Genetic determinants of Tibetan high-altitude adaptation

Abstract

Some highland populations have genetic adaptations that enable their successful existence in a hypoxic environment. Tibetans are protected against many of the harmful responses exhibited by non-adapted populations upon exposure to severe hypoxia, including elevated hemoglobin concentration (i.e., polycythemia). Recent studies have highlighted several genes subject to natural selection in native high-altitude Tibetans. Three of these genes, EPAS1, EGLN1 and PPARA, regulate or are regulated by hypoxia inducible factor, a principal controller of erythropoiesis and other organismal functions. Uncovering the molecular basis of hypoxic adaptation should have implications for understanding hematological and other adaptations involved in hypoxia tolerance. Because the hypoxia response involves a variety of cardiovascular, pulmonary and metabolic functions, this knowledge would improve our understanding of disease mechanisms and could ultimately be translated into targeted therapies for oxygen deprivation, cardiopulmonary and cerebral pathologies, and metabolic disorders such as diabetes and obesity.

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).…”

“…For well over a century, the unique suite of physiological adaptations to chronic hypoxia observed among long-term resident populations has been well documented (for review, see Hornbein and Schoene 2001). Studies conducted over the past decade as well as more recent genomic studies support a genetic basis for these adaptations (Simonson et al 2012;Scheinfeldt and Tishkoff 2013). Interestingly, the patterns of genetic changes differ among the three populations.…”

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

“…Separate genomic studies detailed variants in Tibetan highlanders in the genes EPAS1 (encoding HIF-2α) and EGLN1 (one of the prolyl hydroxylases that regulate HIF1α/2α). [100][101][102][103][104] Furthermore, a genetic mutation resulting in HIF-2α overexpression was associated with development of PH. 105 Andeans have lived at high altitude for approximately 11,000 years.…”

Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing

“…These studies consistently identified genetic signatures in the EGLN1 (also known as prolyl hydroxylase domain protein 2, or PHD2) 2 and EPAS1 (also known as hypoxia-inducible factor-2␣, or HIF2A) genes in the Tibetan population (10).…”