Polyploidisation Explication Essay


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Fish possess homologs of HIF-α and HIF-α that share strong similarity with those of humans. They may play roles similar to those of their mammalian counterparts in expression of oxgen-dependent genes [13]. The sequence of HIF-α gene had been extensively characterized in fishes. The first fish HIF-α gene was identified in rainbow trout (Oncorhynchus mykiss) in 2001 [50]. The sequence was slightly shorter than that of mammals. It included bHLH-PAS and ODD domains and proline and asparagine residues, which were relatively conserved in the deduced rainbow trout HIF-α protein. Subsequently, HIF-α gene was reported from killfish (Fundulus heteroclitus), grass carp (Ctenopharyngodon idellus), crucian carp (Carassius carassius), zebrafish (Danio rerio), Atlantic croaker (Micropogonias undulatus), asp (Aspius aspius), three-spined stickleback (Gasterosteus aculeatus), Russian sturgeon (Acipencer gueldenstaedtii), naked carp (Gymnocypris przewalskii), Wuchang bream (Megalobrama amblycephala), Chinese sucker (Myxocyprinus asiaticus), bighead carp (Hypophthalmichthys nobilis), silver carp (Hypophthalmichthys molitrix), Prenant’s schizothoracin (Schizothorax prenanti), Namucuo naked carp (Gymnocypris namensis), and so on [10],[12],[51]-[58].

Although previous studies identified HIF-α in schizothoracine fish, the present study is the first to identify teleost-specific duplicated HIF-α paralogs. It not only provides new information for HIF research in teleosts but also supplies a foundation for further study of the adaptation of schizothoracine fish to high altitudes and low oxygen levels in the Tibetan Plateau. Each schizothoracine fish HIF-α was smaller than the corresponding human HIF-α. The hif-1αA/B and HIF-2αA/B of schizothoracine fish shared more than 46 and 53% similarity with human HIF-1α and HIF-2α, respectively. hif-1αB and HIF-2αB shared more sequence identities with human HIF-1α and HIF-2α than hif-1αA and HIF-2αA did in all species except Gd. pachycheilus. The bHLH-PAS domain of HIF-αs N-terminal was highly conserved, but the ODD domain of the C-terminal was less conserved, especially in regions in the vicinity of the oxygen-dependent proline hydroxylation sites. A Cyprinidae-specific deletion (LxxLAP) in the NODD domain of hif-1αA may have occurred in all six schizothoracine fish, and a schizothoracine-specific mutation LxxLAP mutated to PxxLAP in the CODD domain of the specialized and highly specialized schizothoracine fish hif-1αB. The HIF hydroxylase pathway was regulated by the PHD family of oxygen-dependent prolyl hydroxylases in metazoans [19]. In mammals, the Pro-564 in the CODD domain is the primary critical substrate in PHD binding to HIF-1α [31]. It was here deduced that although the deletion and mutation were all located in the ODD domain, the change in the CODD domain of hif-1αB was more important than the deletion in the NODD domain of hif-1αA was in the evolution of schizothoracine fish.

The HIF pathway plays a pivotal role in the response to hypoxia, and the PHD family of oxygen-dependent prolyl hydroxylases plays a critical role in regulating HIF stability [19]. Some candidate genes associated with the HIF pathway showed signals of positive selection in species living in the Tibetan Plateau. For instance, EPAS1 (HIF-2α), EGLN1, and PPARA were detected in Tibetans [59],[60]; ADAM17 in the yak [61]; ADORA2A, CCL2, ENG, PIK3C2A, PKLR, ATP12A, and NOS3 in the Tibetan antelope [62]; SRF, TXNRD2, and WNT7B in the ground tit [63]; and EPAS1, SIRT7, PLXNA4, and MAFG in the Tibetan mastiff [64]. In this study, computational estimation suggested that the specialized and highly specialized schizothoracine fish hif-1αB have experienced significantly selective pressure. Positively selected sites were detected in HIF-1α, HIF-2α, and HIF-2α, respectively in schizothoracine fish, Tibetans, and Tibetan mastiff. This shows that fish and mammals developed different mechanisms for adapting to the special environment of the Tibetan Plateau.

Functional analysis was performed by transfecting schizothoracine fish HIF-α in HEK 293 T cells. Results showed that the expression level of HIF-1α differed from that of HIF-2α. Hypoxia was found to increase the abundance of hif-1αA/B but not that of HIF-2αA/B. The decrease in the protein levels of HIF-2αA/B may be attributable to the combined impact of the reduced protein synthesis under hypoxic conditions and the rapid folding rate of HIF-α protein in mammalian cells [65]. The luciferase assay showed that all the HIF-αs characterized in this study were capable of forming functional heterodimers with human HIF-α and could activate HRE reporter gene, but they performed different levels of oxygen-dependent regulation. Each HIF-α (hif-1αA/B and HIF-2αA/B) was able to upregulate luciferase activity under normoxic conditions, and hif-1αB was more significant, suggesting that hif-1αB was more stable under normoxic conditions. The transcriptional activity of hif-1αB was higher than that of other HIF-1αs under hypoxic conditions, and transcriptional activity was stronger under hypoxic conditions than under normoxic conditions. These results were also supported by structural analysis. For hif-1αB, the bHLH-PAS domain, which is responsible for heterodimerization with HIF-α and DNA binding, was conserved; and the ODD domain, which interacts with PHD, was mutated [10],[19],[22],[66],[67]. It was also discovered that HIF-2αA/B downregulated luciferase activity under hypoxic conditions. This was consistent with the decrease observed in protein levels of HIF-2αA/B after hypoxia treatment.

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