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

Abstract

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.

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

“…It has been shown that Paramecia can become extinct by the accumulation of harmful mutations when cultured for a long period without conjugations (Holmes and Holmes, 1986 ). As mentioned above, however, our disparity mutagenesis model predicts an increased mutation rate threshold; i.e., in the case of the knapsack problem without sex (Wada et al, 1993 ), in our evolution experiments with living microorganisms (Tanabe et al, 1999 ; Shimoda et al, 2006 ) and in the case of human tumor expansion (Furusawa, 2013 ). These systems were carried out without relation to sex.…”

“…The disparity mutagenesis model is deduced from the principles of the “Disparity Theory of Evolution” (Furusawa and Doi, 1992 , 1998 ; Furusawa, 2013 ) and provides an explanation for why living things do not become extinct even when mutation rates exceed the threshold. The theory and model predict that the error frequency is significantly higher in the lagging DNA strand, since a more complex system is used in the synthesis of the lagging strand compared to that of the leading strand (Furusawa and Doi, 1992 ).…”

“…Collectively, the following conclusions can be deduced from experiments using disparity-mutators of living organisms: (1) Growth rates of disparity mutators and of the intact cells are nearly equal, when cultured in normal conditions. This feature would be an essential condition for evolution experiments, because a delayed cell-cycle will work against the rate of accumulating mutations, resulting in delayed adaptive evolution; (2) The principle of the disparity mutagenesis model may be applicable to all living prokaryotes and eukaryotes; (3) A prolonged period of high mutation rates, during which most likely average mutation rates exceed the threshold value, does not necessarily lead to the death of organisms; (4) To attain a final intended phenotype, a number of appropriate mutations should be introduced in a correct order (Furusawa, 2013 ) and most probably, genome-wide changes with mutations are necessary. These might be the reasons why final phenotypes were so stable.…”