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Lineage as a conception of space in compartmental stochastic processes across cellular populations

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SDBW03 - Advances in numerical and analytic approaches for the study of non-spatial stochastic dynamical systems in molecular biology

Co-author: Arnab Bandyopadhyay (University of Kansas)

Cytoplasmic regulatory networks often approximate well-mixed reaction kinetics in single cells, but with variability from cell to cell. As a result, inheritance dynamics and kin correlations have been implicated in effects on cell cycle, regulatory networks, and modulation of population growth rate. Based on an experimental result in our lab suggesting lineage correlations in bacterial growth arrest, we developed a cellular stochastic simulation framework to analyse the role of lineage in bacterial cells regulating growth rate by means of an intracellular molecular network. The simulation framework thus models both intrinsic and inherited noise sources while maintaining lineage data between cell agents assigned individual unique identifiers.

Our initial application of the framework demonstrates the role of lineage in the probability of bacterial growth arrest controlled by an endogenous toxin from a toxin-antitoxin system. These systems have tight binding between toxin and antitoxin, so that there is a discrete critical threshold in the toxin:antitoxin ratio below which a cell is essentially toxin-free and growth is unrestricted, and above which toxin rapidly slows the growth rate. The subset of high-toxin cells crossing into the growth arrested state are associated with antibiotic persistence. Our implementation of a simple toxin-antitoxin system in the simulation framework revealed the statistical dependence of growth arrest on cellular lineage: after several generations of growth, the probability of cellular growth arrest began to depend on lineage distance. Clusters of closely related cell agents had a high probability of transitioning into growth arrest, while the rest of the lineage continued to grow withou t restriction.

We consider various quantities of interest in multiscale lineage simulations, and conclude that growth transitions in a cellular colony cannot be fully understood without quantitative knowledge of its lineage.

This talk is part of the Isaac Newton Institute Seminar Series series.

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