Analysis of hypoxia-inducible factor alpha polyploidization reveals adaptation to Tibetan plateau in the evolution of schizothoracine fish

Lihong Guan, Wei Chi, Wuhan Xiao, Liangbiao Chen, Shunping He

BackgroundHypoxia-inducible factor (HIF) is a master regulator that mediates major changes in gene expression under hypoxic conditions. Though HIF family has been identified in many organisms, little is known about this family in schizothoracine fish.ResultsDuplicated hif-¿ (hif-1¿A, hif-1¿B, hif-2¿A, and hif-2¿B) genes were identified in schizothoracine fish. All the deduced HIF-¿s protein contains the main domains (bHLH-PAS, ODDD, and TAD), also found in humans. Evidence suggests a Cyprinidae-specific deletion, specifically, a conserved proline hydroxylation motif LxxLAP, in the NODD domain of schizothoracine fish HIF-1¿A. In addition, a schizothoracine-specific mutation was observed in the CODD domain of the specialized and highly specialized schizothoracine fish HIF-1¿B, which is the proline hydroxylation motif mutated into PxxLAP. Standard and stochastic branch-site codon model analysis indicated that only HIF-1¿B has undergone positive selection, which may have led to changes in function. To confirm this hypothesis, HIF-¿s tagged with Myc were transfected into HEK 293 T cells. Each HIF-1¿B was found to significantly upregulate luciferase activity under normoxic and hypoxic conditions, which indicated that the HIF-1¿B protein was more stable than other HIF-¿s.ConclusionsAll deduced HIF-¿s protein of schizothoracine fish contain important domains, like their mammalian counterparts, and each HIF-¿ is shorter than that of human. Our experiments reveal that teleost-specific duplicated hif-¿ genes played different roles under hypoxic conditions, and HIF-1¿B may be the most important regulator in the adaptation of schizothoracine fish to the environment of the Tibetan Plateau.