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Timing robustness in the budding and fission yeast cell cycles.

Mangla K, Dill DL, Horowitz MA - PLoS ONE (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Computer Science, Stanford University, Stanford, California, United States of America.

ABSTRACT
Robustness 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.

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Fission yeast models.(A) Fission yeast model derived from Sveiczer, et al, 2004 [23]. (B) Revised speed-independent model.
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pone-0008906-g002: Fission yeast models.(A) Fission yeast model derived from Sveiczer, et al, 2004 [23]. (B) Revised speed-independent model.

Mentions: We created two other Boolean models based on more recent papers, published in 2001 and 2004 [22], [23], shown in Figure 2. The 2004 paper has more hazards than the 2001 paper, and fixing the hazards in the 2004 paper results in a model that is very similar to that from the 2001 paper. The first hazard from the 2004 model is that SK can degrade before Cdc2 is produced. This allows Ste9 and Rum1 to reactivate and prevent production of Cdc2, halting the cell cycle. This hazard can be eliminated by replacing SK self-inhibition with inhibition of SK by Cdc2, as hypothesized in in the 2001 paper.


Timing robustness in the budding and fission yeast cell cycles.

Mangla K, Dill DL, Horowitz MA - PLoS ONE (2010)

Fission yeast models.(A) Fission yeast model derived from Sveiczer, et al, 2004 [23]. (B) Revised speed-independent model.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2813865&req=5

pone-0008906-g002: Fission yeast models.(A) Fission yeast model derived from Sveiczer, et al, 2004 [23]. (B) Revised speed-independent model.
Mentions: We created two other Boolean models based on more recent papers, published in 2001 and 2004 [22], [23], shown in Figure 2. The 2004 paper has more hazards than the 2001 paper, and fixing the hazards in the 2004 paper results in a model that is very similar to that from the 2001 paper. The first hazard from the 2004 model is that SK can degrade before Cdc2 is produced. This allows Ste9 and Rum1 to reactivate and prevent production of Cdc2, halting the cell cycle. This hazard can be eliminated by replacing SK self-inhibition with inhibition of SK by Cdc2, as hypothesized in in the 2001 paper.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Computer Science, Stanford University, Stanford, California, United States of America.

ABSTRACT
Robustness 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.

Show MeSH