Contribution of Retrotransposons to the Pathogenesis of Type 1 Diabetes and Challenges in Analysis Methods.

Type 1 diabetes (T1D) is one of the most common chronic diseases of the endocrine system, associated with several life-threatening comorbidities. While the etiopathogenesis of T1D remains elusive, a combination of genetic susceptibility and environmental factors, such as microbial infections, are thought to be involved in the development of the disease. The prime model for studying the genetic component of T1D predisposition encompasses polymorphisms within the HLA (human leukocyte antigen) region responsible for the specificity of antigen presentation to lymphocytes. Apart from polymorphisms, genomic reorganization caused by repeat elements and endogenous viral elements (EVEs) might be involved in T1D predisposition. Such elements are human endogenous retroviruses (HERVs) and non-long terminal repeat (non-LTR) retrotransposons, including long and short interspersed nuclear elements (LINEs and SINEs). In line with their parasitic origin and selfish behaviour, retrotransposon-imposed gene regulation is a major source of genetic variation and instability in the human genome, and may represent the missing link between genetic susceptibility and environmental factors long thought to contribute to T1D onset. Autoreactive immune cell subtypes with differentially expressed retrotransposons can be identified with single-cell transcriptomics, and personalized assembled genomes can be constructed, which can then serve as a reference for predicting retrotransposon integration/restriction sites. Here we review what is known to date about retrotransposons, we discuss the involvement of viruses and retrotransposons in T1D predisposition, and finally we consider challenges in retrotransposons analysis methods.

Cellular and extracellular levels of retrovirus-host interactions on the example of the bovine leukose virus. 2. critical stages - multiplicity and versatility (review)

The wide spread of viral infections and the ease of overcoming the species-specific barriers require the identification of critical stages in the virus interaction with multicellular organisms of mammals and the analysis of key molecular genetic systems involved. To date, a large amount of data has already been accumulated on the diversity and complexity of such systems, as well as the involvement in them the wide range of metabolic pathways. In this regard, attempts to identify some common elements that are implemented in different infectious processes are of particular relevance. This paper is such attempt made on the example of the analysis of the main events of cattle infection by bovine leukemia virus (BLV). Systems involved in the entry of BLV genetic material into the cytoplasm of host cells, the suppression of innate and adaptive immunity, as well as interactions between the genomes of the BLV provirus and the host genome are the identified critical stages. The direct participants in the reception of viral proteins are parts of some host tansmembrane systems (G.Yu. Kosovsky et al., 2017;V.I. Glazko et al., 2018;L. Bai et al., 2019;H. Sato et al., 2020). During virus reproduction in host cells, host enzymes modify virus envelope proteins by (A. De Brogniez et al., 2016;W. Assi et al., 2020). Importantly, modifications of SARS-CoV-2 spike proteins, as well as BLV envelope proteins, have a significant impact on their pathogenicity (M. Hoffmann et al., 2020). Pathogenicity and depressing effect of both BLV and SARS-CoV-2 on innate and adaptive immunity is realized in part through the activation of T regulatory cells and an increase in the expression of the growth transforming factor TGF-b (L.Y. Chang et al., 2015;G.Yu. Kosovsky et al., 2017;W. Chen et al., 2020). Intracellular mechanisms of protection against retrotranspositions, recombinations between viruses and host retrotransposons, the formation of new elements of host regulatory networks such as microRNAs, and the integration of proviral DNA into the host genome are closely related and controlled by interfering RNA (RNAi) systems with the key gene dicer1 (P.V. Maillard et al., 2019;E.Z. Poirier et al., 2021;G.Y. Kosovsky et al., 2020). These systems can provide a certain left-pointing-double-angle resistance right-pointing-double-angle of the host genome both to the integration of exogenous genetic material and to transpositions of own mobile genetic elements. Apparently, it is the polygenicity of the control of these critical stages of viral infection that leads to difficulties in predicting their development and developing methods for their prevention.

mRNA Vaccines: Why Is the Biology of Retroposition Ignored?

The major advantage of mRNA vaccines over more conventional approaches is their potential for rapid development and large-scale deployment in pandemic situations. In the current COVID-19 crisis, two mRNA COVID-19 vaccines have been conditionally approved and broadly applied, while others are still in clinical trials. However, there is no previous experience with the use of mRNA vaccines on a large scale in the general population. This warrants a careful evaluation of mRNA vaccine safety properties by considering all available knowledge about mRNA molecular biology and evolution. Here, I discuss the pervasive claim that mRNA-based vaccines cannot alter genomes. Surprisingly, this notion is widely stated in the mRNA vaccine literature but never supported by referencing any primary scientific papers that would specifically address this question. This discrepancy becomes even more puzzling if one considers previous work on the molecular and evolutionary aspects of retroposition in murine and human populations that clearly documents the frequent integration of mRNA molecules into genomes, including clinical contexts. By performing basic comparisons, I show that the sequence features of mRNA vaccines meet all known requirements for retroposition using L1 elements-the most abundant autonomously active retrotransposons in the human genome. In fact, many factors associated with mRNA vaccines increase the possibility of their L1-mediated retroposition. I conclude that is unfounded to a priori assume that mRNA-based therapeutics do not impact genomes and that the route to genome integration of vaccine mRNAs via endogenous L1 retroelements is easily conceivable. This implies that we urgently need experimental studies that would rigorously test for the potential retroposition of vaccine mRNAs. At present, the insertional mutagenesis safety of mRNA-based vaccines should be considered unresolved.