Abstract
This article challenges the notion of the randomness of mutations in eukaryotic cells by unveiling stress-induced human non-random genome editing mechanisms. To account for the existence of such mechanisms, I have developed molecular concepts of the cell environment and cell environmental stressors and, making use of a large quantity of published data, hypothesised the origin of some crucial biological leaps along the evolutionary path of life on Earth under the pressure of natural selection, in particular, (1) virus–cell mating as a primordial form of sexual recombination and symbiosis; (2) Lamarckian CRISPR-Cas systems; (3) eukaryotic gene development; (4) antiviral activity of retrotransposon-guided mutagenic enzymes; and finally, (5) the exaptation of antiviral mutagenic mechanisms to stress-induced genome editing mechanisms directed at “hyper-transcribed” endogenous genes. Genes transcribed at their maximum rate (hyper-transcribed), yet still unable to meet new chronic environmental demands generated by “pollution”, are inadequate and generate more and more intronic retrotransposon transcripts. In this scenario, RNA-guided mutagenic enzymes (e.g., Apolipoprotein B mRNA editing catalytic polypeptide-like enzymes, APOBECs), which have been shown to bind to retrotransposon RNA-repetitive sequences, would be surgically targeted by intronic retrotransposons on opened chromatin regions of the same “hyper-transcribed” genes. RNA-guided mutagenic enzymes may therefore “Lamarkianly” generate single nucleotide polymorphisms (SNP) and gene copy number variations (CNV), as well as transposon transposition and chromosomal translocations in the restricted areas of hyper-functional and inadequate genes, leaving intact the rest of the genome. CNV and SNP of hyper-transcribed genes may allow cells to surgically explore a new fitness scenario, which increases their adaptability to stressful environmental conditions. Like the mechanisms of immunoglobulin somatic hypermutation, non-random genome editing mechanisms may generate several cell mutants, and those codifying for the most environmentally adequate proteins would have a survival advantage and would therefore be Darwinianly selected. Non-random genome editing mechanisms represent tools of evolvability leading to organismal adaptation including transgenerational non-Mendelian gene transmission or to death of environmentally inadequate genomes. They are a link between environmental changes and biological novelty and plasticity, finally providing a molecular basis to reconcile gene-centred and “ecological” views of evolution.
Highlights
The lowest error rates per nucleotide are reported for eukaryotes, while the highest mutation rates are observed in viroids, which are short single-stranded circular RNA without a protein coat and likely the first virus-like structures and survivors of the hypothetical “RNA world” stage in the evolutionary history of life on Earth [2,3]
The authors showed that DBR1, necessary for both debranching intronic lariats and retro-transposition [87,88], was required for activation-induced deaminase (AID) localization to S region DNA during class-switch recombination (CSR) [95], suggesting that stable intronic lariats, containing repetitive sequences of the S region, have to be processed by DBR1 before carrying out their targeting functions. These data indicate that the RNA-mediated mechanism of AID targeting to Ig S single-stranded DNA (ssDNA) regions is mediated by intronic repetitive sequences generated by Ig hyper-transcribed genes, i.e., inadequate genes which produce immunoglobulin proteins that are unable to respond to new environmental conditions
When the cell environment is sufficiently stable and cell reversible/epigenetic/homeostatic mechanisms are sufficient to respond to normal molecular fluctuations the cell eukaryotic genome is adequate
Summary
The modern synthesis of evolution is a gene-centred theory based on Darwinian natural selection and Mendelian genetics. The lowest error rates per nucleotide are reported for eukaryotes, while the highest mutation rates are observed in viroids, which are short single-stranded circular RNA without a protein coat and likely the first virus-like structures and survivors of the hypothetical “RNA world” stage in the evolutionary history of life on Earth [2,3] This evidence suggests that error rates have been progressively reduced over evolutionary time and biological complexity [1,2], raising the possibility that new evolutionary mechanisms, able to generate novelties, have been developed during the evolution of increasingly complex organisms. It would appear that known mechanisms of adaptation are unable to explain the above-mentioned observations regarding other eukaryotic genes
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