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<jats:p>Tibetans have adapted to the chronic hypoxia of high altitude and display a distinctive suite of physiologic adaptations, including augmented hypoxic ventilatory response and resistance to pulmonary hypertension. Genome-wide studies have consistently identified compelling genetic signatures of natural selection in two genes of the Hypoxia Inducible Factor pathway, <jats:italic>PHD2</jats:italic> and <jats:italic>HIF2A</jats:italic>. The product of the former induces the degradation of the product of the latter. Key issues regarding Tibetan <jats:italic>PHD2</jats:italic> are whether it is a gain-of-function or loss-of-function allele, and how it might contribute to high-altitude adaptation. Tibetan PHD2 possesses two amino acid changes, D4E and C127S. We previously showed that in vitro, Tibetan PHD2 is defective in its interaction with p23, a cochaperone of the HSP90 pathway, and we proposed that Tibetan <jats:italic>PHD2</jats:italic> is a loss-of-function allele. Here, we report that additional PHD2 mutations at or near Asp-4 or Cys-127 impair interaction with p23 in vitro. We find that mice with the Tibetan <jats:italic>Phd2</jats:italic> allele display augmented hypoxic ventilatory response, supporting this loss-of-function proposal. This is phenocopied by mice with a mutation in <jats:italic>p23</jats:italic> that abrogates the PHD2:p23 interaction. <jats:italic>Hif2a</jats:italic> haploinsufficiency, but not the Tibetan <jats:italic>Phd2</jats:italic> allele, ameliorates hypoxia-induced increases in right ventricular systolic pressure. The Tibetan <jats:italic>Phd2</jats:italic> allele is not associated with hemoglobin levels in mice. We propose that Tibetans possess genetic alterations that both activate and inhibit selective outputs of the HIF pathway to facilitate successful adaptation to the chronic hypoxia of high altitude.</jats:p>

Original publication

DOI

10.1073/pnas.1920546117

Type

Journal article

Journal

Proceedings of the National Academy of Sciences

Publisher

Proceedings of the National Academy of Sciences

Publication Date

15/05/2020

Pages

201920546 - 201920546