Epistasis and Its Relationship to Canalization in the RNA Virus φ6

Abstract

Although deleterious mutations are believed to play a critical role in evolution, assessing their realized effect has been difficult. A key parameter governing the effect of deleterious mutations is the nature of epistasis, the interaction between the mutations. RNA viruses should provide one of the best systems for investigating the nature of epistasis because the high mutation rate allows a thorough investigation of mutational effects and interactions. Nonetheless, previous investigations of RNA viruses by S. Crotty and co-workers and by S. F. Elena have been unable to detect a significant effect of epistasis. Here we provide evidence that positive epistasis is characteristic of deleterious mutations in the RNA bacteriophage φ6. We estimated the effects of deleterious mutations by performing mutation-accumulation experiments on five viral genotypes of decreasing fitness. We inferred positive epistasis because viral genotypes with low fitness were found to be less sensitive to deleterious mutations. We further examined environmental sensitivity in these genotypes and found that low-fitness genotypes were also less sensitive to environmental perturbations. Our results suggest that even random mutations impact the degree of canalization, the buffering of a phenotype against genetic and environmental perturbations. In addition, our results suggest that genetic and environmental canalization have the same developmental basis and finally that an understanding of the nature of epistasis may first require an understanding of the nature of canalization. W HEN mutations occur together, their realized efa genome with other mutations more rapidly than a mutation in a genome without additional mutations. fects depend on the epistasis, or interaction, between them. In the absence of epistasis, mutations act However, despite the importance of these acknowledged roles for epistasis, quantitative measurements of independently and are expected to have a multiplicative effect on fitness (additive on a log scale). When epistasis epistasis are still not numerous and the few existing measurements have often been challenged (Chao 1988; is present, it can be of two forms: negative if the fitness of organisms bearing two mutations is lower than ex- (Wagner and Krall 1993). In infectivity and number of mutations in polioviruses and most cases, the impact of epistasis stems from the fact found evidence for positive epistasis (their Figure 4). that natural selection is more or less effective in changHowever, in both studies the statistical power of the ing the frequency of advantageous or deleterious mutadata was limited. Although Elena's result did not find tions depending on the form of epistasis. Thus, negative a significant deviation from log-linearity, an epistatic epistasis decreases the load of deleterious mutations effect up to a magnitude of 70.5% of the effect of individbecause selection eliminates a mutation that occurs in ual mutations could have been missed by the power of his analysis. Our own reanalysis of Crotty ...

Genetics of phenotypic plasticity: QTL analysis in barley, Hordeum vulgare

“…In the epistatic model (Scheiner and Lyman, 1989), plasticity genes interact epistatically with, and thus regulate, the 'constitutive' loci that determine the mean value of the trait. In a limited number of modelsDrosophila melanogaster (Scharloo, 1991), tomato (Eshed and Zamir, 1996) and RNA viruses (Burch and Chao, 2004)there is evidence that canalization and phenotypic plasticity may be explained by epistatic mechanisms. The role of epistasis in the elaboration of phenotypic plasticity should be a subject of future studies.…”

The contribution of epistasis to the architecture of fitness in an RNA virus

“…The first of them, with foot-and-mouth disease virus, failed to find such epistasis (12). The second, with the segmented bacteriophage 6, found antagonistic epistasis (13). Nonetheless, these were mutationaccumulation studies, and therefore their conclusions have to be understood with caution for the reasons given above.…”

Predicting Virus Evolution: The Relationship between Genetic Robustness and Evolvability of Thermotolerance

“…Thus, the population is propagated via daily plaque-to-plaque transfers imposing an extremely small population size, allowing the effects of genetic drift to be relatively more important than natural selection in dictating evolutionary change. This propagation scheme enables a phage population to accumulate non lethal mutations at random (Chao 1990;Burch and Chao 2004). Because random mutations are expected to be deleterious on average, mean fitness of a virus population is expected to decline through time as random mutations accumulate.…”

“…The 60 phage populations were subjected to 20 consecutive days of extreme bottlenecking, providing the opportunity for ~1.3 mutations to fix in each population, based on an estimated rate of 0.067 mutations per generation in phage φ6 (Burch and Chao 2004). To examine how the amassed mutations affected phenotypic fitness (W, relative growth rate on the host bacteria), we measured log 10 W of each prebottleneck and postbottleneck population.…”