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2015 ; 11
(12
): e1004674
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Sources of Variability in a Synthetic Gene Oscillator
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Veliz-Cuba A
; Hirning AJ
; Atanas AA
; Hussain F
; Vancia F
; Josi? K
; Bennett MR
PLoS Comput Biol
2015[Dec]; 11
(12
): e1004674
PMID26693906
show ga
Synthetic gene oscillators are small, engineered genetic circuits that produce
periodic variations in target protein expression. Like other gene circuits,
synthetic gene oscillators are noisy and exhibit fluctuations in amplitude and
period. Understanding the origins of such variability is key to building
predictive models that can guide the rational design of synthetic circuits. Here,
we developed a method for determining the impact of different sources of noise in
genetic oscillators by measuring the variability in oscillation amplitude and
correlations between sister cells. We first used a combination of microfluidic
devices and time-lapse fluorescence microscopy to track oscillations in cell
lineages across many generations. We found that oscillation amplitude exhibited
high cell-to-cell variability, while sister cells remained strongly correlated
for many minutes after cell division. To understand how such variability arises,
we constructed a computational model that identified the impact of various noise
sources across the lineage of an initial cell. When each source of noise was
appropriately tuned the model reproduced the experimentally observed amplitude
variability and correlations, and accurately predicted outcomes under novel
experimental conditions. Our combination of computational modeling and time-lapse
data analysis provides a general way to examine the sources of variability in
dynamic gene circuits.
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