Gene products that are beneficial in one environment may become burdensome in another, prompting the emergence of diverse regulatory schemes that carry their own bioenergetic cost. By ensuring that regulators are only expressed when needed, we demonstrate that autoregulation generally offers an advantage in an environment combining mutation and time-varying selection. Whether positive or negative feedback emerges as dominant depends primarily on the demand for the target gene product, typically to ensure that the detrimental impact of inevitable mutations is minimized. While self-repression of the regulator curbs the spread of these loss-of-function mutations, self-activation instead facilitates their propagation. By analyzing the transcription network of multiple model organisms, we reveal that reduced bioenergetic cost may contribute to the preferential selection of autoregulation among transcription factors. Our results not only uncover how seemingly equivalent regulatory motifs have fundamentally different impact on population structure, growth dynamics, and evolutionary outcomes, but they can also be leveraged to promote the design of evolutionarily robust synthetic gene circuits.
© 2023. The Author(s).