'Glocal' robustness analysis and model discrimination for circadian oscillators. 2009

Marc Hafner, and Heinz Koeppl, and Martin Hasler, and Andreas Wagner
School of Computer and Communication Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

To characterize the behavior and robustness of cellular circuits with many unknown parameters is a major challenge for systems biology. Its difficulty rises exponentially with the number of circuit components. We here propose a novel analysis method to meet this challenge. Our method identifies the region of a high-dimensional parameter space where a circuit displays an experimentally observed behavior. It does so via a Monte Carlo approach guided by principal component analysis, in order to allow efficient sampling of this space. This 'global' analysis is then supplemented by a 'local' analysis, in which circuit robustness is determined for each of the thousands of parameter sets sampled in the global analysis. We apply this method to two prominent, recent models of the cyanobacterial circadian oscillator, an autocatalytic model, and a model centered on consecutive phosphorylation at two sites of the KaiC protein, a key circadian regulator. For these models, we find that the two-sites architecture is much more robust than the autocatalytic one, both globally and locally, based on five different quantifiers of robustness, including robustness to parameter perturbations and to molecular noise. Our 'glocal' combination of global and local analyses can also identify key causes of high or low robustness. In doing so, our approach helps to unravel the architectural origin of robust circuit behavior. Complementarily, identifying fragile aspects of system behavior can aid in designing perturbation experiments that may discriminate between competing mechanisms and different parameter sets.

UI MeSH Term Description Entries
D008962 Models, Theoretical Theoretical representations that simulate the behavior or activity of systems, processes, or phenomena. They include the use of mathematical equations, computers, and other electronic equipment. Experimental Model,Experimental Models,Mathematical Model,Model, Experimental,Models (Theoretical),Models, Experimental,Models, Theoretic,Theoretical Study,Mathematical Models,Model (Theoretical),Model, Mathematical,Model, Theoretical,Models, Mathematical,Studies, Theoretical,Study, Theoretical,Theoretical Model,Theoretical Models,Theoretical Studies
D002940 Circadian Rhythm The regular recurrence, in cycles of about 24 hours, of biological processes or activities, such as sensitivity to drugs or environmental and physiological stimuli. Diurnal Rhythm,Nyctohemeral Rhythm,Twenty-Four Hour Rhythm,Nycthemeral Rhythm,Circadian Rhythms,Diurnal Rhythms,Nycthemeral Rhythms,Nyctohemeral Rhythms,Rhythm, Circadian,Rhythm, Diurnal,Rhythm, Nycthemeral,Rhythm, Nyctohemeral,Rhythm, Twenty-Four Hour,Rhythms, Circadian,Rhythms, Diurnal,Rhythms, Nycthemeral,Rhythms, Nyctohemeral,Rhythms, Twenty-Four Hour,Twenty Four Hour Rhythm,Twenty-Four Hour Rhythms

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