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A mathematical and computational approach for integrating the major sources of cell population heterogeneity

Stamatakis, M; Zygourakis, K; (2010) A mathematical and computational approach for integrating the major sources of cell population heterogeneity. Journal of Theoretical Biology , 266 (1) 41 - 61. 10.1016/j.jtbi.2010.06.002. Green open access

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Abstract

Several approaches have been used in the past to model heterogeneity in bacterial cell populations, with each approach focusing on different source(s) of heterogeneity. However, a holistic approach that integrates all the major sources into a comprehensive framework applicable to cell populations is still lacking.In this work we present the mathematical formulation of a cell population master equation (CPME) that describes cell population dynamics and takes into account the major sources of heterogeneity, namely stochasticity in reaction, DNA-duplication, and division, as well as the random partitioning of species contents into the two daughter cells. The formulation also takes into account cell growth and respects the discrete nature of the molecular contents and cell numbers. We further develop a Monte Carlo algorithm for the simulation of the stochastic processes considered here. To benchmark our new framework, we first use it to quantify the effect of each source of heterogeneity on the intrinsic and the extrinsic phenotypic variability for the well-known two-promoter system used experimentally by Elowitz et al. (2002). We finally apply our framework to a more complicated system and demonstrate how the interplay between noisy gene expression and growth inhibition due to protein accumulation at the single cell level can result in complex behavior at the cell population level.The generality of our framework makes it suitable for studying a vast array of artificial and natural genetic networks. Using our Monte Carlo algorithm, cell population distributions can be predicted for the genetic architecture of interest, thereby quantifying the effect of stochasticity in intracellular reactions or the variability in the rate of physiological processes such as growth and division. Such in silico experiments can give insight into the behavior of cell populations and reveal the major sources contributing to cell population heterogeneity. © 2010 Elsevier Ltd.

Type: Article
Title: A mathematical and computational approach for integrating the major sources of cell population heterogeneity
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jtbi.2010.06.002
Publisher version: http://dx.doi.org/10.1016/j.jtbi.2010.06.002
Language: English
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Chemical Engineering
URI: https://discovery.ucl.ac.uk/id/eprint/1356182
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