The theory and practice of evolvability: Effects and mechanisms of mutation rate plasticity

进化性的理论与实践：突变率可塑性的影响和机制

• 批准号: BB/L009579/1
• 负责人: Christopher Knight
• 金额: $ 59.28万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL009579%2F1
• 关键词: theory; practice; evolvability; Effects; mechanisms

Spontaneous mutation is a key engine of evolution and is central to organisms' 'evolvability'. Thus understanding mutation is important for understanding the fundamentals of the mechanisms that have generated all the diversity of life we see today. It is also important for combatting undesirable evolution, such as antibiotic resistance in microbes. Others have found that mutation rates can vary between organisms (genotypes) and locally within an organism's genome and that rates can evolve by natural selection. We have found that the chances that a single genotype mutates can also vary, mediated by cell-cell communication. Variation of this type is predicted by mathematical theory to increase organisms' evolvability, allowing them to adapt quicker. However, there are still important gaps in our understanding of this area. Firstly, we do not know whether the system we have identified actually has this predicted effect on evolution. Secondly we do not understand the mechanism - what signal mediates the cell-cell communication used here and how it acts. Finally, while the theory predicted the existence of variable mutation rates of the sort we observe and their beneficial effect on evolvability, it didn't predict the sort of cell-cell communication mechanism we have identified and cannot yet deal with such processes.In this project we shall address each of these issues, considering the rate of evolution of antibiotic resistance in the gut microbe Escherichia coli. Firstly we shall investigate the mechanism by which cell-cell signals affect mutation rate. We already know that this mechanism requires a particular gene (luxS) whose removal affects multiple signalling molecules. By experimentally manipulating genes and small molecules involved in the biochemical network in which luxS is involved and its downstream effects, we shall understand better how this signalling is achieved. Secondly we shall develop the theory and carry out computational experiments to include the sort of cell-cell communication mechanisms we observe and understand how exactly they may affect the course of evolution. This will also provide new hypotheses that may be tested in the lab. Finally we shall test whether and when this control of mutation rate actually is beneficial to the organism's evolution (as predicted by theory) by watching evolution happen in the laboratory with and without the ability to vary mutation rate in this way. Together, this work will link the theory and reality of evolvability, using very different scientific disciplines to determine when, how and why organisms vary their mutation rates.

自发突变是进化的关键引擎，是生物体“进化性”的核心。因此，理解突变对于理解产生我们今天看到的所有生命多样性的机制的基本原理非常重要。它对于对抗不希望的进化也很重要，例如微生物中的抗生素耐药性。其他人发现，突变率可以在生物体（基因型）之间和生物体基因组内局部变化，并且可以通过自然选择进化。我们已经发现，单个基因型突变的机会也可以变化，由细胞间通讯介导。数学理论预测，这种类型的变异会增加生物体的进化能力，使它们能够更快地适应。然而，在我们对这一领域的理解方面仍然存在重大差距。首先，我们不知道我们已经确定的系统是否真的对进化有这种预测的影响。其次，我们不了解机制-什么信号介导这里使用的细胞与细胞之间的通信以及它是如何起作用的。最后，虽然该理论预测了我们观察到的可变突变率的存在及其对进化性的有益影响，但它没有预测我们已经确定的细胞间通讯机制，也无法处理这些过程。在本项目中，我们将讨论这些问题，考虑肠道微生物大肠杆菌中抗生素耐药性的进化速度。首先，我们将研究细胞间信号影响突变率的机制。我们已经知道，这种机制需要一个特定的基因（luxS），其去除会影响多种信号分子。通过实验操纵基因和小分子参与的生化网络中，其中luxS参与及其下游的影响，我们将更好地了解如何实现这种信号。其次，我们将发展理论并进行计算实验，以包括我们观察到的细胞间通讯机制，并了解它们如何确切地影响进化过程。这也将提供可以在实验室中测试的新假设。最后，我们将通过观察在实验室中发生的进化，在有和没有以这种方式改变突变率的能力的情况下，测试这种对突变率的控制是否以及何时实际上有利于生物体的进化（如理论所预测的那样）。总之，这项工作将把进化性的理论和现实联系起来，使用非常不同的科学学科来确定生物体何时、如何以及为什么改变它们的突变率。

项目成果

Opposing effects of final population density and stress on Escherichia coli mutation rate.

• DOI: 10.1038/s41396-018-0237-3
• 发表时间: 2018-12
• 期刊: The ISME journal
• 作者: Krašovec R;Richards H;Gifford DR;Belavkin RV;Channon A;Aston E;McBain AJ;Knight CG
• 通讯作者: Knight CG

Monotonicity of fitness landscapes and mutation rate control.

• DOI: 10.1007/s00285-016-0995-3
• 发表时间: 2016-12
• 期刊: JOURNAL OF MATHEMATICAL BIOLOGY
• 影响因子: 1.9
• 作者: Belavkin, Roman V.;Channon, Alastair;Aston, Elizabeth;Aston, John;Krasovec, Rok;Knight, Christopher G.
• 通讯作者: Knight, Christopher G.

Where antibiotic resistance mutations meet quorum-sensing.

• DOI: 10.15698/mic2014.07.158
• 发表时间: 2014-06-25
• 期刊: Microbial cell (Graz, Austria)
• 作者: Krašovec R;Belavkin RV;Aston JA;Channon A;Aston E;Rash BM;Kadirvel M;Forbes S;Knight CG
• 通讯作者: Knight CG

Opposing effects of population density and stress on Escherichia coli mutation rate

种群密度和应激对大肠杆菌突变率的相反影响

• DOI: 10.1101/256305
• 发表时间: 2018
• 作者: Krašovec R

Geometric Science of Information

信息几何科学

• DOI: 10.1007/978-3-642-40020-9_45
• 发表时间: 2013
• 作者: Benning M