Most copy number variations (CNVs) in the human genome display incomplete penetrance with unknown underlying mechanisms. One such mechanism may be epigenetic modification, particularly DNA methylation. The IMMP2L gene is located in a critical region for autism susceptibility on chromosome 7q (AUTS1). The level of DNA methylation was assessed by bisulfite sequencing of 87 CpG sites in the IMMP2L gene in 3 families with maternally inherited 7q31.1 microdeletions affecting the IMMP2L gene alone. Bisulfite sequencing revealed comparable levels of DNA methylation in the probands, healthy siblings without microdeletions, and their fathers. In contrast, a reduced DNA methylation index and increased IMMP2L expression were observed in lymphocytes from the healthy mothers compared with the probands. A number of genes were upregulated in the healthy mothers compared to controls and downregulated in probands compared to mothers. These genes were enriched in components of the ribosome and electron transport chain, as well as oxidative phosphorylation and various degenerative conditions. Differential expression in probands and mothers with IMMP2L deletions relative to controls may be due to compensatory processes in healthy mothers with IMMP2L deletions and disturbances of these processes in probands with intellectual disability. The results suggest a possible partial compensation for IMMP2L gene haploinsufficiency in healthy mothers with the 7q31.1 microdeletion by reducing the DNA methylation level. Differential DNA methylation of intragenic CpG sites may affect the phenotypic manifestation of CNVs and explain the incomplete penetrance of chromosomal microdeletions.

The Hi-C technique is widely employed to study the 3-dimensional chromatin architecture and to assemble genomes. The conventional in situ Hi-C protocol employs restriction enzymes to digest chromatin, which results in nonuniform genomic coverage. Using sequence-agnostic restriction enzymes, such as DNAse I, could help to overcome this limitation.

High frequency of aneuploidy in meiosis and cleavage stage coincides with waves of epigenetic genome reprogramming that may indicate a possible association between epigenetic mechanisms and aneuploidy occurrence. This study aimed to assess the methylation level of the long interspersed repeat element 1 (LINE-1) retrotransposon in chorionic villi of first trimester miscarriages with a normal karyotype and aneuploidy.

Human ring chromosomes are often unstable during mitosis, and daughter cells can be partially or completely aneuploid. We studied the mitotic stability of four ring chromosomes, 8, 13, 18, and 22, in long-term cultures of skin fibroblasts and induced pluripotent stem cells (iPSCs) by GTG karyotyping and aCGH. Ring chromosome loss and secondary aberrations were observed in all fibroblast cultures except for r(18). We found monosomy, fragmentation, and translocation of indexed chromosomes. In iPSCs, aCGH revealed striking differences in mitotic stability both between iPSC lines with different rings and, in some cases, between cell lines with the same ring chromosome. We registered the spontaneous rescue of karyotype 46,XY,r(8) to 46,XY in all six iPSC lines through ring chromosome loss and intact homologue duplication with isoUPD(8)pat occurrence, as proven by SNP genotype distribution analysis. In iPSCs with other ring chromosomes, karyotype correction was not observed. Our results suggest that spontaneous correction of the karyotype with ring chromosomes in iPSCs is not universal and that pluripotency is compatible with a wide range of derivative karyotypes. We conclude that marked variability in the frequency of secondary rearrangements exists in both fibroblast and iPSC cultures, expanding the clinical significance of the constitutional ring chromosome.

Antipsychotic-induced metabolic syndrome (MetS) is a multifactorial disease with a genetic predisposition. Serotonin and its receptors are involved in antipsychotic-drug-induced metabolic disorders. The present study investigated the association of nine polymorphisms in the four 5-hydroxytryptamine receptor (HTR) genes HTR1A, HTR2A, HTR3A, and HTR2C and the gene encoding for the serotonin transporter SLC6A4 with MetS in patients with schizophrenia.

As the interest in genetic resequencing increases, so does the need for effective mathematical, computational, and statistical approaches. One of the difficult problems in genome annotation is determination of precise positions of transcription start sites. In this paper, we present TransPrise-an efficient deep learning tool for predicting positions of eukaryotic transcription start sites. TransPrise offers significant improvement over existing promoter-prediction methods. To illustrate this, we compared predictions of TransPrise with the TSSPlant approach for well-annotated genome of Oryza sativa. Using a computer with a graphics processing unit, the run time of TransPrise is 250 min on a genome of 374 Mb long.We provide the full basis for the comparison and encourage users to freely access a set of our computational tools to facilitate and streamline their own analyses. The ready-to-use Docker image with all the necessary packages, models, and code as well as the source code of the TransPrise algorithm are available at http://compubioverne.group/ . The source code is ready to use and to be customized to predict TSS in any eukaryotic organism.

The human serine protease serine 2 TMPRSS2 is involved in the priming of proteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and represents a possible target for COVID-19 therapy. The TMPRSS2 gene may be co-expressed with SARS-CoV-2 cell receptor genes angiotensin-converting enzyme 2 (ACE2) and Basigin (BSG), but only TMPRSS2 demonstrates tissue-specific expression in alveolar cells according to single-cell RNA sequencing data. Our analysis of the structural variability of the TMPRSS2 gene based on genome-wide data from 76 human populations demonstrates that a functionally significant missense mutation in exon 6/7 in the TMPRSS2 gene is found in many human populations at relatively high frequencies, with region-specific distribution patterns. The frequency of the missense mutation encoded by rs12329760, which has previously been found to be associated with prostate cancer, ranged between 10% and 63% and was significantly higher in populations of Asian origin compared with European populations. In addition to single-nucleotide polymorphisms, two copy number variants were detected in the TMPRSS2 gene. A number of microRNAs have been predicted to regulate TMPRSS2 and BSG expression levels, but none of them is enriched in lung or respiratory tract cells. Several well-studied drugs can downregulate the expression of TMPRSS2 in human cells, including acetaminophen (paracetamol) and curcumin. Thus, the interactions of TMPRSS2 with SARS-CoV-2, together with its structural variability, gene-gene interactions, expression regulation profiles, and pharmacogenomic properties, characterize this gene as a potential target for COVID-19 therapy.

The role of molecular genetic factors in cardiovascular disease (CVD) development has been actively studied in recent years. In patients with acute myocardial infarction and heart failure, the genetic component contributes to the determination of inflammation and persistence of inflammatory mediators in the myocardium. The genetic component in combination with traditional CVD risk factors determines the clinical course of the disease, the severity and its outcome. This review summarizes the data on relationship of proand anti-inflammatory cytokines with coronary artery disease and its clinical manifestations.

Влияние молекулярно-генетических факторов на развитие сердечно-сосудистых заболеваний (ССЗ) уже на протяжении ряда лет является предметом активного изучения. У пациентов с острым инфарктом миокарда и сердечной недостаточностью в детерминации общего воспалительного фона и персистенции воспалительных медиаторов в миокарде очевидно наличие генетической компоненты. Генетический фон в комбинации с традиционными факторами риска ССЗ определяет характер клинического течения болезни, степень тяжести и ее исход. В настоящем обзоре обобщены данные ассоциативных исследований генов про- и противовоспалительных цитокинов с ишемической болезнью сердца и ее клиническими проявлениями.

Изучали скорость поглощения кислорода митохондриями, выделенными из лейкоцитов периферической крови пациентов с острым инфарктом миокарда и здоровых добровольцев. Установлено, что для митохондрий лейкоцитов пациентов с острым инфарктом миокарда характерно достоверно значимое снижение скорости поглощения кислорода и уровня сопряжения процессов окисления и фосфорилирования.

Медико-генетическая помощь населению включает в себя диагностику, лечение и профилактику специфической группы болезней – наследственной патологии (моногенной, хромосомной и

мультифакториальной). Профилактика и диагностика наследственной патологии достигаются при осуществлении следующих основных подходов: медико-генетическое консультирование; пренатальная, преимплантационная диагностика; массовое скринирование новорожденных на наследственные болезни; диспансеризация, включающая проспективное консультирование семей высокого риска и активное выявление гетерозиготных носителей мутантных генов; контроль за мутагенными факторами окружающей среды.

In studies of many medical and biological problems, there is a clear underestimation of the fundamental role of mitochondria in the evolution of eukaryotic organisms on the planet, including fungi, plants and fauna. It is important to take into consideration numerous fundamental functions of mitochondria when studying the human physiology and pathology, aging mechanisms. In this lecture, we briefly discuss the origin of mitochondria and their importance in the emergence of plants, which appeared on the planet 1-1.5 billion years later than eukaryotes with mitochondria, and served as the food basis for the rapid evolution of all species of the animal world. In the course of transformation of protobacteria into mitochondria, approximately 1000-1500 genes were transferred to the nucleus of eukaryotes, and the remaining 37 mitochondrial genes (mtDNA) exist in all types of animals. The presence of mitochondria in eukaryotes led to increased production of reactive oxygen species and accelerated mutations in mtDNA. The spread of sexual reproduction may have been the way of protection against the accumulation of harmful mutations in mtDNA. At the same time, in all animal species mtDNA is inherited only maternally. In humans, the maternal inheritance of mtDNA led to uneven distribution, in small or inbred populations in particular, of a number of diseases with large prevalence in men, as well as male infertility, and in general accelerated aging and shorter lifespan in men, as compared with women. These negative consequences of the maternal inheritance of mtDNA were termed as ""mother's curse"". Recent studies have shown that mtDNA mutations are not the cause of human aging. The crisis of the mitochondrial free radical theory of aging is largely associated with the neglect of the protonated form of the superoxide radical, the perhydroxyl radical, which activates the peroxidation of polyunsaturated fatty acids in mitochondrial phospholipids. This results in production of various biologically active molecules and toxins. Therefore, initially aging may lack the manifestation of specific symptoms because of gradual accumulation of a wide variety of disorders and damages to the structure and functions of mitochondria and cells that finally lead to the development of diseases. The pathologies appear primarily in those organs that have a wide range of functional activity and a high dependence on oxygen consumption, namely the heart, brain, skeletal muscles and vascular epithelium.

Изучение многих медико-биологических проблем характеризуется явной недооценкой фундаментальной роли митохондрий в эволюции практически всех эукариотических организмов на планете, включая грибы, растения и животный мир. Тем более важно учитывать фундаментальные и разносторонние функции митохондрий при изучении физиологии и патологии человека, механизмов старения. В данной лекции мы коротко рассматриваем происхождение митохондрий, их роль в возникновении растений, которые появились на планете на 1-1,5 миллиарда лет позднее эукариот с митохондриями, и послужили пищевой основой для бурной эволюции всех видов животного мира. В ходе превращения протобактерии в митохондрию примерно 1000- 1500 генов было передано в ядро эукариот, а оставшиеся в мтДНК 37 генов присутствуют практически у всех видов животных. Появление митохондрий у эукариот привело к повышению продукции активных форм кислорода и ускорению мутаций мтДНК. Предполагается, что появление полового размножения в ходе эволюции явилось способом защиты от накопления вредных мутаций в популяции...

Ключевым этапом в исследованиях, направленных на изучение роли отдельных типов клеток в функционировании артерий человека in vivo как в норме, так и при поражении атеросклерозом, является получение суспензии клеток из стенки кровеносного сосуда. К настоящему времени разработан ряд подходов к дезагрегации артерий. В обзоре систематизированы опубликованные ранее данные и методики, представлен алгоритм оптимизации процедуры дезагрегации артерий, а также описаны возникающие проблемы и способы их решения.

Исследования феномена сочетания одновременно нескольких болезней у отдельного индивидуума, актуализированные во второй половине XIX в., спустя 150 лет активно анализируются с использованием генетических подходов. В статье представлен обзор результатов таких исследований в отношении аллергических заболеваний, в частности особого их варианта, так называемого «атопического марша», последовательного развития экземы, аллергического ринита и астмы (синтропия «атопический марш»). Обобщены результаты генетических и эпидемиологических исследований, проведен анализ работ поиска полногеномных ассоциаций, рассмотрена роль мутаций в гене филаггрина ( FLG ) в развитии данной синтропии.