One finding of particular interest was that several whole pathways are especially rich in PSGs. Examples include the classical and alternative pathways for complement-mediated immunity and the FAS/p53 apoptotic pathway ( Figures S1, S4 and S5). These findings suggest that positive selection may frequently act directly on whole protein complexes or pathways (see [77, 78] ). Alternatively, adaptive changes in one protein may sometimes have a cascade effect, leading to changes in other genes that bring a system back into equilibrium. Whether or not all changes affecting a pathway are driven by positive selection, one might expect to see similarities in the selection histories of gene with closely related functions. Indeed, we have found that genes with similar selection histories on average have substantially greater similarity in their GO categories than do genes with more divergent histories ( Figure S6 ). The observations that multiple interacting genes often show evidence of positive selection and that positive selection is frequently episodic may well be connected. For example, in some cases a transient external force could induce a burst of changes in multiple genes that participate in the same pathway, either separately or by triggering a cascade of interdependent events. Further unraveling the (co-)evolutionary histories of interacting PSGs promises to be a fertile area for future Table 3 . Summary of individual PSGs discussed in this article.