Insertion Mutations of the s haggy Gene, Encoding Protein Kinase GSK3, Extend Drosophila melanogaster Lifespan Abstract The shaggy gene of Drosophila melanogaster encodes highly conserved serine-threonine protein kinase GSK3 (Glycogen Syntase Kinase 3), which plays an important role in different signaling pathways and metabolic processes. This study is the first to demonstrate that shaggy mutations affect lifespan, with an increase in longevity associated with a decrease in synapse activity. The results from this study on changes in shaggy expression in mutants suggest that the observed phenotypic changes are based on an alternation in the expression of minor shaggy transcripts induced by mutational changes in their regulatory region.

Clusters of Repetitive DNA Sequences in Chromosomes of Voles of the Subgenus Microtus ( Microtus , Arvicolidae) Abstract The study is focused on the analysis of the mechanisms underlying the formation and distribution of repeat clusters in mammalian chromosomes, as exemplified by a group of closely related species of voles of the subgenus Microtus (Microtus, Arvicolini). The distribution of repetitive sequences that are the parts of de novo formed heterochromatic regions of Microtus arvalis in two chromosomal forms of this species and three closely related species, M. rossiaemeridionalis, M. kirgisorum, and M. transcaspicus, was analyzed in detail. Possible relationships between the introduction of repetitive sequences, their transpositions, amplification, and the formation of reproductive isolation, which can lead to speciation, are discussed.

Epigenetics of Aggressive Behavior Abstract Multiple studies demonstrating the association of aggressive behavior with allelic variants of neurotransmitter system genes appear to be controversial, while “risk” alleles have no effect on impaired gene expression and functioning of encoded proteins. To explain these associations, we suggested the role of deregulated epigenetic processes caused by the changes in the spatial configuration of transcribed proteins owing to the impaired interaction with noncoding RNAs, which results in modified functioning of genetic networks. Stressful life events occurring during the pre- and postnatal period causing changes in DNA methylation and histone modifications, which disrupt expression of neurotransmitter genes with a long-lasting effect, represent the key factors causing the manifestation of aggressive behavior. The role of stressful life events in epigenome modifications is assumed to be caused by stress-sensitive transposable elements (TEs), whose processing results in the formation of noncoding RNAs probably affecting histone modifications and methylation of certain genomic loci. Transposable elements represent the key sources of sites of binding to transcription factors and regulate genome expression, while their ability to locus-specific transpositions under the stress and self-regulation by noncoding RNAs can explain both the long-term effect of behavioral impairments and their transgenerational transfer. Prevention of behavioral impairments and phenotypic manifestations of genetic liability to aggressive behavior requires the examination of the individual nature of epigenetic modifications for the further targeted action and their correction.

Genome-Wide Association Study Reveals Two Nucleotide Variants Associated with Educational Attainment in Koreans Abstract Genome-wide association studies for educational attainment have been limited to Europeans, but genetic factors might be largely related to cultural environments and thus dependent on populations. We aimed to identify genetic associations with educational attainment in Koreans. We analyzed genome-wide associations with the schooling years of 8770 individuals who participated in the Korea Association Resource cohort employing a mixed model. The analysis revealed two nucleotide variants (rs6467024 and rs16951883) using a genome-wide significance threshold (P < 5 × 10–8), and six variants (rs9844107, rs11114203, rs12273277, rs16869287, rs1526390, and rs6856418) using a suggestive threshold (5 × 10–8 < P < 1 × 10–6). They are located in proximity to the genes that encode GRIN2A, SLIT2, AGTR1, PAWR, and TBC1D1, which are involved in cognitive functions and/or psychiatric diseases. We found two novel genetic associations with educational attainment, which largely corresponded to associations with cognitive functions and psychiatric diseases.

Germline and Somatic Mutations of Genes Involved in Tumor Formation in Sporadic Renal Angiomyolipoma Abstract Angiomyolipoma (AML) is one of the most frequent and, at the same time, AML molecular genetics is one of the least studied among benign tumors. We performed deep sequencing of 409 genes involved in oncogenesis in tumor samples and peripheral blood of patients with sporadic AML of the kidney. We recorded mutations in the TSC2 gene in 65% of samples, which is consistent with international results. As a result of our work, we uncovered mutations in the SETD2, PDGFRA, STK36, SYNE1, PIK3CD, NF1, TOP1, and ITGB3 genes in sporadic renal AML for the first time. In two samples, we were able to clarify the clinical and morphological diagnosis by finding mutations in the genes in tumors lacking TSC2 gene lesions. Mutations in MET and CDC73 are also causative for other types of renal tumors: papillary renal cell carcinoma and CDC73-related disorders, respectively. The latter disease is accompanied by kidney cysts and hamartomas. The obtained results demonstrate a promising potential of mutational profiling of sporadic renal angiomyolipoma (sAML). Genotyping of sAML is particularly important for clarification of the clinical diagnosis in ambiguous cases, as well as for a more in-depth understanding of AML molecular genetics and etiopathogenesis, and for the identification of new molecular targets for personalized AML therapies.

Genome Studies by Means of DNA Markers of the Blackcurrant Abstract The paper provides an overview of foreign and Russian studies of the genus Ribes genome by means of DNA markers. A list of methods for DNA extraction from currants is given. Studies on the use of different types of DNA markers (RAPD, AFLP, ISSR, SSR) for genetic diversity, identification of varieties, molecular phylogeny, and systematics are represented. In the works of various research teams, a high level of polymorphism revealed by microsatellite markers is shown. Examples and prospects for their use in development of identification tools, validations of pedigrees, and collection management are represented. The paper describes genetic maps of blackcurrant developed by means of AFLP, SSR, SNP DNA markers. A list of QTL (quantitative trait loci) localized on genetic maps is represented. The published techniques for marker-assisted selection are described: DNA markers of gene Се and gene Р of blackcurrant resistance to gall mite and DNA markers of green and black color of berries. The method of gene Ce detection improved by the authors is described. Blackcurrant is the most widely studied by means of DNA markers crop of genus Ribes L. The prospects for further development of genome studies of currants and the possibilities that these studies will open for further human-directed improvement of these economically important crops are considered.

Gene Regulatory Elements Extraction in Breast Cancer by Hi-C Data Using a Meta-Heuristic Method Abstract Detection of gene regulatory elements and the interactions among them may be conducive to diagnosis and treatment of many diseases and maladies as cancer. In this regards, Hi-C techniques such as HiCUP, HiC-Pro, HiC-bench, etc., are capable of detecting the gene regulatory elements and their interactions. Extracting only the fixed length gene regulatory elements, these techniques are not able to detect many of gene regulatory elements as they may be of variable-lengths. In this research, we intend to use a two-objective Meta heuristic method based on simulation annealing to provide a method capable of detecting and extracting sequences of variable-length regulators from the genome, and also calculating the interactions between them. In fact, these gene regulatory elements can be potential promoters/enhancers that could play a significant role in the incidence and exacerbation of cancer. To measure the performance and effectiveness of the suggested method, the proposed method is implemented on Hi-C data regarding patients with breast cancer in two blood cells GM12878 and CD34+. Then, the results of implementing the proposed method are compared with the HiCUP and HiC-Pro methods. The results show that the proposed method has a better performance than the HiCUP and HiC-Pro methods. In addition, the proposed method has been investigated for the detection and extraction of gene regulatory elements involved in the occurrence and exacerbation of this type of cancer. Experimental studies have shown that the two promoters BLC6 and HOTTIP discovered by the proposed method have had a significant effect on the incidence and severity of breast cancer in the both genetically engineered blood cells GM12878 and CD34+.

Molecular Genetic Analysis of the Relationships and Origin of Smelt ( Hypomesus , Osmeridae), a New Component of the Fauna of the Barents Sea Abstract This study examines the relationships and origin of a population of smelt (genus Hypomesus) that was recently found in the Barents Sea at a significant distance from the western boundary of its geographic range. Genetic analysis clearly identified this species as pond smelt H. olidus and showed its phylogenetic closeness and shared demographic history with H. olidus from the basin of the Bering Sea. Genetic differentiation indices suggest long isolation of populations of the Pacific and Barents Sea basins. The statistical estimates of historical demographic events, coupled with the paleographic data for the Arctic areas of Russia, show that certain populations of H. olidus might have survived in glacial refugia of the Polar Ural region. H. olidus might have passed repeatedly through a bottleneck in past glacial refugia, as well as in the recent time because of the harsh Arctic conditions.

Evaluation of Risk Factors for the Birth of Children with Chromosomal Imbalance in Carriers of Autosomal Reciprocal Translocations Abstract An important problem of genetic counseling is to determine the personalized risk of the birth of a child with an unbalanced karyotype in families with reciprocal translocation carriers. The risks of the formation of zygotes with chromosomal imbalance among carriers of balanced autosomal translocations vary significantly. These risks will depend on the most probable type of malsegregation for each specific translocation, leading to the formation of unbalanced gametes, and the probable viability of zygotes, embryos, fetuses, or newborns with unbalanced karyotype. In turn, these probabilities depend on many factors, including cytogenetic and quantitative characteristics of the translocation. During regression analysis of several independent factors and characteristics affecting the segregation behavior of the quadrivalent in meiosis I from 49 autosomal reciprocal translocations, it was found that the terminal location of breakpoints on the chromosomes involved in the translocation is statistically significant, i.e., independently associated with the risk of the birth of a viable child with chromosomal imbalance.

Candidate SNP Markers of Atherosclerosis That May Significantly Change the Affinity of the TATA-Binding Protein for the Human Gene Promoters Abstract Atherosclerosis (AS) and AS-related pathologies such as coronary heart disease, myocardial infarction, angina pectoris, and stroke are the leading causes of death in the world. The atherogenesis can be influenced by many factors, in particular, overweight, hypertension, diabetes, hyperlipoproteinemia, and other diseases in anamnesis, as well as genetic predisposition, which may be due to single nucleotide polymorphisms (SNPs) in some cases. In this work, we studied only those regions of promoters of the human protein-coding genes where SNP markers of changes in the affinity of the TATA-binding protein (TBP) for these promoters have already been associated with the atherosclerosis-related pathologies. As a result, within the dbSNP database, we found those unannotated SNPs which change such affinity just as the known biomedical SNP markers do here (according to the predictions made by our Web service SNP_TATA_Z-tester, http://wwwmgs.bionet.nsc.ru/cgi-bin/mgs/tatascan_fox/start.pl). For example, the known SNP marker rs35036378 of the high risks of the primary pT1 tumor reduces the TBP affinity for the ESR2 gene promoter and, thus, the estrogen receptor β abundancy in blood, which is a known physiological marker of calcification of blood vessels in atherogenesis. Near this known SNP marker, we found an unannotated SNP rs766797386, which can also reduce the TBP affinity for the same promoter and, thus, decrease the abundance of the estrogen receptor β in blood. Thus, we propose rs766797386 as a candidate SNP marker for accelerated atherogenesis due to calcification of blood vessels. The possibility of using a diet of natural food with high abundance of calcium (Ca), which is recommended by nutritionists to slow down calcification in the case when individuals have SNP markers of accelerated calcification, is discussed in contrast to the use of Ca-enriched nutritional supplements that can cause the opposite effect. In the same way, a total of 33 candidate SNP markers were predicted and discussed to accelerate or slow down atherogenesis. After clinical verification, the candidate SNP markers predicted by this work can help those who would like to slow down atherogenesis through lifestyle corrections using their genome sequencing data.