Генетические маркеры человека, сцепленные с X-хромосомой (кратко – X-сцепленные), применяются в области популяционной генетики, медицинской генетики, а также для ДНК-идентификации индивида в криминалистике и судебной медицине. Нами предложена панель XSNPid, состоящая из 66 несцепленных однонуклеотидных маркеров Х-хромосомы, и разработан протокол их мультиплексного генотипирования с помощью методов многолокусной ПЦР и масс-спектрометрии MALDI-TOF. Панель XSNPid генотипируется в составе двух мультиплексов (на 36 и 30 маркеров). Разработанный протокол обеспечивает эффективное чтение генотипов: доля определяемых генотипов составляет 98.29%. Для русской популяции характерен высокий уровень генного разнообразия (0.461) по X-сцепленным SNP, включенным в панель. 63 из 66 маркеров, обеспечивающих высокую эффективность генотипирования и независимое наследование, пригодны для целей ДНК-идентификации. Для панели XSNPid характерна очень высокая дискриминационная способность при исследовании русской популяции. Вероятность совпадения генотипов у двух неродственных индивидов составляет 9 × 10–27 для женщин и 2 × 10–18 для мужчин. При сравнении с другими ближайшими аналогами наборов X-хромосомных SNP, панель XSNPid обладает, кроме более высокой дискриминирующей способности, также большей емкостью мультиплексов, что делает ее более экономически выгодной и требует меньших затрат времени при использовании. Панель XSNPid – удобный инструмент не только для индивидуальной ДНК-идентификации, но и для популяционно-генетических исследований.

A group of patients with ischemic heart disease and myocardial infarction (N = 156) and a reference population sample (N = 300) were genotyped for 58 single nucleotide polymorphisms (SNPs) in the genes involved in extracellular matrix function and collagen metabolism or associated with cardiovascular diseases and atherosclerotic plaque stability. Genotyping was performed by mass-spectrometry with two multiplex sets of 27 and 31 SNPs. The study revealed different genetic composition of predisposition to cardiovascular disease continuum (CVDC) syntropy (patients with concomitant conditions: hypercholesterolemia, hypertension, and type-II diabetes mellitus, N = 96) and to isolated myocardial infarction (without these conditions, N = 60). Only the KIAA1462 gene (rs3739998) showed associations with both CVDC syntropy (OR = 1.71; 95% CI 1.19–2.45; р = 0.003) and isolated infarction (OR = 1.58; 95% CI 1.05–2.40; р = 0.028). Isolated myocardial infarction was also associated with LIG1 (rs20579) (OR = 2.08; 95% CI 1.06–4.17; р = 0.028) and ADAMDEC1 (rs3765124) (OR = 1.63; 95% CI 1.07–2.50; р = 0.020). CVDC syntropy was associated with CDKN2BAS1 (rs1333049) (OR = 1.48; 95% CI 1.03–2.12; р = 0.029) and APOA2 (rs5082) (OR = 1.47; 95% CI 1.02–2.11; р = 0.035). So, genes involved in fibrogenesis contribute to predisposition to the myocardial infarction as well. Isolated myocardial infarction and CVDC syntropy can be considered as pathogenetically different cardiovascular conditions, with different genes that contribute to the susceptibility.

В группе больных с ишемической болезнью сердца и инфарктом миокарда (N = 156), а также в популяционной выборке (N = 300) изучены 58 однонуклеотидных замен (SNP) в генах, вовлеченных в функционирование внеклеточноего матрикса, в метаболизм коллагена или ассоциированных с болезнями сердечно-сосудистого континуума и стабильностью атеросклеротической бляшки. Генотипирование выполняли при помощи масс-спектрометрии (две мультиплексные панели, включающие 27 и 31 SNP). В подгруппе больных с “синтропией сердечно-сосудистого континуума” (инфаркт миокарда с несколькими сопутствующими заболеваниями, такими, как артериальная гипертония, сахарный диабет типа 2 и гиперхолестеринемия, 96 человек) и в подгруппе с “изолированным” инфарктом миокарда (в отсутствие всех указанных заболеваний, 60 человек) “структура” генетической предрасположенности к этим двум формам течения ишемической болезни сердца различна. Показано, что только ген KIAA1462 (rs3739998) ассоциациирован как с “изолированным” инфарктом миокарда (OR = 1.58; 95% CI 1.05–2.40; р = 0.028), так и с сочетанной формой патологии (OR = 1.71; 95% CI 1.19–2.45; р = 0.003). С “изолированным” инфарктом миокарда ассоциированы также гены LIG1 (rs20579) (OR = 2.08; 95% CI 1.06–4.17; р = 0.028) и ADAMDEC1 (rs3765124) (OR = 1.63; 95% CI 1.07–2.50; р = 0.020). С синтропией сердечно-сосудистого континуума ассоциированы гены CDKN2BAS1 (rs1333049) (OR = 1.48; 95% CI 1.03–2.12; р = 0.029) и APOA2 (rs5082) (OR = 1.47; 95% CI 1.02–2.11; р = 0.035). Таким образом, установлено, что гены, участвующие в процессах фиброгенеза, вносят свой вклад в развитие предрасположенности к инфаркту миокарда. Синтропию сердечно-сосудистого континуума и “изолированный” инфаркт миокарда можно рассматривать как патогенетически обособленные формы сердечно-сосудистых заболеваний, подверженность которым определяется генами различных функциональных классов

Tuberculosis (TB) is a common infectious disease caused by M. tuberculosis. The risk of the disease is dependent on complex interactions between host genetics and environmental factors. Accumulated genomic data, along with novel methodological approaches such as associative networks, facilitate studies into the inherited basis of TB. In the current study, we carried out the reconstruction and analysis of an associative network representing molecular interactions between proteins and genes associated with TB. The network predominantly comprises of well-studied key proteins and genes which are able to govern the immune response against M. tuberculosis. However, this approach also allowed us to reveal 12 proteins encoded by genes, the polymorphisms of which have never been studied in relation to M. tuberculosis infection. These proteins include surface antigens (CD4, CD69, CD79, CD80, MUC16) and other important components of the immune response, inflammation, pathogen recognition, cell migration and activation (HCST, ADA, CP, SPP1, CXCR4, AGER, PACRG). Thus, the associative network approach enables the discovery of new candidate genes for TB susceptibility.

Medieval era encounters of nomadic groups of the Eurasian Steppe and largely sedentary East Europeans had a variety of demographic and cultural consequences. Amongst these outcomes was the emergence of the Lipka Tatars-a Slavic-speaking Sunni-Muslim minority residing in modern Belarus, Lithuania and Poland, whose ancestors arrived in these territories via several migration waves, mainly from the Golden Horde. Our results show that Belarusian Lipka Tatars share a substantial part of their gene pool with Europeans as indicated by their Y-chromosomal, mitochondrial and autosomal DNA variation. Nevertheless, Belarusian Lipkas still retain a strong genetic signal of their nomadic ancestry, witnessed by the presence of common Y-chromosomal and mitochondrial DNA variants as well as autosomal segments identical by descent between Lipkas and East Eurasians from temperate and northern regions. Hence, we document Lipka Tatars as a unique example of former Medieval migrants into Central Europe, who became sedentary, changed language to Slavic, yet preserved their faith and retained, both uni- and bi-parentally, a clear genetic echo of a complex population interplay throughout the Eurasian Steppe Belt, extending from Central Europe to northern China.

Tuberculosis is a global pressing healthcare issue in the modern world. Host genetics is an important modifier of the disease risk. Genetic and genomic studies aim to reveal key inherited variants of the human genome associated with the susceptibility to tuberculosis. Much attention is given to the study of differential genetic susceptibility to various stages of tuberculous infection, particularly latent tuberculosis, the detection of which is most challenging. Susceptibility genes have been identified and most of which exhibit a relatively small effect on the disease risk. On the other hand, a proportion of children suffer from Mendelian susceptibility to tuberculosis associated with rare mutations with deterministic effect in genes for the components of cellular immunity against intra-cellular infections. This review focuses on the current achievements in genomic studies devoted to the identification of genes important for the implementation of the immune response and protection against the development of the infection in different populations in the world.

Background: The majority of miscarriages are sporadic; however, 1-5% of couples experience recurrent pregnancy loss (RPL). Approximately 50-60% of miscarriages result from chromosomal abnormalities. Currently, there are conflicting reports regarding the rates of chromosomal abnormalities between recurrent and sporadic pregnancy losses.

Methods: A retrospective comparative cytogenetic analysis of 442 RPL and 466 sporadic abortions (SA) was performed. Maternal age and medical background were evaluated, and chromosomal abnormality rates were compared between groups.

Results: The frequency of embryos with abnormal karyotypes was significantly higher in SA compared to RPL (56.7 and 46.6%, respectively), and abortions from women under 30 years of age were the main contributor to this difference. An age-dependent increase in the abnormal karyotype rate was observed in two groups of women - those with SA [53.0 and 70.1% for younger and older (≥35-year-old) mothers, respectively] and those with idiopathic RPL without any concomitant reproductive pathology (46.5 and 78.4% for younger and older mothers) - but not in the group of women with RPL associated with concomitant reproductive pathology. The incidence of recurrent abnormal karyotypes in subsequent miscarriages was significantly higher than random probability (odds ratio = 22.75).

Conclusion: Our findings highlight the variability in the risk of aneuploidy in recurrent abortion.

The widespread application of array comparative genomic hybridization (aCGH) has provided new insights into the clinical significance of copy number variations (CNVs) in the human genome. Many microdeletion syndromes have recently been linked to corresponding reciprocal microduplication syndromes related to CNVs in the same chromosomal regions. However, the extent of CNVs may not be restricted to only microduplications but may also include microtriplications or even quadruplications. 4q21 microdeletion syndrome is one of these recently described syndromes. The phenotype includes growth restriction, neonatal hypotonia, severe developmental delay, absent or delayed speech, and distinct facial features. The minimal critical deleted region, which is 1.3 Mb in size, contains the PRKG2, RASGEF1B, HNRNPD, HNRPDL, and ENOPH1 genes. Here, we report a 5.4-year-old girl with developmental delay, absence of speech, muscular hypertension, macrocephaly, a broad forehead, frontal bossing, relatively elongated extremities, a vascular malignant hemangioma in anamnesis, and elongated sigmoid colon. aCGH revealed a microtriplication at 4q21.21-q21.22 that was 1.61 Mb in size. This de novo microtriplication included nine genes (BMP3, PRKG2, RASGEF1B, HNRNPD, HNRPDL, ENOPH1, TMEM150C, LINC00575, and SCD5) and overlapped with the minimal critical region for 4q21 microdeletion syndrome. Some clinical features of the patient were similar to those of 4q21 microdeletion (macrocephaly, frontal bossing, developmental delay, absence of speech, and anxiety), whereas others were mirrored (elongated extremities and muscular hypertension). The first identified case of a de novo microtriplication at 4q21.21-q21.22 emphasizes the clinical significance of CNVs at 4q21 for patients with developmental delay and absence of speech

Objectives: An established theory for the pathogenesis of tardive dyskinesia is disturbed dopaminergic receptor sensitivity and/or dopaminergic intracellular signaling. We examined associations between genetic variants of neurotransmitter receptors and tardive dyskinesia.

Methods: We assessed tardive dyskinesia in Caucasian psychiatric inpatients from Siberia (N = 431) and a long-stay population from the Netherlands (N = 168). These patients were genotyped for 43 tag single nucleotide polymorphisms in five neurotransmitter receptor genes, and the results for the two populations were compared.

Results: Several significant associations with tardive dyskinesia were identified, but only GRIN2A (rs1345423) was found in both patient populations. This lack of agreement was probably due to the small effect size of the associations, the multiple testing and the small sample size of the Dutch patient population. After reviewing the literature, we propose that the constitutive stimulatory activity of serotonergic type 2 receptors may be relevant.

Conclusions: Inactivity of the serotonergic, type 2C receptor or blockade of these receptors by atypical antipsychotic drugs may decrease the vulnerability to develop tardive dyskinesia

Background: Asthma is a disease affecting more boys than girls in childhood and more women than men in adulthood. The mechanisms behind these sex-specific differences are not yet understood.

Objective: We analyzed whether and how genetic factors contribute to sex-specific predisposition to childhood-onset asthma.

Methods: Interactions between sex and polymorphisms on childhood asthma risk were evaluated in the Multicentre Asthma Genetics in Childhood Study (MAGICS)/Phase II International Study of Asthma and Allergies in Childhood (ISAAC II) population on a genome-wide level, and findings were validated in independent populations. Genetic fine mapping of sex-specific asthma association signals was performed, and putatively causal polymorphisms were characterized in vitro by using electrophoretic mobility shift and luciferase activity assays. Gene and protein expression of the identified gene doublesex and mab-3 related transcription factor 1 (DMRT1) were measured in different human tissues by using quantitative real-time PCR and immunohistochemistry.

Results: Polymorphisms in the testis-associated gene DMRT1 displayed interactions with sex on asthma status in a population of primarily clinically defined asthmatic children and nonasthmatic control subjects (lowest P = 5.21 × 10(-6)). Replication of this interaction was successful in 2 childhood populations clinically assessed for asthma but showed heterogeneous results in other population-based samples. Polymorphism rs3812523 located in the putative DMRT1 promoter was associated with allele-specific changes in transcription factor binding and promoter activity in vitro. DMRT1 expression was observed not only in the testis but also in lung macrophages.

Conclusion: DMRT1 might influence sex-specific patterns of childhood asthma, and its expression in testis tissue and lung macrophages suggests a potential involvement in hormone or immune cell regulation.

Background: Asthma is a heterogeneous disease in which age of onset plays an important role.

Objective: We sought to identify the genetic variants associated with time to asthma onset (TAO).

Methods: We conducted a large-scale meta-analysis of 9 genome-wide association studies of TAO (total of 5462 asthmatic patients with a broad range of age of asthma onset and 8424 control subjects of European ancestry) performed by using survival analysis techniques.

Results: We detected 5 regions associated with TAO at the genome-wide significant level (P < 5 × 10-8). We evidenced a new locus in the 16q12 region (near cylindromatosis turban tumor syndrome gene [CYLD]) and confirmed 4 asthma risk regions: 2q12 (IL-1 receptor-like 1 [IL1RL1]), 6p21 (HLA-DQA1), 9p24 (IL33), and 17q12-q21 (zona pellucida binding protein 2 [ZPBP2]-gasdermin A [GSDMA]). Conditional analyses identified 2 distinct signals at 9p24 (both upstream of IL33) and 17q12-q21 (near ZPBP2 and within GSDMA). Together, these 7 distinct loci explained 6.0% of the variance in TAO. In addition, we showed that genetic variants at 9p24 and 17q12-q21 were strongly associated with an earlier onset of childhood asthma (P ≤ .002), whereas the 16q12 single nucleotide polymorphism was associated with later asthma onset (P = .04). A high burden of disease risk alleles at these loci was associated with earlier age of asthma onset (4 vs 9-12 years, P = 10-4).

Conclusion: The new susceptibility region for TAO at 16q12 harbors variants that correlate with the expression of CYLD and nucleotide-binding oligomerization domain 2 (NOD2), 2 strong candidates for asthma. This study demonstrates that incorporating the variability of age of asthma onset in asthma modeling is a helpful approach in the search for disease susceptibility genes.

X chromosome genetic markers are widely used in basic population genetic research as well as in forensic genetics. In this paper we analyze the genetic diversity of 62 X chromosome SNPs in 4 populations using multiplex genotyping based on multi-locus PCR and MALDI-TOF mass spectrometry, and report forensic and population genetic features of the panel of X-linked SNPs (XSNPid). Studied populations represent Siberian (Buryat and Khakas), North Asian (Khanty) and Central Asian (Kazakh) native people. Khanty, Khakas and Kazakh population demonstrate average gene diversity over 0.45. Only East Siberian Buryat population is characterized by lower average heterozygosity (0.436). AMOVA analysis of genetic structure reveals a relatively low but significant level of genetic differentiation in a group of 4 population studied (FST=0.023, p=0.0000). The XSNPid panel provides a very high discriminating power in each population. The combined probability of discrimination in females (PDf) for XSNPid panel ranged between populations from 0.99999999999999999999999982 in Khakas to 0.9999999999999999999999963 in Buryats. The combined discriminating power in males (PDm) varies from 0.999999999999999792 to 0.9999999999999999819. The developed multiplex set of X chromosome SNPs can be a useful tool for population genetic studies and for forensic identity and kinship testing.

The sex ratio in the first trimester of pregnancy shifts toward males due to increased elimination of female embryos. One reason for this phenomenon may be disruption of X chromosome inactivation. In this paper, we have analyzed the nature of the X chromosome inactivation in extraembryonic tissues of induced and spontaneous abortuses with 46,XX karyotype. Both equiprobable and asymmetric inactivation have been found in chorionic cytotrophoblast from spontaneous and induced abortuses. In the extraembryonic mesoderm of the control group of embryos, only equiprobable inactivation has been found, whereas this parameter was shifted in 15% of spontaneous abortions. The highest incidence of the selective inactivation of one of the parent homologues was found in the group with a lack of development of embryos and embryos from women with recurrent miscarriages. One of the reasons for the observed results can be compartmentalization of cells in the blastocyst leading to the nonrandom redistribution of cells and the predominance in the inner mass of cells with an active X chromosome with aberrations incompatible with normal embryonic development.

Introduction: Long-term levodopa treatment of Parkinson’s disease (PD) is frequently complicated by spontaneously occurring involuntary muscle movements called dyskinesia. The exact pathological mechanism of this complication has not yet been elucidated. We have previously demonstrated that in PD patients the vulnerability to develop peripheral but not orofacial dyskinesia is associated with the presence of two variants of the GRIN2A gene. Moreover, we have shown that in tardive dyskinesia (TD) orofacial dyskinesia is associated with other polymorphisms as compared with peripheral dyskinesia. In the present study we investigate whether the peripheral versus orofacial nature of levodopa-induced dyskinesia (LID) in PD can be explained by considering polymorphisms for dopaminergic and serotonergic receptors. Materials and Methods: 101 Russian patients with PD (38M/63F) were examined. Genotyping was carried out on 19 SNPs for 3 neurotransmitter genes: 10 SNPs for DRD3 gene (rs11721264, rs167770, rs3773678, rs963468, rs7633291, rs2134655, rs9817063, rs324035, rs1800828, rs167771), 1 SNP for DRD4 gene (rs3758653), and 8 SNPs for HTR2C gene (rs6318, rs5946189, rs569959, rs17326429, rs4911871, rs3813929, rs1801412, rs12858300). Results: Genotyping patients with PD and LID revealed that only rs3773678 (DRD3, dominant, p = 0.042) was associated with orofacial dyskinesia. Conclusion: The findings of the current study are not related to LID in PD itself, but to other forms of orofacial dyskinesia in this patient group.

Генотоксическое действие ионизирующего излучения в ранний период эмбрионального развития может привести к фатальным последствиям. В то же время проблема радиочувствительности эмбриональных и экстраэмбриональных дифференцированных клеток зародышей человека остается слабо исследованной. В настоящей работе проведен анализ эффективности системы репарации двунитевых разрывов ДНК экстраэмбриональных фибробластов зародышей человека. Показано, что в экстраэмбриональных фибробластах способность к репарации радиационно-индуцированных повреждений ДНК, вероятно, отражает потенциал репарации спонтанных двунитевых разрывов ДНК.