Frontier Bioscience - Evolutionary consequences of mutation rate variation in bacteria

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.