Molecular evolution of the thyrotrophin-releasing hormone precursor in vertebrates: insights from comparative genomics.

Human preprothyrotrophin-releasing hormone (ppTRH) includes six copies of the TRH sequence, the rat and mouse precursors have five, and those of non-mammalian vertebrates have up to eight. In the present study, the evolutionary basis of this variation was investigated using ppTRH gene sequences extracted from available vertebrate genomic databases. A structure based on eight TRH repeats appears to be the norm for non-mammalian vertebrates, but in all mammals except monotremes this number is reduced to a maximum of six. In some species, one (or more) of the TRH repeats has been mutated, probably rendering it functionless and, in a few species, one or two copies of the TRH sequence have been deleted completely. Sequences of regions between the TRH sequences are poorly conserved, despite reports that several active peptides are produced from these regions. The 5' untranslated region of ppTRH is also very variable but, in eutherians, the promoter region immediately upstream of the gene is quite strongly conserved. In particular, those sequences identified as being involved in transcriptional regulation are well conserved in most eutherians, although they are largely absent from other vertebrates. In most species, gene order around the ppTRH locus is conserved, although exceptions include man and chimpanzee, as well as rat and mouse. The comparative genomics approach thus provides a wider view than previously available of the range of ppTRH genes in vertebrates, and of the species specificity displayed by this molecule.