Epigenetic switching as a strategy for quick adaptation while constraining biochemical noise

Epigenetic switches are bistable, molecular systems built from self-reinforcing feedback loops that can spontaneously switch between heritable phenotypes in the absence of DNA mutation. It has been hypothesized that epigenetic switches first evolved as a mechanism of bet-hedging and adaptation, but the evolutionary trajectories and conditions by which an epigenetic switch can outcompete adaptation through genetic mutation remain unknown. Here, we used computer simulations to evolve a mechanistic, biophysical model of a self-activating genetic circuit, which can both adapt genetically through mutation and exhibit epigenetic switching. We evolved these genetic circuits under a fluctuating environment that alternatively selected for low and high protein expression levels. In all tested conditions, the population first evolved by genetic mutation to regimes of high nonlinearity to decrease the genetic adaptation time after each environmental transition. Once at high nonlinearity, epigenetic switching became accessible and could start competing with genetic adaptation as a possible strategy. We show the existence of a trade-off between either minimizing the adaptation time or increasing the robustness of the phenotype to biochemical noise. Epigenetic switching was superior in a fast fluctuating environment because it adapted faster than genetic mutation after an environmental transition. Conversely, genetic adaptation was favored in a slowly fluctuating environment because it minimized the noise load during the constant environment between transitions. These simple trade-offs reliably predict the conditions and trajectories under which an epigenetic switch evolved to outcompete genetic adaptation, shedding light on possible mechanisms by which bet-hedging strategies might emerge and persist in natural populations.