Stable maintenance of hidden switches as a strategy to increase the gene expression stability

In response to severe genetic and environmental perturbations, wild-type organisms can express hidden alternative phenotypes adaptive to such adverse conditions. While our theoretical understanding of the population-level fitness advantage and evolution of phenotypic switching under variable environments has grown, the mechanism by which these organisms maintain phenotypic switching capabilities under static environments remains to be elucidated. Here, using computational simulations, we analyzed the evolution of gene circuits under natural selection and found that different strategies evolved to increase the gene expression stability near the optimum level. In a population comprising bistable individuals, a strategy of maintaining bistability and raising the potential barrier separating the bistable regimes was consistently taken. Our results serve as evidence that hidden bistable switches can be stably maintained during environmental stasis-an essential property enabling the timely release of adaptive alternatives with small genetic changes in the event of substantial perturbations.