Letter

Nature 444, 929-932 (14 December 2006) | doi:10.1038/nature05385; Received 1 September 2006; Accepted 27 October 2006; Published online 19 November 2006

Robustness–epistasis link shapes the fitness landscape of a randomly drifting protein

Shimon Bershtein1, Michal Segal1, Roy Bekerman1, Nobuhiko Tokuriki1 and Dan S. Tawfik1

  1. Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel

Correspondence to: Dan S. Tawfik1 Correspondence and requests for materials should be addressed to D.S.T. (Email: tawfik@weizmann.ac.il).

The distribution of fitness effects of protein mutations is still unknown1, 2. Of particular interest is whether accumulating deleterious mutations interact, and how the resulting epistatic effects shape the protein's fitness landscape. Here we apply a model system in which bacterial fitness correlates with the enzymatic activity of TEM-1 beta-lactamase (antibiotic degradation). Subjecting TEM-1 to random mutational drift and purifying selection (to purge deleterious mutations) produced changes in its fitness landscape indicative of negative epistasis; that is, the combined deleterious effects of mutations were, on average, larger than expected from the multiplication of their individual effects. As observed in computational systems3, 4, 5, negative epistasis was tightly associated with higher tolerance to mutations (robustness). Thus, under a low selection pressure, a large fraction of mutations was initially tolerated (high robustness), but as mutations accumulated, their fitness toll increased, resulting in the observed negative epistasis. These findings, supported by FoldX stability computations of the mutational effects6, prompt a new model in which the mutational robustness (or neutrality) observed in proteins, and other biological systems, is due primarily to a stability margin, or threshold, that buffers the deleterious physico-chemical effects of mutations on fitness. Threshold robustness is inherently epistatic—once the stability threshold is exhausted, the deleterious effects of mutations become fully pronounced, thereby making proteins far less robust than generally assumed.

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