Variable patterns in the molecular evolution of the hypoxia-inducible factor-1 alpha (HIF-1α) gene in teleost fishes and mammals

The hypoxia-inducible factor-1 alpha (HIF-1α) protein is the major regulator of oxygen-dependent gene expression and a member of the bHLH–PAS family of transcription factors. In this study we compared and contrasted the rate and mode of HIF-1α molecular evolution between teleost fishes and mammals, as well as within teleost fishes and mammals. Various likelihood methods for estimating codon substitutions were used to detect different modes of selection. Although the overall evolutionary rate in teleost HIF-1α was at least twice as fast as in mammalian HIF-1α, the crucial interaction domains were observed to be under stringent negative selection in all vertebrates. Relaxed negative selection on less crucial regions of teleost HIF-1α compared to mammalian HIF-1α was detected, but no evidence for positive selection that was supported by all methods was found. We suggest that the relaxed selective constraints in teleost HIF-1α may be associated with the variable environmental oxygen levels to which teleosts have been exposed during their evolutionary history. However, in teleosts the positions with partial support for positive selection were not found in the vicinity of the HIF-1α domains which confer the oxygen sensitivity, but in the bHLH–PAS domain responsible for DNA binding and dimerization. The pattern of selection in the bHLH–PAS domain has some similarities with the patterns observed in the adaptive evolution of the homeodomain of Hox genes and may be typical in the molecular evolution of transcription factors.