Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 27, Pages 11107-11112Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0904837106
Keywords
cell-level model; evolutionary strategy; gene regulatory network; mathematical model; mouse
Categories
Funding
- U. S. Army Research Office [DAAD19-03-D-0004, W911NF-07-1-0279]
- National Institutes of Health [GM078993, R01 GM074868, R01 MH051573, K08 MH067657, R01 MH082945]
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Circadian timekeeping by intracellular molecular clocks is evident widely in prokaryotes and eukaryotes. The clockworks are driven by autoregulatory feedback loops that lead to oscillating levels of components whose maxima are in fixed phase relationships with one another. These phase relationships are the key metric characterizing the operation of the clocks. In this study, we built a mathematical model from the regulatory structure of the intracellular circadian clock in mice and identified its parameters using an iterative evolutionary strategy, with minimum cost achieved through conformance to phase separations seen in cell-autonomous oscillators. The model was evaluated against the experimentally observed cell-autonomous circadian phenotypes of gene knockouts, particularly retention of rhythmicity and changes in expression level of molecular clock components. These tests reveal excellent de novo predictive ability of the model. Furthermore, sensitivity analysis shows that these knockout phenotypes are robust to parameter perturbation.
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