Synthetic Gene Circuits: Evolution of Drug Resistance Evolution in Fluctuating Drug Conditions*

Genetically identical cells can produce different levels of gene expression products due to stochastic or “noisy” processes inside the cell. This phenomenon has been shown to enable bacterial and fungal cell populations with resistance to constant drug treatment. We investigated drug resistance arising from gene expression noise using genetically engineered yeast (S. cerevisiae) exposed to fluctuating drug conditions. Growth rates, gene expression means, and noise levels were experimentally measured for a drug resistance gene controlled by an inducible synthetic gene circuit. These laboratory evolution experiments were conducted for low-, medium-, and high-drug concentrations. Our results show that most replicates evolved to lower gene expression in low-drug conditions, and increase gene expression in higher-drug conditions. Counterintuitively, for all drug concentrations, the gene expression noise levels were often lower in fluctuating drug conditions compared to constant drug conditions.