An analytical framework for phenotypic selection of fitness-conferring genes

by Marc Sturrock, Anna Sturrock

Genetically identical cells differ in how much of any given protein they carry because gene expression is noisy. Under stress, such as when exposed to an antibiotic or a chemotherapy drug, the cells that happen to hold high levels of a useful survival protein outlast their less lucky neighbours, leaving the population transiently enriched for the survival phenotype without any genetic change. We derive an exact theory of when this happens. When stress kills cells outright, as in cancer chemotherapy, ordinary baseline noise is enough. When stress only slows growth, a cellular memory loop is required. Either way, this transient phenotypic resistance buys cells time during which permanent drug-resistance mutations can arise.

Image Description: An exact framework for the selective enrichment of fitness-conferring genes. Top: under growth-driven selection, a feedback loop linking growth to protein production enriches the survival gene relative to a neutral reference. Bottom: under death-driven selection, enrichment arises from ordinary gene-expression noise alone, with no feedback required.