Accuracy and limitations of extrinsic noise models to describe gene expression in growing cells

Abstract

The standard model describing the fluctuations of mRNA numbers in single cells is the telegraph model which includes synthesis and degradation of mRNA, and switching of the gene between active and inactive states. While commonly used, this model does not describe how fluctuations are influenced by the cell cycle phase, cellular growth and division, and other crucial aspects of cellular biology. Here we derive the analytical time-dependent solution of an extended telegraph model that explicitly considers the doubling of gene copy numbers upon DNA replication, dependence of the mRNA synthesis rate on cellular volume, gene dosage compensation, partitioning of molecules during cell division, cell-cycle duration variability, and cell-size control strategies. Based on the time-dependent solution, we obtain the analytical distributions of transcript numbers for lineage and population measurements in steady-state growth and also find a linear relation between the Fano factor of mRNA fluctuations and cell volume fluctuations. We show that generally the lineage and population distributions in steady-state growth cannot be accurately approximated by the steady-state solution of extrinsic noise models, i.e. a telegraph model with parameters drawn from probability distributions. This is because the mRNA lifetime is often not small enough compared to the cell cycle duration to erase the memory of division and replication. Accurate approximations are possible when this memory is weak, e.g. for genes with bursty expression and for which there is sufficient gene dosage compensation when replication occurs.