One and a half centuries have passed since Darwin wrote in The Origin of Species “our ignorance of the laws of variation is profound”. Despite enormous progress in understanding these “laws”, we are still grappling with important aspects of this issue. For many genetic circuits that have evolved to different forms in extant species, little is known about the evolutionary pathways connecting the ancestral and modern forms. Our ignorance of the laws of variation and evolutionary pathways make it impossible to predict (in a probabilistic sense) evolutionary outcomes.
Addressing these challenges will necessarily require a deep understanding of how gene regulatory networks have evolved. Genes do not function in isolation; rather, they interact with each other to form complex networks that respond to environmental inputs and developmental programs. Such networks determine the complex relationship between genotype and phenotype, and may severely constrain the possible variations observed in nature. As a consequence, the emergence of complex phenotypes that distinguish one species from the next likely requires coordinated changes of many network components, as well as the regulatory relationships between them.
Organisms devote a significant fraction of their genomes to producing proteins and RNAs, and to cis-regulatory sequences that specify when and where the expression of each gene should be turned on or off. Although there are many forms of this regulation, we will focus on transcription networks, in particular sequence-specific DNA-binding proteins and the cis-regulatory sequences they recognize.
The importance of regulatory evolution in driving phenotypic diversity was recognized soon after the discovery of gene regulation. Jacob and Monod [1
] speculated on the role of the operator sequence mutations in evolution. Britten and Davidson [3
] proposed that repetitive sequences may drive evolutionary novelty by reshaping the genomic regulatory program. King and Wilson [4
] argued, based on the observation that homologous protein sequences in human and chimp are very similar, that “regulatory mutations may account for their biological differences”. In the past decade, studies of single genes in animals have demonstrated that changes in transcriptional regulation can underlie important morphological and physiological changes (see [5
] for a review). These examples include lactase persistence in human subpopulations [6
]; the reduction in pelvic armor of the fresh water stickleback fish relative to their marine form [8
]; changes in insect wing morphology and coloring pattern [9
]; and differences in trichomes among flies [11
]. It has been argued, based on examples and on theoretical grounds, that certain types of phenotypic change are more likely to result from cis
-regulatory changes rather than from coding changes. Consistent with the important roles transcriptional regulation plays during development, it was observed that regulatory mutations occur with high frequency in morphological changes [12
Recent advances in DNA sequencing technology and functional genomics have led to new investigations into the evolution of transcriptional networks in simple model organisms. For several reasons, yeasts have turned out to be particularly useful for such investigations. First, the genomes of a large number of yeast species, covering a wide range of evolutionary distances, have been sequenced, making it possible to carry out detailed and informative comparative sequence analysis. Second, it is relatively simple to make genetic manipulations in many yeast species. Third, the small size of the genome and well-defined regulatory regions allow accurate mapping of cis
-regulatory sequences via functional genomics and bioinformatics. Fourth, because yeasts do not undergo complex developmental programs, their transcription circuits are often simpler than those of animals and plants. Finally, the relatively short generation times make it feasible to carry out in vitro
evolution experiments under controlled environments [14
In the last few years, a number of transcriptional circuits have been characterized in different yeast species. These studies have led to some new insights into the evolution of transcription networks. From these studies, it has become clear that transcription networks are surprisingly plastic, with large-scale rewiring being common. A number of recent reviews, each with a different perspective, have been devoted to this topic [17
]. Here, we describe some new findings and some emerging themes. Rather than providing a comprehensive account, we will focus on a few selected examples to illustrate a common phenomenon or potentially general mechanism. We first describe a few scenarios for network rewiring (using examples from yeasts and, in some cases, animals), followed by a discussion of potential evolutionary pathways that may connect the ancestral form to the extant forms. At the end, we speculate on what we have learned from yeast that may help us to understand evolution of transcription networks in general.