Memory and fitness define the gene expression distribution.

<p>(A) The cellular memory and fitness of the cellular states interacted in multiple ways that ultimately defined the overall cell population fitness and the distribution of gene expression. Contrary to the naïve expectations illustrated in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002480#pcbi-1002480-g002" target="_blank">Figure 2A</a>, we observed that (i) the fractions of cells in the ON and OFF states did not reflect the switching rates between these states; and (ii) forcing most cells into the protected ON state did not provide optimal fitness during drug treatment. (B) Simulated cell population fitness as a function of ATc when the environment switches either randomly or periodically between 0 mg/ml Zeocin (normal) and 2 mg/ml Zeocin (toxic), with the average duration of the normal and toxic environments indicated in the figure. The red circles indicate the ATc concentration (ATc = 100 ng/ml) necessary for setting the phenotypic switching rates to confer optimal fitness based on the Kussell-Leibler theory. (C) Illustration of how cell linage statistics (purple outline) can be different from population snapshot statistics (orange outline). Cells tend to switch predominantly to the high expression state and rarely switch back. Consequently, individual cell lineages over time tend to spend most of their time in the high expression state. However, cellular fitness in the high expression state is lower. As a result, population snapshot measurements will observe more low expressor cells due to the higher cellular fitness of the low-expressing state.