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AbstractRobustness of biological models has emerged as an important principle in systems biology. Many past analyses of Boolean models update all pending changes in signals simultaneously (i.e., synchronously), making it impossible to consider robustness to variations in timing that result from noise and different environmental conditions. We checked previously published mathematical models of the cell cycles of budding and fission yeast for robustness to timing variations by constructing Boolean models and analyzing them using model-checking software for the property of speed independence. Surprisingly, the models are nearly, but not totally, speed-independent. In some cases, examination of timing problems discovered in the analysis exposes apparent inaccuracies in the model. Biologically justified revisions to the model eliminate the timing problems. Furthermore, in silico random mutations in the regulatory interactions of a speed-independent Boolean model are shown to be unlikely to preserve speed independence, even in models that are otherwise functional, providing evidence for selection pressure to maintain timing robustness. Multiple cell cycle models exhibit strong robustness to timing variation, apparently due to evolutionary pressure. Thus, timing robustness can be a basis for generating testable hypotheses and can focus attention on aspects of a model that may need refinement.
CitationMangla K, Dill DL, Horowitz MA (2010) Timing Robustness in the Budding and Fission Yeast Cell Cycles. PLoS ONE 5: e8906. Available: http://dx.doi.org/10.1371/journal.pone.0008906.
SponsorsThis research has been funded in part by a King Abdullah University of Science and Technology (KAUST) research grant under the KAUST-Stanford Academic Excellence Alliance program, and by a seed grant from the Stanford University Department of Computer Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Any opinions, findings, and conclusions or recommendations expressed in this paper are those of the authors and do not necessarily reflect the views of any of the funders.
PublisherPublic Library of Science (PLoS)
PubMed Central IDPMC2813865
CollectionsPublications Acknowledging KAUST Support
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