Mutators Enhance Adaptive Micro-Evolution in Pathogenic Microbes

Abstract

Adaptation to the changing environmental conditions experienced within a host requires genetic diversity within a microbial population. Genetic diversity arises from mutations which occur due to DNA damage from exposure to exogenous environmental stresses or generated endogenously through respiration or DNA replication errors. As mutations can be deleterious, a delicate balance must be obtained between generating enough mutations for micro-evolution to occur while maintaining fitness and genomic integrity. Pathogenic microorganisms can actively modify their mutation rate to enhance adaptive micro-evolution by increasing expression of error-prone DNA polymerases or by mutating or decreasing expression of genes required for DNA repair. Strains which exhibit an elevated mutation rate are termed mutators. Mutators are found in varying prevalence in clinical populations where large-effect beneficial mutations enhance survival and are predominately caused by defects in the DNA mismatch repair (MMR) pathway. Mutators can facilitate the emergence of antibiotic resistance, allow phenotypic modifications to prevent recognition and destruction by the host immune system and enable switching to metabolic and cellular morphologies better able to survive in the given environment. This review will focus on recent advances in understanding the phenotypic and genotypic changes occurring in MMR mutators in both prokaryotic and eukaryotic pathogens.

Importance of the Aspergillus fumigatus Mismatch Repair Protein Msh6 in Antifungal Resistance Development

“…On the other hand, the abundance of strains found with mutations in msh 6 among clinical strains suggests that these changes could provide some benefits. Therefore, the potentially increased adaptative capacity to different situations, such as antifungal exposure or host immune system attack, could provide a benefit in certain conditions [ 28 , 51 , 52 , 53 , 54 ]. Because all msh 6 mutated strains were located in a specific cluster, we decided to investigate if an alteration of the MMR pathway functions could derive in a mutator phenotype with an increased mutation frequency in comparison with their parental strain [ 30 ].…”

“…This pathway is constituted by two protein complexes: MutS, which recognizes and binds to the mismatch, and MutL, which interacts with the mistake and removes the strand [ 27 ]. Multiple homologs of these proteins have been identified among the eukaryotic microorganisms, best characterized in Saccharomyces cerevisiae [ 28 ]. Although the MMR has been poorly investigated in A. fumigatus compared to S. cerevisiae , the genes comprising it are well conserved through all phylum Ascomycota , including msh 1, msh 2, msh 3, msh 4, msh 6, and mlh 1 [ 29 ].…”

“…Although the MMR has been poorly investigated in A. fumigatus compared to S. cerevisiae , the genes comprising it are well conserved through all phylum Ascomycota , including msh 1, msh 2, msh 3, msh 4, msh 6, and mlh 1 [ 29 ]. Defects in MMR, such as gene loss or alterations of the pathways, can cause alterations in the recognition and repair of mutations, creating, in this scenario, an increased mutation rate associated with mutator phenotypes [ 28 , 29 , 30 ].…”

Rapid evolution of an adaptive multicellular morphology of Candida auris during systemic infection

“…Microevolution is a common adaptive strategy used by both prokaryotic and eukaryotic pathogens to generate genetic and phenotypic diversity to ultimately increase survival under changing environmental conditions 18 – 20 , 22 , 23 , 64 – 66 . Through adaptive microevolution under these changing conditions, cells within a population possessing beneficial mutations predominate the population in a short period of time.…”

Molecular basis of the phenotypic variants arising from a Pseudoalteromonas lipolytica mutator

“…Since introducing large numbers of mutations can be harmful, bacteria often balance a trade-off between genetic innovation and genetic fidelity to achieve a compromise in bacterial fitness [10]. To improve fitness in specific environmental niches, mutSdeficient strains often introduce further mutations in specific targets to change their phenotypic characteristics, such as increasing or decreasing polysaccharide production, as well as resistance to different types of antibiotics [11,12].…”