Intrinsic and extrinsic noise of gene expression in lineage trees

Cell-to-cell heterogeneity is driven by stochasticity in intracellular reactions and the population dynamics. While these sources are usually studied separately, we develop an agent-based framework that accounts for both factors while tracking every single cell of a growing population. Apart from the common intrinsic variability, the framework also predicts extrinsic noise without the need to introduce fluctuating rate constants. Instead, extrinsic fluctuations are explained by cell cycle fluctuations and differences in cell age. We provide explicit formulas to quantify mean molecule numbers, intrinsic and extrinsic noise statistics in two-colour experiments. We find that these statistics differ significantly depending on the experimental setup used to observe the cells. We illustrate this fact using (i) averages over an isolated cell lineage tracked over many generations as observed in the mother machine, (ii) population snapshots with known cell ages as recorded in time-lapse microscopy, and (iii) snapshots with unknown cell ages as measured from static images or flow cytometry. Applying the method to models of stochastic gene expression and feedback regulation elucidates that isolated lineages, as compared to snapshot data, can significantly overestimate the mean number of molecules, overestimate extrinsic noise but underestimate intrinsic noise and have qualitatively different sensitivities to cell cycle fluctuations.