Parallel Evolution between Aromatase and Androgen Receptor in the Animal Kingdom

There are now many known cases of orthologous or unrelated proteins in different species that have undergone parallel evolution to satisfy a similar function. However, there are no reported cases of parallel evolution for proteins that bind a common ligand but have different functions. We focused on two proteins that have different functions in steroid hormone biosynthesis and action but bind a common ligand, androgen. The first protein, androgen receptor (AR), is a nuclear hormone receptor and the second one, aromatase (cytochrome P450 19 [CYP19]), converts androgen to estrogen. We hypothesized that binding of the androgen ligand has exerted common selective pressure on both AR and CYP19, resulting in a signature of parallel evolution between these two proteins, though they perform different functions. Consistent with this hypothesis, we found that rates of amino acid change in AR and CYP19 are strongly correlated across the metazoan phylogeny, whereas no significant correlation was found in the control set of proteins. Moreover, we inferred that genomic toolkits required for steroid biosynthesis and action were present in a basal metazoan, cnidarians. The close similarities between vertebrate and sea anemone AR and CYP19 suggest a very ancient origin of their endocrine functions at the base of metazoan evolution. Finally, we found evidence supporting the hypothesis that the androgen-to-estrogen ratio determines the gonadal sex in all metazoans.