Epigenetic switching as a strategy for quick adaptation while attenuating 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 towards a region of genotypes where genetic adaptation can occur faster after each environmental transition. Once in this region, the self-activating genetic circuit can exhibit epigenetic switching, which starts competing with genetic adaptation. We show 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, while still attenuating the effect of biochemical noise on the phenotype. Conversely, genetic adaptation was favored in a slowly fluctuating environment because it maximized the phenotypic robustness to biochemical noise during the constant environment between transitions, even if this resulted in slower adaptation. This simple trade-off predicts 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. Author summary Epigenetic switches regulate cell fate decisions during development in multicellular organisms, but their origin predates multicellularity because they are found in viruses, bacteria, and unicellular eukaryotes. It has been suggested that epigenetic switches first evolved as a mechanism of bet-hedging and adaptation to fluctuating environments. To discern the evolutionary pressures that select for epigenetic switches, we used computer simulations to evolve a mechanistic, biophysical model of a self-activating genetic circuit, which can both adapt genetically and exhibit epigenetic switching. Unlike laboratory evolution experiments, this in silico experiment was run many times over a range of evolutionary parameters (population size, selection pressure, mutation step-size, fluctuation frequency) and different model assumptions to uncover statistical regularities in the evolutionary trajectories. Using this computational approach, we could elucidate simple principles that predict the conditions that favor adaptation by epigenetic switching over genetic mutation in a fluctuating environment.