHLBI NIH HHS K08 HL119355 / NHLBI NIH HHS R00 HL118215 / NHLBI NIH HHS HG005846 / NHGRI NIH HHS HL098062 / NHLBI NIH HHS UL1 TR001067 / NCATS NIH HHS I01 BX001140 / BLRD VA
- Language
- English
- Date published
- 09/01/2014
- Academic Unit
- Surgery
- Record Identifier
- 9985224317802771
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