Growth rate-dependent mutations and phenotypic switching facilitate rapid adaptation.

The mutation rates of many species are regulated in response to internal and external conditions. Studies in several model organisms have shown that mutation rates can be modulated by the organism's growth rate, particularly through stress-induced mutagenesis. Here, we investigate the functional consequences of this coupling. Using a model of asexual evolution on a high-dimensional, single-peaked fitness landscape, we show that regulating mutation rate through growth rate provides an efficient strategy for rapid adaptation. This mechanism maximizes growth by balancing mutation and selection pressures. We approximate the optimal coupling as a biphasic response function that prescribes a low, constant mutation rate at high growth rates, which gradually increases once growth falls below a critical threshold. This adaptive strategy depends on two key parameters: mutational gain and critical growth rate, both determined by environmental conditions. This raises the question of how organisms establish these parameters in fluctuating environments. We demonstrate that weak selection in well-adapted populations, combined with long-term phenotypic fluctuations, can generate variability in these parameters. Such standing variation prepares populations for rapid evolution following environmental change. Our findings connect this adaptive strategy to specific molecular regulatory circuits and provide predictions for sequential antibiotic treatment regimens.