Beyond modular enhancers: new questions in cis-regulatory evolution

Our understanding of how cis-regulatory elements work has advanced rapidly, outpacing our evolutionary models. In this review, we consider the implications of new mechanistic findings for evolutionary developmental biology. We focus on three different debates: whether evolutionary innovation occurs more often via the modification of old cis-regulatory elements or the emergence of new ones; the extent to which individual elements are specific and autonomous or multifunctional and interdependent; and how the robustness of cis-regulatory architectures influences the rate of trait evolution. These discussions lead us to propose new questions for the evo-devo of cis-regulation.