Hypobaric hypoxia at high-altitude (HA, above 2500meter) is a chief driving force for acclimatization and adaptation in sojourners and permanent residents, respectively. Genetics alongwith environmental alliances and epigenetic conflicts plays a pertinent role in modulating the morphological characteristics and physiological processes.
Last two decades have witnessed a greater amount of data on genetics presentation under the given conditions and a greater number of genes have been identified with a bigger role under hypobaric hypoxia. EGLN1, a cellular oxygen-sensor, emerged as a significant adaptation marker in all the HA populations. Likewise, Endothelial PAS domain protein 1 (EPAS1), the HIF-2α subunit of the hypoxia-inducible factor (HIF) complex remains highly promising.
Among other candidates, endothelin 1, endothelial nitric oxide synthase and apelin are worth mentioning. However, it is no secret that in spite of so much focus, several of the reported polymorphisms failed to replicate across highland populations and even in sojourners. Likewise, with few exceptions, the rosy inflow of GWAS has yielded inconsistent results. This has initiated wider investigations of the genome, only to find the complex epigenetic system regulating the function of SNPs/genes under the given conditions. Currently, the polymorphisms in EGLN1 and EPAS1 have been the major focus of attraction and specific variants and insertion/deletions have found greater role in adaptation and or maladatation. The cogency of the search for pertinent genes in complex diseases nevertheless must be reconsidered to unveil their interactions with epigenetic markers and environmental factors and their downstream effect on the phenotype. Biological systems are complex, and it is important to switch to non-linear, non-traditional genetics approaches to predict functionality.
In this context my talk will focus on EGLN1 and EPAS1.