Mechanisms of mutational robustness in transcriptional regulation

Abstract

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.

Keywords: homotypic clusters; redundancy; regulatory networks; shadow enhancers; transcription factor binding sites.

Figure 1

Mechanisms of mutational robustness in transcriptional regulation. Robustness can be conferred by (A) individual transcription factor binding sites, (B) homotypic clusters of such sites, (C) redundant enhancers, (D) individual transcription factors, and (E) redundant transcription factors. Small colored boxes represent transcription factor binding sites, ellipsoids represent transcription factors, and the arrow represents the transcription start site of the gene indicated by the large black rectangle. The lightly shaded ellipses in (E) represent paralogs of the transcription factors (red ellipses) in (D). Both the red and green transcription factors regulate the expression of the black gene. These regulatory interactions are part of a larger regulatory network, whose structural properties can also influence the robustness of transcriptional regulation.