Abstract
How do adapting populations navigate the tensions between the costs of gene expression and the benefits of gene products to optimize the levels of many genes at once? Here we combined independently-arising beneficial mutations that altered enzyme levels in the central metabolism of Methylobacterium extorquens to uncover the fitness landscape defined by gene expression levels. We found strong antagonism and sign epistasis between these beneficial mutations. Mutations with the largest individual benefit interacted the most antagonistically with other mutations, a trend we also uncovered through analyses of datasets from other model systems. However, these beneficial mutations interacted multiplicatively (i.e., no epistasis) at the level of enzyme expression. By generating a model that predicts fitness from enzyme levels we could explain the observed sign epistasis as a result of overshooting the optimum defined by a balance between enzyme catalysis benefits and fitness costs. Knowledge of the phenotypic landscape also illuminated that, although the fitness peak was phenotypically far from the ancestral state, it was not genetically distant. Single beneficial mutations jumped straight toward the global optimum rather than being constrained to change the expression phenotypes in the correlated fashion expected by the genetic architecture. Given that adaptation in nature often results from optimizing gene expression, these conclusions can be widely applicable to other organisms and selective conditions. Poor interactions between individually beneficial alleles affecting gene expression may thus compromise the benefit of sex during adaptation and promote genetic differentiation.
Highlights
The concept of a fitness landscape unites the three levels of evolutionary change – genotype, phenotype, and fitness – into a mathematical picture of the potential for, and constraints upon, adaptive evolution
In order to study how evolution would simultaneously optimize expression of multiple genes, we have developed a model system of an engineered Methylobacterium extorquens AM1 (EM) in which we altered its central metabolism to be dependent upon a foreign pathway (Figure 1A for details)
To explore the pattern of epistatic interactions between beneficial mutations affecting expression of the GSH-dependent pathway, we combined beneficial plasmid mutations that emerged during experimental evolution and affected distinct traits [34]
Summary
The concept of a fitness landscape unites the three levels of evolutionary change – genotype, phenotype, and fitness – into a mathematical picture of the potential for, and constraints upon, adaptive evolution. Antagonism between adaptive mutations might imply that these populations are summiting peaks in their fitness landscapes with just a handful of genetic changes. In order to definitely link diminishing returns to the ascent of local peaks, as well as to understand the existence of the peaks themselves, we must understand the phenotypes that link genotype and fitness in the adaptive landscape. Convenient formulations such as Fisher’s geometric model for adaptation near a single peak [18] have been used to interpret the trend toward antagonism [19]. What remains unclear is what types of physiological interactions give rise to fitness landscapes of varying shape and form, as well the constraints upon mutational changes to underlying phenotypes
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