other organisms is combinatorics (John and Miklos, 1988; Gerhart and Kirschner, 1997), the use of subsets of the same components in different combinations to get different outcomes, an interpretation we favor.
Why are such sequences conserved? All functioning proteins have specialized surface sites for precise interactions. At these sites, nonsynonymous amino acid substitutions are almost always detrimental to function and are eliminated by purifying selection, whereas synonymous substitutions are not (neutral or nearly neutral DNA changes), indicating that the conserved genes did undergo sequence change, like other DNA regions. For evolution, this deep conservation overwhelmingly documents the descent of animals from ancestors and has helped clarify phylogenetic relationships.
Functional conservation might seem to constrain phenotypic change because most sequence changes of those DNA regions encoding functional proteins and RNAs are lethal. (Note that the regulatory parts of proteins and RNAs are, we think, more changeable.) These DNA regions are effectively excluded from the list of targets at which genetic change could generate viable selectable phenotypic variation. They just cannot be tinkered with. Was evolution impeded by this vast functional conservation? We suggest that so much gene sequence is precluded from viable change that we should even revise our question about phenotypic variation to ask: what are the special properties of animals’ phenotypes that allow phenotypic variation to be generated in seemingly copious amounts and great anatomical and physiological variety? These conserved processes have, we think, facilitated or deconstrained evolution because of their special properties of robustness and adaptability, their modularity and compartmentalization, their capacity for weak regulatory linkage, and their exploratory behavior. These properties make regulatory change efficacious and phenotypic variation copious and varied. We subsequently consider these properties and their consequences for regulation.
Linkage, which denotes the connecting of processes to each other or to particular conditions, is central to our theory because different core processes must become linked, by regulatory means, in different combinations, and operated in different amounts, states, times, and places for the generation of new anatomical and physiological traits. Regulatory linkage pervades development and physiology. In general, a regulatory signal or input from one process or condition impinges on another process, which gives a response or output. The two are linked. Can regulatory linkages be made and changed easily, or do they require multiple complex instructions and precise stereochemical complementarity of the input and output? We