Unveiling Human Non-Random Genome Editing Mechanisms Activated in Response to Chronic Environmental Changes: I. Where Might These Mechanisms Come from and What Might They Have Led To?

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.

Upregulation of the Renin–Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients

“…It is now emerging that SARS-CoV-2 infection leads to the appearance of various autoimmune and inflammatory diseases, whose molecular mechanisms are still unknown [76]. In this regard, I have recently described how the majority of protein structures can be "edited" by an intronic-mediated mechanism resembling that of immunoglobulin somatic hypermutation [77]. In particular, this occurs when genes are transcribed at their maximum rate ("hyper-transcribed") and yet still are unable to meet environmental demands, i.e., their protein products are inadequate, and in this case, new genetic attempts can incidentally generate more adequate and functional proteins [77].…”

“…In this regard, I have recently described how the majority of protein structures can be "edited" by an intronic-mediated mechanism resembling that of immunoglobulin somatic hypermutation [77]. In particular, this occurs when genes are transcribed at their maximum rate ("hyper-transcribed") and yet still are unable to meet environmental demands, i.e., their protein products are inadequate, and in this case, new genetic attempts can incidentally generate more adequate and functional proteins [77]. However, the majority of genetic attempts can generate dysfunctional proteins and/or proteins that can be recognised as extraneous (non-self) by the immune system, ultimately leading to autoimmunity [77].…”

“…In particular, this occurs when genes are transcribed at their maximum rate ("hyper-transcribed") and yet still are unable to meet environmental demands, i.e., their protein products are inadequate, and in this case, new genetic attempts can incidentally generate more adequate and functional proteins [77]. However, the majority of genetic attempts can generate dysfunctional proteins and/or proteins that can be recognised as extraneous (non-self) by the immune system, ultimately leading to autoimmunity [77]. It is tempting to speculate that, triggered by SARS-CoV-2 infection, hypertranscription of ACE2downstream and immune-response pathways may induce the generation of several new gene attempts encoding non-functional proteins and/or new proteins which can be sensed as non-self by the immune system.…”

Non-Random Genome Editing and Natural Cellular Engineering in Cognition-Based Evolution

“…Importantly, infective RNA networks all have a crucial role in natural genetic engineering. These help to create novelty and effect evolutionary transitions through intrinsic cooperation, community associations, and de novo nucleotide sequence insertions or deletions [ 12 , 63 , 114 , 115 , 116 ]. RNA networks of all types, such as group 1 or group 2 introns, retrotransposons, retroviruses, RNA viruses, LINEs, and SINEs, can enter and integrate into chromosomal DNA.…”

Yin-Yang Balance of ACE/ACE2 Pathways: The Rational for Administration of ACE2 Pathway Inhibitors in Patients Infected by SARS-CoV-2

“…Indeed, inhibition of ADAM17 enzymatic activity has been already proposed about ten years ago by Haga and colleagues [15], although inhibition of ADAM17 is expected to increase membrane ACE2 expression and the probability of viral entry. Nevertheless, in the early phases of the disease in absence of systemic ACE2 pathway upregulation and, in particular, of ACE2-mediated immune suppression, it is expectable that maintenance/recovery of correct organismal immune responses in concert with cellular adaptive immune responses mediated by APOBEC systems [55] may anyway work to induce both an effective "immunization" and the viral eradication. However, of more interest are the inhibitor of ACE2 and renin.…”