Mutation rates are crucial to an organism. By creating variation within an organismâs genome, they produce the variation needed by natural selection. Therefore, the rate that mutations arise could affect the rate that organism adapts and evolves. Since most mutations are deleterious to an organismâs fitness however, the mutation rate should be minimised as far as possible. This occurs in a wide range of species spanning the tree of life where mutation rate associates inversely with the organismâs effective population size, which equates to the balance between the powers of selection and genetic drift. Such mutation rates are variable, having not evolved to a constant but vary depending upon the environment. Through the work in this thesis I answer questions regarding the evolution and mechanistic control of this environmental mutation rate plasticity with regard to the population density of a culture. Mutation rates have previously been shown to have an inverse association with population density at a locus in one bacterium. In the first experimental chapter, this association is found within the last 75 years of published literature and then is shown empirically to be present, but variable, in both pro-and eukaryotes. Intriguingly, this negative density associated mutation rate plasticity (DAMP) requires the same intracellular housekeeping Nudix hydrolase protein, in both domains, that hydrolyses the mutagenic nucleotide 8-oxo-dGTP. I extend this work further in the second experimental chapter, discovering that DAMP is present within two species of the final domain of life to be empirically tested, the Archaea, showing DAMPâs evolution at broad evolutionary scales. DAMP is then shown to also evolve at a fine evolutionary scale in the third experimental chapter. Between strains of the bacterium E. coli both the average mutation rate and the degree of DAMP exhibited has evolved. Furthermore, there is evidence for both a phylogenetic signal of DAMP and also an association of its degree with the average mutation rate. In the final experimental chapter I investigate the molecular mechanisms involved in modulating DAMP, discovering four more Nudix hydrolase genes that affect DAMP in contrasting ways. DAMP is then shown to be pervasive across the culture cycle, with the mutation rate affected by the concentration of the intracellular nucleotide pool. These results all combine to indicate that DAMP is a highly evolving trait, which potentially has a wide phylogenetic spread and ancient evolutionary origin.
|Date of Award||1 Aug 2019|
- The University of Manchester
|Supervisor||Andrew Mcbain (Supervisor) & Chris Knight (Supervisor)|