Evolution and plasticity of the control of breathing in high-altitude natives: Insights from deer mice

Breathing and the hypoxic ventilatory response are vital determinants of gas exchange and metabolism in hypoxia. High-altitude natives are valuable models for elucidating how plasticity and evolutionary adaptation can shape the control of breathing in chronic hypoxia. Here, we review studies on this issue in deer mice, a species found from sea level to over 4300 m elevation. Distinct populations from high and low altitudes have been bred in captivity and compared in common conditions of normoxia or hypoxia. Low-altitude populations exhibit ventilatory acclimatization to hypoxia (VAH), in which chronic hypoxia enhances total ventilation and helps offset declines in arterial O₂ pressure. In contrast, high-altitude populations do not express VAH, but instead exhibit a fixed increase in total ventilation in hypoxia and a deeper more effective breathing pattern than lowlanders. Studies of F2 inter-population hybrids suggested that these evolved changes in breathing in highlanders could be largely attributed to sequence variants in two genes. Specifically, the more effective breathing pattern of highlanders was associated with genetic variation in α-globin, whereas the lack of VAH was associated with variation in the hypoxia-inducible factor 2α (HIF-2α) gene Epas1. However, in contrast to the lack of plasticity in highlanders during adulthood alone, life-long hypoxia exposure throughout development and adulthood has a strong effect on the HVR, further augmenting total ventilation and tidal volume. Altogether, these findings in deer mice suggest that the control of breathing in high-altitude natives is shaped by the integration of their unique genotype and developmental environment, improving resilience to harsh and hypoxic environments.