High-Altitude Adaptation: Mechanistic Insights from Integrated Genomics and Physiology

Abstract

Population genomic analyses of high-altitude humans and other vertebrates have identified numerous candidate genes for hypoxia adaptation, and the physiological pathways implicated by such analyses suggest testable hypotheses about underlying mechanisms. Studies of highland natives that integrate genomic data with experimental measures of physiological performance capacities and subordinate traits are revealing associations between genotypes (e.g., hypoxia-inducible factor gene variants) and hypoxia-responsive phenotypes. The subsequent search for causal mechanisms is complicated by the fact that observed genotypic associations with hypoxia-induced phenotypes may reflect second-order consequences of selection-mediated changes in other (unmeasured) traits that are coupled with the focal trait via feedback regulation. Manipulative experiments to decipher circuits of feedback control and patterns of phenotypic integration can help identify causal relationships that underlie observed genotype-phenotype associations. Such experiments are critical for correct inferences about phenotypic targets of selection and mechanisms of adaptation.

Keywords: EPAS1; adaptation; altitude; genotype–phenotype association; hypoxia; hypoxia-inducible factor.

Fig. 1.

In high-altitude Quechua, noncoding SNPs in EGLN1 are associated with aerobic exercise capacity (VO₂max) in hypoxia. (A) Marginal mean values of VO₂max for three alternative EGLN1 SNP genotypes (error bars = SEM) in a sample of Peruvian Quechua highlanders and non-Hispanic lowlanders. (B) Genotype frequencies for EGLN1 rs1769793 in Peruvian Quechua and non-Hispanic lowlanders from Syracuse, NY. The “TT” genotype is associated with high VO₂max in hypoxia. (C) Allele frequencies of the T allele from the 1000 Genomes Project. Arrows denote frequencies for the Peruvian Quechua (PQU) and non-Hispanic Syracuse (SYR) population samples. Quechua have the highest recorded allele frequency of T worldwide. Data from Brutsaert et al. (2019) with permission.

Fig. 2.

Relationship between Hb concentration and VO₂max in 21 male Tibetan subjects at 4,200 m. From Simonson et al. (2015) with permission.

Fig. 3.

Variation in hematological traits among lowland natives at sea level and acclimatized lowlanders, native Tibetans (Sherpa), and Andeans at high altitude. (A) Andeans exhibit an elevated Hb concentration at high altitude relative to acclimatized lowlanders (LL HA) and Tibetans at high altitude. (B) Tibetans exhibit a significantly elevated plasma volume compared with acclimatized lowlanders (LL HA) and Andeans at high altitude. (C) Due to plasma volume expansion, Tibetans maintain blood volumes that are just as high as those of Andeans, but at a much lower Hb concentration. Consequently, Tibetan highlanders benefit from an augmented blood O₂ transport capacity while avoiding viscosity-related impairments of cardiac function and microcirculatory blood flow. (D) Circulating Hb mass is positively correlated with VO₂max in Tibetans tested at 5,050 m. LL SL, lowland natives tested at sea level; LL HA, lowland natives tested at high-altitude (5,050 m). Modified from Stembridge et al. (2019) with permission.

Fig. 4.

In North American deer mice (Peromyscus maniculatus), coding polymorphism in EPAS1 exhibits a striking pattern of altitudinal variation and contributes to variation in heart rate in hypoxia. (A) The derived amino acid variant exhibits a steep altitudinal cline in frequency from the Great Plains to the crest of the Front Range of the Southern Rocky Mountains. LN (Lincoln, NE; 430 m) and ME (summit of Mt. Evans; 4350 m) denote opposite ends of the altitudinal transect. (B) When exposed to severe hypoxia (12 kPa O₂, the PO₂ at the native altitude of the tested mice), high-altitude mice that were homozygous for the highland EPAS1 variant exhibited significantly higher resting heart rates than mice homozygous for the wild-type allele. From Schweizer et al. (2019) with permission.

Fig. 5.

In vivo experiments on knock-in mice reveal that the Tibetan EGLN1 (PHD2) allele is associated with an enhanced ventilatory response to hypoxia. Relative to mice that carry the wild-type human PHD2 allele, mice that are homozygous for the Tibetan-specific allele exhibit a greater hypoxic ventilatory response (HVR) when exposed to acute hypoxia (12% O₂/3% CO₂). The schematic diagram shows that Tibetan-specific mutations at PHD2 sites 4 and 17 impair the binding interaction between PHD2 and p23, a co-chaperone of the HSP90 pathway. Relative to wild-type PHD2, the zinc finger (ZF) binding domain of Tibetan PHD2 binds less readily to the “PXLE” motif of p23. Consequently, Tibetan PHD2 hydroxylates HIF-α less efficiently than the wild-type PHD2 (as indicated by difference in thickness of the arrow connecting PHD2 to HIF-α). Modified from Song et al. (2020) with permission.

Fig. 6.

Following acclimation, high-altitude deer mice (Peromyscus maniculatus) exhibit a higher thermogenic capacity in hypoxia relative to lowland conspecifics and the exclusively lowland white-footed mice (P. leucopus). Thermogenic capacity is measured as cold-induced VO₂max in hypoxia. Data are means ± SEM. **Significant pairwise difference between highland deer mice and both lowland taxa within the same acclimation treatment. ***Data from Tate et al. (2020) with permission.