[A perspective on the application of CRISPR/CAS9 genome editing system to study of molecular-genetic basis of mental disorders]. / Perspektivy ispol'zovaniya sistemy genomnogo redaktirovaniya CRISPR/Cas9 dlya izucheniya molekulyarno-geneticheskikh osnov psikhicheskikh rasstroistv.

Schizophrenia, depression, bipolar disorder and autism spectrum disorders are common mental disorders that are among the leading causes of disability worldwide. The major complication to effective therapies for mental disorders is the poor understanding of their pathogenic mechanisms. Currently, an increasing number of research groups are focusing on uncovering the molecular mechanisms of mental disorders and developing novel therapies using the CRISPR/Cas9 (Clustered, Regularly Interspaced, Short Palindromic Repeats (CRISPR) - CRISPR-associated system 9 (Cas9)) system to determine the molecular mechanisms of developing mental disorders and novel therapy. The CRISPR/Cas9 system is the most promising among genome editing tools. Numerous advantages of the CRISPR/Cas9 system and its successful application in some studies provide wide opportunities for genome therapy and regeneration medicine. In this review we shortly describe structure and function of the CRISPR/Cas9 system and its application to study the molecular-genetic basis of mental disorders in human.

[Predictors of therapeutic efficacy of immune response checkpoint inhibitors in clear cell renal cell carcinoma].

Immunotherapy in oncologic diseases involves the use of drugs which stimulate the immune system and indirectly suppress tumor cells growth. These agents have expanded the treatment options for cancer patients. Despite the impressive success achieved in the development of immune checkpoint inhibitors (ICIs) and subsequent approval in a broader spectrum of malignant tumors, most patients are not responded the therapy. Currently available predictive markers of efficacy are nonspecific. However, microRNAs are of particular interest, which regulate gene expression and are involved in the carcinogenesis and therapy resistance. Therefore, it is clear that for the most efficient and cost-effective use of ICIs, it is important to have validated biomarkers that will accurately predict the therapeutic response. The published results on molecular genetic changes in patients with renal cell carcinoma (RCC) were analyzed and summarized in order to determine possible prognostic biomarkers when prescribing ICI therapy.

Targeted next-generation sequencing of 21 candidate genes in hereditary ovarian cancer patients from the Republic of Bashkortostan.

About 5-10% of all ovarian cancer cases show familial clustering, and some 15-25% of familial ovarian cancer cases are mediated by high-penetrance mutations in the BRCA1 and BRCA2 genes. Only few other genes have been identified for familial ovarian cancer.We conducted targeted next-generation sequencing of the protein coding region of 21 candidate genes, including UTR regions, in genomic DNA samples of 48 patients with familial ovarian cancer from the Republic of Bashkortostan. We identified deleterious variants in BRCA1, BRCA2, CHEK2, MSH6 and NBN in a total of 16 patients (33%). The NBN truncating variant, p.W143X, had not previously been reported. Seven patients (15%) were carriers of the c.5266dupC variant in BRCA1, supporting a Russian origin of this founder allele. An additional 15 variants of uncertain clinical significance were observed. We conclude that our gene panel explains about one-third of familial ovarian cancer risk in the Republic of Bashkortostan.

Individual Differences in Relative Telomere Length in Mentally Healthy Subjects: The Effect of TERT Gene Polymorphism and Urban Residency.

The changes in the telomere length caused by the terminal underreplication in the existing literature are related to depressive disorders. However, the use of the telomere length as a biomarker of depressive states is ambiguous, which is due to the effect of various environmental factors on both the psychoemotional state and cellular aging of an organism. In order to identify the possible use of the relative telomere length (RTL) measured in peripheral blood leukocytes as a biomarker of enhanced liability to depression prior to the clinical symptoms, as well as to determine the link between telomere length, sociodemographic factors, allelic variants of the genes involved in the regulation of telomere elongation, and depression level, the association analysis of reverse transcriptase (TERT rs7726159), telomerase RNA component (TERC rs1317082), and the CST complex encoding protein (OBFC1 rs2487999) gene polymorphisms was performed with RTL and depression level in mentally healthy individuals (N = 1065) aged 18-25 years. Together with genetic variants, the examined regression models included various sociodemographic parameters as predictors. As a result of statistical analysis, we failed to observe the association between RTL and individual differences in depression level in the studied sample. Nevertheless, multiple regression analysis allowed us to construct a statistically significant model of individual variance in RTL (P = 4.3е-4; r 2 = 0.018), which included rs7726159 in the TERT gene (P = 0.020; ß = 0.078) and such environmental predictors as age (P = 0.001; ß = -0.027) and place of residence in childhood (urban/rural area) (P = 0.048; ß = 0.063). The data obtained confirm the involvement of TERT gene variants and age in telomere length in mentally healthy individuals aged 18-25 years and indicate a negative effect of urban residency on telomere length shortening, which reflects the cellular aging of an organism.

The role of inflammatory system genes in individual differences in nonverbal intelligence.

Nonverbal intelligence represents one of the components of brain cognitive functions, which uses visual images and nonverbal approaches for solving required tasks. Interaction between the nervous and immune systems plays a specif ic role in individual differences in brain cognitive functions. Therefore, the genes encoding pro- and antiinflammatory cytokines are prospective candidate genes in the study of nonverbal intelligence. Within the framework of the present study, we conducted the association analysis of six SNPs in the genes that encod proteins involved in inf lammatory response regulation in the central nervous system (CRP rs3093077, IL1А rs1800587, IL1B rs16944, TNF/ LTA rs1041981, rs1800629, and P2RX7 rs2230912), with nonverbal intelligence in mentally healthy young adults aged 18- 25 years without cognitive decline with inclusion of sex, ethnicity and the presence of the "risky" APOE ε4 allele as covariates. Considering an important role of environmental factors in the development of brain cognitive functions in general and nonverbal intelligence in particular, we conducted an analysis of gene-by-environment (G × E) interactions. As a result of a statistical analysis, rs1041981 and rs1800629 in the tumor necrosis factor gene (TNF) were shown to be associated with a phenotypic variance in nonverbal intelligence at the haplotype level (for АА-haplotype: ßST = 1.19; p = 0.033; pperm = 0.047) in carriers of the "risky" APOE ε4 allele. Gene-by-environment interaction models, which determined interindividual differences in nonverbal intelligence, have been constructed: sibship size (number of children in a family) and smoking demonstrated a modulating effect on association of the TNF/LTA (rs1041981) (ß = 2.08; ßST = 0.16; p = 0.001) and P2RX7 (rs2230912) (ß = -1.70; ßST = -0.10; p = 0.022) gene polymorphisms with nonverbal intelligence. The data obtained indicate that the effect of TNF/LTA on the development of cognitive functions is evident only in the presence of the "unfavorable" APOE ε4 variant and/or certain environmental conditions.

The relationship of lamins with epigenetic factors during aging.

The key factor of genome instability during aging is transposon dysregulation. This may be due to senile changes in the expression of lamins, which epigenetically modulate transposons. Lamins directly physically interact with transposons. Epigenetic regulators such as SIRT7, BAF, and microRNA can also serve as intermediaries for their interactions. There is also an inverse regulation, since transposons are sources of miRNAs that affect lamins. We suggest that lamins can be attributed to epigenetic factors, since they are part of the NURD, interact with histone deacetylases and regulate gene expression without changing the nucleotide sequences. The role of lamins in the etiopathogenesis of premature aging syndromes may be associated with interactions with transposons. In various human cells, LINE1 is present in the heterochromatin domains of the genome associated with lamins, while SIRT7 facilitates the interaction of this retroelement with lamins. Both retroelements and the nuclear lamina play an important role in the antiviral response of organisms. This may be due to the role of lamins in protection from both viruses and transposons, since viruses and transposons are evolutionarily related. Transposable elements and lamins are secondary messengers of environmental stressors that can serve as triggers for aging and carcinogenesis. Transposons play a role in the development of cancer, while the microRNAs derived from them, participating in the etiopathogenesis of tumors, are important in human aging. Lamins have similar properties, since lamins are dysregulated in cancer, and microRNAs affecting them are involved in carcinogenesis. Changes in the expression of specif ic microRNAs were also revealed in laminopathies. Identif ication of the epigenetic mechanisms of interaction of lamins with transposons during aging can become the basis for the development of methods of life extension and targeted therapy of age-associated cancer.

[The potential role of mirnas in the pathogenesis of hemorrhagic fever with renal syndrome].

Hemorrhagic fever with renal syndrome (HFRS) is an acute natural focal viral disease caused by viruses of the genus hantavirus, characterized by damage to small blood vessels, kidneys, lungs and other organs of a person. MicroRNAs (miRNAs) are 18-22 nucleotide endogenously expressed RNA molecules that inhibit gene expression at the post-transcriptional level by binding to the 3-untranslated region of the target mRNA. It has been proven that miRNAs play a significant role in various biological processes, including the cell cycle, apoptosis, cell proliferation and differentiation. It has been proven that miRNAs may be involved in the pathogenesis of infectious diseases, including HFRS. Hantavirus infection predominantly affects endothelial cells and causes dysfunction of the endothelium of capillaries and small vessels. It is known that the immune response induced by Hantavirus infection plays an important role in disrupting the endothelial barrier. In a few studies, both in vitro and in vivo, it has been shown that endothelial dysfunction and the immune response after infection with Hantavirus can be partially regulated by miRNAs by acting on certain genes. Most of the miRNAs is expressed within the cells themselves. However, in some biological fluids of the human body, for example, plasma or blood serum, numerous miRNAs, called circulating miRNAs, have been found. Circulating miRNAs can be secreted by cells into human biological fluids as part of extracellular vesicles as exosomes or be part of an RNA-bound protein complex as miRNA-Argonaute 2 (Ago2). These miRNAs are resistant to nucleases, which makes them attractive as potential biomarkers in various human diseases. There is no specific antiviral therapy for HFRS, and the determination of laboratory parameters that are used to diagnose, assess the severity, and predict the course of the disease remains a challenge due to the peculiarities of the pathophysiology and clinical course of the disease. Studying the role of miRNAs in HFRS seems to be expedient for the development of specific and effective therapy, as well as for use as diagnostic and prognostic biomarkers (in relation to circulating miRNAs).

The role of the KIBRA and APOE genes in developing spatial abilities in humans.

In the contemporary high-tech society, spatial abilities predict individual life and professional success, especially in the STEM (Science, Technology, Engineering, and Mathematics) disciplines. According to neurobiological hypotheses, individual differences in cognitive abilities may be attributed to the functioning of genes involved in the regulation of neurogenesis and synaptic plasticity. In addition, genome-wide association studies identified rs17070145 located in the KIBRA gene, which was associated with individual differences in episodic memory. Considering a significant role of genetic and environmental components in cognitive functioning, the present study aimed to estimate the main effect of NGF (rs6330), NRXN1 (rs1045881, rs4971648), KIBRA (rs17070145), NRG1 (rs6994992), BDNF (rs6265), GRIN2B (rs3764030), APOE (rs7412, rs429358), and SNAP25 (rs363050) gene polymorphisms and to assess the effect of gene-environment interactions on individual differences in spatial ability in individuals without cognitive decline aged 18-25 years (N = 1011, 80 % women). Spatial abilities were measured using a battery of cognitive tests including the assessment of "3D shape rotation" (mental rotation). Multiple regression analysis, which was carried out in the total sample controlling for sex, ethnicity and the presence of the "risk" APOE ε4 allele, demonstrated the association of the rs17070145 Т-allele in the KIBRA gene with enhanced spatial ability (ß = 1.32; pFDR = 0.037) compared to carriers of the rs17070145 CC-genotype. The analysis of gene-environment interactions revealed that nicotine smoking (ß = 3.74; p = 0.010) and urban/rural residency in childhood (ß = -6.94; p = 0.0002) modulated the association of KIBRA rs17070145 and АРОЕ (rs7412, rs429358) gene variants with individual differences in mental rotation, respectively. The data obtained confirm the effect of the KIBRA rs17070145 Т-allele on improved cognitive functioning and for the first time evidence the association of the mentioned genetic variant with spatial abilities in humans. A "protective" effect of the APOE ε2 allele on enhanced cognitive functioning is observed only under certain conditions related to childhood rearing.

[The role of transposable elements in endocrine changes during aging.]

Species-specific changes in the endocrine system are key factors in aging. Therefore, to prolong life, it is necessary to find regulators of the highest level, the changes of which lead to physiological aging. The molecular drivers that control dynamics of hormone levels can be transposons. This is due to the use of nucleotide sequences of transposons as binding sites that perceive specific signals of ribozymes, transcription factors, hormones and their messengers. At the same time, transposons are evolutionary sources of ribozymes and proteins that have DNA-binding domains. Starting from zygote division, the species-specific composition and distribution of transposons in the genome serves as a biological coding, which is necessary for the sequential expression of genes specific to cell types and stage of development. We suggest that hormonal regulation is one of the components of this complex system of regulation of ontogenesis under the control of transposons. To confirm our hypothesis, this review contains articles that prove the importance of transposons for species-specific control of endocrine system genes, as well as the effect of hormones on transposon activity. The research of these relationships is promising for the development of methods for the effective prolongation of life, since epigenetic changes under the influence of transposons are reversible.

Longitudinal genetic studies of cognitive characteristics.

The present review describes longitudinal studies of cognitive traits and functions determining the causes of their variations and their possible correction to prevent cognitive impairment. The present study reviews the involvement of such environmental factors as nutrition, prenatal maternal stress, social isolation and others in cognitive functioning. The role of epigenetic factors in the implementation of environmental effects in cognitive characteristics is revealed. Considering the epigenome significance, several studies were focused on the design of substances affecting methylation and histone modification, which can be used for the treatment of cognitive disorders. The appropriate correction of epigenetic factors related to environmental differences in cognitive abilities requires to determine the mechanisms of chromatin modifications and variations in DNA methylation. Transposons representing stress-sensitive DNA elements appeared to mediate the environmental influence on epigenetic modifications. They can explain the mechanism of transgenerational transfer of information on cognitive abilities. Recently, large-scale meta-analyses based on the results of studies, which identified genetic associations with various cognitive traits, were carried out. As a result, the role of genes actively expressed in the brain, such as BDNF, COMT, CADM2, CYP2D6, APBA1, CHRNA7, PDE1C, PDE4B, and PDE4D in cognitive abilities was revealed. The association between cognitive functioning and genes, which have been previously involved in developing psychiatric disorders (MEF2C, CYP2D6, FAM109B, SEPT3, NAGA, TCF20, NDUFA6 genes), was revealed, thus indicating the role of the similar mechanisms of genetic and neural networks in both normal cognition and cognitive impairment. An important role in both processes belongs to common epigenetic factors. The genes involved in DNA methylation (DNMT1, DNMT3B, and FTO), histone modifications (CREBBP, CUL4B, EHMT1, EP300, EZH2, HLCS, HUWE1, KAT6B, KMT2A, KMT2D, KMT2C, NSD1, WHSC1, and UBE2A) and chromatin remodeling (ACTB, ARID1A, ARID1B, ATRX, CHD2, CHD7, CHD8, SMARCA2, SMARCA4, SMARCB1, SMARCE1, SRCAP, and SS18L1) are associated with increased risk of psychiatric diseases with cognitive deficiency together with normal cognitive functioning. The data on the correlation between transgenerational epigenetic inheritance of cognitive abilities and the insert of transposable elements in intergenic regions is discussed. Transposons regulate genes functioning in the brain due to the processing of their transcripts into non-coding RNAs. The content, quantity and arrangement of transposable elements in human genome, which do not affect changes in nucleotide sequences of protein encoding genes, but affect their expression, can be transmitted to the next generation.

Involvement of transposable elements in neurogenesis.

The article is about the role of transposons in the regulation of functioning of neuronal stem cells and mature neurons of the human brain. Starting from the first division of the zygote, embryonic development is governed by regular activations of transposable elements, which are necessary for the sequential regulation of the expression of genes specific for each cell type. These processes include differentiation of neuronal stem cells, which requires the finest tuning of expression of neuron genes in various regions of the brain. Therefore, in the hippocampus, the center of human neurogenesis, the highest transposon activity has been identified, which causes somatic mosaicism of cells during the formation of specific brain structures. Similar data were obtained in studies on experimental animals. Mobile genetic elements are the most important sources of long non-coding RNAs that are coexpressed with important brain protein-coding genes. Significant activity of long non-coding RNA was detected in the hippocampus, which confirms the role of transposons in the regulation of brain function. MicroRNAs, many of which arise from transposon transcripts, also play an important role in regulating the differentiation of neuronal stem cells. Therefore, transposons, through their own processed transcripts, take an active part in the epigenetic regulation of differentiation of neurons. The global regulatory role of transposons in the human brain is due to the emergence of protein-coding genes in evolution by their exonization, duplication and domestication. These genes are involved in an epigenetic regulatory network with the participation of transposons, since they contain nucleotide sequences complementary to miRNA and long non-coding RNA formed from transposons. In the memory formation, the role of the exchange of virus-like mRNA with the help of the Arc protein of endogenous retroviruses HERV between neurons has been revealed. A possible mechanism for the implementation of this mechanism may be reverse transcription of mRNA and site-specific insertion into the genome with a regulatory effect on the genes involved in the memory.

The role of polymorphic variants of arginase genes (ARG1, ARG2) involved in beta-2-agonist metabolism in the development and course of asthma.

Asthma is a common severe disease of the respiratory tract, it leads to a significant impairment in the quality of a patient's life unless effectively treated. Uncontrolled asthma symptoms are a cause of disease progression and development, they lead to an increase in the patient's disability. The sensitivity to asthma therapy largely depends on the interaction of genetic and epigenetic factors, which account for about 50-60 % of variability of therapeutic response. Beta-2-agonists are some of the major class of bronchodilators used for asthma management. According to published data, allelic variants of the arginase ARG1 and ARG2 genes are associated with a risk of asthma development, spirometry measures and efficacy of bronchodilator therapy. High arginase activity results in a low level of plasma L-arginine and in a decrease in nitric oxide, and, as a result, in an increase in airway inflammation and remodeling. Arginase genetic polymorphisms (rs2781667 of the ARG1 gene, rs17249437, rs3742879, rs7140310 of the ARG2 gene) were studied in 236 children with asthma and 194 unrelated healthy individuals of Russian, Tatar and Bashkir ethnicity from the Republic of Bashkortostan. Association analysis of the studied polymorphisms with asthma development and course, the sensitivity to therapy in patients was carried out. It was found that the rs2781667*C allele of the ARG1 gene is a marker of an increased risk of asthma in Tatars. In Russians, the association of rs17249437*TT and rs3742879*GG genotypes of the ARG2 gene with a decrease in spirometry measures (FEV1, MEF25) was established. In Russians and Tatars receiving glucocorticoid monotherapy or combination therapy, the association of the rs17249437*T allele and rs17249437*TT genotype of the ARG2 gene with a partially controlled and uncontrolled course of asthma was shown.

The Role of Reverse Transcriptase in the Origin of Life.

It has been suggested that RNA polymerase ribozyme displaying reverse transcriptase and integrase activities has played a vital role in the origin of life on Earth. Here, we present a hypothesis that formation of universal ancestral units of all living organisms - retroelements - in the evolution was mediated by reverse transcriptase. The propensity of retroelements to mutations and their insertion capacity have formed a basis for the origin of complex DNA structures - primary genomes - that have given rise to archaea, eukaryotes, bacteria, and viruses. Conserved properties of retroelements have been preserved throughout the evolution; their modifications have facilitated the emergence of mechanisms for the interactions between proteins and nucleic acids. Life has evolved due to insertional mutagenesis and competition of autonomously replicating polynucleotides that allowed to preserve structures with adaptive properties. We hypothesize that natural selection of mechanisms for the defense against insertions based on the ribonuclease activity of reverse transcriptase ribozyme has led to the emergence of all universal enzymatic systems for the processing of RNA molecules. These systems have been and still remain the key sources of structural and functional transformations of genomes in the course of evolution. The data presented in this review suggest that the process of translation, which unifies the nucleic acid and protein worlds, has developed as a modification of the defense mechanisms against insertions. Polypeptides formed by this defense system have potentiated the activity of ribozymes in the composition of ribonucleoproteins (RNPs) and even functionally replaced them as more efficient catalysts of biological reactions. Here, we analyze the mechanisms of retroelement involvement in the structural and regulatory transformations of eukaryotic genomes supposedly reflecting the adaptive principles that had originated during the beginning of life on Earth. Simultaneously with the evolution of existing proteins, retroelements have served as sources of new ribozymes, such as long non-coding RNAs. These ribozymes can function in complexes with proteins in the composition of RNPs, as well as display independent catalytic and translational activities; their genes have a potential for the transformation into protein-coding genes. Hence, the conserved principles of RNA, DNA, and proteins interregulation formed at the time of life origin on Earth have been used throughout the evolution.

Selective Heterozygous Advantage of Carriers of с.-23+1G>A Mutation in GJB2 Gene Causing Autosomal Recessive Deafness 1A.

We present the results of analysis of skin epidermis thickness in individuals with recessive mutation c.-23+1G>A in the GJB2 gene in comparison with individuals without this mutation living in Eastern Siberia (Yakut population). We examined 152 individuals with different genotypes by GJB2 gene mutation c.-23+1G>A. Homozygotes and heterozygotes by c.-23+1G>A have thicker epidermal layer (0.245 mm and 0.269 mm, respectively) in comparison with individuals without this mutation (0.193 mm) (p<0.05). The obtained data support the hypothesis about selective advantage of carriers of mutant GJB2 gene alleles and partly explain extremely high carrier frequency (10.3%) of c.-23+1G>A mutation in the GJB2 gene in Yakut population in Eastern Siberia.

[Genetics and epigenetics of attention deficit hyperactivity disorder]. / Genetika sindroma defitsita vnimaniia i giperaktivnosti.

Molecular genetic studies of attention deficit hyperactivity disorder (ADHD) have demonstrated the involvement of multiple genes in the etiology of ADHD. A polygenic hypothesis of the etiopathogenesis was formulated without clear knowledge of common mechanisms of ADHD development. Twin, family and adoption studies have established the heritability of 70-80% for ADHD. Association studies have shown the relationship between ADHD and genes of dopaminergic (DRD4, DRD5, SLC6A3), serotoninergic (HTR1B, 5-HTTLPR), glutamatergic (mGluR, NDRG2) systems, metabolic pathways (SLC2A3, SLC6A4, CDH13, CFOD1, GFOD1), membrane proteins (KChIP1, ITGA1, SNAP-25) as well as tumour-suppressor (NDRG2, NF1) and cytokine genes. The marked comorbidity of ADHD with other psychiatric disorders and shared genetic risk factors were determined. Studies of a role of copy number variations (CNVs) provided more promising evidence that suggested the possible involvement of retroelements as the unifying factors of disease etiopathogenesis. Transposons, which are sensitive to stress, may cause CNVs and are key regulators of brain development and functioning. The dysregulation of transposons is thought to be important in changes in tuning of gene regulatory pathways and epigenetic regulation of neurons in ADHD that may be a common principle underlying the heterogeneous nature of ADHD. Research on noncoding RNAs will help to confirm the hypothesis and develop diagnostic algorithms of examination of ADHD patients as an important step in the implementation of personalized medicine in psychiatry.

[Epigenetic hypothesis of the role of peptides in aging.]

In regulation of gene expression in the ontogenesis of multicellular eukaryotes, in addition to transcription factors, an important role is played by epigenetic factors that control the release of genetic information in each cell division. Many binding sites for the transcription factors were derived from transposons sequences. Mobile elements are also important sources of non-coding RNA. Due to this, transposons have an indirect effect on gene expression and genome methylation. In evolution, transposons serve as important sources for the origin of new protein and proteins domains. A number of studies have identified that long non-coding RNAs and microRNAs can be translated into functional peptides. At the same time, transposons remain active in the hypothalamus of adult humans, which is consistent with the transcription of non-coding RNAs in these structures, which may be key in aging.

The Role of Transposable Elements in Emergence of Metazoa.

Systems initially emerged for protecting genomes against insertions of transposable elements and represented by mechanisms of splicing regulation, RNA-interference, and epigenetic factors have played a key role in the evolution of animals. Many studies have shown inherited transpositions of mobile elements in embryogenesis and preservation of their activities in certain tissues of adult organisms. It was supposed that on the emergence of Metazoa the self-regulation mechanisms of transposons related with the gene networks controlling their activity could be involved in intercellular cell coordination in the cascade of successive divisions with differentiated gene expression for generation of tissues and organs. It was supposed that during evolution species-specific features of transposons in the genomes of eukaryotes could form the basis for creation of dynamically related complexes of systems for epigenetic regulation of gene expression. These complexes could be produced due to the influence of noncoding transposon-derived RNAs on DNA methylation, histone modifications, and processing of alternative splicing variants, whereas the mobile elements themselves could be directly involved in the regulation of gene expression in cis and in trans. Transposons are widely distributed in the genomes of eukaryotes; therefore, their activation can change the expression of specific genes. In turn, this can play an important role in cell differentiation during ontogenesis. It is supposed that transposons can form a species-specific pattern for control of gene expression, and that some variants of this pattern can be favorable for adaptation. The presented data indicate the possible influence of transposons in karyotype formation. It is supposed that transposon localization relative to one another and to protein-coding genes can influence the species-specific epigenetic regulation of ontogenesis.

[Prospects for the search for peptides for specific regulation of aging.]

We propose a hypothesis that the causes of aging are not random events, but regular processes due to the dysfunction of species-specific transposons. The hypothesis is justified by the fact that the average life expectancy differs significantly between species. In addition, genomes of different species differ in the composition and arrangement of transposons in them, which control the differentiation of cells in different tissues and at different stages of development. We presented literature data confirming this assumption and substantiating the key role of transposons in regulating gene expression in ontogenesis. In the terminally differentiated cells, the mechanisms of the silencing of mobile elements are activated, which are depleted, which leads to the dysfunction of gene-regulated regulatory networks controlled by transposons, the aging and development of age-associated pathology. Mobile elements are capable of transposing into strictly defined genomic loci, transcribed into functional RNAs that are translated into peptides. We propose that the detection of changes in the activity of specific mobile elements associated with aging through the analysis of non-coding RNA of transposon origin can be the basis for developing ways to increase life expectancy and targeted therapy for age-related pathologies, including malignant tumors. A promising direction in this respect may be the study of peptides that affect the expression of specific transposons and non-coding RNAs.

[The role of interactions of transposons with epigenetic factors in the aging process].

The review considers modern theories of aging mechanisms and data on epigenetic regulation of ontogenesis. Transposons may be the material bases of the epigenetic control system, their movements affect the differentiation of cells and can cause genomic instability. Control systems aimed at protecting against foreign DNA (splicing machine, microRNA processing) became the basis of regulatory networks of genomes underlying cell differentiation. Transposon sequences are the basis for non-coding RNAs that suppress the expression of the transposons themselves and protein-coding genes at the posttranscriptional level, as well as by altering the activity of methyltransferases and modifying the histone modification. Influence on transposons provides a basis for combating aging and age-associated pathologies. In particular, it is possible to influence the change in the length of telomeres, the origin of which is associated with retroelements, by regulating the activity of transposons.

[Clinical and epidemiological characteristics of hereditary motor-sensory neuropathy 1X caused by the mutation c. 259C> G (p. P87A) in the GJB1 gene of patients from the Republic of Bashkortostan]. / Kliniko-épidemiologicheskie kharakteristiki nasledstvennoi motorno-sensornoi neiropatii 1Kh tipa, obuslovlennoi mutatsiei s. 259S>G (r. R87A) v gene GJBI, u patsientov Respubliki Bashkortostan.

BACKGROUND: Hereditary motor-sensory neuropathy 1X (НМСН 1X) is the second frequent form of hereditary motor-sensory neuropathies caused by mutations in the GJB1 gene (gap junction B1 type). The authors have established earlier that the с.259C>G (р.P87A) mutation is the most frequent cause of НМСН 1Ð¥ (92%) in patients from the Republic of Bashkortostan. AIM: To study in details the territorial ethnic distribution and clinical manifestations of the с.259C>G (р.P87A) in the GJB1 gene in patients with НМСН 1Ð¥ from the Republic of Bashkortostan. MATERIAL AND METHODS: Clinical/neurological data were assessed in 52 patients (32 men and 20 women) from 13 families with this НМСН 1Ð¥ mutation in accordance to the diagnostic criteria of the European neuromuscular center. Twenty-three patients underwent standard electroneuromyographic study ('Nicolet Viking quest') using cutaneous electrodes. Data analysis was performed with Statistica ver.6.0 ('Stat Soft, Inc.', 2003) software. RESULTS: The с.259C>G (р.P87A) mutation was more frequent in Bashkir (61%) and Russian (31%) families from 6 areas of the Republic of Bashkortostan. The age-at-onset was 13.24±4.33 years in men. In women, the age-at-onset varied from 7 to 45 years, it was difficult to detect this parameter in several patients due to the absence of complaints and symptoms of disease. A comparative analysis revealed the higher degree of peripheral nerve lesions in men compared to women. There was the distinct difference in electrophysiological parameters (excitation spreading velocity and M-response amplitude) along motor fibers of the middle nerves between men and women that indicated the predominantly demyelinating character of the pathological process in men and the axonal character in women. CONCLUSION: Clear clinical/electrophysiological sex differences (intra- and inter family) were shown in patients with НМСН IX with the с.259C>G (р.P87A) mutation in the GJB1 gene. The disease was less severe and often with the absence of symptoms in women. Genetic testing for mutations in the GJB1 gene, including the с.259C>G (р.P87A) mutation, can be recommended to female patients with excitation spreading velocity >38m/s.