From Single-Cell Genetic Architecture to Cell Population Dynamics: Quantitatively Decomposing the Effects of Different Population Heterogeneity Sources for a Genetic Network with Positive Feedback Architecture

Phenotypic cell-to-cell variability or cell population heterogeneity originates from two fundamentally different sources: unequal partitioning of cellular material at cell division and stochastic fluctuations associated with intracellular reactions. We developed a mathematical and computational framework that can quantitatively isolate both heterogeneity sources and applied it to a genetic network with positive feedback architecture. The framework consists of three vastly different mathematical formulations: a), a continuum model, which completely neglects population heterogeneity; b), a deterministic cell population balance model, which accounts for population heterogeneity originating only from unequal partitioning at cell division; and c), a fully stochastic model accommodating both sources of population heterogeneity. The framework enables the quantitative decomposition of the effects of the different population heterogeneity sources on system behavior. Our results indicate the importance of cell population heterogeneity in accurately predicting even average population properties. Moreover, we find that unequal partitioning at cell division and sharp division rates shrink the region of the parameter space where the population exhibits bistable behavior, a characteristic feature of networks with positive feedback architecture. In addition, intrinsic noise at the single-cell level due to slow operator fluctuations and small numbers of molecules further contributes toward the shrinkage of the bistability regime at the cell population level. Finally, the effect of intrinsic noise at the cell population level was found to be markedly different than at the single-cell level, emphasizing the importance of simulating entire cell populations and not just individual cells to understand the complex interplay between single-cell genetic architecture and behavior at the cell population level.