Environmental dependence of genetic constraint

The epistatic interactions that underlie evolutionary constraint have mainly been studied for constant external conditions. However, environmental changes may modulate epistasis and hence affect genetic constraints. Here we investigate genetic constraints in the adaptive evolution of a novel regulatory function in variable environments, using the lac repressor, LacI, as a model system. We have systematically reconstructed mutational trajectories from wild type LacI to three different variants that each exhibit an inverse response to the inducing ligand IPTG, and analyzed the higher-order interactions between genetic and environmental changes. We find epistasis to depend strongly on the environment. As a result, mutational steps essential to inversion but inaccessible by positive selection in one environment, become accessible in another. We present a graphical method to analyze the observed complex higher-order interactions between multiple mutations and environmental change, and show how the interactions can be explained by a combination of mutational effects on allostery and thermodynamic stability. This dependency of genetic constraint on the environment should fundamentally affect evolutionary dynamics and affects the interpretation of phylogenetic data.
Author Summary Epistatic interactions limit the number of adaptive trajectories to peaks on evolutionary fitness landscapes, and may therefore hamper the progress of evolution. Recent research has focused on adaptive landscapes in one constant environment. However, adaptive evolution is generally known to occur in variable, heterogeneous environments. Here, we have constructed fitness landscapes of three inverse lac repressor variants in two contrasting environments. We find that the epistatic interactions between the pairs of mutations are profoundly altered upon an environmental change. We develop a new graphical method to analyze the underlying higher-order interactions between genetic changes and the environment, and explain the complex environmental dependencies in terms of simple molecular mechanisms. Our results show that the information about epistatic interactions acquired in one environment does not inform on the true limitations of adaptive evolution. We argue that this dependency of genetic constraints on the environment will have important effects on the progress of adaptation in heterogeneous environments, and will affect our ability to establish realistic genealogies from the phylogenic record.