Mechanisms of mutational robustness in transcriptional regulation

Robustness is the invariance of a phenotype in the face of environmental or genetic change. The phenotypes produced by transcriptional regulatory circuits are gene expression patterns that are to some extent robust to mutations. Here we review several causes of this robustness. They include robustness of individual transcription factor binding sites, homotypic clusters of such sites, redundant enhancers, transcription factors, redundant transcription factors, and the wiring of transcriptional regulatory circuits. Such robustness can either be an adaptation by itself, a byproduct of other adaptations, or the result of biophysical principles and non-adaptive forces of genome evolution. The potential consequences of such robustness include complex regulatory network topologies that arise through neutral evolution, as well as cryptic variation, i.e., genotypic divergence without phenotypic divergence. On the longest evolutionary timescales, the robustness of transcriptional regulation has helped shape life as we know it, by facilitating evolutionary innovations that helped organisms such as flowering plants and vertebrates diversify.