Human adaptation to extreme climatic and geographic conditions mediated by natural selection may be one of the major factors for formation of genetic structure in North Eurasian populations. Using data on a genome-wide set of single nucleotide polymorphisms (SNPs), we searched for the signals of positive selection in five populations of Siberia and the Russian European North. From 113 to 185 genomic regions with extended homozygous haplotypes blocks containing altogether 771 genes were found in each of the populations. Cross-population search of the selection targets resulted in about 150 genomic regions, 57 of which overlap with the results of haplotype analysis in individual populations. Genomic loci with the most profound signals of positive selection in northern populations include regions of SLC30A9, CACNA1C, KCNQ5, ABCA1, ALDH1A2, CSMD1, RBFOX1, and WWOX, as well as some other genes. Bioinformatics analysis demonstrated that major biological processes where selection targets are implicated are those conferring the response to external stimuli, including proteins, nutrients, and glucose, and defense reactions, including inflammatory immune response. The network of protein-protein interactions of genes under positive selection forms distinct clusters related to a number of biological processes indicated above. Results of the study indicate that non-neutral microevolution mechanisms may play a substantial role in genetic structuring of the human populations during long-term adaptation to unfavorable environmental conditions.

Адаптация популяций человека к экстремальными климато-географическим условиям среды обитания, опосредованная естественным отбором, может являться одним из основных факторов формирования генетической структуры популяций Северной Евразии. Используя данные полногеномного набора однонуклеотидных полиморфных маркеров (SNP), мы провели поиск сигналов направленного отбора в 5 популяциях Сибири и европейской части России. Для каждой из популяций обнаружено от 113 до 185 регионов генома, формирующих протяженные гомозиготные блоки гаплотипов, содержащие в совокупности 771 ген. Кросс-популяционный поиск мишеней отбора выявил еще около 150 участков генома, в том числе – 57 пересекающихся с результатами гаплотипического анализа в отдельных популяциях. Среди локусов генома, несущих наиболее выраженные сигналы направленного отбора в северных популяциях, можно выделить области генов SLC30A9, CACNA1C, KCNQ5, ABCA1, ALDH1A2, CSMD1, RBFOX1, WWOX и ряд других. Биоинформационный анализ показал, что основными биологическими процессами, в которые вовлечены мишени отбора в северных популяциях, являются процессы ответа на внешние стимулы, включая белки, нутриенты и глюкозу, и защитные реакции организма, включая воспалительный ответ. Сеть белок-белковых взаимодействий продуктов генов, находящихся в регионах направленного отбора в геноме, формирует выраженные кластеры, соотносящиеся с некоторыми из указанных биологических процессов. Результаты работы свидетельствуют, что механизмы не-нейтральной микроэволюции могут играть существенную роль в формировании генетической структуры популяций человека в ходе долговременной адаптации к неблагоприятным условиям среды обитания.

Histamine is a biologically active substance of local effect, but is involved in the regulation of different processes in the body, including the pathogenesis of diseases. In the present review, molecular genetic, clinical, and experimental studies on the role of histamine and key genes of its metabolism in the pathogenesis of diseases are summarized. Data on associated polymorphic variants (30 SNPs, 1 CNV) of key histamine metabolism genes with multifactorial diseases are given, including HDC (involved in the synthesis of histamine), HNMT, AOC1, MAOB, ALDH7A1 (involved in the processes of histamine degradation), and HRH1, HRH2, HRH3, HRH4 (histamine receptors): associations were established with allergic and oncological diseases, diseases of nervous and cardiovascular systems, gastrointestinal tract, metabolic disorders, etc. A nonrandomness of established associations of histamine metabolic pathway genes with pathological conditions is supported by clinical observations and experimental studies performed on model objects and cell lines. Moreover, according to clinical and experimental data, a wider range of pathological conditions in which risk structural and functional peculiarities of key histamine metabolic pathway genes will make a certain contribution can be expected. The questions of the complexity of determining the significance of histamine level and structural and functional peculiarities of histamine metabolic pathway genes in terms of a positive/negative effect on the body, as well as some possible reasons for inconsistency of association studies performed in different ethnoterritorial groups, are discussed.

Гистамин является биологически активным веществом локального действия, но вовлечен в регуляцию различных процессов в организме, в том числе и в патогенез болезней. В настоящем обзоре представлены обобщения молекулярно-генетических, клинических и экспериментальных исследований, посвященных изучению роли гистамина и ключевых генов его метаболизма в патогенезе болезней. Приводятся данные об ассоциированных полиморфных вариантах (30 SNP, 1 CNV) ключевых генов метаболизма гистамина с многофакторными заболеваниями, в том числе HDC (участвует в синтезе гистамина), HNMT, AOC1, MAOB, ALDH7A1 (вовлечены в процессы деградации гистамина) и HRH1, HRH2, HRH3, HRH4 (рецепторы гистамина): ассоциации установлены с аллергическими и онкологическими заболеваниями, болезнями нервной и сердечно-сосудистой системы, желудочно-кишечного тракта, обменными нарушениями и др. О неслучайности установленных ассоциаций генов гистаминового метаболического пути с патологическими состояниями свидетельствуют клинические наблюдения и экспериментальные исследования, выполненные на модельных объектах и клеточных линиях. Более того, согласно клиническим и экспериментальным данным можно ожидать более широкий спектр патологических состояний, в формирование риска которых определенный вклад будут вносить структурно-функциональные особенности ключевых генов гистаминового метаболического пути. Обсуждаются вопросы сложности определения значимости уровня гистамина и структурно-функциональных особенностей генов гистаминового метаболического пути с позиций благоприятного/негативного влияния на функционирование организма, а также некоторые возможные причины противоречивости ассоциативных исследований, выполненных в разных этнотерриториальных группах.

Using chromosome microarray analysis, 52 samples of placental tissues from first trimester human spontaneous abortions were examined. One hundred twenty copy number variations (CNVs) were identified, affecting one or more genes (total of 427 genes). Using enrichment analysis with the mammalian phenotype ontology, all genes were divided into 183 categories (p ≤ 0.05). The embryogenesis category included 22 genes: AIP, BMP4, BMP5, CDKN1C, EXT1, GAB1, H19, HOXD13, IGF2, KIT, LDHA, NKX2-5, NRK, PEG3, PHLDA2, SMCHD1, SMN1, TBX3, TGIF1, TH, TLX2, and TRR. In this paper, the functions of each of the above genes and pathological phenotypes associated with mutations in them are discussed. A hypothesis of the pleiotropic effect of genes involved in CNVs in spontaneous abortions is proposed.

С помощью микроматричного хромосомного анализа исследованы 52 образца плацентарных тканей спонтанных абортусов человека первого триместра беременности. Выявлены 120 вариаций числа копий участков ДНК (CNV), затрагивающих один или несколько генов (всего 427 генов). С использованием биоинформационного алгоритма анализа обогащения при применении онтологии “Фенотип млекопитающих” все гены были разделены на 183 категории (р ≤ 0.05). Категория “Эмбриогенез” включала 22 гена: AIP, BMP4, BMP5, CDKN1C, EXT1, GAB1, H19, HOXD13, IGF2, KIT, LDHA, NKX2-5, NRK, PEG3, PHLDA2, SMCHD1, SMN1, TBX3, TGIF1, TH, TLX2, TRRAP. Рассмотрены функции каждого из приведенных генов и патологические состояния, ассоциированные с мутациями в них; высказана гипотеза о плейотропном эффекте генов, вовлеченных в CNV у спонтанных абортусов.

Abstract: Differential gene expression during development is maintained by complex regulatory epigenetic mechanisms that provide the formation of different specialized cell types. Subsequently, a multicellular organism is a mosaic of cells with differing epigenetic characteristics. It seems likely that exceeding the limits of normal epigenetic variability may cause the occurrence of pathological mosaic states in which one part of the cell population has a normal epigenotype, while the other part carries modified epigenetic information. In this review, using the genomic imprinting as a classical epigenetic phenomenon, for the first time, the prevalence of epigenetic mosaicism and the mechanisms of its origin, as well as its role in the etiology of hereditary disorders, determined by the dysfunction of imprinted genomic loci are summarized.

Дифференциальный характер генной экспрессии в развитии организма поддерживается сложными регуляторными эпигенетическими механизмами, обеспечивающими формирование различных специализированных типов клеток. В результате многоклеточный организм представляет собой мозаику клеток с различающимися эпигенетическими характеристиками. Высоко вероятно, что выход за границы нормальной эпигенетической вариабельности может обусловливать возникновение патологичных мозаичных состояний, при которых одна часть клеточной популяции обладает нормальным эпигенотипом, а другая несет измененную эпигенетическую информацию. В настоящем обзоре на примере явления геномного импринтинга как классического эпигенетического феномена впервые обобщены данные о распространенности эпигенетического мозаицизма, механизмов его возникновения и роли в этиологии наследственных болезней, обусловленных дисфункцией импринтированных локусов генома.

Human induced pluripotent stem cells (iPSCs) are a promising source of cells for regenerative medicine, study of the pathogenesis of various diseases, screening of pharmacological drugs, and other clinical and basic research. However, the maintenance of the genetic stability of the cells during reprogramming, long-term culture, and directed differentiation is necessary for the use of iPSCs. Large chromosomal aberrations affect the quality of iPSCs most adversely, so the review focuses on the analysis of chromosomal abnormalities, including the recurrent aneuploidy; the sources of its origin, the effect of reprogramming, and long-term culture on the accumulation of chromosome aberrations are discussed. Cases of spontaneous correction of the iPSCs karyotype and the possibility of induced correction of the large chromosomal abnormalities by removing or silencing the extra homologue are considered.

Индуцированные плюрипотентные стволовые клетки (ИПСК) человека являются многообещающим источником клеток для регенеративной медицины, изучения процессов патогенеза различных заболеваний, скрининга фармакологических препаратов и других клинических и фундаментальных исследований. Однако для применения ИПСК необходимо сохранение генетической стабильности клеток при репрограммировании, длительном культивировании и направленной дифференцировке. Крупные хромосомные аберрации наиболее негативно влияют на качество ИПСК, поэтому обзор в основном сосредоточен на анализе хромосомных аномалий, в том числе так называемых рекуррентных (повторяющихся) анеуплоидий, анализируются источники их возникновения, влияние процессов репрограммирования и длительного культивирования на накопление хромосомных аберраций. Рассмотрены случаи самопроизвольной коррекции кариотипа в ИПСК и возможность исправления крупных хромосомных аномалий с помощью удаления или функционального выключения лишнего гомолога.

Sex hormones, regulating normal physiological processes of most tissues and organs, are considered to be one of the key factors in the development of hormone-dependent cancer and formation of the hormone-resistant tumor phenotype. Recently, the importance of the system for control of hormone receptors expression mediated by nuclear peptides became evident. This system is involved in the regulation of normal physiological processes, in the pathogenesis of many diseases as well as oncogenesis. In the review, we discuss the relationships of the two regulatory peptides – Brn-3α, TRIM16 with hormone receptors. The transcription factor Brn-3α is able to affect the transcription activity of androgen and estrogen receptors. It is observed the participation of TRIM16 protein in the pathogenesis of hormone-dependent tumors due to its ""anti-estrogenic effect"". Additionally, they are involved in the key intracellular processes, such as proliferation, cell differentiation, and programmed death - apoptosis. Thus, Brn-3α and TRIM16 are associated with cancer development and progression. By understanding these alterations, we can identify potential markers and novel biochemical therapeutic targets. It makes clear the association between classical hormone-dependent tumors and less sensitive ones with the modification in the level of hormone receptors.

Background: Hyperprolactinemia (HPRL) is a classical side effect of antipsychotic drugs primarily attributed to blockade of dopamine D2 receptors (DRD2s) on the membranes of lactotroph cells within the pituitary gland. Certain antipsychotic drugs, e.g. risperidone, are more likely to induce HPRL because of relative accumulation within the adenohypophysis. Nevertheless, due to competition for pituitary DRD2s by high dopamine levels may limit antipsychotic-induced HPRL. Moreover, the activity of prolactin-producing lactotrophs also depends on other hormones which are regulated by the extra-pituitary activity of dopamine receptors, dopamine transporters, enzymes of neurotransmitter metabolism and other factors. Polymorphic variants in the genes coding for these receptors and proteins can have functional significance and influence on the development of hyperprolactinemia.

Methods: A set of 41 SNPs of genes for dopamine receptors DRD1, DRD2, DRD3, DRD4, the dopamine transporter SLC6A3 and dopamine catabolizing enzymes MAOA and MAOB was investigated in a population of 446 Caucasians (221 males/225 females) with a clinical diagnosis of schizophrenia (according to ICD-10: F20) with and without HPRL who were treated with classical and/or atypical antipsychotic drugs. Additive genetic model was tested and the analysis was carried out in the total group and in subgroup stratified by the use of risperidone/paliperidone.

Results: One statistically significant association between polymorphic variant rs1799836 of MAOB gene and HPRL in men was found in the total group. Furthermore, the rs40184 and rs3863145 variants in SLC6A3 gene appeared to be associated with HPRL in the subgroup of patients using the risperidone/paliperidone, but not with HPRL induced by other antipsychotic drugs.

Conclusions: Our results indicate that genetic variants of MAOB and SLC6A3 may have consequences on the modulation of prolactin secretion. A further search for genetic markers associated with the development of antipsychotic-related hyperprolactinemia in schizophrenic patients is needed.

We provide an overview of the recent achievements in psychiatric genetics research in the Russian Federation and present genotype-phenotype, population, epigenetic, cytogenetic, functional, ENIGMA, and pharmacogenetic studies, with an emphasis on genome-wide association studies. The genetic backgrounds of mental illnesses in the polyethnic and multicultural population of the Russian Federation are still understudied. Furthermore, genetic, genomic, and pharmacogenetic data from the Russian Federation are not adequately represented in the international scientific literature, are currently not available for meta-analyses and have never been compared with data from other populations. Most of these problems cannot be solved by individual centers working in isolation but warrant a truly collaborative effort that brings together all the major psychiatric genetic research centers in the Russian Federation in a national consortium. For this reason, we have established the Russian National Consortium for Psychiatric Genetics (RNCPG) with the aim to strengthen the power and rigor of psychiatric genetics research in the Russian Federation and enhance the international compatibility of this research.The consortium is set up as an open organization that will facilitate collaborations on complex biomedical research projects in human mental health in the Russian Federation and abroad. These projects will include genotyping, sequencing, transcriptome and epigenome analysis, metabolomics, and a wide array of other state-of-the-art analyses. Here, we discuss the challenges we face and the approaches we will take to unlock the huge potential that the Russian Federation holds for the worldwide psychiatric genetics community.

Background: Tuberculosis (TB) is one of the most significant health-care problems worldwide. The host's genetics play an important role in the development of TB in humans. The disease progresses through several stages, each of which can be under the control of different genes. The precise genes influencing the different stages of the disease are not yet identified. The aim of the current study was to determine the associations between primary and secondary TB and the polymorphisms of novel candidate genes for TB susceptibility, namely CD79A, HCST, CXCR4, CD4, CD80, CP, PACRG, and CD69.

Methods: A total of 357 patients with TB (130 cases with primary TB and 227 cases with secondary TB) from the Siberian region of Russia as well as 445 healthy controls were studied. The study was performed at the Research Institute of Medical Genetics, Tomsk NRMC, Tomsk, Russia, between July 2015 and November 2016. Genotyping was carried out using MALDI-TOF mass spectrometry and PCR-RFLP. The associations between the single-nucleotide polymorphisms and TB were assessed using logistic regression adjusting for covariates (age and gender). Multiple testing was addressed via the experiment-wise permutation approach. The statistical significance threshold was a P value less than 0.05 for the permutation P values. The analyses were done in R 3.2 statistical software.

Results: An association was established between the rs1880661 variant of the CD80 gene and secondary TB and the rs10945890 variant of the PACRG gene and both primary and secondary TB. However, the same allele of PACRG appeared to be both a risk factor for reactivation (secondary TB) and a protector against primary infection.

Conclusion: The results suggested that the CD80 and PACRG genes were associated with susceptibility to different forms of TB infection in the Russian population.

Psoriasis (PS) and psoriatic arthritis (PsA) are subtypes of psoriatic disease (PD), a chronic inflammatory disorder with predominantly cutaneous manifestations. PsA is developed in approximately one third of patients with PS. These two phenotypes are immune-mediated diseases with different heredity that might in part be explained by different genetic factors. We carried out an analysis of association between haplotypes of cytokine genes (TNFA, IL4 and IL10) and PD in Russians from East Siberian region of Russia. The haplotypes were not found to be associated with either PS or PsA. However, meta-analyses with published data suggested associations between PS and IL4 rs2243250 and TNFA rs1800629 polymorphisms, while PsA was found to be associated with IL4 rs2243250 only. The results provide further insight into understanding of genetic factors predisposing to PD.