Upregulation of Genes Involved in Gluconeogenesis and the Glyoxylate Cycle Suppressed the Drug Sensitivity of an<i>N</i>-Glycan-Deficient<i>Saccharomyces cerevisiae</i>Mutant

2014

Front. Genet.

In animals including humans, mutation rates per generation exceed a perceived threshold, and excess mutations increase genetic load. Despite this, animals have survived without extinction. This is a perplexing problem for animal and human genetics, arising at the end of the last century, and to date still does not have a fully satisfactory explanation. Shortly after we proposed the disparity theory of evolution in 1992, the disparity mutagenesis model was proposed, which forms the basis for an explanation for an acceleration of evolution and species survival. This model predicts a significant increase of the mutation threshold values if the fidelity difference in replication between the lagging and leading strands is high enough. When applied to biological evolution, the model predicts that living things, including humans, might overcome the lethal effect of accumulated deleterious mutations and be able to survive. Artificially derived mutator strains of microorganisms, in which an enhanced lagging-strand-biased mutagenesis was introduced, showed unexpectedly high adaptability to severe environments. The implications of the striking behaviors shown by these disparity mutators will be discussed in relation to how living things with high mutation rates can avoid the self-defeating risk of excess mutations.

Section: Discussionmentioning

confidence: 99%

Section: Acceleration Of Evolution Using Disparity-mutators Of Livingmentioning

confidence: 97%

The disparity mutagenesis model predicts rescue of living things from catastrophic errors

2014

Front. Genet.

“…Using disparity mutators of microorganisms, there have been several reports: (1) improvement of the nature of the yeast cell-wall (Abe et al, 2009a), (2) mutated yeasts having multi-stress tolerance which might be useful, e.g., for bio-ethanol production (Abe et al, 2009b), and (3) improvement of the therapeutic glycoprotein productivity of gene-engineered yeasts, which is toxic for the replication of the host yeast (Abe et al, 2009c), and (4) up-regulation of N 2 O reductase activity in a nitrogen-fixing bacterium (Itakura et al, 2008). We have also established several tolerant S. cerevisiae mutants tolerant against pH 2.5, pH 10.3, 2% of isooctane, and 10% of hexane, toluene, chloroform, cyclohexane, and isooctane, respectively (unpublished).…”

Section: Acceleration Of Evolution Using Living Microorganisms With Bmentioning

confidence: 99%

Implications of fidelity difference between the leading and the lagging strand of DNA for the acceleration of evolution

2012

Front. Oncol.

Without exceptions, genomic DNA of living organisms is replicated using the leading and the lagging strand. In a conventional idea of mutagenesis accompanying DNA replication, mutations are thought to be introduced stochastically and evenly into the two daughter DNAs. Here, however, we hypothesized that the fidelity of the lagging strand is lower than that of the leading strand. Our simulations with a simplified model DNA clearly indicated that, even if mutation rates exceeded the so-called threshold values, an original genotype was guaranteed in the pedigree and, at the same time, the enlargement of diversity was attained with repeated generations. According to our lagging-strand-biased-mutagenesis model, mutator microorganisms were established in which mutations biased to the lagging strand were introduced by deleting the proofreading activity of DNA polymerase. These mutators (“disparity mutators”) grew normally and had a quick and extraordinarily high adaptability against very severe circumstances. From the viewpoint of the fidelity difference between the leading and the lagging strand, the basic conditions for the acceleration of evolution are examined. The plausible molecular mechanism for the faster molecular clocks observed in birds and mammals is discussed, with special reference to the accelerated evolution in the past. Possible applications in different fields are also discussed.

“…There are several other experiments in which yeast disparity-mutators displayed high adaptabilities to different conditions [29][30][31] .…”

Section: Mutator Of Budding Yeastmentioning

confidence: 99%

The role of disparity-mutagenesis model on tumor development with special reference to increased mutation rate

2013

JST

Human solid tumors are believed to have very high mutation rates at least in the early stage of extension. Irrespective of whether the increased mutation rate is a necessary condition for the tumor development or not, extremely high mutation rates such as in excess of the so-called "threshold" would before long result in the natural death of tumor cells. In reality, however, we are dying by cancer. Thus, it has been hypothesized that tumor cells should make a quick transition from the higher mutation state to the lower one. According to our "disparity-mutagenesis model", however, carcinogenesis could continue without any incident even under a prolonged period of high mutation rates. Namely, if lagging-strand-biased mutations far beyond the threshold of mutation rate are introduced in tumor cells, the tumor could progress to malignant extension without extinction. The results of evolution experiments using mutator microorganisms are discussed in terms of carcinogenesis.