Tibetan PHD2 , an allele with loss-of-function properties

Significance Tibetans have lived for thousands of years at an altitude where oxygen concentrations are low (hypoxia). They are known to have physiologic adaptations, including increased breathing responses to low oxygen and decreased blood pressure in the lungs. Tibetans also are known to have mutations in two genes,PHD2 andHIF2A , that are central components of a molecular hypoxia response pathway. We provide evidence here that Tibetan PHD2 promotes increased breathing responses to hypoxia. The TibetanHIF2A gene is likely to account for the decreased blood pressure in the lungs. Thus, the hypoxia response pathway has been altered in Tibetans to facilitate adaptation to the hypoxia of high altitude.