ABSTRACT
Stochasticity from gene expression in single cells is known to drive metabolic heterogeneity at the level of cellular populations, which is understood to have important consequences for issues such as microbial drug tolerance and treatment of human diseases like cancer. Despite considerable advancements in profiling the genomes, transcriptomes, and proteomes of single cells, it remains difficult to experimentally characterise their metabolism at genome-scale. Computational methods could bridge this gap toward a systems understanding of single-cell biology. To address this challenge, we developed stochastic simulation algorithm with flux-balance analysis embedded (SSA-FBA), a computational framework for simulating the stochastic dynamics of the metabolism of individual cells using genome-scale metabolic models with experimental estimates of gene expression and enzymatic reaction rate parameters. SSA-FBA extends the constraint-based modelling formalism of metabolic network modelling to the single-cell regime, enabling simulation when experimentation is intractable. We also developed an efficient implementation of SSA-FBA that leverages the topology of embedded FBA models to significantly reduce the computational cost of simulation. As a preliminary case study, we built a reduced single-cell model of Mycoplasma pneumoniae, and used SSA-FBA to illustrate the role of stochasticity on the dynamics of metabolism at the single-cell level.
SIGNIFICANCE Due to fundamental challenges limiting the experimental characterisation of metabolism within individual cells, computational methods are needed to help infer the metabolic behaviour of single cells from information about their transcriptomes and proteomes. In this paper, we present SSA-FBA, the first systematic framework for modelling the stochastic dynamics of single cells at the level of genome-scale metabolic reaction networks. We provide a robust and efficient algorithm for simulating SSA-FBA models, and apply it to a case study involving the metabolism, RNA and protein synthesis and turnover of a single Mycoplasma pneumoniae cell.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Final accepted version accommodating referee comments