High-Altitude Andean H194R HIF2A Allele Is a Hypomorphic Allele

Area of Science:

• Human Genetics
• Physiological Adaptation
• Molecular Biology

Background:

• Andean populations have long inhabited high altitudes, facing challenges from low oxygen levels.
• Previous research indicated positive selection on the HIF2A (hypoxia-inducible factor 2 alpha) gene in Andeans.
• The functional impact of the selected HIF2A allele on altitude adaptation remained unclear.

Purpose of the Study:

• To investigate the genetic variation and functional consequences of the HIF2A locus in Peruvian Andeans.
• To determine the mechanism by which a specific Andean HIF2A variant may confer altitude adaptation.

Main Methods:

• Whole genome sequencing of 46 Peruvian Andean individuals.
• Genotyping of the Andean-specific single nucleotide variant (SNV) rs570553380 (H194R) in 299 individuals.
• In vitro assays to assess protein-protein interactions and a knockin mouse model to evaluate physiological effects.

Main Results:

• Confirmed positive selection on HIF2A in Andeans, associated with the H194R substitution (rs570553380).
• The H194R variant positively correlated with increased fraction of exhaled nitric oxide.
• In vitro studies showed impaired HIF-2α binding to its partner; mouse models exhibited reduced hypoxia-induced pulmonary Endothelin-1 and protection against pulmonary hypertension.

Conclusions:

• The Andean H194R HIF2A allele functions as a hypomorphic (partial loss-of-function) variant.
• This allele is associated with altered nitric oxide metabolism and protection against hypoxia-induced pulmonary hypertension.
• Provides a molecular mechanism for HIF2A-mediated adaptation to high-altitude environments.