[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.

[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 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.

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.

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.

[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 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.

[Two novel mutations in gene SPG4 in patients with autosomal dominant spastic paraplegia].

Hereditary spastik paraplegias (HSP) are a group of neurodegenerative disorders with primary lesion of the pyramidal tract. The most frequent autosomal dominant form of the disease in Europeans is HSP associated with mutations in the spastin gene (SPG4). Analysis of the gene SPG4 was carried out in 52 unrelated families with HSP from Bashkortostan by SSCP and following sequencing. Previously undescribed frameshift mutations c.322del29 (p.Val108SerfsX18) and c.885del10 (p.Thr295ThrfsX16) were detected in two unrelated families. Clinical studies have shown that, in both families, the disease corresponds to an uncomplicated form of hereditary spastic paraplegia, a main feature of which is the lower spastic paraparesis without any other symptoms.

[Mutational landscape of prostate tumors revealed by whole-exome sequencing].

The results of the whole-exome DNA sequencing of eight prostate adenocarcinoma patients are presented. DNA was isolated from the peripheral blood as well as healthy and tumor prostate tissue from each patient. Bioinformatics analysis was conducted and the most significant mutations in prostate cancer patients were revealed. The obtained data could be important for understanding of the molecular mechanisms of prostate cancer pathogenesis and facilitate development of new approaches for treatment of the disease.

[The search for new candidate genes involved in ovarian cancer pathogenesis by exome sequencing].

Ovarian cancer is one of the most insidious of tumors among gynecological cancers in the world. BRCA1 and BRCA2 mutations are associated with high risk of ovarian cancer; however, they are causative only in a fraction of cases. The search for new genes would expand our understanding of the mechanisms underlying malignant ovarian tumors and could help to develop new methods of early diagnosis and treatment of the disease. The present study involved exome sequencing of eight DNA samples extracted from the blood of ovarian cancer patients. As a result of the study, 53057 modifications in one sample were identified on average. Of them, 222 nucleotide sequence modifications in DNA located in exons and splice sites of 203 genes were selected. On the basis of the function of these genes in the cell and their involvement in carcinogenesis, 40 novel candidate genes were selected. These genes are involved in cell cycle control, DNA repair, apoptosis, regulation of cell invasion, proliferation and growth, transcription, and also immune response and might be involved in development of ovarian cancer.

The Role of Transposable Elements in Ontogenesis.

The article describes the role of transposable elements in the ontogenesis of eukaryotes. Adaptive and controlled transposition of mobile elements occurs at different stages of development of an organism, causing dramatic changes in the regulation of gene expression, representing a cascade of reactions inherited genome evolutionary fixed at the species level. At this cascade of reactions involved regulatory system of tissue-specific expression of proteins splice variants in connection with the role of adaptive genes mosaic structure to numerous transpositions and the interconnectedness of mechanisms their evolutionary stabilization. Important role in the transposition of mobile elements and their interaction with groups of genes play epigenetic mechanisms - DNA methylation, histone modification, the expression of non-coding RNA. The genome structures responsible for the epigenetic regulation can have a transposons origin. In contrast to the previously established hypotheses on transpositions of mobile elements in the ontogenesis as a chaotic process, causing the destabilization of genotype, with a modern viewpoint, this mechanism has a species-specific patterns, formed evolutionarily. Mechanisms of the evolutionary transformation of genomes by natural selection create a relatively stable complex regulatory epigenetic characteristics of transpositions in the process of individual development, acting among individuals of the same species. The stability of the complex genomic information regulation in ontogenesis provides a specific set of transposons. Changing this regulation set transposons can cause fatal for the development of events. Dysregulation of transposons, not involved in the developmental restructuring, can give the inheritance of these changes. The aging process is a consequence of the evolutionary relationship of species-specific features of the regulation of mobile elements in ontogenesis, aimed at continuity and continuous increase in living matter for maximum adaptability. In the overall scheme of ontogenetic development process can be described as a way to implement the established evolutionary genomic information in time by means of gradually stabilized complex interaction of regulators of transpositions of mobile elements of the genome with a differentiated pattern of gene expression and regulation of splicing variants of their products. These transpositions vary with each cell division, especially by implementing the expression of sets of genes, the products of which affect the nature of the further transposition and change of regulation in the subsequent stages of development of an organism.

[MicroRNAs as potential noninvasive markers in the diagnosis of urological malignancies].

Small non-coding RNAs (microRNAs) are involved in almost all biological mechanisms of carcinogenesis. Due to their stability in biological fluids microRNAs may serve a perspective biomarker for diagnosis and prognosis of oncological diseases. The review is dedicated to the analysis of microRNAs, as potential diagnostic markers of urological malignancies. Recent advances in the knowledge of miRNAs origin in body fluids, their stability and application as a potentially new class of biomarkers in medicine are summarized and discussed in the article.

[Brain neurotransmitter systems gene Polymorphism: the Search for pharmacogenetic markers of efficacy of haloperidol in Russians and Tatars].

Antipsychotics are the main drugs for the treatment of severe mental illness--schizophrenia affects about 1% of the population. The mechanism of action of neuroleptics is still up to the end. Several studies in the field of pharmacogenetics confirm enourmous influence of several neurotransmitter systems in the brain on the efficiency and the development of side effects. In this paper, we analyzed the association of nine polymorphic variants of five genes of dopaminergic and serotonergic systems DRD4, HTR2A, TPH1, SLC18A1, COMT in Russian and Tatars patients living in the Republic of Bashkortostan (RB) with the efficiency of a typical antipsychotic haloperidol on the scale of positive and negative systems of PANSS. The study established pharmacogenetic markers of increased and decreased effectiveness of therapy with haloperidol in the treatment groups. The results of this study confirm the importance of changes in the nucleotide sequences of the studied genes of the serotoninergic and dopaminergic systems (HTR2A, TPH1, SLC18A1 COMT, DRD4) in the formation of individual sensitivity to haloperidol. The results of our work considered as preliminary contact, requires an increase in the number of samples studied.

[Current State of Research in Ethnogenomics: Genome-Wide Analysis and Uniparental Markers].

A short review of the current state in ethnogenomics was carried out. The main breakthroughs in the field are described, and small-scale historical overview is presented. The methods and approaches currently used in Y-chromosome, mitochondrial DNA and genome-wide studies are listed.

[Genetic and environmental aspects of mathematical disabilities].

Mathematics has become highly important in today's high-tech life. Success in everyday life requires the presence of mathematical knowledge, which, in turn, appears to be the basis for any innovative scientific activity. However, a large percentage of the population demonstrates mathematical disabilities. Mathematical abilities and disabilities represent a complex and multifactorial phenomenon caused by the influence of both genetic and environmental factors. The present review is focused on studies based on a candidate gene approach and on genome-wide association studies previously reporting associations between gene polymorphisms and cognitive impairments, particularly mathematical disabilities. According to the first approach, learning and memory formation are influenced by variants in neurotransmitter system genes, genes involved in the working memory and synaptic plasticity. The results of the second approach demonstrates that the matrix metalloproteinase 7 gene (MMP7), the glutamate receptor ionotropic kainate 1 gene (GRIK1), and the dynein axonemal heavy chain 5 gene (DNA H5) are responsible for developing mathematical disabilities.

[The Role of Neurotrophins and Neurexins Genes in the Risk of Paranoid Schizophrenia in Russians and Tatars].

Schizophrenia affects about 1% of the population. Its etiology is not fully understood. Environmental conditions certainly contribute to the development of schizophrenia, but the determining factor is genetic predisposition: the coefficient of heritability of schizophrenia is about 80%, which is typical for the most highly heritable multifactorial diseases. Polymorphic loci of genes of enzymes and receptors involved in the processes of neuroprotection and neurotrophia play significant role in the development of this disease. In this paper we investigated 48 polymorphic variants of genes of the neurotrophins and neurexins family (BDNF, NTRK2, NTRK3, NGF, NXPH1, and NRXN1) in Russian and Tatar cases and in a control group living in the Republic of Bashkortostan. The results of this study confirm the important role of neurotrophin and neurexin genes in paranoid schizophrenia development.

[The Role of MiRNAs in the Development of Prostate Cancer].

MicroRNAs (MiRNAs) act as key post-transcriptional regulators of gene expression. This review examines current advances in the study of the role of miRNAs in cancer, including prostate cancer. Issues devoted to the nomenclature, biogenesis, the role of miRNAs as oncogenes and tumor suppressors, and their role in the diagnosis, treatment, and prognosis of prostate cancer are discussed. Assessment ofthe role of miRNAs in the development of prostate cancer will promote early diagnosis and will be important for the development of new approaches to the disease treatment.

[Association of Polymorphic Variants of Gene MUC19 with Asthma in Russians According to the Results of a Genome-Wide Study].

Asthma is a heterogeneous multifactorial disease that is characterized in most cases by chronic respiratory tract inflammation. We carried out a GWAS in order to identify susceptibility genes for asthma in individuals of different ethnic backgrounds. The study sample consisted of 358 unrelated patients with asthma (160 Russians, 125 Tatars, and 73 Bashkirs) and 369 individuals of a control group (152 Russians, 117 Tatars, and 100 Bashkirs). DNA samples were genotyped with an Illumina human610 quad array (Illumina) as part of the project GABRIEL. Replication of the results of genome-wide analysis was carried out on an additional independent sample of 310 asthma patients (132 Russians, 105 Tatars, and 73 Bashkirs) and 310 individuals in a control group (131 Russians, 106 Tatars, and Bashkirs 77). Genome-wide analysis showed an association of asthma in Russians with the polymorphic loci of gene MUC19 (12q12) encoding gel-forming mucin 19. The highest level of association with asthma was found in rs2933346, which is located in intron 52 of this gene (p = 2.59 x 10(-6)). Seven polymorphic loci of gene MUC19 (rs1492313, rs2588401, rs2588402, rs2638863, rs2638864, rs1352940, and rs2933373), which are in close linkage disequilibrium among themselves and rs2933346, are associated with asthma with the same p-value (p = 4.96 x 10(-6)). The replicative study of rs1492313 in the independent sample of individuals confirmed the presence of the association of the polymorphic loci of this gene with the development of asthma in Russians. According to our data, the association of polymorphic variants of gene MUC19 with asthma has not been previously identified in any study. Our results indicate the important role of polymorphic variants of gene MUC19 in the formation of a predisposition to the development of asthma in individuals of Russian ethnicity.