Gene loss and compensatory evolution as a source of metabolic pre-adaptations

Gene loss is common, yet whether it is merely an evolutionary dead-end or can promote future adaptation to new environments remains debated. Here, we systematically tested whether harmful loss of metabolic genes, followed by compensatory evolution, generates pre-adaptations to alternative nutrients in Escherichia coli. Our analysis revealed a striking outcome beyond simple growth restoration, where repair of a genetic defect yielded growth exceeding the unperturbed wild type on carbon sources not encountered during evolution. Such latent growth gains occurred across multiple deletion backgrounds and carbon sources, with growth rate increases up to 46% relative to the wild type. In some cases, the corresponding ancestral deletion strain failed to grow on these carbon sources, indicating functional innovations relative to the deletion ancestor. Genetic reconstruction and transcriptomic profiling implicate regulatory reprogramming, particularly in carbon catabolite repression and nutrient uptake, as mechanisms underlying latent growth gains. In conclusion, evolutionary recovery from gene loss can rapidly produce pre-adaptations to future environments in the absence of direct selection.