Abstract
The extent and nature of epistatic interactions between mutations are issues of fundamental importance in evolutionary biology. However, they are difficult to study and their influence on adaptation remains poorly understood. Here, we use a systems-level approach to examine epistatic interactions that arose during the evolution of Escherichia coli in a defined environment. We used expression arrays to compare the effect on global patterns of gene expression of deleting a central regulatory gene, crp. Effects were measured in two lineages that had independently evolved for 20,000 generations and in their common ancestor. We found that deleting crp had a much more dramatic effect on the expression profile of the two evolved lines than on the ancestor. Because the sequence of the crp gene was unchanged during evolution, these differences indicate epistatic interactions between crp and mutations at other loci that accumulated during evolution. Moreover, a striking degree of parallelism was observed between the two independently evolved lines; 115 genes that were not crp-dependent in the ancestor became dependent on crp in both evolved lines. An analysis of changes in crp dependence of well-characterized regulons identified a number of regulatory genes as candidates for harboring beneficial mutations that could account for these parallel expression changes. Mutations within three of these genes have previously been found and shown to contribute to fitness. Overall, these findings indicate that epistasis has been important in the adaptive evolution of these lines, and they provide new insight into the types of genetic changes through which epistasis can evolve. More generally, we demonstrate that expression profiles can be profitably used to investigate epistatic interactions.
Highlights
Epistatic interactions are revealed when the contribution of a mutation to an organism’s phenotype depends on the genetic background in which it occurs
Most systems-level studies have focused on deletion and other knockout mutations, and it is not clear whether findings of widespread epistasis are representative of mutations involved in adaptive evolution
We used a novel approach to examine the evolution of interactions arising between a key regulatory gene, crp, and mutations that occurred during the adaptation of a bacterium, Escherichia coli, to a laboratory environment
Summary
Epistatic interactions are revealed when the contribution of a mutation to an organism’s phenotype depends on the genetic background in which it occurs. Approaches based on quantitative-trait loci have been increasingly used to study epistasis [11,12,13,14,15] These techniques have the advantage of being quite general, they suffer from some shortcomings including low statistical power, difficulty in detecting some types of epistatic interactions, and inapplicability to non-recombining organisms [11,16]. Systems-level approaches have been developed that avoid some of these problems [17,18] These approaches typically assess epistatic interactions by comparing the individual and pair-wise effects of large numbers of defined mutations, allowing the outline of functional biological modules and biochemical pathways to be determined [19,20,21,22,23]. Most systems-level studies have focused on deletion and other knockout mutations, and it is not clear whether findings of widespread epistasis are representative of mutations involved in adaptive evolution
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