Letter Fitness Costs of Minimal Sequence Alterations Causing Protein

Destabilization of a protein impairs its metabolic efficiency. It is less clear how often destabilization also results in a gain of toxicity. We derived collections of temperature-sensitive, and thus structurally unstable, mutants of the yeast ADE2 and LYS2 genes by introducing single or very few amino acids substitutions. Overexpression of these mutant proteins led to a common, although unequal, fitness decrease. Interestingly, although the mutant proteins were functionally redun-dant, higher expression levels were associated with higher fitness. This result suggests that growth was hampered not by the accumulation of damaged chains but by the activities needed to remove them or by the damage caused before they were removed. Our results support the idea that any protein can become toxic when destabilized by a point mutation. Key words: thermal sensitivity, fitness cost, Saccharomyces cerevisiae. Proteins are often only marginally stable and are therefore readily destabilized in the crowded interior of the cell (Ellis 2001; Hartl et al. 2011). It has been proposed that protein stability is under the constant and fine control of natural selection (DePristo et al. 2005; Tartaglia et al. 2007; Lehner 2011). Mutations that make proteins less stable or that facil