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Robustness from flexibility in the fungal circadian clock

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Akman, Ozgur E., Rand, D. A. (David A.), Brown, Paul E. and Millar, A. J. (Andrew J.). (2010) Robustness from flexibility in the fungal circadian clock. BMC Systems Biology, Vol.4 (No.88). ISSN 1752-0509

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Official URL: http://dx.doi.org/10.1186/1752-0509-4-88

Abstract

Background Robustness is a central property of living systems, enabling function to be maintained against environmental perturbations. A key challenge is to identify the structures in biological circuits that confer system-level properties such as robustness. Circadian clocks allow organisms to adapt to the predictable changes of the 24-hour day/night cycle by generating endogenous rhythms that can be entrained to the external cycle. In all organisms, the clock circuits typically comprise multiple interlocked feedback loops controlling the rhythmic expression of key genes. Previously, we showed that such architectures increase the flexibility of the clock's rhythmic behaviour. We now test the relationship between flexibility and robustness, using a mathematical model of the circuit controlling conidiation in the fungus Neurospora crassa. Results The circuit modelled in this work consists of a central negative feedback loop, in which the frequency (frq) gene inhibits its transcriptional activator white collar-1 (wc-1), interlocked with a positive feedback loop in which FRQ protein upregulates WC-1 production. Importantly, our model reproduces the observed entrainment of this circuit under light/dark cycles with varying photoperiod and cycle duration. Our simulations show that whilst the level of frq mRNA is driven directly by the light input, the falling phase of FRQ protein, a molecular correlate of conidiation, maintains a constant phase that is uncoupled from the times of dawn and dusk. The model predicts the behaviour of mutants that uncouple WC-1 production from FRQ's positive feedback, and shows that the positive loop enhances the buffering of conidiation phase against seasonal photoperiod changes. This property is quantified using Kitano's measure for the overall robustness of a regulated system output. Further analysis demonstrates that this functional robustness is a consequence of the greater evolutionary flexibility conferred on the circuit by the interlocking loop structure. Conclusions Our model shows that the behaviour of the fungal clock in light-dark cycles can be accounted for by a transcription-translation feedback model of the central FRQ-WC oscillator. More generally, we provide an example of a biological circuit in which greater flexibility yields improved robustness, while also introducing novel sensitivity analysis techniques applicable to a broader range of cellular oscillators.

Item Type:	Journal Article
Subjects:	Q Science > QK Botany Q Science > QP Physiology
Divisions:	Faculty of Science > Mathematics Faculty of Science > Centre for Systems Biology
Library of Congress Subject Headings (LCSH):	Circadian rhythms, Conidia -- Mathematical models, Neurospora crassa
Journal or Publication Title:	BMC Systems Biology
Publisher:	BioMed Central Ltd.
ISSN:	1752-0509
Date:	24 June 2010
Volume:	Vol.4
Number:	No.88
Number of Pages:	16
Identification Number:	10.1186/1752-0509-4-88
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
Funder:	Engineering and Physical Sciences Research Council (EPSRC), Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), European Union (EU)
Grant number:	BB/D019621/1 (BBSRC & EPSRC), 005137 (EU),
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URI:	http://wrap.warwick.ac.uk/id/eprint/3343