Mutator

Bacteria contain a number of error prevention and error correction systems that maintain genome stability. However, strains exhibiting elevated mutation frequencies have recently been reported amongst natural populations of pathogenic Escherichia coli, Salmonella enterica, Pseudomonas aeruginosa, Neisseria meningitidis, Helicobacter pylori and Streptococcus pneumoniae. The majority of naturally occurring, strong mutators contain defects in the methyl-directed mismatch repair (MMR) system, with mutations in mutS predominating. MMR-deficient strains possess superior genetic backgrounds for the selection of some antibiotic-resistance mutations since mutation frequencies up to 1000-fold higher than normal strains have been reported, and resistance levels achieved in mutators can be greater than those arising in non-mutator hosts. MMR is a major constraint to interspecies recombination events. Removal of this barrier, as in the case of MMR defective mutators, also enhances the frequency of horizontal gene transfer, which is an important mechanism of acquired drug resistance in bacteria. Permanent global mutator status is associated with loss of fitness as mutators accumulate deleterious mutations more frequently than non-mutators. Fitness limitations of mutators may be overcome simply by the high bacterial cell densities that can be achieved during acute infection or by the adoption of transient mutator status. Mutators are a risk factor during the treatment of bacterial infections as they appear to enhance the selection of mutants expressing high- and low-level antibiotic resistance and have the capacity to refine existing plasmid-located resistance determinants.Mutator (Mu) element insertion has become the main way of mutating and cloning maize genes, but we are only beginning to understand how this transposon system is regulated. Mu elements are under tight developmental control and are subject to a form of epigenetic regulation that shares some features with the regulation of paramutable maize genes. Mu-like elements (MULEs) are widespread among angiosperms, and multiple diverged functional variants appear to have coexisted in genomes for long periods. In addition to its utility, the means by which this widespread and highly mutagenic system is held in check should help us to address fundamental issues concerning the stability of genomes.We investigate the mutator model for the asymmetric transition rates between the wild-type and mutator type. When the mutator gene changes its type, both mutation rate of genome and fitness landscape are changed. We look at smooth symmetric fitness landscapes both for the wild type (normal allele of special gene) and mutator type (mutator allele). In some cases involving small degree of transition rates asymmetry (or not too large genome length) where we have smooth large genome length limit, the large system of ODE can be replaced by Hamilton–Jacobi equation. We derive here the analytical results for the mean fitness and population distribution in steady state including the finite size corrections. We have observed that some interesting oscillations arise involving longer genomes, and we cannot map the large system of ODE to the single partial differential equation HJE using a simple ansatz. We assume that the found counter-intuitive phenomenon should exist for evolution on fluctuating landscapes also, for asymmetric transition rates. Actually, the asymmetry of transition (mutation) rates is an important characteristics of evolutionary dynamics.Recent evidence supports the existence of a mutator phenotype in cancer cells, although the mechanistic basis remains unknown. In this paper, it is shown that this enhanced genetic instability is generated by an amplified measurement uncertainty on genetic information during DNA replication. At baseline, an inherent measurement uncertainty implies an imprecision of the recognition, replication and transfer genetic information, and forms the basis for an intrinsic genetic instability in all biological cells. Genetic information is contained in the sequence of DNA bases, each existing due to proton tunnelling, as a coherent superposition of quantum states composed of both the canonical and rare tautomeric forms until decoherence by interaction with DNA polymerase. The result of such a quantum measurement process may be interpreted classically as akin to a Bernoulli trial, whose outcome X is random and can be either of two possibilities, depending on whether the proton is tunnelled (X = 1) or not (X = 0). This inherent quantum uncertainty is represented by a binary entropy function and quantified in terms of Shannon information entropy H(X) = −P(X = 1)log2 P(X = 1) − P(X = 0)log2 P(X = 0). Enhanced genetic instability may either be directly derived from amplified uncertainty induced by increases in quantum and thermodynamic fluctuation, or indirectly arise from the loss of natural uncertainty reduction mechanisms.This review analyzes the concept and evidence in support of a mutator phenotype in human cancer. The large number of mutations reported in tumor cells cannot be accounted for by the low mutation rates observed in normal somatic cells; rather, it must be a manifestation of a mutator phenotype present early during the tumorigenic process. The interaction between increased mutagenesis and clonal selection provides a mechanism for the selection of cells with increased proliferative advantage. The concept of a mutator phenotype in cancer has gained considerable support from the findings of enormous numbers of somatic mutations in repetitive sequences in human tumors. Moreover, cell lines exhibiting microsatellite instability demonstrate an increased mutation frequency in expressed genes. A knowledge of mechanisms that generate multiple mutations in cancer cells has important implications for prevention. For many tumors, a delay in the rate of accumulation of mutations by a factor of two could drastically reduce the death rates from these tumors.The maize mutator system, Mu, behaves in a non-Mendelian manner that may be expected if it were an extremely active controlling-element system. To test this hypothesis, the maize controlling-element systems, adtDt, DsAc ( MP), IEn, and rcuFcu were tested for mutation activity. DsAc and rcuFcu tests were the only ones in which new mutants were induced, but at a frequency much lower than that found in Mu crosses. The mutation frequency in these controlling-element systems does not differ statistically from that found in control (Non-Mu) populations.

Tests also were made to determine if Mu will substitute for the regulatory element of any of the 4 conotrolling-element. All tests were negative, suggesting that, if Mu is a controlling-element system, it is a different one from those previously described.