Epistasis-mediated compensatory evolution in a fitness landscape with adaptational tradeoffs

The evolutionary adaptation of an organism to a stressful environment often comes at the cost of reduced fitness. For example, resistance to antimicrobial drugs frequently reduces growth rate in the drug-free environment. This cost can be compensated without loss in resistance by mutations at secondary sites when the organism evolves again in the stress-free environment. Here, we analytically and numerically study evolution on a simple model fitness landscape to show that compensatory evolution can occur even in the presence of the stress and without the need for mutations at secondary sites. Fitness in the model depends on two phenotypes-the null-fitness defined as the fitness in the absence of stress, and the resistance level to the stress. Mutations universally exhibit antagonistic pleiotropy between the two phenotypes, that is they increase resistance while decreasing the null-fitness. Initial adaptation in this model occurs in a smooth region of the landscape with a rapid accumulation of stress resistance mutations and a concurrent decrease in the null-fitness. This is followed by a second, slower phase exhibiting partial recovery of the null-fitness. The second phase occurs on the rugged part of the landscape and involves the exchange of high-cost resistance mutations for low-cost ones. This process, which we call exchange compensation, is the result of changing epistatic interactions in the genotype as evolution progresses. The model provides general lessons about the tempo and mode of evolution under universal antagonistic pleiotropy with specific implications for drug resistance evolution.