Benefit of transferred mutations is better predicted by the fitness of recipients than by their ecological or genetic relatedness

Abstract

The effect of a mutation depends on its interaction with the genetic background in which it is assessed. Studies in experimental systems have demonstrated that such interactions are common among beneficial mutations and often follow a pattern consistent with declining evolvability of more fit genotypes. However, these studies generally examine the consequences of interactions between a small number of focal mutations. It is not clear, therefore, that findings can be extrapolated to natural populations, where new mutations may be transferred between genetically divergent backgrounds. We build on work that examined interactions between four beneficial mutations selected in a laboratory-evolved population of Escherichia coli to test how they interact with the genomes of diverse natural isolates of the same species. We find that the fitness effect of transferred mutations depends weakly on the genetic and ecological similarity of recipient strains relative to the donor strain in which the mutations were selected. By contrast, mutation effects were strongly inversely correlated to the initial fitness of the recipient strain. That is, there was a pattern of diminishing returns whereby fit strains benefited proportionally less from an added mutation. Our results strengthen the view that the fitness of a strain can be a major determinant of its ability to adapt. They also support a role for barriers of transmission, rather than differential selection of transferred DNA, as an explanation of observed phylogenetically determined patterns of restricted recombination among E. coli strains.

Patterns and mechanisms of diminishing returns from beneficial mutations

“…In another study (Wang, et al 2016), several substitutions observed from an experimental evolution study of Escherichia coli were tested on a number of strains picked from the E. coli phylogeny. The authors asked whether the higher the ecological similarity between the E. coli strains used in the experimental evolution and tested now, the closer the growth effects of the substitutions in the two strains, but found only a marginally significant result.…”

“…Diminishing returns epistasis is conventionally demonstrated by showing that the same mutation causes a smaller growth rate increase in a relatively fit strain than in a relatively unfit strain (MacLean, et al 2010;Chou, et al 2011;Khan, et al 2011;Kryazhimskiy, et al 2014;Wang, et al 2016). If the observed diminishing returns epistasis is genuine and general, it should also be testable by comparing the mean benefits of the mutation in two sets of strains that differ in mean growth rate (see Materials and Methods).…”

“…It is believed to explain at least in part why experimental evolution of microbes almost invariantly shows a decreasing speed of adaptation as the fitness of the population rises (Wiser, et al 2013;Couce and Tenaillon 2015). Diminishing returns epistasis has been indirectly inferred from the dynamics of adaptation (Moore, et al 2000;Kryazhimskiy, et al 2009;Perfeito, et al 2014;Good and Desai 2015) and directly demonstrated by engineering the same mutation in multiple strains of different fitnesses (MacLean, et al 2010;Chou, et al 2011;Khan, et al 2011;Kryazhimskiy, et al 2014;Wang, et al 2016). While diminishing returns epistasis appears common among fixed mutations in experimental evolution, it is unknown whether it is restricted to experimental evolution, where fixed beneficial mutations are de novo and tend to have large effects (Orr 2002;Rokyta, et al 2005), or is also widespread among standing genetic variants.…”

“…A commonly considered hypothesis termed the global epistasis hypothesis posits that "the effect of each mutation depends on all other mutations, but only through their combined effect on fitness" and that "each individual beneficial mutation provides a smaller advantage in a fitter genetic background" (Kryazhimskiy, et al 2014). Although this hypothesis is currently regarded as the leading description and explanation of diminishing returns epistasis (Kryazhimskiy, et al 2014;Wang, et al 2016), to what extent it is true and why it may be true remain unanswered. Note that the diminishing returns relationship between the activity of an enzyme and the flux of the relevant metabolic pathway is well explained by the metabolic control theory (Kacser and Burns 1981;Dykhuizen, et al 1987;Chou, et al 2014), but this theory cannot explain diminishing returns epistasis arising from interactions among mutations of different genes.…”

Candida albicansgenetic background influences mean and heterogeneity of drug responses and genome stability during evolution to fluconazole

“…Moreover, closely related strains can differ in the classification of genes that are essential for viability under a specific growth condition (39) . The same is true of mutations classified as beneficial in one strain background (including different mutations in the same gene, 40) , which can be neutral or deleterious in other backgrounds (e.g., [41][42][43][44] . Different strain backgrounds also may exhibit different mutation rates, thereby affecting the frequency with which genetic variation arises (45,46) .…”