Role Of Retroelements In The Development Of COVID-19 Neurological Consequences

Retroelements play a key role in brain functioning in humans and other animals, since they represent dynamic regulatory elements controlling the expression of specific neuron types. The activity of retroelements in the brain is impaired under the influence of SARS-CoV-2, penetrating the blood-brain barrier. We propose a new concept, according to which the neurological complications of COVID-19 and their long-term effects are caused by modified expression of retroelements in neurons due to viral effect. This effect is implemented in several ways: a direct effect of the virus on the promoter regions of retroelement-encoding genes, virus interaction with miRNAs causing silencing of transposons, and an effect of the viral RNA on the products of retroelement transcription. Aging-related physiological activation of retroelements in the elderly is responsible for more severe course of COVID-19. The associations of multiple sclerosis, Parkinson’s disease, Guillain-Barré syndrome, acute disseminated encephalomyelitis with coronavirus lesions also indicate the role of retroelements in such complications, because retroelements are involved in the mechanisms of the development of these diseases. According to meta-analyses, COVID-19-caused neurological complications ranged 36.4-73%. The neuropsychiatric consequences of COVID-19 are observed in patients over a long period after recovery, and their prevalence may exceed those during the acute phase of the disease. Even 12 months after recovery, unmotivated fatigue, headache, mental disorders, and neurocognitive impairment were observed in 82%, 60%, 26.2-45%, and 16.2-46.8% of patients, correspondingly. These manifestations are explained by the role of retroelements in the integration of SARS-CoV-2 into the human genome using their reverse transcriptase and endonuclease, which results in a long-term viral persistence. The research on the role of specific retroelements in these changes can become the basis for developing targeted therapy for neurological consequences of COVID-19 using miRNAs, since epigenetic changes in the functioning of the genome in neurons, affected by transposons, are reversible

ЭПИГЕНЕТИКА КАНЦЕРОГЕНЕЗА

Currently, the key mechanisms of carcinogenesis are epigenetic events. Epigenetic factors include DNA methylation, histone modifications, microRNA expression and higher chromatin organization. Non-coding RNAs include microRNAs, small interfering RNAs or siRNAs, piRNAs, long noncoding RNAs or lncRNAs. According to recent data, most of these RNAs are directly formed from mobile genetic elements or have a transposon origin. Non-coding RNAs specifically affect the methylation of the genome and the modification of histones in ontogenesis. This is facilitated by evolutionarily programmed features of activation of transposons, since non-coding RNAs are formed from transposons. Thus, the material basis of epigenetic heredity are the transposons. Stress and aging increase the likelihood of developing cancer. This can be explained by an increase in the number of abnormal activation of mobile genetic elements that are sensitive to stress and hormones. Abnormal activation of transposons in cells leads to genomic instability-most such cells undergo apoptosis. However, in some cases, progressive genomic instability leads to damage to oncospressor genes and oncogenes activation - as a result of apoptosis does not occur, and cells acquire the ability of uncontrolled proliferation with the accumulation of a variety of mutations due to the progressive genomic instability caused by the mobilization of transposons. In each type of malignant tumors, specific cascade mechanisms of activation of mobile genetic elements with the participation of non-coding RNA are triggered. The study of epigenetic mechanisms of development of each type of cancer will enable to develop effective methods for early molecular genetic diagnosis of cancer, as well as targeted therapy at different stages of carcinogenesis.В настоящее время ключевыми механизмами канцерогенеза признаны эпигенетические события, к которым относятся специфические изменения метилирования ДНК, модификации гистонов, экспрессия микроРНК и высшая хроматиновая организация. Согласно последним данным, некодирующие РНК (микроРНК, малые интерферирующие РНК или siРНК, piРНК, длинные некодирующие РНК или lncРНК) в большинстве своем либо непосредственно образуются из мобильных генетических элементов, либо имеют транспозонное происхождение. Некодирующие РНК специфически влияют на метилирование генома и модификации гистонов в онтогенезе, чему способствуют эволюционно запрограммированные особенности активации транспозонов, из последовательностей которых происходят данные РНК. Таким образом, материальной основой эпигенетической наследственности служат транспозоны. Под действием стресса и при старении увеличивается вероятность развития онкопатологии, что объясняется повышенной вероятностью аномальной активации мобильных генетических элементов, чувствительных к стрессовым воздействиям и изменению уровня гормонов. Аномальная активация транспозонов в клетках ведет к геномной нестабильности – большинство подобных клеток подвергаются апоптозу. Однако в некоторых случаях прогрессирующая геномная нестабильность ведет к повреждению генов онкосупрессоров и активации онкогенов - в результате апоптоза не происходит, а клетки обретают способность неконтролирующей пролиферации с накоплением множества мутаций вследствие прогрессирующей геномной нестабильности, вызванной мобилизацией транспозонов. В каждом типе злокачественных опухолей запускаются свои каскадные механизмы активации мобильных генетических элементов с участием некодирующих РНК. Исследование эпигенетических механизмов развития каждого типа рака даст возможность разработать эффективные методы ранней молекулярно-генетической диагностики онкопатологии, а также таргетной терапии на разных стадиях развития патологического процесса

Analysis of Polymorphism of Uniparental Markers in Reindeer-Herding Populations: The Tozhu Tuvans of Russia and The Tsaatans Of Mongolia

We analyzed the data on the variability of the Y chromosome and mitochondrial DNA (mtDNA) in populations of the Tsaatans of Mongolia and the Tozhu Tuvans of Russia. The populations studied are characterized by low genetic diver¬sity for both marker systems. The analysis of Y chromosome haplogroups in the Tsaatan and Tozhu revealed three hap¬logroups in the Tsaatan and seven haplogroups in the Tozhu. The composition of the haplogroups is coherent to literature data on the Tuvans, which is explained by common origin. According to the data on mitochondrial DNA variability, 12 haplogroups were determined in 46 Tozhus, of which C4b (30.43%) and F1b1b (23.91%) are major haplogroups. According to the HVS–1 (HyperVariable Segment) data, 15 haplotypes were found in the Tozhu Tuvans and the diversity coefficient of 0.8677 turned out to be much lower than among the Torghut of Mongolia (0.9857). In 23 Tsaatans, 14 haplogroups were determined; the most common of which are C4b (22.73%) and C5a1 (18.18%). According to HVS-1, 14 haplotypes were revealed in the Tsaatan, the diversity is 0.9486. The data obtained on uniparental marker systems in the Tozhus and Tsaatans are due to the isolated and inaccessible taiga region and the manifestation of the “founder effect”. The Tsaatans are less polymorphic in terms of the variety of Y chromosome haplogroups, while the Tozhus are less polymorphic in terms of mitochondrial DNA, which is probably a consequence of a high rate of endogamic marriages in the populations studied

Between Lake Baikal and the Baltic Sea: Genomic History of the Gateway to Europe

Background: The history of human populations occupying the plains and mountain ridges separating Europe from Asia has been eventful, as these natural obstacles were crossed westward by multiple waves of Turkic and Uralic speaking migrants as well as eastward by Europeans. Unfortunately, the material records of history of this region are not dense enough to reconstruct details of population history. These considerations stimulate growing interest to obtain a genetic picture of the demographic history of migrations and admixture in Northern Eurasia. Results: We genotyped and analyzed 1076 individuals from 30 populations with geographical coverage spanning from Baltic Sea to Baikal Lake. Our dense sampling allowed us to describe in detail the population structure, provide insight into genomic history of numerous European and Asian populations, and significantly increase quantity of genetic data available for modern populations in region of North Eurasia. Our study doubles the amount of genome-wide profiles available for this region. We detected unusually high amount of shared identical-by-descent (IBD) genomic segments between several Siberian populations, such as Khanty and Ket, providing evidence of genetic relatedness across vast geographic distances and between speakers of different language families. Additionally, we observed excessive IBD sharing between Khanty and Bashkir, a group of Turkic speakers from Southern Urals region. While adding some weight to the “Finno-Ugric” origin of Bashkir, our studies highlighted that the Bashkir genepool lacks the main “core”, being a multi-layered amalgamation of Turkic, Ugric, Finnish and Indo-European contributions, which points at intricacy of genetic interface between Turkic and Uralic populations. Comparison of the genetic structure of Siberian ethnicities and the geography of the region they inhabit point at existence of the “Great Siberian Vortex” directing genetic exchanges in populations across the Siberian part of Asia. Slavic speakers of Eastern Europe are, in general, very similar in their genetic composition. Ukrainians, Belarusians and Russians have almost identical proportions of Caucasus and Northern European components and have virtually no Asian influence. We capitalized on wide geographic span of our sampling to address intriguing question about the place of origin of Russian Starovers, an enigmatic Eastern Orthodox Old Believers religious group relocated to Siberia in seventeenth century. A comparative reAdmix analysis, complemented by IBD sharing, placed their roots in the region of the Northern European Plain, occupied by North Russians and Finno-Ugric Komi and Karelian people. Russians from Novosibirsk and Russian Starover exhibit ancestral proportions close to that of European Eastern Slavs, however, they also include between five to 10 % of Central Siberian ancestry, not present at this level in their European counterparts. Conclusions: Our project has patched the hole in the genetic map of Eurasia: we demonstrated complexity of genetic structure of Northern Eurasians, existence of East-West and North-South genetic gradients, and assessed different inputs of ancient populations into modern populations

Identification of a new locus at 16q12 associated with time-to-asthma onset

International audienceBackground: Asthma is a heterogeneous disease in which age-of-onset plays an important role.Objective: We sought to identify the genetic variants associated with time-to-asthma onset.Methods: We conducted a large-scale meta-analysis of nine genome-wide association studies of time-to-asthma onset (total of 5,462 asthmatics with a broad range of age-of-asthma onset and 8,424 controls of European ancestry) performed using survival analysis techniques.Results: We detected five regions associated with time-to-asthma onset at genome-wide significant level (P<5x10-8). We evidenced a new locus in 16q12 region (near cylindromatosis turban tumor syndrome gene (CYLD)) and confirmed four asthma risk regions: 2q12 (IL1RL1), 6p21 (HLA-DQA1), 9p24 (IL33) and 17q12-q21 (ZPBP2-GSDMA). Conditional analyses identified two distinct signals at 9p24 (both upstream of IL33) and at 17q12-q21 (near ZPBP2 and within GSDMA). These seven distinct loci explained together 6.0% of the variance in time-to-asthma onset. In addition, we showed that genetic variants at 9p24 and 17q12-q21 were strongly associated with an earlier onset of childhood asthma (P≤0.002) whereas 16q12 SNP was associated with a later asthma onset (P=0.04). A high burden of disease risk alleles at these loci was associated with earlier age-of-asthma onset (4 years versus 9-12 years, P=10-4).Conclusion: The new susceptibility region for time-to-asthma onset at 16q12 harbors variants that correlate with the expression of CYLD and NOD2 (nucleotide-binding oligomerization domain 2), two strong candidates for asthma. This study demonstrates that incorporating the variability of age-of-asthma onset in asthma modeling is a helpful approach in the search for disease susceptibility genes

Diversity of Y-chromosomal and mtDNA Markers Included in Mediscope Chip within Two Albanian Subpopulations from Croatia and Kosovo: Preliminary Data

The aim of this preliminary study is to analyze genetic specificity of Kosovo Albanians comparing with neighboring populations using new genetic tool - MEDISCOPE gene chip, to investigate the feasibility of this approach. We collected 37 DNA samples (9 Croats, 17 Albanians from Croatia and 11 Albanians from Kosovo) from unrelated males born in Croatia and Kosovo. Additionally, samples were expanded with female individuals and mtDNA analysis included a total of 61 samples (15 Croats, 23 Albanians from Croatia and 23 Albanians from Kosovo). This pilot study suggests that the usage of the MEDISCOPE chip could be recognized as an efficient tool within recognition of the population genetic specificity even within extremely small sample size