Adaptive strategies of aquatic mammals: Exploring the role of the HIF pathway and hypoxia tolerance.

Aquatic mammals (marine and freshwater species) share significant and similar adaptations, enabling them to tolerate hypoxia during regular breath-hold diving. Despite the established importance of HIF1A, a master regulator in the molecular mechanism of hypoxia response, and other associated genes, their role in the evolutionary adaptation of aquatic mammals is not fully understood. In this study, we investigated this topic by employing a candidate gene approach to analyze 11 critical genes involved in the HIF1A signaling pathway in aquatic mammals. Our gene analyses included evaluating positive and negative selection, relaxation or constriction of selection, and molecular convergence compared to other terrestrial mammals, including subterranean mammals. Evidence of selection suggested a significant role of negative selection, as well as relaxation of the selective regime in cetaceans for most of these genes. We found that the glutamine 68 variant in the HIF3α protein is unique to cetaceans and initial evaluations indicated a destabilizing effect on protein structure. However, further analyses are necessary to evaluate its functional impact and adaptive relevance in this taxon.