Метилирование ДНК является одним из важнейших механизмов управления программой индивидуального развития организма.Нарушение такой программы может быть связано с летальным эффектом в эмбриогенезе. Цель исследования: анализ масштабных нарушений метилирования генома в зародышевой части плаценты при невынашивании беременности. Был проведен анализ профилей метилирования генома ворсин хориона спонтанных абортусов c нормальным кариотипом (n=7) и медицинских абортусов (n=7). Профили метилирования получены путём бисульфитного массового параллельного секвенирования ограниченного набора локусов (RRBS). Дифференциальное метилирование выявленных регионов у спонтанных абортусов объясняется в первую очередь нарушениями при установлении тканеспецифичного профиля метилирования в зародышевой части плаценты, а также при деметилировании отцовского генома в волне репрограммирования на стадии дробления.

Aortic aneurysm (AA) and atherosclerosis (AS) are characterized by ambiguous comorbid relationships between them. This review discusses the molecular mechanisms of the development of these pathologies caused by heterogeneity, plasticity, intercellular interactions, embryonic origin, and regional specificity of arterial cells revealed using single-cell transcriptomics approach in humans and in animal models. The importance of interplay between genetic and environmental factors determining functional state of the vessels and development of pathology through dynamic changes in the arterial cellular composition within the ontogenetically regulated spatiotemporal continuum is emphasized, which creates conditions for the development of comorbidity between the diseases. Understanding the key molecular mechanisms underlying the comorbidity of AA and AS is important for the development of new therapeutic strategies for these pathological conditions.

Breast cancer is number one in terms of indicators of mortality and morbidity in women. In the postgenomic era, it was revealed that the development of pathology is linked with specificities of gene expression including transcriptional, posttranscriptional, translational, and epigenetic regulation. In the research, biomaterial of 16 patients (8 patients with stage I/II luminal A breast cancer and 8 healthy women) was included. Functional enrichment analysis using the WebGestalt source and different databases (Gene Ontology, KEGG) showed alterations in expression of genes involved in immunological response, metabolism of carbohydrates, glutathione, and nicotinamide, DNA repair, ion transport, and intracellular signals transition. The results obtained expand our vision about specificities of the transcriptome of blood mononuclear cells during breast cancer at an early stage.

Рак молочной железы занимает первое место по показателям смертности и заболеваемости у женщин. В постгеномный период было обнаружено, что развитие патологии связано с особенностями экспрессии генов, включая транскрипционную, посттранскрипционную, трансляционную и эпигенетическую регуляцию. В исследование был включен биоматериал 16 человек (8 пациенток с диагнозом люминальный А-тип рака молочной железы, I/II стадии и 8 здоровых женщин). Функциональный анализ обогащения с использованием ресурса WebGestalt и различных баз данных (GeneOntology, KEGG) указал на изменение экспрессии генов, вовлеченных в процессы иммунологического ответа, метаболизма углеводов, глутатиона и никотинамида, репарации ДНК, ионного транспорта и передачи внутриклеточных сигналов. Полученные результаты расширяют представления об особенностях транскриптома мононуклеаров крови при раке молочной железы ранней стадии.

To study the prevalence and associations of chronic fatigue syndrome (CFS) with other clinical and neuropsychological manifestations of Parkinson’s disease (PD) and serum infl ammatory markers and genetic polymorphisms. Materials and methods. The study involved 533 patients with PD. All patients underwent clinical neurological examination and neuropsychological testing using validated questionnaires: the Hospital Anxiety and Depression Scale, the Beck Depression Inventory II, the Montreal Cognitive Assessment Scale, the Apathy Scale, the SAQ questionnaire to assess the number of daytime sleep attacks, and scales for assessing autonomic disorders in patients with PD. Fatigue was assessed using the Fatigue Severity Scale (FSS). Serum concentrations of a group of infl ammatory markers (slCAM-1, sVCAM-1, NCAM, CCL5, PAI-1, and MPO) were assessed in 144 PD patients. A case-control study of CCL5 (rs2107538) and PAI-1 (rs2227631) gene polymorphisms was performed in relation to the development of PD and in groups differing in terms of the presence/absence of CFS in patients with PD. In addition, the association of these polymorphisms with variation in the serum levels of the corresponding proteins was studied. Genotyping of the CCL5 (rs2107538) and PAI-1 (rs2227631) gene polymorphisms was performed using real-time PCR with TaqMan probes. Results. CFS was present in 66.7% of cases in the group of PD patients. In addition, non-motor symptoms were more common in patients with CFS, i.e., emotional-affective, cognitive, and autonomic disorders and pain. A strong correlation was found between the severity of CFS, assessed in points on the FSS questionnaire and the serum CCL5, sVCAM-1, NCAM, and slCAM-1 concentrations. In newly diagnosed patients with PD who were not taking antiparkinsonian drugs at the time of the study and had CFS, stronger correlations were noted between serum infl ammatory markers and the severity of the signs of CFS. Comparison of the distributions of genotypes and alleles of the CCL5 (rs2107538) and PAI-1 (rs2227631) gene polymorphisms in the PD and control groups revealed a number of differences (p < 0.05). However, the rs2107538 and rs2227631 polymorphisms studied here did not affect the variability of serum CCL5 or PAI-1 protein levels; nor did they affect the development of CFS in patients with PD. Conclusions. CFS was common in PD, and patients with PD and CFS were characterized by elevated levels of serum markers CCL5, sVCAM-1, slCAM-1, and NCAM, indicating the importance of the infl ammatory component in the development of neurodegenerative disease. In addition, the clinical course of PD in patients with CFS was burdened by other non-motor manifestations, including emotional-affective, cognitive, and autonomic disorders and pain. These results highlight the potential contribution of the inflammatory component to the development of PD-associated fatigue, starting from the earliest clinical stages of the disease.

Преждевременное половое созревание (ППС, OMIM 176400, 615346) – заболевание, которое вызвано преждевременной реактивацией гипоталамо-гипофизарно-гонадной оси. В определении сроков полового созревания ведущую роль играют генетические, эпигенетические и экологические факторы. В последние годы варианты в генах KISS1, KISS1R, MKRN3 и DLK1 были идентифицированы как генетические причины ППС. Гены MKRN3 и DLK1 являются импринтированными, в связи с чем эпигенетические модификации, такие как метилирование ДНК, изменяющее экспрессию данных генов, также могут рассматриваться в качестве причины ППС. Цель настоящего исследования – определение индекса метилирования центров импринтинга генов DLK1 и MKRN3 у девочек с клинической картиной ППС. Анализ индекса метилирования центров импринтинга генов DLK1 и MKRN3 проводили в группе из 45 девочек (возраст 7.2±1.9 года) с клинической картиной ППС и нормальным кариотипом методом таргетного массового параллельного секвенирования после обработки ДНК бисульфитом натрия. Контрольная группа состояла из девочек без ППС (n = 15, возраст 7.9±1.6 года). Различий по возрасту между группами не выявлено (p > 0.8). Анализ индекса метилирования центров импринтинга генов DLK1 и MKRN3 не показал различий между пациентами с ППС и контрольной группой. Группа пациентов с изолированным адренархе имела повышенный индекс метилирования центра импринтинга гена MKRN3 (72±7.84 против 56.92±9.44 %, p = 0.005). В группе пациентов с центральным ППС 3.8 % пациентов имели пониженный индекс метилирования центра импринтинга гена DLK1 и 11.5 % – гена MKRN3. Таким образом, показано, что не только генетические варианты, но и нарушение индекса метилирования центров импринтинга генов DLK1 и MKRN3 могут быть причиной ППС. 

Aortic aneurysm and atherosclerosis are characterized by high clinical heterogeneity. The uncertainty in their comorbidity evaluations may be related to polyetiology of these diseases and the presence of not only common but also specific risk factors, as well as the complex pathogenesis of these conditions. The aim of this review is to summarize information on the prevalence and risk factors of aortic aneurysm and atherosclerosis, explaining the possible mechanisms underlying the comorbidity of these pathologies. We conducted a search for scientific publications in Russian (eLIBRARY.RU) and international (PubMed) electronic libraries, prioritizing works published in the last 10 years. Aortic aneurysm and atherosclerosis exhibit an age-dependent pattern of prevalence. The high prevalence of atherosclerosis compared to aortic aneurysm, along with the approximately similar age ranges for the manifestation of these pathologies,is related to their comorbidity. Conversely, these diseases share some common risk factors, albeit with varying contributions to atherosclerosis and aortic aneurysm of different localizations. Type 2 diabetes mellitus and lipid metabolism profiles are examples of risk factors with multidirectional influences. To understand the reasons for the discordant estimates of comorbidity between aortic aneurysm and atherosclerosis from an epidemiological perspective, a comprehensive approach to patient characterization, including a detailed analysis of risk factors recorded in the analyzed groups, is essential.

Familial hypercholesterolaemia is a common monogenic disorder characterized by high plasma cholesterol levels leading to chronic cardiovascular disease with high risk and often early manifestation due to atherosclerotic lesions of the blood vessels. The atherosclerotic lesions in familial hypercholesterolaemia are mainly caused by pathogenic variants of the low-density lipoprotein receptor (LDLR) gene, which plays an important role in cholesterol metabolism. Normally, cholesterol-laden low-density lipoproteins bind to the LDLR receptor on the surface of liver cells to be removed from the bloodstream by internalisation with hepatocytes. In familial hypercholesterolaemia, the function of the receptor is impaired and the uptake of low-density lipoproteins is significantly reduced. As a result, cholesterol accumulates in the subendothelial space on the inner wall of blood vessels, triggering atherogenesis, the formation of atherosclerotic plaques. At present, there are no effective and universal approaches to the diagnosis and treatment of familial hypercholesterolaemia. A relevant approach to study the molecular genetic mechanisms of the disease and to obtain systems for screening chemical compounds as potential drugs is the generation of cellular models based on patient-specific induced pluripotent stem cells. The aim of our work was to derive an isogenic genetically modified induced pluripotent stem cell line by correcting the pathogenic allelic variant c.530C of the LDLR gene in the original iPSC previously obtained from a compound heterozygote patient with familial hypercholesterolaemia. The resulting isogenic iPSC line differs from the original by only one corrected nucleotide substitution, allowing us to study the direct effect of this pathogenic genetic variant on physiological changes in relevant differentiated cells. CRISPR/Cas-mediated base editing was used to correct the single nucleotide substitution. The resulting genetically modified iPSC line has pluripotency traits, a normal karyotype, a set of short tandem repeats identical to that in the original line and can be used to obtain differentiated derivatives necessary for the elaboration of relevant cell models

Precocious puberty (PP, OMIM 176400, 615346) is an autosomal dominant disorder caused by the premature reactivation of the hypothalamic-pituitary-gonadal axis. Genetic, epigenetic, and environmental factors play a decisive role in determining the timing of puberty. In recent years, genetic variants in the KISS1, KISS1R, MKRN3, and DLK1 genes have been identified as genetic causes of PP. The MKRN3 and DLK1 genes are imprinted, and therefore epigenetic fications, such as DNA methylation, which alter the expression of these genes, can also contribute to the development of PP. The aim of this study is to determine the methylation index of the imprinting centers of the DLK1 and MKRN3 genes in girls with a clinical presentation of PP. The methylation index of the imprinting centers of the DLK1 and MKRN3 genes was analyzed in a group of 45 girls (age 7.2±1.9 years) with a clinical presentation of PP and a normal karyotype using targeted massive parallel sequencing after sodium bisulfite treatment of DNA. The control group consisted of girls without PP (n = 15, age 7.9±1.6 years). No significant age differences were observed between the groups (p > 0.8). Analysis of the methylation index of the imprinting centers of the DLK1 and MKRN3 genes revealed no significant differences between patients with PP and the control group. However, in the group of patients with isolated adrenarche, an increased methylation index of the imprinting center of the MKRN3 gene was observed (72±7.84 vs 56.92±9.44 %, p = 0.005). In the group of patients with central PP, 3.8 % of patients showed a decreased methylation index of the imprinting center of the DLK1 gene, and 11.5 % of probands had a decreased methylation index of the imprinting center of the MKRN3 gene. Thus, this study demonstrates that not only genetic variants but also alterations in the methylation index of the imprinting centers of the DLK1 and MKRN3 genes can contribute to the development of PP.

Новая коронавирусная инфекция (COVID-19) - острое инфекционное заболевание, вызываемое вирусом SARS-CoV-2. Пандемия COVID-19 стала глобальным вызовом для здравоохранения и науки, а в области генетики человека привела к всплеску исследований роли генетики организма-хозяина в подверженности и тяжести течения инфекционного заболевания. Несмотря на негенетическую этиологию COVID-19, полногеномные ассоциативные исследования и работы по полногеномному и полноэкзомному анализу выявили целый ряд участков генома, достоверно ассоциированных с восприимчивостью к инфекции и тяжестью течения заболевания, модифицирующих риск развития COVID-19 на индивидуальном уровне. Эти данные не могут являться основанием для определения групп риска или прогноза тяжести течения болезни, однако полезны для понимания патогенетики болезни и для разработки подходов к ее диагностике и терапии. Исследования на уровне постгеномных механизмов регуляции реализации генетической информации выявили специфические паттерны экспрессии и метилирования генома в ответе на вирус и в ходе прогрессии заболевания и показали потенциал для разработки таргетных подходов для терапии и профилактики COVID-19. Вызовы для генетики как науки, возникшие с развитием пандемии COVID-19, ответы на них, опыт и накопленные данные, несомненно, найдут отражение в дальнейших обоснованных подходах к диагностике, профилактике и лечению как COVID-19, так и других быстро распространяющихся инфекционных заболеваний.

The novel coronavirus infection (COVID-19) is an acute infectious disease caused by the SARS CoV2 virus. The COVID-19 pandemic has become a global challenge for health and science, and in the field of human genetics, it has led to a surge in research on the role of host genetics in susceptibility to and severity of infectious diseases. Despite the nongenetic etiology of COVID-19, genome-wide association studies and whole-genome and whole-exome analyses have identified a number of genomic regions that are significantly associated with susceptibility to infection and disease severity, modifying the risk of developing COVID-19 at the individual level. These data cannot serve as a basis for identifying risk groups or predicting the severity of the disease, but are useful for understanding the pathogenesis of the disease and developing approaches to its diagnosis and therapy. Studies at the level of post-genomic mechanisms regulating the implementation of genetic information have revealed specific patterns of expression and methylation of the genome in response to the virus and during disease progression and have shown the potential for developing targeted approaches for the treatment and prevention of COVID-19. The challenges for genetics as a science that have arisen with the development of the COVID-19 pandemic, the answers to them, the experience, and accumulated data will undoubtedly be reflected in further substantiated approaches to the diagnosis, prevention, and treatment of both COVID-19 and other rapidly spreading infectious diseases.

Background: Effective molecular diagnosis of congenital diseases hinges on comprehensive genomic analysis, traditionally reliant on various methodologies specific to each variant type-whole exome or genome sequencing for single nucleotide variants (SNVs), array CGH for copy-number variants (CNVs), and microscopy for structural variants (SVs).

Methods: We introduce a novel, integrative approach combining exome sequencing with chromosome conformation capture, termed Exo-C. This method enables the concurrent identification of SNVs in clinically relevant genes and SVs across the genome and allows analysis of heterozygous and mosaic carriers. Enhanced with targeted long-read sequencing, Exo-C evolves into a cost-efficient solution capable of resolving complex SVs at base-pair accuracy.

Results: Applied to 66 human samples Exo-C achieved 100% recall and 73% precision in detecting chromosomal translocations and SNVs. We further benchmarked its performance for inversions and CNVs and demonstrated its utility in detecting mosaic SVs and resolving diagnostically challenging cases.

Conclusions: Through several case studies, we demonstrate how Exo-C's multifaceted application can effectively uncover diverse causative variants and elucidate disease mechanisms in patients with rare disorders.

Khamnigan is a poorly documented and endangered Mongolic language. This study examines basic word lists from eight Khamnigan communities in China, Mongolia and Russia, revealing strong lexical similarities indicative of dialectal variation within a single language. Specific affinities were found between certain pairs of communities, with the China variety closely related to Tarbaljei and Mogoitui (in Russia), the Mongolian Bayan-Uul variety to Dadal (in Mongolia) and Tarbaljei (in Russia), and the Tarbaljei variety to Mogoitui (in Russia). Lexical analysis places Khamnigan in the Northern Mongolic subgroup, with a division into the Buriad-Khamnigan and Mongol-Oirat-Ordos-Barga clusters. Geographical patterns suggest later influences on idiom evelopment, with common lexical innovations linking Khamnigan varieties to neighboring languages: East Buriad, Khalkha, and Old and New Barga.

Genome sequencing of 1537 individuals from 139 ethnic groups reveals the genetic characteristics of understudied populations in North Asia and South America. Our analysis demonstrates that West Siberian ancestry, represented by the Kets and Nenets, contributed to the genetic ancestry of most Siberian populations. West Beringians, including the Koryaks, Inuit, and Luoravetlans, exhibit genetic adaptation to Arctic climate, including medically relevant variants. In South America, early migrants split into four groups—Amazonians, Andeans, Chaco Amerindians, and Patagonians—~13,900 years ago. Their longest migration led to population decline, whereas settlement in South America’s diverse environments caused instant spatial isolation, reducing genetic and immunogenic diversity. These findings highlight how population history and environmental pressures shaped the genetic architecture of human populations across North Asia and South America.