A new design framework for engineering evolutionarily robust gene circuits

用于工程进化鲁棒基因电路的新设计框架

• 批准号: 2686012
• 金额: --
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2686012
• 关键词: new; design; framework; engineering; evolutionarily

Synthetic Biology, EngineeringEngineering artificial gene networks in microorganisms has a range of applications in medicine, industrial bioprocessing and environmental science. However, such engineered strains often show poor growth. During population growth, non-functional strains emerge due to the natural process of DNA mutation. These new mutant strains have higher growth rate and so dominate the population resulting in a breakdown of engineered function over time. This creates a fundamental roadblock to the implementation of engineered biological solutions. The ability to construct synthetic gene circuits reliably and efficiently with evolutionary robustness would represent a milestone in our efforts to scale-up the engineering of biology. However, evolution remains the 'elephant in the room' for the effective application of these engineered biological systems with evolution often neglected during the system design process. We aim to develop a design framework which enable gene circuits to be engineered with long term function. We will do this by: (1) using state of the art mathematical modelling to obtain detailed quantitative understanding of how evolutionary pressures affect the performance and functionality of engineered gene circuits over time (2) leveraging this understanding to generate design principles that will allow the efficient and reliable design of engineered circuits with increased evolutionary robustness Methodology: In this project, we will develop multiscale models of microbial gene expression, growth and population competition capable of predicting the population-wide performance of a gene circuit. We will develop mutation algorithms which realistically capture the impact DNAmutations have on key circuit parameters, such as transcription and translation rates. We will couple our mutation scheme with our multiscale models to enable the simulation of gene circuits over the course of volutionary time. We will use tools to identify the modes of failure in gene circuit topologies over the course of evolutionary time and develop control strategies to increase long term performance.

合成生物学，工程微生物中的工程人工基因网络在医学，工业生物加工和环境科学中有一系列应用。然而，这样的工程菌株通常显示出较差的生长。在种群增长过程中，由于DNA突变的自然过程，出现了非功能性菌株。这些新的突变菌株具有更高的生长速率，因此在种群中占主导地位，导致工程功能随时间推移而崩溃。这为工程生物解决方案的实施创造了根本性的障碍。构建具有进化鲁棒性的可靠有效的合成基因电路的能力将代表我们扩大生物工程的努力的里程碑。然而，进化仍然是这些工程生物系统的有效应用的“房间里的大象”，在系统设计过程中，进化往往被忽视。我们的目标是开发一个设计框架，使基因电路工程与长期的功能。为此，我们将：（1）使用现有技术的数学建模来获得进化压力如何随时间影响工程化基因电路的性能和功能的详细定量理解（2）利用这种理解来产生设计原理，该设计原理将允许具有增加的进化鲁棒性的工程化电路的有效和可靠的设计。在这个项目中，我们将开发微生物基因表达，生长和种群竞争的多尺度模型，能够预测基因电路的种群范围内的性能。我们将开发突变算法，这些算法可以真实地捕获DNA突变对关键电路参数（如转录和翻译速率）的影响。我们将结合我们的突变方案与我们的多尺度模型，使基因电路在进化时间的过程中的模拟。我们将使用工具来识别基因电路拓扑结构在进化过程中的故障模式，并开发控制策略以提高长期性能。