Evolution of complex gene regulatory circuits by addition of refinements.

How do complex gene regulatory circuits evolve? These circuits involve many interacting components, which work together to specify patterns of gene expression. They typically include many subtle mechanistic features, but in most cases it is unclear whether these features are essential for the circuit to work at all, or if instead they make a functional circuit work better. In the latter case, such a feature is here termed 'dispensable', and it is plausible that the feature has been added at a late stage in the evolution of the circuit. This review describes experimental tests of this question, using the phage λ gene regulatory circuit. Several features of this circuit are found to be dispensable, in the sense that the circuitry works without these features, though not as well as the wild type. In some cases, second-site suppressor mutations are needed to confer near-normal behavior in the absence of such a feature. These findings are discussed here in the context of a two-stage model for evolution of gene regulatory circuits. In this model, a circuit evolves by assembly of a primitive or basic form, followed by adjustment of parameters and addition of qualitatively new features. Pathways are suggested for the addition of such features to a more basic form. Selected examples in other systems are described. Some of the dispensable features of phage λ may be evolutionary refinements. Finding that a feature is dispensable, however, does not prove that it is a late addition - it is possible that it was essential early in evolution, and became dispensable as the circuit evolved. Conversely, a late addition might have become essential. As ongoing work provides additional examples of dispensable features, it may become clearer how often they represent refinements.