Adaptive cis-regulatory changes may involve few mutations.

A long-standing debate in evo-devo research concerns the relative role of protein-coding and cis-regulatory regions in adaptation. Recent studies of genetic adaptation have revealed that the number of substitutions contributing to phenotypic variation is lower in cis-regulatory than in structural regions, which has led to the idea that cis-regulatory regions are less important in phenotypic adaptation. However, the number of substitutions is not the only important factor, the "size" of the adaptive contribution of these substitutions is important too. A geometrical reasoning predicts that, given their lesser pleiotropic effects, cis-regulatory substitutions should have a larger average adaptive contribution than protein-coding substitutions. Thus it is possible that even with a lower number of adaptive mutations, cis-regulatory regions may contribute at the same level or even more than protein-coding regions.