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

Shimon Bershtein, Michal Segal, Roy Bekerman, Nobuhiko Tokuriki and Dan S. Tawfik ()
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Shimon Bershtein: Weizmann Institute of Science
Michal Segal: Weizmann Institute of Science
Roy Bekerman: Weizmann Institute of Science
Nobuhiko Tokuriki: Weizmann Institute of Science
Dan S. Tawfik: Weizmann Institute of Science

Nature, 2006, vol. 444, issue 7121, 929-932

Abstract: Abstract 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 β-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.

Date: 2006
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DOI: 10.1038/nature05385

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