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.

Keywords: EGLN1; EPAS1; Tibetan; adaptation; evolution; hypoxia-inducible factor.

Fig. 1.

Cumulative frequency distribution of hemoglobin concentrations in US residents at sea level and Tibetan and Bolivian Aymara natives at 4,000 m. A: results for men. B: results for women. [From Beall et al. (7).]

Fig. 2.

Birth weight plotted against altitude of residence for Tibetans and Han Chinese, showing a significantly smaller birth weight fall with increasing altitude in Tibetans than in Han Chinese. Values are means ± SE. [From Moore et al. (57).]

Fig. 3.

Genome-wide allelic differentiation scans comparing Tibetan highlanders and HapMap Han Chinese. Eight single nucleotide polymorphisms near EPAS1 achieved genome-wide significance. [From Beall et al. (8).]

Fig. 4.

Schematic representation of the regulation of hypoxia-inducible factor (HIF)-α by hypoxia. In the presence of oxygen (O₂) and iron (Fe²⁺), prolyl hydroxylase domain (PHD) enzymes hydroxylate specific proline residues in HIF-α, increasing the binding of the Von Hippel-Lindau (VHL) tumor suppressor protein. This targets HIF-α for ubiquitination and mediates its proteosmal degradation. In hypoxia, HIF-α accumulates, dimerizes with HIF-β, binds to DNA, and transcriptionally regulates hypoxia-responsive genes. [Courtesy of Dr. Federico Formenti, University of Oxford, Oxford, UK.]