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A mechanistic model of the BLADE platform predicts performance characteristics of 256 different synthetic DNA recombination circuits

Jack E. Bowyer, Chloe Ding, Benjamin H. Weinberg, Wilson W. Wong, View ORCID ProfileDeclan G. Bates
doi: https://doi.org/10.1101/2020.04.06.027409
Jack E. Bowyer
1School of Engineering, University of Warwick, Coventry, CV47AL, UK
2Warwick Integrative Synthetic Biology Centre, University of Warwick, Coventry, CV47AL, UK
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Chloe Ding
4Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA
5Biological Design Center, Boston University, Boston, MA 02215, USA
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Benjamin H. Weinberg
3Department of Genetics, Harvard Medical School, Boston, MA 02115
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Wilson W. Wong
4Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA
5Biological Design Center, Boston University, Boston, MA 02215, USA
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Declan G. Bates
1School of Engineering, University of Warwick, Coventry, CV47AL, UK
2Warwick Integrative Synthetic Biology Centre, University of Warwick, Coventry, CV47AL, UK
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  • ORCID record for Declan G. Bates
  • For correspondence: d.bates@warwick.ac.uk
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Abstract

Boolean logic and arithmetic through DNA excision (BLADE) is a recently developed platform for implementing inducible and logical control over gene expression in mammalian cells, which has the potential to revolutionise cell engineering for therapeutic applications. This 2-input 2-output platform can implement 256 different logical circuits that exploit the specificity and stability of DNA recombination. Here, we develop the first mechanistic mathematical model of the 2-input BLADE platform based on Cre- and Flp-mediated DNA excision. After calibrating the model on experimental data from two circuits, we demonstrate close agreement between model outputs and data on the other 111 circuits that have so far been experimentally constructed using the 2-input BLADE platform. Model simulations of the remaining 143 circuits that have yet to be tested experimentally predict excellent performance of the 2-input BLADE platform across the range of possible circuits. Circuits from both the tested and untested subsets that perform less well consist of a disproportionally high number of STOP sequences. Model predictions suggested that circuit performance declines with a decrease in recombinase expression and new experimental data was generated that confirms this relationship.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted April 06, 2020.
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A mechanistic model of the BLADE platform predicts performance characteristics of 256 different synthetic DNA recombination circuits
Jack E. Bowyer, Chloe Ding, Benjamin H. Weinberg, Wilson W. Wong, Declan G. Bates
bioRxiv 2020.04.06.027409; doi: https://doi.org/10.1101/2020.04.06.027409
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A mechanistic model of the BLADE platform predicts performance characteristics of 256 different synthetic DNA recombination circuits
Jack E. Bowyer, Chloe Ding, Benjamin H. Weinberg, Wilson W. Wong, Declan G. Bates
bioRxiv 2020.04.06.027409; doi: https://doi.org/10.1101/2020.04.06.027409

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