Evolution of a bistable genetic system in fluctuating and nonfluctuating environments

Epigenetic mechanisms can generate bacterial lineages capable of spontaneously switching between distinct phenotypes. Currently, mathematical models and simulations propose epigenetic switches as a mechanism of adaptation to deal with fluctuating environments. However, bacterial evolution experiments for testing these predictions are lacking. Here, we exploit an epigenetic switch in <i>Salmonella enterica,</i> the <i>opvAB</i> operon, to show clear evidence that OpvAB bistability persists in changing environments but not in stable conditions. Epigenetic control of transcription in the <i>opvAB</i> operon produces OpvAB^OFF (phage-sensitive) and OpvAB^ON (phage-resistant) cells in a reversible manner and may be interpreted as an example of bet-hedging to preadapt <i>Salmonella</i> populations to the encounter with phages. Our experimental observations and computational simulations illustrate the adaptive value of epigenetic variation as an evolutionary strategy for mutation avoidance in fluctuating environments. In addition, our study provides experimental support to game theory models predicting that phenotypic heterogeneity is advantageous in changing and unpredictable environments.