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(BBSRC DTP) Mechanisms of mutation rate plasticity


Project Description

The chance that an organism mutates, for instance that a microbe mutates to resist an antibiotic, can depend on that organism’s environment. We have recently discovered that the density of the population that an organism belongs to is closely associated with this mutation rate – high density populations of a wide range of organisms have roughly ten-fold lower mutation rates than sparser populations [1]. Genetic experiments give some clues as to how this comes about. It involves both proteins dealing with oxidatively damaged nucleotides in the cell [1] and, in the bacterium E. coli, cell-cell signalling and a gene involved in the activated methyl cycle [2]. The point of this project is to take these clues and put them together with known information about the processes involved, to create quantitative, dynamic models of mutational processes, and then to test them in the lab.

Density-associated mutation-rate plasticity (DAMP), as this phenomenon is known, has huge potential, for instance in finding small molecules able to reduce the probability that organisms develop antibiotic resistance. These could be used alongside antibiotics to enable an infection to be cleared before resistance arises. But this will only become possible if we understand the mechanism(s) by which it occurs, and how it interacts with other mechanisms [3]. Focused experiments, for instance using alternative approaches to mutation rate estimation (e.g. [3]) will make it possible to test predictions from dynamic models and feed back into improving those models and thereby understanding.

This interdisciplinary combination of in-silico and lab-based study of evolution, can provide new insights into the mechanics of how evolution works. This represents a unique opportunity for applicants interested in both computational biology approaches and lab work, allowing the student to address fundamental questions of evolutionary biology, while training in computational and wet-lab techniques: a combination which lends itself to multiple future career paths.

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

[1] Krašovec, R., Richards, H., Gifford, D.R., Hatcher, C., Faulkner, K.J., Belavkin, R.V., Channon, A., Aston, E., McBain, A.J. and Knight, C.G. (2017) Spontaneous mutation rate Is a plastic trait associated with population density across domains of life. PLoS Biology, 15, e2002731. doi:10.1371/journal.pbio.2002731
[2] Krašovec, R., Belavkin, R.V., Aston, J.A.D., Channon, A., Aston, E., Rash, B.M., Kadirvel, M., Forbes, S. and Knight, C.G. (2014) Mutation rate plasticity in rifampicin resistance depends on Escherichia coli cell–cell interactions. Nature communications, 5, 3742. doi:10.1038/ncomms4742
[3] Krašovec, R., Richards, H., Gifford, D.R., Belavkin, R.V., Channon, A., Aston, E., McBain, A.J. and Knight, C.G. (2018) Opposing effects of final population density and stress on Escherichia coli mutation rate. The ISME Journal. doi:10.1038/s41396-018-0237-3
[4] Jee, J., Rasouly, A., Shamovsky, I., Akivis, Y., Steinman, S.R., Mishra, B. and Nudler, E. (2016) Rates and mechanisms of bacterial mutagenesis from maximum-depth sequencing. Nature, 534, 693-696. doi:10.1038/nature18313

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