Genetika

A number of experimental studies are described that challenge the significance of synaptic plasticity and prove the role of transposable elements in memory consolidation. This is due to the cis-regulatory influence of activated transposable elements on gene expression, as well as insertions into new genomic loci near the genes involved in brain functioning. RNAs and proteins of endogenous retroviruses are transported to dendritic synapses and transmit information to change gene expression in neighboring cells through the formation of virus-like particles in vesicles. Due to this, the relationship between synaptic plasticity and nuclear coding is ensured, since transposable elements are also drivers of epigenetic regulation due to relationship with the non-coding RNAs derived from them. Our analysis of the scientific literature allowed us to identify the role of 17 microRNAs derived from transposable elements in normal memory formation. In neurodegenerative diseases with memory impairment, we identified impaired expression of 44 microRNAs derived from transposable elements. This demonstrates the potential for targeting pathological transposon activation in neurodegenerative diseases for memory restoration using microRNAs as tools.

MLE of D. melanogaster is a conserved protein in higher eukaryotes, an ortholog of human DHX9 helicase. In mammals, this helicase has been shown to participate in different stages of gene expression. In D. melanogaster, the role of MLE as one of the components of the species-specific Dosage Compensation Complex has been extensively studied. However, the role of MLE in other processes has remained poorly understood. In this work, for the first time, the mle[9] mutation is mapped at the molecular level and shown to be caused by a deletion resulting in the loss of a highly conserved motif III in the catalytic core of the molecule. Thus, mle[9] specifically disrupts the helicase activity of the protein without affecting the function of other domains. The study of phenotypic manifestations of the mutation in females showed that in the homozygous state it has a pleiotropic effect. Without affecting survival, it significantly reduces fertility and lifespan. In addition, the duplication of scutellar macrochaetae was observed with high frequency. These results confirm that in D. melanogaster MLE helicase is involved in a wide range of gene expression regulation processes distinct from its role in dosage compensation.

Human cytochrome P450 2F1, as well as its orthologue 2F3in domestic goat,is considered to bea rather unusual enzyme. The only type of reaction it catalyzes has been described: the conversion of skatole, a product of anaerobic tryptophan metabolism, into a pulmonary toxin. Endogenous substrates of CYP2F are unknown, and although more than 30 years have passed since the discovery of the enzyme, its biological role remains unclear. We hypothesized that the physiological functions of CYP2F can be specifically implemented in the brain, remaining previously unnoticed due to the high compartmentalization of the organ. Using open data, we studied the covariation of the expression of CYP2F1 and genes for behavioral traits: in the human brain, as well as the polymorphism of their orthologues and CYP2F3 in 180 populations of domestic animals goats (Capra hircus). Two SNPs were found in the CYP2F3 gene, one of which had pronounced traces of selection, and the frequency of homozygotes increased with geographic distance from the center of domestication. Expression of CYP2F1 mRNA in the human brain also had regional specificity. In both species, factor analysis revealed the relationship between CYP2F1/3 and a number of genes regulating behavior: the serotonin transporter SLC6A4 and its receptor HTR2A3, the ABCB1 transporter, the purine receptor P2RX7, the GABA receptor GABRA4, the circadian rhythm regulator PER3 and T-cadherin CDH13. Thus, analysis of the genomic data of the domestic goat and human transcriptomic data revealed the evolutionary and functional relationships of CYP2F cytochromes and neurochemical systems for regulating behavior. This evidence of the cerebral function of the enzyme is indirect, since it is based on correlation analysis, but indicates the promise of further search in this direction.

Inherited retinal diseases (IRDs) are a clinically heterogeneous group of retinal pathologies associated with vision loss due to dysfunction or degeneration of photoreceptor and retinal pigment epithelium. Autosomal recessive forms of IRDs account for more than 55% of all diseases in this group on average worldwide. This study presents data on frequent pathogenic and likely pathogenic variants in recessive IRDs genes obtained from a retrospective analysis of high-throughput sequencing data from a large Russian cohort of patients with suspected hereditary non-syndromic retinal pathology. Data from 1470 unrelated patients were analyzed. Pathogenic and likely pathogenic variants were identified in the zygosity required for the development of the diseasein 643 patients (43.74%). It was found that 9 genes (ABCA4, CNGB3, USH2A, RPE65, CRB1, CNGA3, CEP290, GUCY2D, PDE6H) account for 73.3% of all molecularly confirmed cases of IRDs in Russian patients. An analysis of the spectrum of nucleotide variants of these genes was carried out, and 17 variants were identified that occur with an allelic frequency of more than 1% for each gene. In light of obtained data, the diagnostic systems based on the multiplex ligation-dependent probe amplification reaction (MLPA) were developed. The informativity of the two systems for diagnosing autosomal recessive non-syndromic forms of inherited retinal diseases is 16.4%, the informativity for all forms of non-syndromic retinal diseases exceeds 7%. For a group of patients with achromatopsia, a study using one of the systems will make it possible to establish a diagnosis in 62.5% of cases.

Coronary heart disease (CHD) is a common pathology, and its development is mediated by a large number of genetic factors, environmental factors and their combinations. In this regard, the objective of the study was a bioinformatic analysis of the involvement of susceptibility genes to CHD in the implementation of signaling and metabolic pathways. The list of susceptibility genes was compiled using GWAS, DisGeNET and GeneCards databases. Pathway enrichment analysis was performed using the ClueGO v2.5.9 Cytoscape v3.9.1 plugin. As a result of the study, it was established that these genes are involved in the implementation of various mechanisms of development of CHD, including disorders of lipid metabolism, changes in the activity of elements of the complement system, and endothelial function. Hereditary factors can influence changes in the processes of regulation of thrombus formation, vascular tone, the balance of pro- and antioxidant factors, endothelial permeability, water and sodium adsorption, as well as the processes of angiogenesis. In this case, the genes under study may be involved in the implementation of one or several signaling/metabolic pathways.

The level of chromosomal abnormalities in the somatic cells of adult individuals is characterized by significant interindividual variability, which may be partly affected by the genetic and epigenetic background. The epigenetic landscape in cells is largely determined by genome methylation. This study aimed to analyse the relationships between global genome methylation and the frequencies of chromosome abnormalities in lymphocytes of plutonium workers. The frequencies of chromosome aberrations, micronuclei, aneuploidy of chromosomes 2, 7, 8, 12, X and Y and sister chromatid exchanges were analysed in the lymphocytes of 40 male workers from a nuclear chemical facility (Seversk, Russia) with incorporated plutonium-239 and 49 healthy male volunteers who had no occupational exposure to ionizing radiation. The long interspersed nuclear elements-1 (LINE-1) methylation index was assessed as a well-known marker of global genome methylation. The frequencies of centromere-negative micronuclei (4.74 ± 2.26‰ vs. 3.02 ± 1.69‰), chromosome-type aberrations (0.81 ± 0.79 vs. 0.44 ± 0.69%) and total chromosome non-disjunction (0.93 ± 0.43 vs. 0.50 ± 0.25%) were significantly higher in the group of workers than in controls (p < 0.05). The LINE-1 methylation index did not differ significantly between the worker and control groups (74.93 ± 3.63 vs. 73.92 ± 4.62%). Correlations between LINE-1 methylation and the frequency of micronuclei (R = –0.35, p = 0.031) were observed in the control group, whereas correlations of LINE-1 methylation with chromatid-type aberrations (R = –0.42, p = 0.012) (but not chromosome-type aberrations) and with sister chromatid exchanges (R = –0.53, p = 0.004) were observed only in the group of plutonium workers. Thus, LINE-1 hypomethylation after plutonium exposure is associated mainly with chromatid breaks, either repaired or misrepaired.

The high level of karyotypic and molecular genetic variability was previously detected in the Caucasus pine vole Microtus daghestanicus. However, populations of this species were poorly studied in the eastern part of the Greater Caucasus. To reveal their genetic peculiarities and phylogenetic relationships with other conspecific populations we analyzed a sample of Caucasus pine voles from the south of the Chechen Republic (Daikhokh Mount). The immunocytochemical study of synaptonemal complexes in meiotic prophase I demonstrated that the population belongs to the most distributed 54-chromosomal form of M. daghestanicus. The entire mitochondrial cytochrome b gene analysis showed close clustering specimens from Chechen Republic and previously studied Caucasus pine vole from northern Georgia. It indicates that all these specimens belong to a discrete genetic form. In the studied sample from Chechen Republic we revealed variability of the nuclear BRCA1 and XIST genes that probably reflects a complicated history of the population associated with alternation of its isolation from neighbor populations and restoring contacts between them.