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Computational design of synthetic regulatory networks from a genetic library to characterize the designability of dynamical behaviors

Institute of Systems and Synthetic Biology (ISSB), Genopole - Université d'Évry Val d'Essonne - CNRS UPS3201, 91030 Évry Cedex, France.
Nucleic Acids Research (Impact Factor: 8.81). 08/2011; 39(20):e138. DOI: 10.1093/nar/gkr616
Source: PubMed

ABSTRACT The engineering of synthetic gene networks has mostly relied on the assembly of few characterized regulatory elements using rational design principles. It is of outmost importance to analyze the scalability and limits of such a design workflow. To analyze the design capabilities of libraries of regulatory elements, we have developed the first automated design approach that combines such elements to search the genotype space associated to a given phenotypic behavior. Herein, we calculated the designability of dynamical functions obtained from circuits assembled with a given genetic library. By designing circuits working as amplitude filters, pulse counters and oscillators, we could infer new mechanisms for such behaviors. We also highlighted the hierarchical design and the optimization of the interface between devices. We dissected the functional diversity of a constrained library and we found that even such libraries can provide a rich variety of behaviors. We also found that intrinsic noise slightly reduces the designability of digital circuits, but it increases the designability of oscillators. Finally, we analyzed the robust design as a strategy to counteract the evolvability and noise in gene expression of the engineered circuits within a cellular background, obtaining mechanisms for robustness through non-linear negative feedback loops.

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