Constraints on adaptive loss-of-function mutations during microbial metabolic interactions

Adaptive loss-of-function (LOF) mutations are thought to commonly be enriched during microbial metabolic interactions like cross-protection and cross-feeding. This expectation is based on the intuitive assumption that the cost of a gene can be avoided through LOF mutations when the gene product or function is available from a neighbor. However, LOF mutants are not always enriched when a resource is available from producer cells. This deviation from expectations indicates that there are constraints on the benefits from LOF mutations during metabolic interactions. Here, we review three such constraints based on the effects of: (i) resource availability on growth kinetics, (ii) resource availability on gene regulation, and (iii) resource availability, LOF mutations, and environmental factors on broader cell physiology. Together, these constraints provide a nuanced view of adaptive LOF mutations in response to metabolic interactions, including the possibility that some conditions will foster non-adaptive LOF mutants.