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The prevalence of stability-mediated epistasis revealed by laboratory evolution also has important implications for understanding natural protein evolution. As is suggested by Fig. 8.4, whether a mutation is neutral or deleterious can be conditional on the stability of the protein in which it occurs. In contrast, most mathematical treatments of neutral evolution make the (often unspoken) assumption that a constant fraction of mutations is neutral. Several classic results commonly attributed to the neutral theory are no longer necessarily true if the fraction of neutral mutations is conditional on protein stability. In particular, in such a scenario, neutral evolution can lead to overdispersion of the molecular clock (Takahata, 1987; Bloom et al., 2007b), an influence of population size on substitution rate (Bloom et al., 2007b), and a dependence of mutational load and robustness on both population size and the structure of the underlying neutral space (van Nimwegen et al., 1999; Wilke and Adami, 2003; Bloom et al., 2007a). These results suggest the importance of continually updating theories of molecular evolution to reflect expanding knowledge about the details of the molecules in question.

The lessons of directed evolution also caution against attributing all properties of natural proteins to adaptive causes. For example, most enzymes are only marginally more stable than is required by their natural environment (Somero, 1995). This marginal stability was long argued to be an adaptive trait, providing an optimal degree of flexibility that favored high catalytic activity (Somero, 1995; Fields, 2001). This adaptive argument has been undermined by evolutionary engineering experiments demonstrating that enzyme stability can be dramatically increased without concomitant loss of catalytic activity (Serrano et al., 1993; Giver et al., 1998; Van den Burg et al., 1998). Instead, both simulations (Taverna and Goldstein, 2002) and theory (Bloom et al., 2007b; Zeldovich et al., 2007) show that the marginal stability of proteins can arise neutrally because most mutations are destabilizing. Although there are a few proteins whose marginal stability is clearly adaptive (Canadillas et al., 2006), the marginal stability of most proteins is likely the result of neutral mutation-driven processes. Other properties, such as catalytic or substrate promiscuity, that arise naturally during laboratory evolution should probably also be assigned neutral rather than adaptive origins.

Another important contribution of directed evolution has been to demonstrate 2 clear mechanisms whereby neutral mutations shape the available adaptive pathways. Selectively neutral mutations that increase stability can promote evolvability by allowing for subsequent beneficial but destabilizing mutations (Bloom et al., 2006), whereas neutral mutations that alter promiscuous activities (Amitai et al., 2007; Bloom et al., 2007c) can create the starting points for subsequent adaptive evolution. Evolutionary engineers leverage the coupling between neutral and adaptive mutations

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