When transcription regulatory networks are compared among distantly related eukaryotes, a number of striking similarities are observed: a larger-than-expected number of genes, extensive overlapping connections, and an apparently high degree of functional redundancy. It is often assumed that the complexity of these networks represents optimized solutions, precisely sculpted by natural selection; their common features are often asserted to be adaptive. Here, we discuss support for an alternative hypothesis: the common structural features of transcription networks arise from evolutionary trajectories of "least resistance"--that is, the relative ease with which certain types of network structures are formed during their evolution.

Changes in both the coding sequence of transcriptional regulators and in the cis-regulatory sequences recognized by these regulators have been implicated in the evolution of transcriptional circuits. However, little is known about how they evolved in concert. We describe an evolutionary pathway in fungi where a new transcriptional circuit (a-specific gene repression by the homeodomain protein Matα2) evolved by coding changes in this ancient regulator, followed millions of years later by cis-regulatory sequence changes in the genes of its future regulon. By analyzing a group of species that has acquired the coding changes but not the cis-regulatory sites, we show that the coding changes became necessary for the regulator's deeply conserved function, thereby poising the regulator to jump-start formation of the new circuit.

We examine how different transcriptional network structures can evolve from an ancestral network. By characterizing how the ancestral mode of gene regulation for genes specific to a-type cells in yeast species evolved from an activating paradigm to a repressing one, we show that regulatory protein modularity, conversion of one cis-regulatory sequence to another, distribution of binding energy among protein-protein and protein-DNA interactions, and exploitation of ancestral network features all contribute to the evolution of a novel regulatory mode. The formation of this derived mode of regulation did not disrupt the ancestral mode and thereby created a hybrid regulatory state where both means of transcription regulation (ancestral and derived) contribute to the conserved expression pattern of the network. Finally, we show how this hybrid regulatory state has resolved in different ways in different lineages to generate the diversity of regulatory network structures observed in modern species.