mutL as a genetic switch of bacterial mutability: turned on or off through repeat copy number changes

Bacterial adaptation to changing environments can be achieved through the acquisition of genetic novelty by accumulation of mutations and recombination of laterally transferred genes into the genome, but the mismatch repair (MMR) system strongly inhibits both these types of genetic changes. As mutation and recombination do occur in bacteria, it is of interest to understand how genetic novelty may be achieved in the presence of MMR. Previously, we observed associations of a defective MMR genotype, 6bp delta mutL, with greatly elevated bacterial mutability in Salmonella typhimurium. To validate these observations, we experimentally converted the mutL gene between the wild-type and 6bp delta mutL in S. typhimurium and inspected the bacterial mutability status. When 6bp delta mutL was converted to mutL, the originally highly mutable Salmonella strains regained genetic stability; when mutL was converted to 6bp delta mutL, the mutability was elevated 100-fold. Interestingly, mutL cells were found to grow out of 6bp delta mutL cells; the new mutL cells eventually replaced the original 6bp delta mutL population. As conversion between mutL and 6bp delta mutL may occur readily during DNA replication, it may represent a previously unrecognized mechanism to modulate bacterial mutability at the population level, allowing bacteria to respond rapidly to changing environments while minimizing the risks associated with persistent hypermutability.