Cross-Species Insights Into Genomic Adaptations to Hypoxia

Abstract

Over millions of years, vertebrate species populated vast environments spanning the globe. Among the most challenging habitats encountered were those with limited availability of oxygen, yet many animal and human populations inhabit and perform life cycle functions and/or daily activities in varying degrees of hypoxia today. Of particular interest are species that inhabit high-altitude niches, which experience chronic hypobaric hypoxia throughout their lives. Physiological and molecular aspects of adaptation to hypoxia have long been the focus of high-altitude populations and, within the past decade, genomic information has become increasingly accessible. These data provide an opportunity to search for common genetic signatures of selection across uniquely informative populations and thereby augment our understanding of the mechanisms underlying adaptations to hypoxia. In this review, we synthesize the available genomic findings across hypoxia-tolerant species to provide a comprehensive view of putatively hypoxia-adaptive genes and pathways. In many cases, adaptive signatures across species converge on the same genetic pathways or on genes themselves [i.e., the hypoxia inducible factor (HIF) pathway). However, specific variants thought to underlie function are distinct between species and populations, and, in most cases, the precise functional role of these genomic differences remains unknown. Efforts to standardize these findings and explore relationships between genotype and phenotype will provide important clues into the evolutionary and mechanistic bases of physiological adaptations to environmental hypoxia.

Keywords: Andean; EPAS1; Ethiopian; HIF pathway; Tibetan; genomic adaptations; high-altitude adaption; hypoxia.

FIGURE 1

Schematic representation of the oxygen transport cascade. Physiological mechanisms that increase oxygen supply (green arrows) and decreased demand (red arrows) are indicated. Modified with permission from Dzal et al. (2015).

FIGURE 2

Domain structure of human HIF pathway proteins. Domain structure for HIF-1α, HIF-2α, HIF-3α, HIF-1β, and PHD2 are shown. The overall domain layout for the HIF proteins are similar with an N-terminal bHLH domain, followed by two PAS domains and an oxygen dependent degradation domain (absent in HIF-1β). HIF-1α and HIF-2α contain two transactivation domains in the C-terminal portion of the protein, while HIF-3α and HIF-1β have one. PHD2 has a domain layout containing an N-terminal MYND-type (myeloid, Nervy, and DEAF-1) zinc finger domain and a C-terminal prolyl-4-hydroxylase catalytic domain.

FIGURE 3

The HIF pathway. (Left) Under normoxic conditions, PHD2 hydroxylates proline 531 of HIF-2α, which can then be recognized by VHL, targeting it for ubiquitylation and degradation. (Right) Under hypoxic conditions, PHD2 cannot hydroxylate HIF α subunits, allowing it to be stabilized and translocate to the nucleus to dimerize with ARNT; the HIF-α-ARNT complex in the nucleus triggers transcriptional activation at hypoxia response elements (HREs).

FIGURE 4

Known EPAS1 variants mapped to the structure of the DNA binding and dimerization domain of HIF-2α in various species. (Top) “Top” view of HIF-2α structure (PDB ID 4ZPK). (Middle) “Side” view of HIF-2α. Spheres representing locations of interest are mapped onto HIF-2α with magenta representing sites of ubiquitylation in humans (K186, K191, K291, and K299) (Akimov et al., 2018), yellow representing phosphorylation sites (S10, S12, T182, and T324), and green representing the locations of identified variants from genetic studies. The species, variation, and publication are listed in Table 1. (Bottom) “Side” view of HIF-2α bound to ARNT and DNA (PDB ID 4ZPK). HIF-2α is shown in gray. ARNT is shown in blue. The DNA double helix is shown in Orange. Note: Tyr333 in chickens maps to residue Tyr342 in humans.