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(BBSRC DTP) Single-cell measurements of mutation dynamics across bacterial genomes


Faculty of Biology, Medicine and Health

About the Project

Genetic mutations are the raw material of evolution, driving evolutionary innovations. Mutation rate is thus a key factor determining how organisms adapt to new environments and whether they survive a severe environmental challenge, such as antibiotic treatment in the case of bacteria. It is well understood that mutations rates can vary between organisms and between environments. What is much less clear is how mutations rates might vary from one location in a genome to another within a single organism. In bacteria, if mutation rates vary substantially across the genome, as has been previously suggested [1], some genes would evolve resistance faster than others.

This project will focus on the understanding of ‘local’ mutation rates and how potentially heterogenic mutation rates in different genomic regions might affect evolution of antimicrobial resistance. The project will bring together several major state-of-the-art approaches and techniques: fluctuation assays to estimate mutation rate plasticity in bacterial populations [2], synthetic biology tools for testing ‘local’ mutation rates [3], microfluidics [4], and tracking of single molecules of fluorescent proteins to count mutations in a single cell [5]. This inter-disciplinary approach will allow us to identify genomic regions with lower mutation rates and determine the rate of antimicrobial resistance in different genomic regions.

This fundamental study aims to provide new insights into the mechanics of how evolution works and how antimicrobial resistance emerges. The project will not only allow the student to address fundamental questions of evolutionary biology, but will also inform antibiotic drug development and management. The project lies at the interface between basic and applied science. It represents a unique opportunity for applicants that are interested in cutting-edge synthetic biology, microbiology and advanced microscopy. We will provide appropriate training, substantial technical support and expertise for these techniques. Training will be supported through regular meetings of the well-integrated antimicrobial resistance research groups, as well support from state of the art facilities and training from appropriate instrumentation companies (eg. Zeiss). We therefore expect that the project will open up multiple future career paths to the student.

https://www.research.manchester.ac.uk/portal/rok.krasovec.html

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website http://www.manchester.ac.uk/bbsrcdtpstudentships

Funding Notes

Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of scholarships that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website View Website

References

[1] Dillon, M. M., Sung, W., Lynch, M. & Cooper, V. S. Periodic Variation of Mutation Rates in Bacterial Genomes Associated with Replication Timing. mBio 9, e01371-01318, (2018). doi:10.1128/mBio.01371-18

[2] Krašovec, R., Richards, H., Gifford, D.K., 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

[3] Lagator, M., Sarikas, S., Acar, H., Bollback, J. P. & Guet, C. C. Regulatory network structure determines patterns of intermolecular epistasis. eLife 6, e28921, (2017). doi:10.7554/eLife.28921

[4] Dal Co, A., Ackermann, M. & van Vliet, S. Metabolic activity affects the response of single cells to a nutrient switch in structured populations. Journal of The Royal Society Interface 16, 20190182, (2019). doi:10.1098/rsif.2019.0182

[5] Uphoff, S. Lord, N.D., Okumus, B., Potvin-Trottier, L., Sherratt, D.J., Paulsson, J. Stochastic activation of a DNA damage response causes cell-to-cell mutation rate variation. Science 351, 1094-1097, (2016). doi:10.1126/science.aac9786

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