Modeling the evolution of a classic genetic switch

We develop a modeling framework to examine the evolution of the GAL regulatory network. This enables us to translate molecular changes in the regulatory network to changes in quantitative network function. We computationally reconstruct an inferred ancestral version of the network and trace the evolutionary paths in the lineage leading to S. cerevisiae. We explore the evolutionary landscape of possible regulatory networks and find that the operation of intermediate networks leading to S. cerevisiae differs substantially depending on the order in which evolutionary changes accumulate; in particular, we systematically explore evolutionary paths and find that some network features cannot be optimized simultaneously.We find that a computational modeling approach can be used to analyze the evolution of a well-studied regulatory network. Our results are consistent with several experimental studies of the evolutionary of the GAL regulatory network, including increased fitness in Saccharomyces due to duplication and adaptive regulatory divergence. The conceptual and computational tools that we have developed may be applicable in further studies of regulatory network evolution.Regulatory networks are known to underlie many biological processes, and therefore their characterization and analysis forms a central focus of systems biology [1-4]. Despite their importance, relatively little is known about how regulatory networks are formed during evolution and shaped by natural selection.One of the best studied regulatory networks in molecular biology is the "GAL network", which is responsible for the inducible metabolism of galactose in budding yeast. In addition to being extremely well-characterized in S. cerevisiae [5-7] it has also been the subject of a number of quantitative modeling efforts [8-11] and evolutionary studies, which have revealed many interesting patterns of regulatory network evolution [12-15]. Perhaps most general of these evolutionary paradigms is the duplicat