A model of the cell-autonomous mammalian circadian clock.

Abstract:

: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.

authors

Mirsky HP,Liu AC,Welsh DK,Kay SA,Doyle FJ 3rd

doi

10.1073/pnas.0904837106

subject

Has Abstract

pub_date

2009-07-07 00:00:00

pages

11107-12

issue

27

eissn

0027-8424

issn

1091-6490

pii

0904837106

journal_volume

106

pub_type

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