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

Abstract

The tendency for genetic architectures to exhibit epistasis among mutations plays a central role in the modern synthesis of evolutionary biology and in theoretical descriptions of many evolutionary processes. Nevertheless, few studies unquestionably show whether, and how, mutations typically interact. Beneficial mutations are especially difficult to identify because of their scarcity. Consequently, epistasis among pairs of this important class of mutations has, to our knowledge, never before been explored. Interactions among genome components should be of special relevance in compacted genomes such as those of RNA viruses. To tackle these issues, we first generated 47 genotypes of vesicular stomatitis virus carrying pairs of nucleotide substitution mutations whose separated and combined deleterious effects on fitness were determined. Several pairs exhibited significant interactions for fitness, including antagonistic and synergistic epistasis. Synthetic lethals represented 50% of the latter. In a second set of experiments, 15 genotypes carrying pairs of beneficial mutations were also created. In this case, all significant interactions were antagonistic. Our results show that the architecture of the fitness depends on complex interactions among genome components.

Distributions of epistasis in microbes fit predictions from a fitness landscape model

“…Here we show that the distribution of epistasis can be predicted from the distribution of single mutation effects, based on a simple fitness landscape model 6 . We show that this prediction closely matches the empirical measures of epistasis that have been obtained for Escherichia coli 7 and the RNA virus vesicular stomatitis virus 8 . Our results suggest that a simple fitness landscape model may be sufficient to quantitatively capture the complex nature of gene interactions.…”

“…In this data set, single and double mutants were created on an infectious cDNA by site-directed mutagenesis and were recovered after transfection of susceptible cells with the mutant plasmids 8 . As discussed 29 , this recombinant virus was not well adapted to the environment in which measurements were taken, resulting in a proportion (% 5%) of mutations with beneficial effects (of up to log(w i ) ¼ 0.095), so that s o 4 0. s o was measured by maximum-likelihood fitting of a displaced gamma distribution 6 on the distribution of log(w i ) of the mutations used to construct the double mutants.…”

“…Among the 62 double mutants studied, 3 were nonviable (synthetic lethal mutations; w ij ¼ 0) and were removed from the data set, as the model cannot account for lethal mutations. Also, the previously published results 8 are presented separately for pairs of beneficial and deleterious mutations (15 and 44 pairs, respectively, synthetic lethal mutations excluded), whereas the whole set of random mutations (a total of 44 + 15 ¼ 59 pairs) must be used to test the first prediction presented above ( Fig. 2 and Table 1).…”

“…However, despite many examples of epistatic interactions between particular pairs of loci, relatively little is known about the overall distribution of epistasis among random sets of mutations scattered across the genome. A few studies have sought to measure this distribution directly in model systems such as Escherichia coli 7 , RNA viruses 8,10,11 and Saccharomyces cerevisiae 12 . These studies have shown that the variance of epistatic interactions is large compared with their mean, which is always relatively close to zero 10 .…”

Evolution and Emergence of Plant Viruses

“…The intensity and type of epistasis shaping the genome of plant RNA viruses has only been explored, quite recently, for pairs of random mutations introduced in TEV genome (Lalić & Elena, 2012a). Likewise to what has been described for other RNA viruses (e.g., Burch & Chao, 2004;Sanjuán et al, 2004b), the average epistasis for TEV is also negative, that is, two deleterious mutations together are less pernicious that what would be expected from their individual effects. Echoing what we commented above to justify the large deleterious effect of individual mutations, the cause for this dominance of negative epistasis is also related with the lack of genetic redundancy characteristic of RNA genomes, with overlapping genes and multifunctional proteins (Elena et al, 2006).…”