Human adaptation to the hypoxia of high altitude: the Tibetan paradigm from the pregenomic to the postgenomic era

Abstract

The Tibetan Plateau is one of the highest regions on Earth. Tibetan highlanders are adapted to life and reproduction in a hypoxic environment and possess a suite of distinctive physiological traits. Recent studies have identified genomic loci that have undergone natural selection in Tibetans. Two of these loci, EGLN1 and EPAS1, encode major components of the hypoxia-inducible factor transcriptional system, which has a central role in oxygen sensing and coordinating an organism's response to hypoxia, as evidenced by studies in humans and mice. An association between genetic variants within these genes and hemoglobin concentration in Tibetans at high altitude was demonstrated in some of the studies (8, 80, 96). Nevertheless, the functional variants within these genes and the underlying mechanisms of action are still not known. Furthermore, there are a number of other possible phenotypic traits, besides hemoglobin concentration, upon which natural selection may have acted. Integration of studies at the genomic level with functional molecular studies and studies in systems physiology has the potential to provide further understanding of human evolution in response to high-altitude hypoxia. The Tibetan paradigm provides further insight on the role of the hypoxia-inducible factor system in humans in relation to oxygen homeostasis.

Gene Co-Expression Network Analysis Unraveling Transcriptional Regulation of High-Altitude Adaptation of Tibetan Pig

“…Moreover, mounting evidence suggests that the observed physiological adaptations are dependent on the HIF pathway [40–42]. In our study, 16 DEGs were also enriched as members of the HIF pathway (Fig 3 and S2 Table).…”

Human high-altitude adaptation: forward genetics meets the HIF pathway

“…Importantly, studies have shown evidence of natural selection among HIF pathway and hypoxia-related genes (Table 3B). Two genes are particularly noteworthy because of the consistency with which they have been observed in these studies (Simonson et al 2012;Petousi and Robbins 2014). One is HIF2A, which shows evidence of positive directional selection (selection for advantageous mutations that increase fitness of carriers) in all of these genome-wide analyses (Beall et al 2010;Bigham et al 2010;Simonson et al 2010;Yi et al 2010;Peng et al 2011a;Wang et al 2011;Xu et al 2011), and both HIF2A SNP genotypes and haplotypes significantly associate with low hemoglobin concentration in Tibetans (Beall et al 2010;Yi et al 2010).…”

Genetic approaches in comparative and evolutionary physiology

“…For example, the noncoding EPAS1 variants that are present at an elevated frequency among Tibetan highlanders are associated with a reduced hemoglobin concentration (18,172,216), which appears to stem from a blunted erythropoietic response to hypoxia (15-17, 19, 147, 210). There are good reasons to think that this blunted response may be physiologically beneficial under conditions of chronic hypoxia at high altitude (147,148,177,184,199), but that does not mean that hemoglobin concentration was necessarily the trait under direct selection. The reduced hemoglobin concentration may represent a second-order consequence of upstream modifications in O 2 chemosensitivity.…”