[Methylation of Regulatory Regions of DNA Repair Genes in Carotid Atherosclerosis].

The status of DNA methylation in the human genome changes during the pathogenesis of common diseases and acts as a predictor of life expectancy. Therefore, it is of interest to investigate the methylation level of regulatory regions of genes responsible for general biological processes that are potentially significant for the development of age-associated diseases. Among them there are genes encoding proteins of DNA repair system, which are characterized by pleiotropic effects. Here, results of the targeted methylation analysis of two regions of the human genome (the promoter of the MLH1 gene and the enhancer near the ATM gene) in different tissues of patients with carotid atherosclerosis are present. Analysis of the methylation profiles of studied genes in various tissues of the same individuals demonstrated marked differences between leukocytes and tissues of the vascular wall. Differences in methylation levels between normal and atherosclerotic tissues of the carotid arteries were revealed only for two studied CpG sites (chr11:108089866 and chr11:108090020, GRCh37/hg19 assembly) in the ATM gene. Based on this, we can assume the involvement of ATM in the development of atherosclerosis. "Overload" of the studied regions with transcription factor binding sites (according to ReMapp2022 data) indicate that the tissue-specific nature of methylation of the regulatory regions of the MLH1 and ATM may be associated with expression levels of these genes in a particular tissue. It has been shown that inter-individual differences in the methylation levels of CpG sites are associated with sufficiently distant nucleotide substitutions.

[Regulatory Potential of SNP Markers in Genes of DNA Repair Systems].

A broad range of SNP markers associated with diseases and pathogenically significant features were identified in noncoding regions of the human genome. The mechanisms that underlie their associations are a pressing problem. A number of associations was previously observed between polymorphic variants of DNA repair proteins genes and common diseases. To clarify the possible mechanisms of the associations, a detailed annotation of the regulatory potential of the markers was carried out using online resources (GTX-Portal, VannoPortal, Ensemble, RegulomeDB, Polympact, UCSC, GnomAD, ENCODE, GeneHancer, EpiMap Epigenomics 2021, HaploReg, GWAS4D, JASPAR, ORegAnno, DisGeNet, and OMIM). The review characterizes the regulatory potential for the polymorphisms rs560191 (of the TP53BP1 gene), rs1805800, rs709816 (NBN), rs473297 (MRE11), rs189037, rs1801516 (ATM), rs1799977 (MLH1), rs1805321 (PMS2), and rs20579 (LIG1). General characteristics of the markers are considered, and data are summarized to describe their influence on expression of their own and co-regulated genes and binding affinity of transcription factors. The review additionally considers the data on adaptogenic and pathogenic potentials of the SNPs and co-localized histone modifications. A possible involvement in regulating the functions of both their own and nearby genes may explain the associations of the SNPs with diseases and their clinical phenotypes.

MicroRNAs as the Potential Regulators of SARS-CoV-2 Infection and Modifiers of the COVID-19 Clinical Features.

The pandemic of coronavirus disease 2019 (COVID-19) warrants the identification of factors that may determine both risk and severity of infection. The factors include microRNAs that have a wide regulatory potential and hence are particularly interesting. The review focuses on the potential roles of human microRNAs and the viral genome as well as microRNAs in SARS-CoV-2 infection and clinical features of COVID-19. The review summarizes the information about the human microRNAs that are thought to specifically bind to the SARS-CoV-2 genome and considers their expression levels in various organs (cells) in both healthy state and pathologies that are risk factors for severe COVID-19. Potential mechanisms whereby SARS-CoV-2 may affect the clinical features of COVID-19 are discussed in brief. The mechanisms include blocking of human microRNAs and RNA-binding proteins, changes in gene expression in infected cells, and possible epigenetic modifications of the human genome with the participation of coronavirus microRNAs. Supplementary Information: The online version contains supplementary material available at 10.1134/S0026893322010034.

[MicroRNAs as the Potential Regulators of SARS-CoV-2 Infection and Modifiers of the COVID-19 Clinical Features].

The pandemic of coronavirus disease 2019 (COVID-19) warrants the identification of factors that may determine both risk and severity of infection. The factors include micro RNAs that have a wide regulatory potential and hence are particularly interesting. The review focuses on the potential roles of human microRNAs and the viral genome as well as microRNAs in SARS-CoV-2 infection and clinical features of COVID-19. The review summarizes the information about the human microRNAs that are thought to specifically bind to the SARS-CoV-2 genome and considers their expression levels in various organs (cells) in both healthy state and pathologies that are risk factors for severe COVID-19. Potential mechanisms whereby SARS-CoV-2 may affect the clinical features of COVID-19 are discussed in brief. The mechanisms include blocking of human microRNAs and RNA-binding proteins, changes in gene expression in infected cells, and possible epigenetic modifications of the human genome with the participation of coronavirus microRNAs.

Genetic Control of Human Infection with SARS-CoV-2.

In 2019, the SARS-CoV-2 beta-coronavirus, which caused a pandemic of severe acute respiratory viral infection COVID-19 (from COronaVIrus Disease 2019), was first detected. The susceptibility to SARS-CoV-2 and the nature of the course of the COVID-19 clinical picture are determined by many factors, including genetic characteristics of both the pathogen and the human. The SARS-CoV-2 genome has a similarity to the genomes of other coronaviruses, which are pathogenic for humans and cause a severe course of infection: 79% to the SARS-CoV genome and 50% to the MERS-CoV genome. The most significant differences between SARS-CoV-2 and other coronaviruses are recorded in the structure of the gene of the S protein, a key protein responsible for the virus binding to the receptor of the host organism cells. In particular, substitutions in the S protein of SARS-CoV-2, leading to the formation of the furin cleavage site that is absent in other SARS-like coronaviruses, were identified, which may explain the high pathogenicity of SARS-CoV-2. In humans, the genes that are significant for the initial stages of infection include ACE2, ANPEP, DPP4 (encode receptors for coronavirus binding); TMPRSS2, FURIN, TMPRSS11D, CTSL, CTSB (encode proteases involved in the entry of the coronavirus into the cell); DDX1 (the gene of ATP-dependent RNA helicase DDX1, which promotes replication of coronaviruses); and IFITM1, IFITM2, and IFITM3 (encode interferon-induced transmembrane proteins with an antiviral effect). These genes are expressed in many tissues (including those susceptible to the effects of SARS-CoV-2); rare and frequent variants that affect the structure of the encoded protein and its properties and expression level are described in them. A number of common genetic variants with proven functional significance are characterized by the variability in the allele frequency in the world's populations, which can determine interpopulation differences in the prevalence of COVID-19 and in the clinical features of the course of this pathology. The expression level of genes that are important for the formation of the susceptibility to SARS-CoV-2 is affected by epigenetic modifications, comorbidities at the time of infection, taking medications, and bad habits.

[Involvement of Variants in the Genes Encoding BRCA1-Associated Genome Surveillance Complex (BASC) in the Development of Human Common Diseases].

The "Mendelian code" hypothesis postulates a relationship between Mendelian (monogenic) and common pathologies. In this hypothesis, polymorphisms in the genes of Mendelian diseases may have a significant contribution to predisposition to common diseases in which the same biochemical pathways may be involved. In this review a group of genes encoding various proteins participating in the DNA repair, with a particular focus on the BRCA1-associated genome surveillance complex (BASC), is presented through the prism of the "Mendelian code" hypothesis. Here we discuss (1) their main functions in the repair of DNA double-strand breaks (ATM, MRE11, NBN, RAD50, BRCA1, and BLM) and mismatch repair (MSH2, MSH6, MLH1, PMS2, RF-C, and PCNA); (2) the mitochondrial involvement of these proteins; (3) the involvement of BASC proteins in the development of an adaptive immune response. For 13 out of 16 BASC protein encoding genes, mutations leading to monogenic diseases have already been described; for 11, there are associations with common diseases or individual biological processes. Patients with mutations in the genes of the BASC complex and patients with severe combined immunodeficiency share similar symptoms. Polymorphisms within DNA repair genes may play a role in the development of common diseases through the involvement of the immune response. The pleiotropic effects of these genes suggest their participation in the development of various conditions, both in health and pathology.

Role of microRNA in Development of Instability of Atherosclerotic Plaques.

MicroRNAs are small noncoding single-stranded RNAs that regulate gene expression. Today, we see an increasing number of studies highlighting the important role of microRNAs in the development and progression of cardiovascular diseases caused by atherosclerotic lesions of arteries. We review the available scientific data on association of the expression of these biomolecules with instability of atherosclerotic plaques in animal models and humans. We made special emphasis on miR-21, -100, -127, -133, -143/145, -221/222, and -494 because they were analyzed in more than one study. We discuss the possibility of microRNAs using in the diagnosis and therapy of atherosclerosis and its complications.

Variability of Methylation Profiles of CpG Sites in microrNA Genes in Leukocytes and Vascular Tissues of Patients with Atherosclerosis.

In this study, we for the first time described the variability of methylation levels of 71 CpG sites in microRNA genes in leukocytes and blood vessels (coronary artery atherosclerotic plaques, intact internal thoracic arteries, and great saphenous veins) in patients with atherosclerosis using the Infinium HumanMethylation27 BeadChip microarray. Most of the analyzed CpG sites were characterized by the low variability, and most of these low-variable sites were hypomethylated in all tissue samples. CpG sites in coronary artery atherosclerotic plaques and leukocytes were similar in their methylation status. The highest variability of CpG methylation levels between different tissues was found for the CpG sites of the MIR10B gene; the methylation levels of these sites in leukocytes and atherosclerotic arteries were lower than in intact blood vessels. We also found that several cardiovascular disease risk factors, as well as medications, might affect methylation levels of CpG sites in microRNAs.

[The Role of MicroRNA in Atherogenesis].

This review provides modern data on the spectrum and the functional significance of micro-RNAs involved in atherogenesis and on some regulatory mechanisms that ensure the functioning of this class of molecules. We also outline some examples of micro-RNAs use as diagnostic and therapeutic targets.

INFESTATION OF HONEYBEE (APIS MELLIFERA) FAMILIES BY MICROSPORIDIANS OF THE GENUS NOSEMA IN TOMSK PROVINCE

Infestation of bee colonies and apiaries by representatives of the genus Nosema, microsporidian protozoans of European honeybees (Apis mellifera L.), causing nosemosis, in Tomsk Province was investigated. In 2012­2015, nosemosis was detected in 32 out of 124 honeybee colonies (31.3 %) and in 20 out of 64 studied apiaries (25.8 %). The maximal infestation rate of bee colonies and apiaries constituted more than 40 % in 2014­2015. N. apis pathogen was registered in 84.4 % of infected bee colonies (16 apiaries); N. ceranae was identified in 9.4 % of infected bee colonies (2 apiaries); and co-infection (N. apis and N. ceranae) was detected in 6.3 % of infected bee colonies (2 apiaries). The reasons of the spreading of the nosemosis, such as climatic conditions, control of imported bee colonies on the presence of Nosema infection, and some others are discussed.

[Characteristic of the Genetic Variability of Four Polymorphic Variants (rs2069705, rs17880053, rs11126176, and rs804271) in Representative Samples of Indigenous and Alien Populations of Siberia].

The variability of potentially important functional polymorphic variants rs2069705 (5'UTR of the IFNG gene), rs17880053 (near 5'UTR of the IFNGR2), rs11126176 (LOC100287361 pseudogene), and rs804271 (near 5'UTR of the NEIL2 gene) was characterized in representatives of four ethnic groups living in the Siberian region. These ethnic groups included three indigenous Mongoloid ethnic groups (Yakuts, the residents of the Republic of Sakha (Yakutia), Tuvinians from the Republic of Tuva, and Buryats from the Republic Buryatia) and the alien Russian population. All of the examined variants were polymorphic. The frequency of the rs2069705 allele C in Russians was 0.5833, while it was in a range from 0.7842 to 0.8967 in representatives of the indigenous populations. The frequency of rs17880053 deletion was 0.8073 in Russians and from 0.4474 to 0.5521 in the indigenous ethnic groups. The frequency of the rs11126176 allele A was equal to 0.5398 in Russians but was recorded with lower frequencies in indigenous ethnic groups (from 0.2722 to 0.4551). The frequency of the rs804271 allele Gwas 0.5215 in Russians and from 0.2527 to 0.4022 indigenous ethnic groups. With respect to the genotype structure, the alien Russian population was considerably distanced from indigenous Mongoloid populations. Specifically, the genetic distance was 0.0742 between Russians and Yakuts, 0.1365 between Russians and Tuvinians, and 0.1433 between Russians and Buryats. Among the Mongoloid indigenous ethnic groups of Siberia, Tuvinians and Yakuts were the most distant from each other (0.0262). The genetic distance was equal to 0.0151 between Yakuts and Buryats and 0.0127 between Buryats and Tuvinians.

[Genetic diversity of the locus COI-COII of mitochondrial DNA in honeybee populations (Apis mellifera L.) from the Tomsk region].

An assessment of the genetic diversity of the COI-COII mtDNA locus in honeybee populations from the Tomsk region was conducted. Three variants of the COI-COII mtDNA locus were registered: PQQ, PQQQ (typical for Middle Russian race), and Q (typical for southern breeds). It was established that 64% of bee colonies of the maternal line originate from the Middle Russian honeybee race, 28% of bee colonies originate from southern species, and 8% are mixed bee colonies. The southern parts of the region show a higher genetic diversity of honey bees as compared to northern regions, which are dominated by bee colonies (96%) and apiaries (73%) that are homogeneous for the genetic variant of locus COI-COII. The Tomsk region has no large areas with bee colonies maternally originating from the Middle Russian breed; only a few apiaries (both in the northern and southern areas) were revealed in which all bees originated from the Middle Russian breed.

[Genetic subdivision of the Buryat population].

The results of an estimation of the level of subdivision in the Buryat ethnos (obtained oh the basis of data published by a number of research teams) are given. Altogether, information about 34 loci, including 25 diallelic loci and 9 STR loci, was analyzed. The results of the analysis, both for the diallelic polymorphic variants in genes predisposed to multifactorial diseases and for neutral STR markers, indicate the subdivision of the genetic structure of the different territorial groups of Buryats. The peculiarities of the ethnogenesis and heterogeneity of the settlement of Buryat tribes on the territory of residence are considered as one possible (but not the sole) explanation of the genetic heterogeneity of different territorial groups of Buryats. It is indicated that it is important to take into account information about the territorial, ethnic, and tribal affiliation of individuals (included in the studied groups) when planning studies aiming to establish a genetic component of the determination of pathological states in humans.

[The role of genetic factors in the development of chronic dust bronchitis in workers of coal mining enterprises of Kuzbass].

The distribution of genotypes of HP, GC, EsD, AsP and polymorphisms GSTT1 (GST-theta1) and GSTM1 (GST-micro1) and NOS3 (polymorphism VNTR4) in miners with chronic dust bronchitis, and in those without this occupational disease has been studied The carriers of genotypes of genotypes EsD 1-2, AsP bb were shown to be more prone to develop chronic dust bronchitis. Endogenous factors of resistance to the disease are the genotypes GC 1-1, EsD 1-1, AsP bc.

[Functional role of VNTR polymorphism of human genes].

A brief overview of the current views on the functional role of genetic VNTR polymorphism in humans is given. Data on the involvement of VNTRs in the regulation of gene expression and in the formation of complex phenotypes are presented. According to these data, the effects of VNTRs are determined by the number of repeats, the structure of their monomers and flanking haplotypes, epigenetic mechanisms (in the case of localization in imprinted regions) and can be modified by environmental factors. Some possible mechanisms of the influence of VNTRs on the level of expression are considered.

[Genetic demographic study of Shors in Tashtagolskii district of the Kemerovo region: changes in the marriage migration structure].

The changes in the marriage structure with respect to the age at marriage, ethnicity, and spouses' birthplaces during the period of time corresponding to two generations have been analyzed in the rural population of Shors of Tashtagolskii raion of Kemerovo oblast. In general, the Shor population had a high assortative marriage rate with respect to these parameters in the period studied, although there was a temporary tendency towards its decrease. The ages of marriage for both the male and the female Shor populations in the years 2000-2005 were significantly older than in 1940-1945 and 1970-1975. The age-assortative marriage rate was r = = 0.60 in 1940-1945, r = 0.73 in 1970-1975, and r = 0.66 in 2000-2005. The birthplace-assortative marriage rate decreased from 79.63% in 1970-1975 to 70.64% in 2000-2005. The ethnic assortative marriage rate of Shors steadily decreased during the time interval studied; it was 96.92, 89.95, and 80.98% in 1940-1945, 1970-1975, and 2000-2005, respectively, for the total rural population of Tashtagolskii raion.

[Evolutionary ontogenetic aspects of pathogenetics of chronic human diseases].

This article is a review of scientific publications, in which issues of pathogenetics of multifactorial diseases (MFDs) are considered from the viewpoint of evolution and ontogeny. Concepts explaining significance of evolutionary processes in the formation of genetic architecture of human chronic diseases ("thrifty" genomes and phenotypes, "drifting genes," decanalization) are analyzed. The roles of natural selection and genetic drift in the formation of hereditary diversity of genes for susceptibility to MFDs are considered. The modern concept of disease ontogeny (somatic mosaicism, loss ofheterozygosity, paradominant inheritance, epigenetic variability) is discussed. It is demonstrated that the evolutionary and ontogenetic approaches to analysis of genimuc and other "-omic" data are essential for understanding the biology of diseases.

[Simulation of the distribution of spinocerebellar ataxia type 1 in Yakut populations: model parameters and results of simulation].

Demographic and clinical genetic parameters used for simulation modeling of the prevalence of spinocerebellar ataxia type 1 (SCA1) in Yakut populations are described. Demographic parameters of simulated populations and the clinical genetic characteristics of carriers of the SCA1 mutant allele in them have been compared with actual data on Abyisky and Ust-Aldansky uluses of the Republic of Sakha (Yakutia). The results of a series of simulation experiments (without migration or spontaneous mutagenesis) agree with the conclusion that the high prevalence of rate of spinocerebellar ataxia type 1 in Yakut populations may be maintained because of their specific demographic structure. Prediction of the disease prevalence has shown that it will take about 1290 years for natural selection to eliminate the mutation from the population. If medical genetic counseling (MGC) is offered to 1% of the carriers of the mutation, this period will be reduced to 200 years.

[Genetic demographic study of Shors in Tashtagolskii raion of Kemerovo oblast: population dynamics and changes in the sex and age composition].

The population dynamics and changes in the sex and age structure of the Shor populations of four rural district municipalities of Tashtagolskii raion of Kemerovo oblast (Kyzyl-Shorskii, Ust-Anzasskii, Ust-Kolzasskii, and Ust-Kabyrzinsskii) with time have been analyzed. The Shor populations have been found to have contained a high proportion of people under 18 years of age during two periods, 1940-1955 and 1970-1975 (38.12-46.38 and 40.98-54.97%, respectively). However, the population reproduction pattern changed into the "reduced" one in all the municipalities studied by the early 2000s. Although there are some regional variations, a common trend towards rural population aging has formed: the man age in the Tashtagolskii raion population has increased by 7.52 and 6.94 years for men and women, respectively, during two generations; the natural sex ratio has been disturbed in both the prereproductive and reproductive populations. The total population size and effective reproductive size have decreased in three out of the four rural subpopulations studied.

[Marriage structure of Yakut populations: ethnic composition and isonymy inbreeding].

Marriage structure has been analyzed in the populations of the administrative centers of five uluses of the Republic of Sakha (Yakutia). The populations studied differ from one another with respect to ethnic composition, namely in the ratio between the indigenous and immigrant populations (the indigenous populations are larger in three uluses), in the proportions of representatives of indigenous ethnic groups among men and women contracting marriages, and in the frequencies of monoethnic and interethnic marriages. Positive assortative marriage among persons of the same ethnic group has been demonstrated. The total inbreeding estimated by isonymy (F(it)) varies from 0 to 0.007576.