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Adjusting Noise in the Genetic Toggle Switch through Stochastic Circuit Design

机译：通过随机电路设计调整遗传拨动开关中的噪声

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摘要

Bistable genetic circuits are important regulatory elements that can serve as biological switches. However, for a switch to function correctly, the noise inherent to the circuit needs to be taken into account, as it affects the robustness of the system. Using the example of a genetic toggle switch, we analyse the dependence of its intrinsic noise on the biochemical properties of the circuit. To that end, the circuit is described stochastically, and the variances of mRNA and protein fluctuations in each stable expression state are formulated as functions of relevant circuit parameters. This is done with the help of the linear noise approximation. As the obtained dependence is highly complex and difficult to interpret, simplified models with increasing complexity are analyzed successively. First, mRNA levels are eliminated assuming infinitely fast mRNA dynamics. Based on this model, influences of mutual inhibition dynamics and of the distribution of time-scales between the two gene expression systems are evaluated. By introducing translational bursts into the model, the interplay between mRNA and protein dynamics can be studied for quickly degrading mRNAs. Finally, special cases of the full stochastic model are discussed. Our results are verified by stochastic simulations and interpreted from a biological point of view. This enables to suggest genetic modifications for the targeted modulation of transition probabilities between distinct expression states.
机译：双稳态遗传回路是重要的调控元件，可以用作生物开关。但是，为了使开关正常工作，必须考虑电路固有的噪声，因为它会影响系统的鲁棒性。以遗传拨动开关为例，我们分析了其固有噪声对电路生化特性的依赖性。为此，随机地描述了电路，并且将每个稳定表达状态下的mRNA和蛋白质波动的方差表述为相关电路参数的函数。这是借助线性噪声近似来完成的。由于所获得的依赖性非常复杂且难以解释，因此将逐步分析复杂性不断提高的简化模型。首先，假定无限快速的mRNA动力学，消除mRNA水平。基于该模型，评估了相互抑制动力学和两个基因表达系统之间时间尺度分布的影响。通过将翻译爆发引入模型，可以研究mRNA和蛋白质动力学之间的相互作用，以快速降解mRNA。最后，讨论了完全随机模型的特殊情况。我们的结果通过随机模拟验证，并从生物学的角度进行解释。这使得能够提出遗传修饰，以针对不同表达状态之间的转移概率进行靶向调节。

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