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

Dispersal of the human population out of the place of origin in East Africa over the globe proceeded rapidly (on the evolutionary scale) and was associated with change of climatic zones and associated changes in habitat parameters - temperature, humidity, insolation, and infectious load. The aim of the study is to develop a method for genotyping of genetic markers associated with adaptation to climate according to the literature data and functional analysis of genes; and identification of signals of adaptation to cold climate in two indigenous Siberian populations. In the course of study, genes and genetic markers were selected, which show reliable signals of natural selection in populations living in cold arctic and subarctic climates in previously published papers and which are involved in biological processes having a cold adaptation potential. A panel of 28 single nucleotide markers (SNP) was selected, and a method of their multiplex genotyping was developed based on multiplex PCR and separating DNA fragments by MALDI-TOF mass spectrometry. Allele frequencies of 28 SNPs in two indigenous Siberian populations (Yakuts and Kets) were determined. A low level of intrapopulation diversity in these populations and significant genetic differences between them were found. Loci under natural selection conditions were detected by analyzing the distribution of the observed Fst values in comparison with the expected distribution, obtained in the simulation calculations based on the hierarchical island model of population structure. The possible role of selection (p<0.1) in differentiation of populations between allele frequencies was determined for 2 markers - rs133036 in MKL1 gene and rs2305508 in CPT1A gene, which are candidate in terms of climate change adaptation.

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.

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.

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.

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.

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.

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

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.

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.

Исследована генетическая структура шорских популяций и родов (сеоков) по маркерам Y-хромосомы. Результаты анализа частот гаплогрупп и YSTR-гаплотипов свидетельствуют, что шорские сеоки являются родственными объединениями, в большинстве случаев имеющими одного родоначальника по мужской линии. Показано, что генофонд шорцев, а точнее часть, маркируемая гаплогруппами Y-хромосомы, структурирована, прежде всего, по родовому принципу. Для подавляющего большинства образцов показана тесная генетическая близость представителей одного сеока.

Актуальность: гены TOMM40 и APOE расположены в одном локусе на хромосоме 19 (19p13). Анализ вклада полиморфизма этих генов в вариабельность клинически значимых показателей в популяции позволит оценить их роль в формировании заболеваний сердечно-сосудистой системы и их эндофенотипов. Цель: изучить полиморфизм восьми однонуклеотидных замен и политиминового (поли-Т) повтора в локусе TOMM40 / APOE в выборке здоровых индивидуумов и выявить ассоциации полиморфных вариантов с количественными показателями деятельности сердечно-сосудистой системы. Материалы и методы: в двух выборках индивидов, здоровых в отношении сердечно-сосудистых заболеваний (г.Томска, N = 183 и г.Кемерово. N = 183), были изучены полиморфизмы rs741780, rs2075650, rs1160985, rs157580, rs8106922, rs10524523 (поли-Т повтор) в гене TOMM40 и APOE: rs7259620, rs429358 и rs7412. Генотипирование проведено методами ПЦР в реальном времени и фрагментного анализа. Анализ ассоциаций с количественными признаками выполнен путем дисперсионного анализа и непараметрических критериев Манна-Уитни и Краскела-Уоллеса. Результаты. Получены оценки частот аллелей исследованных полиморфизмов у русского населения Западной Сибири, соответствующие характеристикам европеоидных популяций. Редкие аллели rs741780 и rs1160985 ассоциированы с более низкими уровнями триглицеридов (p = 0,031 и p = 0,044, соответственно); длинный аллель (L) поли-Т повтора rs10524523 ассоциирован с более высоким уровнем глюкозы (p = 0,027); rs7412 вносит вклад в вариабельность общего холестерола (р = 0,002) и липопротеидов низкой плотности (р = 0,006); rs2075650 ассоциирован с уровнями систолического артериального давления и липопротеидов низкой плотности в подгруппе мужчин (p = 0,026 и p = 0,002); генотип GG rs8106922 - с уровнем триглицеридов в подгруппе женщин (p = 0,036); rs429358 - с уровнем общего холестерола и липопротеидами низкой плотности (p = 0,002 и p = 0,006). Выводы. Полиморфизмы в локусе генов TOMM40/АРОЕ вносят вклад в изменчивость показателей липидного спектра, уровня глюкозы и артериального давления крови у русского населения Западной Сибири.

Цель - выявить генетические факторы, связанные с личностными признаками, по панели 12 полиморфных маркеров, ассоциированных с деменцией при болезни Альцгеймера, шизофренией и алкоголизмом. Материал и методы. Проанализирована взаимосвязь количественных признаков личности, темперамента и характера, определяемых по психодиагностическим методикам Кеттела (16-факторный личностный опросник, 16PF), акцентуации характера и темперамента К. Леонгарда - Г. Шмишека (тШ), тестам тревожности Спилбергера - Ханина и интеллекта Айзенка (IQ), с полиморфными вариантами 12 генов, вовлеченных в развитие тяжелых психических расстройств - алкоголизм, шизофрению и болезнь Альцгеймера. Образцы ДНК от 150 студентов были прогенотипированы методом ПЦР-ПДРФ. Полученные данные обработаны непараметрическими методами статистики. Результаты. Установлены неслучайные межаллельные ассоциации парных сочетаний полиморфных вариантов GABRA2-PICALM, PICALM-ADCY3, CLU-CBX7 и CLU-ADCY3, вероятно, свидетельствующие об адаптивном отборе, влияющим на поддержание поведенческого гомеостаза в популяции. Обнаружен ряд статистически значимых ассоциаций генетической изменчивости: CLU с самодисциплиной (Q3, 16PF) и экзальтированностью (тШ), PICALM с напряженностью (Q4, 16PF) и неуравновешенностью (тШ), DISC1 с подозрительностью (L, 16PF), экзальтированностью и циклотимией (тШ), ZNF804Aс неуравновешенностью (тШ), SLC6A4 с интеллектуальностью (В, 16PF), ADCY3 с экстраверсией и самостоятельностью (F2 и Q2, 16PF), MIR9-2 с эмоциональной устойчивостью, беспечностью, смелостью в социальных контактах, экстраверсией (C, F, H, F2 по тесту 16PF), гипертимией и дистимией (тШ), с личной тревожностью по тесту Спилбергера - Ханина,CBX7 с общительностью и подозрительностью (A, L, 16PF), SLC6A4 с интеллектуальностью (B, 16PF), SLC6А3 с IQ по тесту Айзенка. Для полиморфизма rs13219354, GAB2 и GABRA2 не выявлено взаимосвязи с признаками, характеризующими интеллект, темперамент и характер. Заключение. Полученные результаты, вероятно, свидетельствуют об общей генетической компоненте психических и неврологических расстройств с вариабельностью когнитивных и личностных признаков.

Описано генетическое разнообразие 60 X-хромосомных однонуклеотидных маркеров (панель XSNPid) в популяциях сибирских татар и тувинцев. Выявлена близость двух популяций по частотам аллелей и относительно низкий уровень их генетической дифференциации (GST = 0.021). Показан высокий дискриминационный потенциал панели XSNPid в исследованных популяциях. Вероятность случайного совпадения мультилокусных генотипов у неродственных мужчин (MP, matching probability) составляет 1.12 ? 10-18 у сибирских татар и 7.77 ? 10-16 у тувинцев. Для женщин этот показатель еще на несколько порядков ниже – 1.51 ? 10-25 у сибирских татар и 1.83 ? 10-23 у тувинцев.

Актуальность. Несмотря на достигнутые успехи в расшифровке генетической компоненты ишемической болезни сердца (ИБС), только малая часть наследуемости заболевания была объяснена. В настоящее время существует небольшой ряд работ, которые изучают вариации по числу копий участков ДНК (copy number variation, CNV) при сердечно-сосудистой патологии. Цель. Оценка уровня CNV в хромосомном регионе 10q24.31 ( ERLIN1 ) в клетках коронарных артерий и лейкоцитов периферической крови (ЛПК) у больных с ИБС. Материалы и методы. Детекция CNV проводилась методом ПЦР в режиме реального времени с использованием TaqMan-зондов в образцах ДНК ЛПК (n = 110) и ДНК атеросклеротических бляшек из коронарных артерий (n = 33) у больных с ИБС, а также в образцах ДНК ЛПК здоровых индивидов (n = 100). Статистический анализ выполнялся с помощью стандартной кривой согласно методу Pfaffl. Результаты и выводы. Установлено, что среди больных ИБС амплификации хромосомного региона 10q24.31 ( ERLIN1 ) регистрировались в 3% случаев, тогда как у 1% здоровых индивидов обнаружена делеция анализируемого региона. Кроме того, у двух пациентов данная амплификация представлена только в ЛПК, но не в атеросклеротических бляшках коронарных артерий.