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

Abstract

As aquatic hypoxia worsens on a global scale, fishes will become increasingly challenged by low oxygen, and understanding the molecular basis of their response to hypoxia may help to better define the capacity of fishes to cope with this challenge. The hypoxia inducible factor (HIF) plays a critical role in the molecular response to hypoxia by activating the transcription of genes that serve to improve oxygen delivery to the tissues or enhance the capacity of tissues to function at low oxygen. The current study examines the molecular evolution of genes encoding the oxygen-dependent HIFα subunit (HIFA) in the ray-finned fishes (Actinopterygii). Genomic analyses demonstrate that several lineages retain four paralogs of HIFA predicted from two rounds of genome duplication at the base of vertebrate evolution, broaden the known distribution of teleost-specific HIFA paralogs, and provide evidence for salmonid-specific HIFA duplicates. Evolution of the HIFA gene family is characterized by widespread episodic positive selection at amino acid sites that potentially mediate protein stability, protein–protein interactions, and transcriptional regulation. HIFA transcript abundance depends upon paralog, tissue, and fish lineage. A phylogenetically-informed gene nomenclature is proposed along with avenues for future research on this critical family of transcription factors.

Hypoxia induces pyroptosis and inflammation in the liver of fat greenling (Hexagrammos otakii)

“…Many current studies on hypoxia are limited to mammals, while fish, which are also vertebrates, are more affected by hypoxia, and the problems in this area need to be addressed [ 25 ]. As the hub of the whole body metabolism, the liver has numerous functions including regulating the metabolism of carbohydrates, fat and protein, bile synthesis, hematopoietic coagulation, and detoxification [ 26 ].…”

Ventilatory responses to hypoxic and hypercapnic environments in naked mole‐rats

“…Hypoxia is a challenging environmental stress, and oxygen availability is one of the most powerful drivers of evolutionary adaptation. 1,2 At the cellular level, low oxygen availability presents an energetic challenge because aerobic respiration is reduced or halted, and thus animals must adapt to achieve energetic homeostasis. [3][4][5][6] In most cases, animals that experience hypoxia in their natural habitat do so on a prolonged or lifelong basis.…”

Hypoxia-inducible factor 1 alpha protein increases without changes in mRNA during acute hypoxic exposure of the Gulf killifish,Fundulus grandis

“…The hypoxia-inducible transcription factors (HIFs) are evolutionarily conserved, central regulators of the molecular responses to low oxygen in animals ( Semenza, 2009 , 2012 ; Majmundar et al, 2010 ; Pamenter et al, 2020 ; Mandic et al, 2021 ; Townley et al, 2022 ). HIF1 was first identified in mammalian cell culture as a protein required for the hypoxic induction of the glycoprotein hormone, erythropoietin ( Semenza and Wang, 1992 ; Maxwell et al, 1993 ).…”

“…Further complicating the interpretation of these studies is the fact that certain fish lineages (e.g. Otocephala, which includes herring, catfish, carp, and zebrafish) retain both paralogs of HIF1A arising from a teleost-specific genome duplication, while more advanced fishes (Euteleost) have retained only a single paralog ( Rytkönen et al, 2013 ; Townley et al, 2022 ). A comparison of the nucleotide sequences of PCR primers or amplification products shows that, more often than not, studies of Otocephala measured transcript levels of the teleost-specific paralog ( HIF1Ab ) different from the one found in Euteleost (T. E. Murphy, personal observations).…”

“…This species is in the order Cyprinidontiformes, which is part of the Euteleost ( Hughes et al, 2018 ), thus possessing a single HIF1A paralog. Comparison of genomic sequences and the order of nearby genes shows that the gene retained in F. grandis and other Euteleost is more closely related to HIF1Aa than HIF1Ab in the Otocephala, which retain both paralogs ( Rytkönen et al, 2013 ; Townley et al, 2022 ). Previous research showed that HIF1α protein increased in several tissues of F. grandis exposed to 1 mg O 2 l −1 (∼13% of the air-saturated oxygen concentration) for 24 h ( Gonzalez-Rosario, 2016 ).…”