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in at least 2 ways: directly selecting for functionally neutral but stabilizing mutations and screening and recombining pools of diverged homologous sequences (Crameri et al., 1998; Landwehr et al., 2007). Natural evolution does not so deliberately exploit the potential benefits of neutral mutations, but genetic drift and preexisting diversity may play a similarly important role in natural adaptive evolution. Indeed, ancestral protein reconstruction experiments have elucidated specific adaptive events that appear to have been contingent on the initial occurrence of approximately neutral substitutions (Ortlund et al., 2007).

The overall picture that emerges from evolutionary engineering is that proteins, although clearly highly refined by evolution, retain a substantial capacity for neutral and adaptive change. In many ways, this picture is complementary to that offered by more traditional biochemical characterizations, which often focus on the exquisitely tuned interactions that can underlie a protein’s evolved function. Directed evolution does not dispute the subtlety of such interactions, nor does it usually offer such a careful description of the details of protein function. But although biochemists typically choose for their studies the most interesting examples, evolutionary engineers by necessity deal with the broader statistics of random mutations and evolutionary possibilities. These statistics suggest that proteins enjoy access to many neutral mutations, which can in turn open new adaptive avenues. Ultimately, a more detailed understanding of these evolutionary pathways will be of value in both protein engineering and evolutionary biology.


F.H.A. is supported by the U.S. Department of Energy and the U.S. Army. J.D.B. is supported by a Caltech Beckman Institute Postdoctoral Fellowship and the Irvington Institute Fellowship Program of the Cancer Research Institute.

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