EVOLUTION OF β-GLUCURONIDASE REGULATION IN THE GENUS MUS.

Despite the central role suggested for regulatory mutations in many evolutionary scenarios, there is relatively little information available about the type and extent of regulatory differences between species, or to what extent differences between species are independent of variation within species. To address this issue we have studied the regulatory system of β-glucuronidase, a gene implicated in a murine androgen-inducible pheromone-signalling system. We examined the changes in β-glucuronidase hormonal regulation which have occurred during the radiation of a group of 12 closely related species of mice by assaying β-glucuronidase activity in six different tissues after treatment with estrogen, and with androgen alone and in combination with either estrogen or growth hormone. We also examined in some detail the extent of variation in regulatory responses within species. We found extensive variation in regulatory phenotypes both within and among the species surveyed, suggesting that many of the species examined are currently polymorphic for various regulatory factors that affect inducibility of β-glucuronidase. The variation we observed reflects changes in the ability of the β-glucuronidase gene to respond to hormonal influences, rather than changes in aspects of the hormonal signalling system exterior to the gene. The marked differences among species in the renal and uterine responses to hormonal induction of β-glucuronidase are not easily related to the phylogeny of the genus Mus. If hormonal induction of the gene for β-glucuronidase is subject to natural selection, it appears to be subject to widely fluctuating selective forces. We review evidence that the apparently disorderly evolution of the hormonal responsiveness of β-glucuronidase does not appear to be a unique property of this regulatory system. In contrast to the evolution of many protein sequences, which are tightly correlated with phylogeny and proceed at a relatively constant rate, some, perhaps many, regulatory phenotypes are in rapid evolutionary flux, providing an extensive range of phenotypes upon which selection can act.