Discussion

In contrast to the common presumption that the passage of time alone serves as a template for random variation of heredity, we showed that the variation of genetic sequence is specified persistently and non-randomly by the temporal resonance of RNA transcription with the binary chemical state of the redox cycle. The rate of genetic variation by RNA transcription persistently increases the total rate of mutation and oscillates asymmetrically with the redox cycle among genes. Moreover, the measured RNA transcription-induced frequency of sequence variation ( Table 1 ) is an underestimation because (1) determining the frequency of sequence variation in un-transcribed regions is challenging due to their scarcity in S. cerevisiae genome, and (2) grouping of individual time points in the two phases of the redox cycle introduces dilution of the relative values at the points of chemical extrema. Additionally, negative selection reduces the observable frequencies of sequence variation at the two phases of the redox cycle. Importantly, a random-based asymmetry in the rate of sequence variation would result in a constant variation among genome-wide transcribed regions relative to the period of the redox cycle, rather than oscillate in phase with the timing of the two phases of the redox cycle. Because time is an essential non-random variable of the information content and processing functions in cellular systems, the redox cycle clearly provides a temporal template for asymmetry in the genome-wide rate of sequence variation.

A biochemical mechanism that can account for the increased total frequency of transcription-induced sequence variation over the replication-based mutation is the asymmetric chemical reactivity between the transcribed and replicated DNA strands. Specifically, the confinement of a single round of replication to the reductive phase of the cycle is protective against variation of sequence by base oxidation [7], [24], while multiple rounds of genome-wide RNA transcription between cell divisions oscillate in the chemical environment of the reactive and unstable products of the oxidizing phase, which results in non-uniform and varied frequency of mutation across the genome. Additionally, it is important to recognize that the periodic oscillation in the frequency of sequence variation for all relevant genetic elements is appropriately in agreement with the central dogma of molecular biology. In contrast to the reality of our results, a random process as previously contemplated by others could only generate aperiodic or irregular values for the same variables of heredity. Moreover, the paradox of biological adaptation by means of such supposedly passive and random events is a priory inconsistent, because it is incorrect to assume that a random process can generate asymmetry without a template, especially for a periodic asymmetry of the redox cycle. Perhaps because the environment is dynamic, it can be non-obvious that the environment varies periodically on a number of different time-scales and its impact is matched by responsively dynamic changes in cellular functions according to the Le Chatelier's principle. The temporally ordered biochemical events and asymmetry of the redox cycle chemistry on DNA vs. RNA provide the non-random basis for a dynamic heredity in response to the environment, consistently with the Le Chatelier's principle.

The concept of adaptation through use and disuse of characteristics, whereby acquired variation outweighs inherited variation was admitted by Darwin [57]. However, Gregor Mendel's subsequent definition of static genetic inheritance [58] supplanted the dynamic notion of inheritance of acquired traits [59]. Our results may fundamentally change the common understanding about the underlying mechanism at work in adaptation and persistence of organisms. While the basis of the observed genetic and phenotypic discontinuity is broadly attributed to a continuum of evolution by passive accumulation of chance mutation, i.e. random alternations followed by selection and determination of a choice, we present evidence for acquired genetic variation that is actively induced by the environment between generations. The discrete and iterative feedback between the environment and heredity is mediated by the redox cycle, which may serve as a template mechanism for spontaneously acquired adaptation and speciation of organisms toward persistence in a dynamically changing environment.