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EASTBIO Evolutionary consequences of mutation rate variation in bacteria

  • Full or part time
    Dr H Alexander
    Dr M El Karoui
  • Application Deadline
    Sunday, January 05, 2020
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

As the ultimate source of new genetic variation, mutations fuel evolutionary change. Mutation rate is thus a key parameter determining how fast populations adapt to new environments, or even whether they survive a severe environmental challenge, such as antibiotic treatment in the case of bacteria. However, since most mutations are deleterious, organisms have multiple mechanisms to avoid mutagenesis. DNA damage response and mismatch repair systems have been particularly well studied in bacteria. With advances in fluorescent protein labelling and high-resolution microscopy, it has recently become possible to visualise mutagenesis within individual bacterial cells. These experiments have revealed cell-to-cell variation in the timing and intensity of responses to DNA damage when bacteria are exposed to environmental stressors, such as antibiotics or other chemicals [1]. This variability arises even in genetically identical cells in a common environment, due to stochasticity in gene expression and distribution of proteins upon cell division. Therefore, individual cells could have different propensities to survive and mutate under environmental stress.
Despite this growing source of data, the significance of this observed variation for bacterial evolution has hardly yet been explored. The vast majority of population genetic models assume a uniform mutation rate. Initial theoretical work relaxing this assumption suggested that variation among individuals [2] and responsiveness to the environment [3] could promote adaptations involving multiple mutations. However, these population-level models were disconnected from the underlying mechanisms, and neglected some important features of bacterial DNA damage responses. For instance, mutation rates should show an intermediate level of correlation from mother to daughter cells due to inheritance of cell contents. Furthermore, mutation rate may be either positively or negatively correlated to cell viability, depending on the particular DNA damage response (“tolerance” vs. “repair”).
This project will explore the evolutionary consequences of cell-to-cell variability in mutagenesis, using data analysis, mathematical modelling, and/or simulations based on empirical observations in bacteria. Potential questions include:
• Under what circumstances can cell-to-cell variation help a bacterial population to survive environmental challenges?
• When is “tolerance” versus “repair” the best response to DNA damage?
• What is the magnitude of mutation rate variation and its correlations among cells?

Depending on student background and interests, these questions could be addressed by:
(a) developing a model accounting for general features of DNA damage responses in bacteria, and deriving predictions through mathematical analysis;
(b) developing a multi-scale model describing a particular intracellular response pathway and its relationship to cell population dynamics, to be explored through computational simulations;
(c) statistically analysing single-cell microscopy data.
Students with diverse backgrounds (e.g. mathematics, physics, statistics, biology), who have strong quantitative skills and interest in bacterial evolution, are encouraged to apply. This interdisciplinary project will be co-supervised by Dr. Helen Alexander (Institute of Evolutionary Biology), Prof. Meriem El Karoui (Institute of Cell Biology), and Dr. Tibor Antal (School of Mathematics). The student will have the opportunity to deepen their understanding of both bacterial cell biology and evolutionary theory, and to gain skills in mathematical modelling, statistics, computation, and communication in an interdisciplinary setting.

Funding Notes

The “Visit Website” button will take you to our Online Application checklist. Complete each step and download the checklist which will provide a list of funding options and guide you through the application process. Follow the instructions on the EASTBIO website (you will be directed here from our application checklist), ensuring you upload an EASTBIO application form and transcripts to your application, and ticking the box to request references. Your referees should upload their references using the EASTBIO reference form, in time for the 5th January deadline so please give them plenty of time to do this by applying early.


[1] S. Uphoff, PNAS 115:E6516-E6525 (2018):
[2] H.K. Alexander et al., Molec Biol Evol 34:419-436 (2018):
[3] Y. Ram & L. Hadany, Proc R Soc B 281:20141025 (2014):

How good is research at University of Edinburgh in Biological Sciences?

FTE Category A staff submitted: 109.70

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