Genetic adaptations shaping survival, pregnancy, and life at high altitude and sea level

Advancements in genetic research have greatly enhanced our understanding of human adaptation to high-altitude environments through the identification of genetic markers linked to hypoxia tolerance. Our recent studies identify key genes associated with haematological and ventilatory traits in Andeans. Adaptive variation at EPAS1, encoding endothelial PAS domain protein 1, a key regulator in the hypoxia-inducible factor (HIF) pathway (the alpha subunit of HIF2), has been associated with relatively low haematocrit at high altitude, which may be linked directly or indirectly to improvements in oxygen transport and/or delivery, while PRKAA1, encoding the AMP-activated protein kinase (AMPK) alpha-1 subunit, has been linked to ventilatory responses during wakefulness that are further associated with sleep phenotypes with metabolic implications. The relevance of these genetic adaptations extends beyond adult physiology; e.g. other studies have associated an adaptive genetic signature at PRKAA1 with pregnancy outcomes in Andean populations. Understanding how adaptive genetic variations in EPAS1 and PRKAA1 contribute to hypoxia tolerance offers a foundation for investigating broader evolutionary mechanisms of high-altitude adaptation, particularly in the contexts of pregnancy and fetal development, where oxygen availability is crucial. Integrative studies that combine molecular, physiological, and evolutionary perspectives offer promise in revealing the complexities of high-altitude adaptation and its relevance to hypoxia-related health challenges in both highland and lowland populations.This article is part of the discussion meeting issue 'Pregnancy at high altitude: the challenge of hypoxia'.