Decomposing variability in protein levels from noisy expression, genome duplication and partitioning errors during cell-divisions

TL;DR

This paper develops analytical formulas to decompose and analyze the sources of variability in protein levels within cells, considering stochastic gene expression, cell division timing, and genome duplication effects.

Contribution

It introduces a novel hybrid approach to decompose total protein noise into distinct biological sources, accounting for cell division and genome duplication.

Findings

Random cell-division times increase extrinsic noise and affect mean protein levels.

Noise can decrease as cell-division stochasticity increases in certain regimes.

Optimal timing of genome duplication minimizes stochastic expression noise.

Abstract

Inside individual cells, expression of genes is inherently stochastic and manifests as cell-to-cell variability or noise in protein copy numbers. Since proteins half-lives can be comparable to the cell-cycle length, randomness in cell-division times generates additional intercellular variability in protein levels. Moreover, as many mRNA/protein species are expressed at low-copy numbers, errors incurred in partitioning of molecules between the mother and daughter cells are significant. We derive analytical formulas for the total noise in protein levels for a general class of cell-division time and partitioning error distributions. Using a novel hybrid approach the total noise is decomposed into components arising from i) stochastic expression; ii) partitioning errors at the time of cell-division and iii) random cell-division events. These formulas reveal that random cell-division times not only generate additional extrinsic noise but also critically affect the mean protein copy numbers and intrinsic noise components. Counter intuitively, in some parameter regimes noise in protein levels can decrease as cell-division times become more stochastic. Computations are extended to consider genome duplication, where the gene dosage is increased by two-fold at a random point in the cell-cycle. We systematically investigate how the timing of genome duplication influences different protein noise components. Intriguingly, results show that noise contribution from stochastic expression is minimized at an optimal genome duplication time. Our theoretical results motivate new experimental methods for decomposing protein noise levels from single-cell expression data. Characterizing the contributions of individual noise mechanisms will lead to precise estimates of gene expression parameters and techniques for altering stochasticity to change phenotype of individual cells.