Selection for Chaperone-Like Mediated Genetic Robustness at Low Mutation Rate: Impact of Drift,Epistasis and Complexity |
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Authors: | Pierre-Alexis Gros Olivier Tenaillon |
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Affiliation: | Université Paris 7 Denis Diderot, Faculté de Médecine Xavier Bichat, 75018 Paris, France and Institut National de la Santé et de la Recherche Médicale U722, 75018 Paris, France |
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Abstract: | Genetic robustness is defined as the constancy of a phenotype in the face of deleterious mutations. Overexpression of chaperones, to assist the folding of proteins carrying deleterious mutations, is so far one of the most accepted molecular mechanisms enhancing genetic robustness. Most theories on the evolution of robustness have focused on the implications of high mutation rate. Here we show that genetic drift, which is modulated by population size, organism complexity, and epistasis, can be a sufficient force to select for chaperone-mediated genetic robustness. Using an exact analytical solution, we also show that selection for costly genetic robustness leads to a paradox: the decrease of population fitness on long timescales and the long-term dependency on robustness mechanisms. We suggest that selection for genetic robustness could be universal and not restricted to high mutation rate organisms such as RNA viruses. The evolution of the endosymbiont Buchnera illustrates this selection mechanism and its paradox: the increased dependency on chaperones mediating genetic robustness. Our model explains why most chaperones might have become essential even in optimal growth conditions.MUTATIONAL (or genetic) robustness is defined as the constancy of a phenotype in the face of deleterious mutations (Sanjuan et al. 2007). Selection drives populations to adapt to their environment by the fixation of successive advantageous mutations. However, in approaching a fitness optimum—i.e., a genotype that is maximally adapted—they have to cope with an increasing proportion of deleterious mutations and, when at the optimum, they experience only neutral and deleterious mutations (Silander et al. 2007). Therefore any mechanism that would reduce the effect of deleterious mutations, i.e., increase mutational robustness, could be favored by natural selection when at, or near, an optimum of fitness. Indeed, the general observation that for a large range of organisms, mutations have little effect on fitness, suggests that selection for robustness is pervasive (Melton 1994; Winzeler et al. 1999). Three main mechanisms that are not mutually exclusive could explain how genetic robustness has arisen. First, in the “intrinsic hypothesis” (de Visser et al. 2003) robustness could simply be a by-product of some biologically relevant functions. Second, mutational robustness could be a by-product of the selection for nongenetic perturbations such as environment changes or intrinsic noise (Wagner 2005). Third, mutational robustness could be selected for because it is adaptive in itself. In the following we restrict our attention to this “adaptive hypothesis” (de Visser et al. 2003).Chaperone proteins, proteins that help other proteins to fold properly, have been shown to buffer the effect of deleterious mutations in diverse organisms (Rutherford 2003). In lineages that have accumulated deleterious mutations, the overexpression of the chaperone GroESL in Escherichia coli (Fares et al. 2002) or Salmonella typhymurium (Maisnier-Patin et al. 2005) resulted in an improved fitness. However, such robustness appears to come at a cost, as the buffering was visible only in carbon-rich media (Fares et al. 2002), and it is also known that GroESL-mediated refolding of proteins is ATP dependent. Chaperones can also buffer against environmental perturbations (such as heat shock); however, the observation that groESL evolved under positive selection and is overproduced in obligate intracellular endosymbionts (Moran 1996; Fares et al. 2004), for which environmental perturbations are assumed to be very weak, suggests that genetic robustness could be the direct target of selection.Selection for a modifier of genetic robustness, i.e., a gene modulating the effect of mutations, has been mainly studied in the context of high mutation rates, as the effect of the modifier allele affects the fitness of mutants (Wagner 2005). Under some theoretical frameworks, it has been suggested that the intensity of selection acting on a modifier of robustness would be of the order of the mutation rate (Gardner and Kalinka 2006). Therefore it has been presumed that selection for genetic robustness is relevant only in very large populations having a high mutation rate, such as RNA virus populations. In agreement with these ideas, artificial life experiments (Wilke and Adami 2001; Azevedo et al. 2006) and experimental data on viruses (Montville et al. 2005; Sanjuan et al. 2007) have shown that robustness varies between organisms and that it can be selected for under high mutation rates. It has also been shown by Krakauer and Plotkin (2002) that drift, i.e., stochastic effects due to the finite size of populations, can promote selection for robustness even when more robust alleles are costly, as suggested in the case of chaperone overexpression. However, again this effect was examined only under high mutation rates.When mutations are very rare, populations experience at the most the presence of a single mutant. In such conditions, the population fitness at equilibrium does not depend on the mutation rate but only on drift (Sella and Hirsh 2005; Tenaillon et al. 2007). Two factors modulate how drift affects fitness:- Epistasis, defined here as a local property of the adaptive landscape, describes how the selective effects of mutations depend on the genetic background in which they arise. Epistasis is negative (positive) if two mutations have a lower (higher) fitness when simultaneously present within a genome than expected if they did not interact. Negative epistasis increases selection against mutation-loaded individuals and therefore reduces the effect of drift on population fitness (Charlesworth 1990; Tenaillon et al. 2007).
- Phenotypic complexity, defined as the number of independent mutable traits that contribute to fitness (Orr 2000; Tenaillon et al. 2007), also affects population fitness in finite populations: complex organisms are more sensitive to the action of drift (Hartl and Taubes 1998; Poon and Otto 2000; Tenaillon et al. 2007).
In this article, we attempt to further clarify the role of drift on the evolution of chaperone-like genetic robustness and to decouple the effect of drift from the effect of the mutation rate. We use Fisher''s geometric model of adaptation (Fisher 1930), to map phenotype to fitness under an assumption of a vanishing mutation rate and extract exact analytical solutions for the genetic properties of the population at mutation–selection–drift equilibrium (MSDE). We examine how these genetic properties change under various population sizes and epistasis parameters and in organisms ranging in phenotypic complexity. |
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