title: A Statistical Approach Reveals Designs for the Most Robust Stochastic Gene Oscillators.
abstract: The engineering of transcriptional networks presents many challenges due to the inherent uncertainty in the system structure, changing cellular context, and stochasticity in the governing dynamics. One approach to address these problems is to design and build systems that can function across a range of conditions; that is they are robust to uncertainty in their constituent components. Here we examine the parametric robustness landscape of transcriptional oscillators, which underlie many important processes such as circadian rhythms and the cell cycle, plus also serve as a model for the engineering of complex and emergent phenomena. The central questions that we address are: Can we build genetic oscillators that are more robust than those already constructed? Can we make genetic oscillators arbitrarily robust? These questions are technically challenging due to the large model and parameter spaces that must be efficiently explored. Here we use a measure of robustness that coincides with the Bayesian model evidence, combined with an efficient Monte Carlo method to traverse model space and concentrate on regions of high robustness, which enables the accurate evaluation of the relative robustness of gene network models governed by stochastic dynamics. We report the most robust two and three gene oscillator systems, plus examine how the number of interactions, the presence of autoregulation, and degradation of mRNA and protein affects the frequency, amplitude, and robustness of transcriptional oscillators. We also find that there is a limit to parametric robustness, beyond which there is nothing to be gained by adding additional feedback. Importantly, we provide predictions on new oscillator systems that can be constructed to verify the theory and advance design and modeling approaches to systems and synthetic biology.
authors.affiliation: Department of Cell and Developmental Biology, ‡Department of Mathematics, and ¶Department of Genetics, Evolution and Environment, University College London , London, WC1E 6BT, U.K.
authors.forename: Mae L
authors.initials: ML
authors.lastname: Woods
authors.affiliation: Department of Cell and Developmental Biology, ‡Department of Mathematics, and ¶Department of Genetics, Evolution and Environment, University College London , London, WC1E 6BT, U.K.
authors.forename: Miriam
authors.initials: M
authors.lastname: Leon
authors.affiliation: Department of Cell and Developmental Biology, ‡Department of Mathematics, and ¶Department of Genetics, Evolution and Environment, University College London , London, WC1E 6BT, U.K.
authors.forename: Ruben
authors.initials: R
authors.lastname: Perez-Carrasco
authors.affiliation: Department of Cell and Developmental Biology, ‡Department of Mathematics, and ¶Department of Genetics, Evolution and Environment, University College London , London, WC1E 6BT, U.K.
authors.forename: Chris P
authors.initials: CP
authors.lastname: Barnes
mesh_terms: D001499:Bayes Theorem; D002453:Cell Cycle / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics; D003198:Computer Simulation; D053263:Gene Regulatory Networks / Q000235:genetics*; D005818:Genetic Engineering / Q000379:methods*; D008957:Models, Genetic; D009010:Monte Carlo Method; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012107:Research Design / Q000706:statistics & numerical data*; D013269:Stochastic Processes; D058615:Synthetic Biology / Q000379:methods
chemical_list: D011506:Proteins; D012333:RNA, Messenger
keywords: circuit topology; oscillations; robustness; sequential Monte Carlo; stochastic processes
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