Evolutionary convergence and niche-specific regulation of core HIF1A pathway genes synergistically drive divergent hypoxia adaptation in mammals.

Mammals native to hypoxic niches thrive in hypoxic environments, unlike humans and non-adapted species which suffer metabolic dysfunction and disease. Despite progress in understanding hypoxic signaling, the evolutionary strategies enabling niche-specific hypoxia adaptation remain unclear. To address this, we analyzed 21 species representing three hypoxic niches (aquatic deep-diving, terrestrial high-altitude, terrestrial burrowing) and non-hypoxic controls based on identified 25 HIF1A pathway-related core genes. In the coding region, selection pressure analysis initially identified key genes: aquatic deep-diving: CREBBP; terrestrial high-altitude: EGLN1, EGLN2, ELOC and TP53; terrestrial burrowing: EGLN3. Convergent amino acid substitution analysis at the protein level validated these findings and further refined the selection to the most representative key genes for each niche (aquatic deep-diving: CREBBP; terrestrial high-altitude: EGLN1; terrestrial burrowing: EGLN3). Subsequently, non-coding region analysis revealed the specific regulatory patterns of the key genes across the three hypoxic niches: aquatic deep-diving corresponds to acute transient hypoxia adaptation, terrestrial high-altitude exhibits chronic fluctuating hypoxia adaptation, and terrestrial burrowing demonstrates long-term stable hypoxia adaptation. In addition, hypoxia adaptation analysis of the solid tumor in several cancers showed that domain mutations in the core gene CREBBP in the HIF1A signaling pathway contribute to the malignant behavior of cancers. This indicates that distinct hypoxic niches and their key genes have evolved unique regulatory mechanisms for adaptation. The study suggests mammals exploit diverse strategies by modulating key HIF1A pathway gene expression, providing novel insights into hypoxic signaling in evolutionary adaptation to oxygen deprivation.