Allele frequencies and genetic diversity in the population of Teleuts were assessed by the Alu repeat polymorphism at eight autosomal loci (ACE, APOA1, PLAT, F13, PV92, A25, CD4, D1). For comparison, the study included previously obtained data on the Alu polymorphism in 19 indigenous populations of Siberia. On the dendrogram of genetic distances, the Teleut population is located in the cluster of Siberian ethnic groups, which are similar in origin, geography, and cultural traditions.

Проанализированы частоты аллелей и генетическое разнообразие популяции телеутов по полиморфизму Alu-повторов в восьми аутосомных локусах (АСЕ, APOA1, PLAT, F13, PV92, A25, CD4, D1). Для сравнения в исследование включены ранее полученные данные по полиморфизму Alu-элемента в 19 популяциях коренных жителей Сибири. На дендрограмме генетических расстояний популяция телеутов располагается в кластере сибирских этносов, близких по происхождению, географии и культурным традициям.

The genetic variability of the DMPK locus has been studied in relation to six SNP markers (rs2070736, rs572634, rs1799894, rs527221, rs915915, and rs10415988) in Yakuts with myotonic dystrophy (MD) in the Yakut population and in populations of northern Eurasia. Significant differences were observed in the allele frequencies between patients and a population sample of Yakuts for three SNP loci (rs915915, rs1799894, and rs0415988) associated with a high chance of disease manifestation. The odds ratios (OR) of MD development in representatives of the Yakut population for these three loci were 2.59 (95% CI, p = 0,004), 4.99 (95% CI, p = 0.000), and 3.15 (95% CI, p = 0.01), respectively. Haplotype TTTCTC, which is associated with MD, and haplotype GTCCTT, which was observed only in Yakut MD patients (never in MD patients of non-Yakut origin), were revealed. A low level of variability in the locus of DMRK gene in Yakuts (H e = 0.283) compared with other examined populations was noted. An analysis of pairwise genetic relationships between populations revealed their significant differentiation for all the examined loci. In addition, a low level of differentiation in territorial groups of Yakut populations (F ST = 0.79%), which was related to the high subdivision of the northern Eurasian population (F ST = 11.83%), was observed.

Изучена генетическая вариабельность локуса DMPK по шести SNP-маркерам (rs2070736, rs572634, rs1799894, rs527221, rs915915, rs10415988) у якутов, больных миотонической дистрофией (МД), в популяции якутов и в популяциях Северной Евразии. Были зафиксированы значимые отличия в частотах аллелей между больными и популяционной выборкой якутов по трем SNP-локусам (rs915915, rs1799894 и rs10415988), что отразилось в высоких значениях вероятности проявления заболевания. Отношение шансов (OR) развития МД у представителей якутской популяции по этим локусам оценивались как 2.59 (95% CI, p = 0.004), 4.99 (95% CI, p = 0.000) и 3.15 (95% CI, p = 0.01) соответственно. Выявлен гаплотип TTTCTC, ассоциированный с MД, и специфический только для больных якутов гаплотип GTCCTT, не встречающийся среди больных МД не якутского происхождения. Отмечен низкий уровень разнообразия в локусе DMPK у якутов (He = 0.283) по сравнению с другими изученными популяциями. Анализ генетических взаимоотношений между парами популяций выявил их достоверную дифференциацию по всем локусам. Кроме того, наблюдался низкий уровень дифференциации территориальных групп якутских популяций (FST = 0.79%) на фоне высокой подразделенности населения Северной Евразии (FST = 11.83%).

This paper reports the results of replicative analysis of associations of 15 SNPs in a region of 14 genes previously identified in genome-wide association studies (GWAS) with early-onset schizophrenia in Kazakhs. An association of early-onset schizophrenia with genetic markers in three genes (VRK2, KCNB2, and CPVL) was found. An association of rs2312147 in the VRK2 gene with schizophrenia was also previously reported in the Chinese population, so this marker may be considered as possibly race-specific. Two groups consisting of four and six genes demonstrating intergenic epistatic interactions were revealed by multifactor dimensionality reduction methods. The gene ontologies of 14 studied genes were reduced to variants of one molecular function (peptidase activity) and one biological process (positive regulation of biosynthesis processes). Bioinformatic analysis of the protein-protein interactions of products of the genes under study demonstrates that the products of six out of 14 genes may be involved in a single interrelated network, the major connecting link of which is represented by their ubiquitination by the UBC protein.

В настоящей работе проведен репликативный анализ ассоциаций 15 SNP в области 14 генов, ранее выявленных в широкогеномных исследованиях (GWAS), с шизофренией с ранним началом у казахов. Обнаружена ассоциация ранней шизофрении с маркерами трех генов (VRK2, KCNB2 и CPVL). Ассоциация rs2312147 гена VRK2 с шизофренией ранее была также реплицирована у китайцев, что позволяет рассматривать этот маркер как вероятный расо-специфичный. С помощью методов снижения размерности многофакторных данных были обнаружены две группы из четырех и шести генов, демонстрирующих межгенные эпистатические взаимодействия. Генные онтологии 14 изученных генов сводятся к вариантам одной молекулярной функции (пептидазная активность) и одному биологическому процессу (положительная регуляция процессов биосинтеза). Биоинформационный анализ белок-белковых взаимодействий продуктов изучаемых генов показывает, что продукты шести из 14 генов могут быть вовлечены в единую взаимосвязанную сеть, главным связующим звеном которой является убиквитинилирование их белком UBC.

The discovery of cell-free DNA in the blastocoele fluid is promising for the development of new noninvasive methods for the preimplantation genetic diagnosis of chromosomal diseases. However, there are no data confirming the concordance between the molecular karyotype of cell-free DNA from blastocoele fluid and the blastocyst cells per se. This paper reports on such concordance according to the results of molecular cytogenetic analysis by comparative genomic hybridization.

Обнаружение фрагментов ДНК в полостной жидкости бластоцеля открывает перспективы в развитии новых методов неинвазивной преимплантационной генетической диагностики хромосомных болезней. Однако до настоящего времени отсутствуют данные, подтверждающие соответствие молекулярного кариотипа внеклеточной ДНК из жидкости бластоцеля и клеток бластоцисты. В настоящей работе сообщается о наличии такого соответствия по результатам молекулярно-цитогенетического анализа хромосомного набора, проведенного с помощью сравнительной геномной гибридизации.

The variability of potentially important functional polymorphic variants rs2069705 (5'UTR of the IFNG gene), rs17880053 (near 5'UTR of the IFNGR2), rs11126176 (LOC100287361 pseudogene), and rs804271 (near 5'UTR of the NEIL2 gene) was characterized in representatives of four ethnic groups living in the Siberian region. These ethnic groups included three indigenous Mongoloid ethnic groups (Yakuts, the residents of the Republic of Sakha (Yakutia), Tuvinians from the Republic of Tuva, and Buryats from the Republic Buryatia) and the arrived Russian population (Tomsk). All of the examined variants were polymorphic. The frequency of the rs2069705 allele C in Russians was 0.5833, while it was in a range from 0.7842 to 0.8967 in representatives of the indigenous populations. The frequency of rs17880053 deletion was 0.8073 in Russians and from 0.4474 to 0.5521 in the indigenous ethnic groups. The frequency of the rs11126176 allele A was equal to 0.5398 in Russians but was recorded with lower frequencies in indigenous ethnic groups (from 0.2722 to 0.4551). The frequency of the rs804271 allele G was 0.5215 in Russians and from 0.2527 to 0.4022 indigenous ethnic groups. With respect to the genotype structure, the arrived Russian population was considerably distanced from indigenous Mongoloid populations. Specifically, the genetic distance was 0.0742 between Russians and Yakuts, 0.13365 between Russians and Tuvinians, and 0.1433 between Russians and Buryats. Among the Mongoloid indigenous ethnic groups of Siberia, Tuvinians and Yakuts were the most distant from each other (0.0262). The genetic distance was equal to 0.0151 between Yakuts and Buryats and 0.0127 between Buryats and Tuvinians.

Охарактеризована изменчивость потенциально функционально значимых полиморфных вариантов rs2069705 (5UTR гена IFNG), rs17880053 (вблизи 5UTR гена IFNGR2), rs11126176 (псевдоген LOC100287361) и rs804271 (вблизи 5UTR гена NEIL2) у представителей четырех этнических групп, проживающих в Сибирском регионе: трех коренных монголоидных этносов – якутов (жители Республики Саха (Якутия)), тувинцев (Республика Тува) и бурят (Республика Бурятия), а также пришлого русского населения (г. Томск). Все изученные варианты были полиморфными. Частота аллеля С по rs2069705 у русских составила 0.5833, у представителей коренных народностей находилась в границах 0.7842–0.8967; частота делеции по rs17880053 у русских – 0.8073, у коренных этносов – 0.4474–0.5521; частота аллеля А по rs11126176 была равна 0.5398 у русских и с меньшей величиной регистрировалась у коренных этносов – 0.2722–0.4551; по rs804271 частота аллеля G у русских – 0.5215 и у коренных этносов – 0.2527–0.4022. По генотипической структуре пришлое русское население существенно дистанцировано от монголоидных коренных популяций – генетические дистанции между русскими и якутами – 0.0742, русскими и тувинцами – 0.1365, русскими и бурятами – 0.1433. Среди монголоидных коренных этносов Сибири наиболее удалены друг от друга тувинцы и якуты – 0.0262, генетические дистанции между якутами и бурятами были равны 0.0151, между бурятами и тувинцами – 0.0127.

In this review, the development of ideas focused on the phenomenon of disease combination (comorbidity) in humans is discussed. The genetic bases of the three forms of the phenomenon, comorbidity (syntropias), inverse comorbidity (dystropias), and comorbidity of Mendelian and multifactorial diseases, are analyzed. The results of personal genome-wide association studies of the genetic risk profile that may predispose an individual to cardiovascular disease continuum (CDC), including coronary heart disease, type 2 diabetes, hypertension, and hypercholesterolemia (CDC syntropy), as well as the results of bioinformatic analysis of common genes and the networks of molecular interactions for two (bronchial asthma and pulmonary tuberculosis) diseases rarely found in one patient (dystropy), are presented. The importance of the diseasome and network medicine concepts in the study of comorbidity is emphasized. Promising areas in genomic studies of comorbidities for disease classification and the development of personalized medicine are designated.

В обзоре рассмотрена динамика представлений о феномене сочетания болезней (коморбидности) у человека. Представлен анализ генетических основ трех форм феномена: коморбидность (синтропии), “обратная коморбидность” (дистропии), а также коморбидность менделевских и многофакторных болезней. Приведены результаты собственного геномного ассоциативного исследования генетического профиля предрасположенности к болезням сердечно-сосудистого континуума (ССК) – ишемической болезни сердца, сахарного диабета 2 типа, артериальной гипертонии и гиперхолестеринемии (синтропия ССК), а также биоинформационный анализ общих генов и сетей молекулярных взаимодействий для двух (бронхиальная астма и туберкулез легких) редко встречающихся у одного пациента болезней (дистропия). Подчеркнута важность концепций “дизисома” и “сетевой медицины” в исследовании коморбидности. Обозначены перспективы геномных исследований коморбидности для классификации болезней и развития персонализированной медицины.

The study aimed to reveal cancer related mutations in DNA repair and cell cycle genes associated with chronic occupational exposure to gamma-radiation in personnel of the Siberian Group of Chemical Enterprises (SGCE). Mutations were analyzed by comparing genotypes of malignant tumors and matched normal tissues of 255 cancer patients including 98 exposed to external gamma-radiation (mean dose 128.1±150.5mSv). Also a genetic association analysis was carried out in a sample of 149 cancer patients and 908 healthy controls occupationally exposed to gamma-radiation (153.2±204.6mSv and 150.5±211.2mSv, respectively). Eight SNPs of genes of DNA excision repair were genotyped (rs13181, rs1052133, rs1042522, rs2305427, rs4244285, rs1045642, rs1805419 and rs1801133). The mutation profiles in heterozygous loci for selected SNP were different between sporadic tumors and tumors in patients exposed to radiation. In sporadic tumors, heterozygous genotype Arg/Pro of the rs1042522 SNP mutated into Arg/0 in 15 cases (9.6%) and 0/Pro in 14 cases (8.9%). The genotype Lys/Gln of the rs13181 SNP mutated into Lys/0 and 0/Gln in 9 and 4 cases, respectively. In tumors of patients exposed to low-level radiation, the rs1042522 Arg/0 mutated genotype was found in 12 cases (12.1%), while in 2 cases (2%) 0/Pro mutation was observed. Finally, the rs13181 0/Gln mutated genotype was observed in 15 cases (16,5%) . Thus, our study showed the difference in patterns of allelic imbalance in tumors appeared under low-level radiation exposure and spontaneous tumors for selected SNPs. This suggests different mechanisms of inactivation of heterozygous genotypes in sporadic and radiation-induced tumors.

Epigenetic mechanisms of gene regulation in context of cardiovascular diseases are of considerable interest. So far, our current knowledge of the DNA methylation profiles for atherosclerosis affected and healthy human vascular tissues is still limited. Using the Illumina Infinium Human Methylation27 BeadChip, we performed a genome-wide analysis of DNA methylation in right coronary artery in the area of advanced atherosclerotic plaques, atherosclerotic-resistant internal mammary arteries, and great saphenous veins obtained from same patients with coronary heart disease. The resulting DNA methylation patterns were markedly different between all the vascular tissues. The genes hypomethylated in athero-prone arteries to compare with atherosclerotic-resistant arteries were predominately involved in regulation of inflammation and immune processes, as well as development. The great saphenous veins exhibited an increase of the DNA methylation age in comparison to the internal mammary arteries. Gene ontology analysis for genes harboring hypermethylated CpG-sites in veins revealed the enrichment for biological processes associated with the development. Four CpG-sites located within the MIR10B gene sequence and about 1 kb upstream of the HOXD4 gene were also confirmed as hypomethylated in the independent dataset of the right coronary arteries in the area of advanced atherosclerotic plaques in comparison with the other vascular tissues. The DNA methylation differences observed in vascular tissues of patients with coronary heart disease can provide new insights into the mechanisms underlying the development of pathology and explanation for the difference in graft patency after coronary artery bypass grafting surgery.

Purpose: Double-strand breaks (DSB) repair and apoptosis are assumed to be key factors in the determination of individual variability in response to radiation treatment. In this study we investigated tumor protein p53 (TP53) binding protein 1 (53BP1) and phosphorylated histone 2A family member X (γH2AX) foci, γH2AX pan-staining and late apoptosis/necrosis (LAN) in lymphocytes from breast cancer (BC) patients undergoing radiotherapy.

Materials and methods: BC patients were subjected to local radiotherapy with fractionated doses using linear accelerator. Adverse reactions of patients were classified according to the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) criteria. Blood samples were collected before treatment, at various time-points during and after radiotherapy. Residual 53BP1 and γH2AX foci, γH2AX pan-staining were analyzed in peripheral blood lymphocytes (PBL) using the Metafer system and confocal laser scanning microscopy. LAN cells were counted by the trypan blue (TB) exclusion assay. Statistical analysis was performed using Mann-Whitney test, Spearman rank correlation test and analysis of covariance (ANCOVA).

Results: No statistically significant changes were observed in the levels of γH2AX foci during radiotherapy. In contrast, radiation-induced residual 53BP1 were detected already after the first fraction. Increased individual variability in the 53BP1 focus formation was observed during treatment. The background level of DNA repair foci and its individual variability in response to radiotherapy decreased after the end of radiotherapy indicating successful removal of DNA-damaging effects. A correlation between stage of cancer and 53BP1 focus formation was established which suggests the prognostic value of this test. We show that the fraction of LAN cells negatively correlates with the level of 53BP1 and positively correlates with individual radiosensitivity. Only weak correlation was observed between γH2AX pan-staining and LAN cells. Due to large interindividual variability, both in vivo assays, LAN and focus formation, have shown relatively low predictive power at the individual level.

Conclusions: It is likely that radiosensitive patients have less efficient mechanisms of elimination of apoptotic cells with DNA damage resulting in accumulation of LAN cells and facilitating adverse reactions. Our data suggested that the grade of adverse reaction may positively correlate with LAN cells in PBL before and during radiotherapy.