Hypobaric hypoxia drives selection of altitude-associated adaptative alleles in the Himalayan population

Genetic variants play a crucial role in shaping the adaptive phenotypes associated with high-altitude populations. Nevertheless, a comprehensive understanding of the specific impacts of different environments associated with increasing altitudes on the natural selection of these genetic variants remains undetermined. Hence, this study aimed to identify genetic markers responsible for high-altitude adaptation with specific reference to different altitudes, majorly focussing on an altitude elevation range of ∼1500 m and a corresponding decrease of ≥5 % in ambient oxygen availability. We conducted a comprehensive genome-wide investigation (n = 192) followed by a validation study (n = 514) in low-altitude and three high-altitude populations (>2400 m) of Nubra village (NU) (3048 m), Sakti village (SKT) (3812 m), and Tso Moriri village (TK) (4522 m). Extensive genetic analysis identified 86 SNPs that showed significant associations with high-altitude adaptation. Frequency mapping of these SNPs revealed 38 adaptive alleles and specific haplotypes that exhibited a strong linear correlation with increasing altitude. Notably, these SNPs spanned crucial genes, such as ADH6 and NAPG along with the vastly studied genes like EGLN1 and EPAS1, involved in oxygen sensing, metabolism, and vascular homeostasis. Correlation analyses between these adaptive alleles and relevant clinical and biochemical markers provided evidence of their functional relevance in physiological adaptation to hypobaric hypoxia. High-altitude population showed a significant increase in plasma 8-isoPGF2α levels as compared to low-altitude population. Similar observation showcased increased blood pressure in NU as compared to TK (P < 0.0001). In silico analyses further confirmed that these alleles regulate gene expression of EGLN1, EPAS1, COQ7, NAPG, ADH6, DUOXA1 etc. This study provides genetic insights into the effects of hypobaric-hypoxia on the clinico-physiological characteristics of natives living in increasing high-altitude regions. Overall, our findings highlight the synergistic relationship between environment and evolutionary processes, showcasing physiological implications of genetic variants in oxygen sensing and metabolic pathway genes in increasing high-altitude environments.