Genomic analysis of hypoxia inducible factor alpha in ray-finned fishes reveals missing Ohnologs and evidence of widespread positive selection

Fishes are increasingly challenged by low dissolved oxygen in nature and their survival relies, in part, upon their molecular responses. This study sheds new light on the evolution and diversity of the hypoxia inducible factor, the master regulator of oxygen-dependent gene expression, in fishes.
Published in Ecology & Evolution
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Although the essential nature of oxygen to animal life has been appreciated for centuries, the molecular mechanisms that allow cells and tissues to respond to decreased oxygen availability (hypoxia) have only come to light over the last 30 years. Semenza and Wang discovered a protein, which they named hypoxia inducible factor 1 (HIF1), that increased the expression of erythropoietin, a glycoprotein hormone that promotes red blood cell production in response to low blood oxygen levels. [1] Subsequent research showed that HIF1 was a dimeric protein of alpha and beta subunits, that the alpha subunit was subject to oxygen-dependent degradation, that multiple forms of alpha and beta subunits are present in mammals, and that the HIF family of transcription factors regulates the expression of numerous genes in diverse cell types during normal mammalian development, as well as in various pathologies associated with low tissue oxygenation. [2,3] Because of its central role in physiology and disease, the discovery of HIF and its mechanism of action resulted in the Nobel Prize in Physiology or Medicine in 2019.

It has also been long-appreciated that many animals occur in environments with variable and sometimes low oxygen availability. This is especially true for aquatic animals because the limited solubility and slow diffusion of oxygen in water result in temporal and spatial hypoxia. Low oxygen occurs naturally in slow moving or poorly mixed streams and basins, in ice-covered lakes, and at intermediate ocean depths where biological oxygen demand exceeds oxygen replenishment. The frequency, severity, and geographic scope of aquatic hypoxia, however, are increasing due to human activities, in particular eutrophication and climate change. Aquatic hypoxia is currently considered to be a major global environmental concern and decreased oxygen concentration is likely to reduce the suitability of many habitats to support healthy populations of fishes and aquatic invertebrates. [4,5]

The report by Ian Townley, Courtney Babin, and others appearing on December 24, 2022, in Scientific Reports [6], examines the evolution of the HIF gene family in the ray-finned fishes. This group, also known as the Actinopterygii, is the most speciose and widespread class of vertebrate animals and includes species that occur in habitats that are subject to diurnal, seasonal, or chronic hypoxia. Similar to earlier investigations [7], we show that different lineages have variable numbers of HIF alpha gene copies (paralogs) that arose during genome duplication at the base of vertebrate evolution, as well as from additional genome duplications during the evolution of fishes, followed by lineage-specific gene loss. We clarify the relationships among paralogs and seek to harmonize their nomenclature based upon presumed shared ancestry. We also provide evidence that positive selection likely contributed to the evolution of this diversity in HIF alpha subunits. Interestingly, several amino acid sites potentially under positive selection are predicted to be involved in subunit dimerization, DNA-binding, or post-translational modification of the alpha subunits.

At present, it is not known whether the reported HIF alpha subunit diversity is related to differences in hypoxia tolerance of certain species or lineages of fish. In agreement with previous observations [7], we show that some species that have remarkable hypoxia tolerance (e.g., common carp) retain certain paralogs that have been lost or truncated in other lineages. A new insight, however, is that closely related and hypoxia-intolerant species (e.g., herrings) have the same set of paralogs. Moreover, we report, for the first time, that salmon and trout possess additional HIF alpha paralogs, which presumably arose in a genome duplication specific to this lineage. Because this group of fish generally occurs in fast-moving, cold water and is relatively intolerant of low oxygen, the maintenance of paralogs does not necessarily confer hypoxia tolerance.

As previously noted, "although genome duplication is neither necessary nor sufficient for the evolution of novelties and the divergence of lineages of organisms, it is a reasonable hypothesis that genome duplication can promote or facilitate the origin of novelty and divergence given the proper ecological context." [8] Thus, it is tempting to speculate that the presence of certain paralogs, and their specific amino acid sequences, alters the oxygen or tissue dependence of HIF expression or target gene specificity, at least in certain fish lineages. But it is also possible that the diversity of HIF alpha subunits among fishes is related to potentially novel oxygen-independent functions of this family of transcription factors. With the current genomic analyses [6], we hope to promote further study of HIF signaling during normal fish development and physiology, as well as in the response of fishes to the current trend of increasing aquatic hypoxia.

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