title: Sources of Variability in a Synthetic Gene Oscillator.
abstract: 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.
authors.affiliation: Department of Biosciences, Rice University, Houston, Texas, United States of America.|Department of Mathematics, University of Houston, Houston, Texas, United States of America.
authors.forename: Alan
authors.initials: A
authors.lastname: Veliz-Cuba
authors.affiliation: Department of Biosciences, Rice University, Houston, Texas, United States of America.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hirning
authors.affiliation: Department of Biosciences, Rice University, Houston, Texas, United States of America.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Atanas
authors.affiliation: Department of Biosciences, Rice University, Houston, Texas, United States of America.
authors.forename: Faiza
authors.initials: F
authors.lastname: Hussain
authors.affiliation: Department of Mathematics, University of Houston, Houston, Texas, United States of America.
authors.forename: Flavia
authors.initials: F
authors.lastname: Vancia
authors.affiliation: Department of Mathematics, University of Houston, Houston, Texas, United States of America.|Department of Biology & Biochemistry, University of Houston, Houston, Texas, United States of America.
authors.forename: Krešimir
authors.initials: K
authors.lastname: Josić
authors.affiliation: Department of Biosciences, Rice University, Houston, Texas, United States of America.|Department of Bioengineering, Rice University, Houston, Texas, United States of America.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Bennett
mesh_terms: D001683:Biological Clocks / Q000235:genetics*; D003198:Computer Simulation; D005786:Gene Expression Regulation / Q000235:genetics; D053263:Gene Regulatory Networks / Q000235:genetics*; D005813:Genes, Synthetic / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009991:Oscillometry / Q000379:methods*