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

自发突变是进化的关键引擎，是生物体“可进化性”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是很重要的。它对对抗不良进化也很重要，比如微生物的抗生素耐药性。其他人发现突变率在不同的生物体（基因型）和生物体基因组的局部范围内是不同的，而且突变率可以通过自然选择而进化。我们发现，单个基因型突变的几率也会因细胞间的交流而变化。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环境。然而，在我们对这一领域的理解上仍有重要的差距。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，我们不了解其中的机制——是什么信号介导了这里使用的细胞间通讯，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那种可变突变率的存在以及它们对可进化性的有益影响，但它没有预测到我们已经确定的那种细胞-细胞通信机制，也无法处理这种过程。在这个项目中，我们将解决这些问题中的每一个，考虑到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-细胞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），它的移除会影响多个信号分子。通过实验操纵luxS参与的生化网络中的基因和小分子及其下游效应，我们将更好地理解这种信号是如何实现的。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-细胞通信机制，并了解它们如何准确地影响进化过程。这也将提供新的假设，可以在实验室中进行测试。最后，我们将通过观察在有或没有以这种方式改变突变率的能力的实验室中发生的进化，来测试这种对突变率的控制是否以及何时实际上对生物体的进化有益（正如理论所预测的那样）。总之，这项工作将把进化论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。

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.