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

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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.