Vavilov Journal of Genetics and Breeding
Peer-rewieved journal "Vavilov Journal of Genetics and Breeding"
Institute of Cytology and Genetics of Siberian Branch of the RAS
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Concept of natural genome reconstruction. Part 5. Analysis of changes in the lifespan of old animals after reinfusion of bone marrow cells derived from old animals and treated with hDNAgr in combination with recombinant human angiogenin
Two series of tests were performed, on mice and rats, to assess the lifespan of old animals reinfused with bone marrow cells from old animals treated with fragmented human DNA (hDNAgr), recombinant human angiogenin, and both preparations together. Animals reinfused with untreated bone marrow cells from old animals or bone marrow cells from young animals were used as comparison groups. Using both outbred mice and CBA/Lac mice, no significant increase in the lifespan of animals reinfused with bone marrow cells treated with the hDNAgr was found compared with the group of mice reinfused with untreated bone marrow cells. Using the CBA/Lac line, mice reinfused with bone marrow cells treated with angiogenin simultaneously died of the characteristic symptom complex at 10 months after treatment. Pathomorphological analysis suggests that the simultaneous death of mice occurred as a result of pathological disorders in the excretory systems of animals. Reinfusion of bone marrow cells from old animals treated with angiogenin and hDNAgr and bone marrow cells taken from young animals significantly increases the lifespan of mice in groups. The combined use of two activators, angiogenin and hDNAgr, increased the average lifespan of 30 % of experimental mice to 35 months compared to 28 months in the control. Using Wistar rats as model animals in the first experiment, a reliable increase in the lifespan of rats with reinfusion of bone marrow cells from old animals treated with the hDNAgr preparation to 28 months was shown compared to the group that received untreated bone marrow cells from old animals, where the average lifespan of rats was 24 months. In the second similar experiment, no reliable difference in the lifespan of rats for the two groups was shown. Animals injected with bone marrow cells treated with angiogenin lived significantly longer than rats from the control group. The analysis of the amount of telomeric DNA in bone marrow cells of rats from the experimental and control groups 12 months after treatment showed that there was no significant increase in telomeric DNA. A molecular/cellular model of aging of the organism associated with the concept of “natural reconstruction of the genome” is considered.
Generation of the RCPCMi014-A and RCPCMi014-B lines from T-lymphocytes of a healthy donor and verification of their monoclonal origin by TCR V(D)J rearrangement analysis
The generation of induced pluripotent stem cells (iPSCs) from peripheral blood T-lymphocytes offers a promising alternative to skin fibroblasts. This approach combines minimally invasive sample collection with rapid isolation of enriched target cell population and provides a lower baseline mutational burden, as T-lymphocytes are shielded from chronic ultraviolet radiation – a major driver of somatic mutations in skin fibroblasts. Objective verification of monoclonality of the resulting iPSC lines is possible due to V(D)J rearrangements in T-cell receptor (TCR) genes, which are formed as a result of somatic recombination in the thymus during the natural maturation of T-lymphocytes. These rearrangements remain unchanged during reprogramming and serve as a unique marker, allowing for reliable identification of monoclonal lines and exclusion of contaminated or polyclonal lines. Reliable verification of the clonal origin of iPSCs can be crucial in experiments that place high demands on genetic homogeneity. This work is dedicated to the generation and comprehensive characterization of monoclonal iPSC lines derived from CD3+ T-lymphocytes of a healthy donor using episomal reprogramming. The resulting lines, RCPCMi014-A (PBM022E5) and RCPCMi014-B (PBM022E7), meet the accepted quality criteria for iPSCs: they demonstrate expression of key pluripotency markers (OCT4, SOX2, SSEA-4, TRA-1-81), the ability to differentiate into derivatives of all three germ layers, and possess a normal karyotype. Both lines showed a high-efficiency capacity to differentiate into definitive endoderm, as assessed by CXCR4 expression, highlighting their potential for developing protocols to generate pancreatic β-cells. The obtained iPSC lines can be used for fundamental research into the mechanisms of pluripotency and differentiation, as well as for creating isogenic iPSC lines with introduced mutations for modeling rare hereditary diseases.
Development of a molecular marker for the Run8 gene for the selection of barley genotypes resistant to smut
Loose smut of barley, caused by the basidiomycete Ustilago nuda (Jens.) Roster, occurs in all regions of the world where this crop is grown. This seed-borne disease causes significant losses in grain production. Selection for resistance to loose smut based on the use of donors with resistance genes is an ecologically and economically safe way to constrain the negative impact of the pathogen on barley. The introduction of molecular genetic approaches into the breeding process makes it possible to control the transfer of resistance genes to hybrid material. The Run8 gene controls resistance to many isolates of loose smut, including in the West Siberian region of Russia. The objective of the current study is to develop a molecular marker for Run8 for the selection of barley genotypes resistant to loose smut from hybrid populations. By comparing the nucleotide sequences of the Run8 gene available from the barley pangenome database, an insertion/deletion of six nucleotide pairs in the coding region of the gene was identified. Based on the identified polymorphism, a molecular marker Hor7050 was developed, which allows differentiating the alleles of Run8. The developed marker was tested on hybrid lines (F5–F6) obtained from crossing cultivar Elf, which is a donor of resistance to loose smut and carries, according to the originators, the Run8 gene, with cultivar Tanai, which has practical resistance to the pathogen. Using the developed marker, 18 hybrids carrying Run8 of Elf were selected from 84 hybrids; however, the phytopathological assessment showed that eight of the selected lines were susceptible to the disease. To clarify the genotype of 18 selected lines, an additional analysis was carried out using the microsatellite marker EBmac0541 linked to Run6. A relationship was established between the presence of the allele of this marker from Elf and resistance to the disease. It is possible that Elf, in addition to Run8, carries Run6, which is effective against race 1 of the causative agent of loose smut. Additional studies are required to clarify the presence of Run6 in the Elf variety. In addition to resistance, the selected lines were characterized by productivity traits. According to the two-year analysis, three productive resistant lines were identified, with Run8 – 32, 65 and 79, significantly exceeding the control Elf in yield. The selected lines were transferred to breeding nurseries for their further evaluation by economically important traits.
Somaclonal variation in Saccharum spp.: unraveling its potential despite current neglect
Hybridization of different landraces or wild crop species facilitates genetic recombination and leads to the development of improved cultivars, particularly in sexually propagated crops. In contrast, genetic recombination via hybridization in asexually propagated crops like sugarcane (Saccharum spp. hybrid) is challenging due to self or cross incompatibility (low fertility). Such crops can be improved by somaclonal variation, which is achieved by tissue culture techniques. As a major contributor to global sugar and bioethanol production, sugarcane suffers substantial yield loss due to various biotic or abiotic stresses, which may be attributed to its poor resistance mechanism. Despite the potential of in vitro culture techniques, somaclonal variation remains underexplored in sugarcane breeding programs. To address the challenges posed to sugarcane under changing environmental dynamics, this review critically evaluates the role of somaclonal variation in sugarcane variety development, its underlying mechanism, practical applications, and factors affecting its occurrence. This review also discusses the limitations and challenges in the practical implementation of this technique in variety development, resulting in its neglect in modern breeding efforts. The focus on the potential of somaclonal variation, sustained by cutting-edge approaches, can unlock its limitations and fulfill the growing future demands of sugar, biofuel, and bioenergy industries.
Factors of wheat frost hardiness – ice recrystallization inhibitor proteins
For winter wheat, winter hardiness is one of the complex traits that determine the successful cultivation of this crop, and the responsible genes are recognized as highly significant for breeding work. The accumulation of proteins that prevent ice recrystallization (ice recrystallization inhibition proteins, IRIP) correlates with the survival of winter wheat, which indicates the importance of taking this trait into account when obtaining more frost-resistant varieties. The importance of IRIPs is determined by their ability to integrate into growing ice crystals, which limits the formation of large ice conglomerates in the tissues of winter plants. Wheat IRIPs, which accumulate mainly in the apoplast of leaves and in the crowns during cold acclimation, are characterized by a typical duality of structural organization that determines both the manifestation of IRI activity and anti-pathogenic properties. The wheat IRIP molecule contains at the C-terminus a conserved NxVx(x)G fragment that repeats several times, forming a β-helix responsible for binding to the ice surface; at the N-terminus, there is an LRR sequence typical of pathogen-activated kinases, as well as a guiding signal peptide. The wheat genome contains up to eleven IRI genes. The TaIRI gene promoter contains typical basic cis-activating elements and some elements that respond to abiotic stress and hormones. Isoforms of proteins responsible for protecting against pathogens (pathogenesis related proteins, PRP), which accumulate in winter wheat during cold acclimation, also have IRI activity. The expression of the IRIP and PRP genes positively correlates with the cold resistance of winter wheat plants. According to modern data, the regulation of the IRIP genes and cold-activated PRP genes is ABA-independent, but depends on the presence of jasmonic acid and on some proteomic transcription factors. The review provides examples of the practical use of isolated winter wheat IRIPs. The issue of the factors regulating the activity of the IRIP genes and cold-activated PRPs is the least developed to date. The association of these proteins with the winter hardiness of wheat indicates the prospects for their further study.
Adaptive responses of pear cultivars to low-temperature stress in the spring period
The pear is one of the most famous pome crops. It occupies about 7 % of the total area of perennial fruit crops in Russia. Orchard plantings are predominantly composed of foreign European cultivars. Spring frosts, which are typical for the southern regions of the country, lead to significant crop losses. This study determined the response characteristics of pear flower buds to low-temperature stress. The Crimean cultivar Dzhankoyskaya Pozdnyaya, two cultivars – Leven and Flamenco – of Krasnodar selection and the interspecific hybrid Kieffer were investigated. Flower buds at different developmental stages were exposed to a climatic chamber for 12 hours at temperatures –1.5…–2 °C. After stress exposure, the activity of certain antioxidant enzymes was determined, along with the content of phenolic compounds, malondialdehyde, and the gene expression level of its enzymes and proteins involved in cold adaptation. It was revealed that the autumn-ripening cultivar Kieffer, under conditions of the Krasnodar region, begins to bloom earlier than other studied cultivars, making it more susceptible to recurrent frosts. This is evidenced by high values of malondialdehyde and the activity level of superoxide dismutase. The Russian cultivars, Leven (winter cultivar) and Flamenco (summer cultivar), showed the highest activity of peroxidase and gene expression of PcDREB2, PcCAP160, PcCOR413, PcPOX1, with a reduced level of malondialdehyde. These cultivars typically emerged from dormancy later compared to Kieffer. The Crimean winter-ripening cultivar was closer to the interspecific hybrid in terms of the studied parameters but showed lower enzyme activity and gene expression levels. The obtained results suggest that under pear cultivation conditions in the southern region of the country, where spring frosts are possible, cultivars with flowering starting in the second-to-third decade of April and high indicators of antioxidant enzyme activity (primarily peroxidase) and gene expression levels of PcDREB2, PcCAP160, and PcCOR413 demonstrate greater resistance.
Characteristics of galacturonate reductase (GalUR) genes in garlic (Allium sativum L.) and changes in their expression in response to abiotic stressors
In plants, the synthesis of L-ascorbic acid (Aa), in addition to the main L-galactose pathway, is carried out by three known alternative pathways. One of them, the D-galacturonic acid pathway, is thought to be specific for tissues with excess D-galacturonate, the substrate of D-galacturonate reductase (GalUR), which belongs to the Aldo-Keto Reductase (AKR) superfamily. In this study, the AKR gene family of garlic Allium sativum L. was identified and seven genes, AsGalUR1–7, presumably encoding GalUR enzymes, were determined. The structure and phylogeny of the AsGalUR1–7 genes and the proteins they encode, as well as the AsGalUR1–7 expression pattern in different organs of the garlic plant (in silico and qRT-PCR), were characterized. Based on the obtained data, the genes were conditionally divided into root (AsGalUR1–4) and leaf (AsGalUR5–7) groups depending on the highest expression level in the underground and aboveground parts of the plant, respectively. The AsGalUR expression in leaves and roots was analyzed in response to drought, salt and cold stresses, as well as exogenous phytohormones (abscisic acid, methyl jasmonate), accompanied by the AsA content measurement. It was shown that hormone treatment suppresses the expression of all analyzed genes in both organ types. Cold conditions stimulate the expression of root group genes and suppress that of leaf group genes in roots, and have the opposite effect in leaves. Osmotic stressors (NaCl, PEG) suppress the transcription of all genes in leaves, but do not change (NaCl) or stimulate (PEG) it in roots, which is accompanied by an increase in AsA accumulation in organs of both types. A positive correlation between the expression of the AsGalUR1 and 4 genes and the AsA content is found in leaves under stress conditions. The data obtained can form the basis for further study of the mechanisms regulating AsA synthesis in garlic and other Allium species.
Transcriptional changes of aquaporin genes in leaves of black medic induced by arbuscular mycorrhizal fungal inoculation under water deficit
One of the current research directions in plant-microbe interactions focuses on the mechanisms of plant adaptation to environmental stress through symbioses with various microorganisms. While the role of arbuscular mycorrhizal fungi in plant adaptation to drought is well-known, the underlying mechanisms of these processes remain poorly understood, particularly in leaf tissues. It is suggested that certain genes from the aquaporin family play a critical role both in adaptation to water deficit and in the development of an effective arbuscular mycorrhizal symbiosis. Thus, the important task in this study of plant-microbe symbioses is to assess the effect of arbuscular mycorrhizal fungal inoculation on the expression of aquaporin genes in leaves. This study utilizes the highly effective plant-microbe model system “Medicago lupulina + Rhizophagus irregularis” under drought stress conditions. A comparative assessment of gene transcription was carried out using the 2–∆∆CT method based on real-time quantitative PCR results: normalization was performed relative to the actin reference gene with non-inoculated plants serving as the control. The study was conducted both at the initial development stage (the 2nd leaf stage), and at the stage of active plant-microbe interaction (the flowering stage). The study revealed genes with significant differential expression under drought conditions when comparing mycorrhizal and non-mycorrhizal Medicago lupulina plants: NIP3;1, NIP4;2, specific NIP7;1, TIP5;1 at the 2nd leaf stage; genes NIP3;1, NIP5;1, NIP6;4, NIP7;1 (specific), PIP1;4, TIP2;3 and specific XIP1;1 at the flowering stage. Previously, in a similar experiment, under well-watering conditions, the same genes did not have differential expression between mycorrhizal and non-mycorrhizal plants. Thus, the listed genes likely participate in the adaptation of the studied plants to drought conditions. The obtained information can be used to develop highly productive plant-microbe systems involving arbuscular mycorrhizal fungi, aimed at transitioning to organic farming, minimizing negative environmental impact, and enhancing plant resistance to water deficit.
A production strain of soybean nodule bacteria RZ300 Bradyrhizobium japonicum resistant to drying on the seed surface: cultural properties and genomic features
Pre-sowing treatment of cultivated legume seeds with nodule bacteria preparations is a standard agronomic practice. This is particularly important in soybean cultivation, as effective microsymbionts of soybeans are often absent from the soil. However, as many studies have shown, the efficacy of biopreparations depends largely on the survival of rhizobial cells on seeds during drying. In this study, we analyzed the viability of three production strains of Bradyrhizobium japonicum Kirchner (634b, 640 and RZ300) on soybean (Glycine max L.) seeds of various origins (varieties: EN Argenta, Bara and Prudence). The experiments evaluated several parameters: inoculant concentrations (10 and 100 %), drying temperatures (5, 15, and 25 °C), and protective polymer-carbohydrate formulations. The experiments revealed that the soybean variety had no noticeable effect on the viability of the studied rhizobial strains, while the strains themselves differed significantly in this regard. The RZ300 strain demonstrated the highest resistance to drying on soybean seeds. A comparative genomic analysis of this strain and the less resistant B. japonicum strain 634b revealed the presence of the opgC gene in the RZ300 strain (encodes the ОpgC protein involved in the biosynthesis of osmoregulated periplasmic glucans (OPGs)). This gene is absent in strain 634b and may potentially determine the increased resistance of nodule bacteria to drying on seeds. An evaluation of various protective formulations demonstrated that formulations based on 50 % sucrose provide the best protection, with rhizobia showing the highest resistance to drying at +5 °C. The results obtained in this study can be used both in the selection of effective inoculant strains and for providing technological support in the development of biological products. The genomic data support the development of genetic screening systems to identify promising strains and the potential introduction of the opgC gene into promising rhizobial strains to improve their manufacturability, i. e. to enable effective early seed inoculation.
Comparative cytogenetic analysis of the germline-restricted chromosome in Fringillidae species (Passeriformes, Aves)
An additional germline-restricted chromosome (GRC) has been found in the germline cells of all studied passerine bird species. It is eliminated from somatic cells during early embryogenesis and from spermatocytes after the first or second division of male meiosis. The GRC is transmitted across generations predominantly via the maternal line. It contains amplified and rearranged copies of genomic regions from the standard chromosome set. Some of these genes are expressed in the gonads of both males and females. However, the function and evolutionary dynamics of the GRC remain unknown. We conducted a comparative cytogenetic analysis of the GRC in five closely related finch species – the Eurasian bullfinch Pyrrhula pyrrhula, the common greenfinch Chloris chloris, the European goldfinch Carduelis carduelis, the common redpoll Acanthis flammea, and the pine grosbeak Pinicola enucleator – using fluorescent in situ hybridization (FISH) with a whole-chromosome DNA probe derived from the bullfinch GRC on spread spermatocytes of these species and immunolocalization of synaptonemal complex (SC) and centromere proteins. We described for the first time the SC karyotype of the pine grosbeak (2n = 82 + GRC). The standard chromosome set consists of nine submetacentric bivalents (seven macroand two microbivalents) and 32 acrocentric microbivalents. All acrocentric microbivalents contain centromeres composed of multiple centromeric domains (metapolycentromeres). The grosbeak GRC is a large acrocentric macrounivalent. Cross-species in situ hybridization of the bullfinch GRC DNA probe showed only weak signals on the GRC of the grosbeak and redpoll, whereas no signal was detected on the greenfinch and goldfinch GRCs. These data are consistent with published results for two other representatives of this family and indicate rapid divergence and high species specificity of GRC sequences within the family Fringillidae. We also detected interspecies differences in the localization of sequences homologous to the bullfinch GRC on the bivalents of the standard set of these species. Thus, our data indicate rapid evolution of the GRC’s genetic composition and reveal species-specific dynamics of increase and decrease in the copy number of detected sequences in the standard chromosome set during the evolution of songbird species.
Genetic diversity of horses of the Sargarinsko-Alexeevskaya and Irmen cultures of the Ob-Irtysh region of Western Siberia and their genetic proximity to modern horses of indigenous breeds
The multidisciplinary approach is in increasing use in modern science for solving complicated problems. Molecular genetics not only helps us understand biological processes, such as evolution and speciation, but also sheds light on numerous historical questions as to the directions of peoples’ migrations, the degree of interpenetration of contemporaneous cultures, and their continuity. In particular, investigation of phylogenetic relationships of domestic animals allows us to detail the interactions between bearers of different archaeological cultures. In the Bronze Age, Inner Asia and adjacent territories were characterized by intense human migrations and rapid spread of productive economies, including livestock farming. Here we examine the phylogenetic patterns of horses from two important Bronze Age Ob-Irtysh cultures in Western Siberia, the Sargarinsko-Alexeevskaya and Irmen ones, and the degree of their genetic proximity to horses from earlier (Andronovo and Eluninskaya) and later (Khereksur and “Deer Stone”, Biykenskaya, Bystryanskaya and Pazyryk) cultures in the region and adjacent territories. Data obtained from sequencing and analysis of mitochondrial genomes reveal differences in the mitochondrial gene pool of horses from the Sargarinsko-Alexeevskaya and Irmen cultures of the south of Western Siberia, highlighting the unique mitochondrial genetic diversity of the original horse herds of these cultures and the lack of close breeding contacts between them. We demonstrate an overlap between the mitochondrial gene pools of horses from the Khereksur and “Deer Stone” cultures of Mongolia and the Andronovo culture. We also established continuity between many of the obtained haplotypes of horses from the Early, Developed, Late Bronze Age, and Early Iron Age in southern Western Siberia, indicating the preservation of a significant part of the maternal gene pool diversity of domestic horses in the region across several historical and cultural periods. The similarity of mitochondrial haplotypes among horses of the Sargarinsko-Alexeevskaya culture, modern horses of the Akhal-Teke breed of Central Asia, and indigenous breeds of East Asia and Southern Europe, as well as between horses of the Irmen culture and modern horses of local breeds in Northern Europe, may reflect the migration routes of bearers of these cultures after their disintegration in the region under study. It also characterizes features of the formation of these breeds in ancient times. However, nuclear genetic markers should also be investigated to corroborate these hypotheses.
Toxic metals and genetic polymorphism in indigenous populations of northern Asia and America
The polymorphism of genes encoding enzymes involved in heavy metal metabolism was analyzed in indigenous Siberian populations based on the mercury, lead, and cadmium contents in the blood of Canadian Inuit carrying different genotypes. Additionally, we examined the polymorphism of genetic loci associated with sensitivity to arsenic exposure in indigenous Siberian populations using data on inorganic arsenic content in the urine of indigenous Andean populations who had consumed drinking water with elevated arsenic levels for thousands of years. A population genetic approach was used to seek genetic markers of toxic metal exposure in humans by analyzing genetic differences between populations living in different natural environments and under different conditions of toxic element contamination. Statistically significant differences were primarily observed between indigenous populations in Northeast Siberia (Siberian Eskimo (Yupik), Chukchi, and Koryaks) and samples from the central (Evens, Evenki, and Yakuts) and southern (Altaians, Shors, and Buryats) regions of Siberia. The maximum population branch statistics (PBS) values, which indicate the probable effect of selection on genetic loci sensitive to mercury exposure, were identified in seven gene loci: MTHFR (rs2274976 and rs1801131), GPX4 (rs713041), ABCB1 (rs1128503), AHR (rs2066853), TXNRD2 (rs5748469), and SEPHS2 (rs1133238). Loci rs713041 (GPX4), rs7483 (GSTM3), and rs2282143 (SLC22A1) can be considered genetic markers of lead exposure. Loci rs2274976 (MTHFR) and rs1056836 (CYP1B1) provide information about cadmium distribution in blood. It was found that protective variants of the AS3MT gene polymorphism are widespread (65.8 %) in the indigenous populations of Northeast Siberia. This is despite the lack of information regarding the long-term consumption of arsenic-contaminated drinking water by indigenous peoples along the Chukotka and Priokhotye coasts. It is hypothesized that seafood, which constitutes the core of the traditional “Arctic” diet of the indigenous populations inhabiting the coastal regions of the northern seas, may potentially be a significant source of arsenic and other toxic elements in Northeast Siberia. Further molecular, biochemical, and toxicological studies are necessary to elucidate the mechanisms by which toxic metals impact the genetic structure of indigenous populations in the Far North over long periods of time.
The association study of genetic variants with developing musical aptitude in humans
The development of musical abilities, including absolute pitch, musical memory, rhythm sense, and musicality, at a high degree is determined by a hereditary component (up to 68 %). The studies implementing a genome-wide linkage and association approach to musical aptitude have revealed more than 100 genetic loci. This spectrum is comprised of the genes encoding for transcription factors and those responsible for neurogenesis and synaptic plasticity, genes fixed as a result of positive selection of musicality, and those related to inner ear formation. Since no studies linking musical aptitude with genes have been previously conducted in Russia, the present study aimed at replicating the association of 17 previously identified genetic variants with developing musical abilities in Russians. Genotyping of SNPs in the GATA2, PCDH7, UNC5C, ASAP1, SBSPON, DCBLD2, KALRN, VLDLR, OTOF, GRIN2B, FoxP1, FoxP2, BDNF, EGR1, and SNCA genes was performed using competitive allele-specific PCR in a sample of students who underwent rigorous contest selection at admission to the conservatory and in the corresponding control group. A series of logistic regression analyses were used both to evaluate the main effect of SNP and to identify the best prognostic model based on various loci. The mathematical model obtained by including only statistically significant SNPs consisted of GATA2 rs9854612, SNCA rs356168, rs3910105, ASAP1 rs3057, and VLDLR rs1454626 (р = 0.0018, pseudo r2 = 0.188, AUC = 0.791). The addition of all examined SNPs as predictors enabled the construction of a statistically significant model with a higher predictive ability (р = 0.012, pseudo r2 = 0.380, AUC = 0.889). The results revealed indicate a potential cumulative gene effect, confirming the involvement of dopaminergic and GABAergic neurotransmission, the reelin pathway and the role of alpha-synuclein in musicality formation.
Diagnostic efficiency of whole exome sequencing in the search for genetic causes of hereditary diseases in Yugra (West Siberia, Russia)
Whole-exome sequencing (WES) has revolutionized the diagnostics of hereditary diseases, yet its efficacy varies across populations. Data on the genetic architecture of rare hereditary disorders in many Russian regions, including the ethnically diverse Khanty-Mansi Autonomous Okrug (Yugra) are scarce. The aim of this study was to evaluate the diagnostic yield of WES for identifying genetic variants associated with hereditary disorders in this ethnically heterogeneous population. The study involved 286 probands with suspected hereditary disorders observed by regional geneticists in the years 2021–2024. WES was performed on the DNBSEQ-G50 platform (MGI, China). Bioinformatic analysis included variant calling and annotation using population databases and pathogenicity prediction tools. Identified variants were classified according to ACMG/Russian Medical Genetics Society guidelines and correlated with clinical phenotypes. Molecular genetic diagnoses were categorized as definitive, partial, potential (based on variants of unknown significance), or unknown. The examined cohort was predominantly pediatric, the most common clinical indications were neurological, dysmorphic, and metabolic disorders. Definitive molecular diagnoses were established in 24.8 % of patients. Inclusion of potential diagnoses increased the total yield to 48.6 %. Diagnostic efficacy varied significantly among disease categories ranging from 58.3 % for renal disorders to 0 % for neurodevelopmental disorders. A total of 420 unique variants were analyzed, and missense changes were the most frequent among clinically significant findings. The most commonly implicated genes were ATP7B, GJB2, ABCA4, and GALT. The study results indicate that WES is an effective first-tier molecular tool for a wide range of suspected hereditary diseases in the Yugra population, with a diagnostic yield comparable to similar studies abroad. The findings support the utility of WES in diverse populations and highlight the potential for increasing yield through trio-WES and periodic data reanalysis.
Rare variants in cholesterol transporter genes in patients with lipid metabolism disorders
Cardiovascular diseases are the leading cause of death both in Russia and in the world. One of the factors predisposing to the development of cardiovascular diseases is lipid metabolism disorders (dyslipidemias), which contribute to the progression of atherosclerosis. Currently, there are known genes associated with the development of monogenic forms of lipid metabolism disorders characterized by marked changes in lipid levels. However, identifying individuals with an increased genetic risk of dyslipidemia remains an unsolved problem, due to the polygenic nature of most cases. The aim of this work was to study the spectrum of rare variants in the cholesterol transporter genes ABCA1, ABCG1, ABCG5, ABCG8 and NPC1L1 that occur in patients with lipid metabolism disorders in the population of the Northwestern region of Russia. The search for rare variants (gnomAD frequency less than 1 %) in the ABCA1, ABCG1, ABCG5, ABCG8 and NPC1L1 genes was performed using targeted sequencing data for 169 patients with lipid metabolism disorders. 14 variants were identified in the ABCA1 gene (17 patients); 4 variants, in the ABCG1 gene (5 patients); 11 variants, in the ABCG5 gene (18 patients); and 7 variants, in the ABCG8 gene (11 patients). The frequency of some of them, according to the RUSeq database, is higher than in the global population. 19 patients (11 %) were carriers of the p.(Val177Ile)/p.(His221Tyr)/p.(Ala271Phe) haplotype in the NPC1L1 gene, which may be specific to the Russian population, meaning that these variants are not rare, but polymorphic, and occur more frequently in patients with impaired lipid metabolism. Influence of the p.(Val177Ile) variant of the NPC1L1 gene on the development of atherosclerosis was assessed using additional sample sets (a group of patients with atherosclerosis, a control group), but no significant differences in genotype frequencies were revealed. Thus, at present, there are insufficient data to support the role of the p.(Val177Ile)/p.(His221Tyr)/p.(Ala271Phe) haplotype of the NPC1L1 gene in the development of dyslipidemia and atherosclerosis. The study draws attention to the population specificity of a number of variants in cholesterol transporter genes, in particular in the NPC1L1 gene, for the Northwestern region of Russia. The data can be further used for design and calculation of genetic risk scores for dyslipidemia.
Mathematical and computational modeling of biosystems at different levels of organization
Modern biology increasingly relies on mathematical and computational modeling to describe complex hierarchically organized biological systems. This review considers models that cover the main levels of biological organization, from the molecular-genetic and cellular levels to tissue/organ, organismal, population and ecological ones. The aim of the work is to systematize the key modeling approaches at each of these levels, to analyze their capabilities and limitations, and to discuss strategies for constructing multiscale and hybrid models that consistently link processes operating at different spatial and temporal scales. We survey classical deterministic and stochastic models based on ordinary and partial differential equations, logical and graph-based models of regulatory networks, cellular automata, agent-based models, as well as flux-balance approaches. Typical examples are given for the modeling of gene regulatory and metabolic networks, chemotaxis, tissue and organ growth, population dynamics and genetic structure, and ecosystem functioning. Special attention is paid to comparing approaches with respect to the scale of description, complexity of modeled processes, data requirements, computational cost and interpretability of results. The analysis shows that hybrid and multiscale models provide an adequate framework to account for nonlinearity, stochasticity and structural heterogeneity of biosystems, but require substantial computational resources and careful data-driven calibration. Methodological and technological trends are outlined, including the development of specialized platforms and model repositories, standards for model representation and tools for reuse of model components.
Evolutionary inferences from the analysis of mutation dynamics in the SARS-CoV-2 replication-transcription complex
The SARS-CoV-2 virus continues to evolve and remains a significant public health threat, while the worldwide monitoring and sequencing of its genomic variants provide a unique opportunity to study its evolution and better understand its molecular mechanisms. In our work, we analyze its replication-transcription complex (RTC) over a 5.5-year period (December 2019–July 2025). This complex is significantly more conserved (as any alteration impairing its function prevents viral replication) than the S-protein (directly impacting infectivity and immune evasion) but still dynamically evolving part of the genome. The study focuses on high-frequency substitutions, their temporal behavior, co-occurrence, and structural context. Using genomes from GISAID, we identified 22 amino acid point mutations present in at least 1 % of currently available sequences, analyzed their weekly dynamics, revealed three distinct temporal patterns, and enumerated frequent co-occurring groups (pairs, triplets, and larger sets) within the same genomes. We mapped the affected residues onto an RTC 3D structure and reviewed the literature to examine the reported functional consequences. Notably, all these substitutions were single-nucleotide. One of the mutations, nsp12:G671S, showed a unique dynamic feature: it emerged, dominated globally for months, disappeared twice, and in 2025 reappeared for the 3rd time, always accompanied with other mutations in the RTC. Thus, it was interesting to trace its dynamics as an indicator of probable changes. In addition, our analysis of mutation and variant timelines suggests that the Delta variant may have emerged 7–8 months earlier than commonly reported. Taken together, these results provide a consolidated view of recurrent RTC variation, its temporal classes, co-occurrence, and structural context, underscoring the value of systematic surveillance of nsp7–nsp14 alongside analyses focused on structural proteins.
Genetic analysis of wheat ear architecture in F2 hybrid of tetraploid wheats Triticum aethiopicum and T. carthlicum and its computer phenotyping
A comprehensive description of plant phenotypes of certain taxa is an important task when describing genera and species, as well as when setting their natural taxonomies. The development of modern technologies of effective phenotyping makes it possible to obtain a large amount of data with a quantitative and/or qualitative description of various traits in plants, mainly based on the analysis of their digital images. The study compared the results of the F2 hybrids assessment – visually and using machine learning methods – of two endemic tetraploid (2n = 4x = 28) wheat species which are Ethiopian wheat (Triticum aethiopicum Jakubz.) and Kartalian or Dika wheat (T. carthlicum Nevski). In the latter case, it is proposed to use the method of a mixture of Gaussian (normal) distributions in plant morphometry in order to identify groups that differ in character values. Most taxonomically important (species-specific) traits are controlled oligogenically and have a clear phenotypic manifestation, so hybridological analysis was an indispensable and basic type of analysis for subsequent detailed phenotyping of wheat spikes using machine-learning methods. According to a number of criteria, the estimates of patterns of inheritance obtained by different methods coincide. Based on the conducted research, we can state that the trait “tetraaristatum” (the presence of awns on both flower and spike glumes) is species-specific (taxonomically important) for T. carthlicum and it can be effectively used for taxonomic purposes both in carrying out hybridological analysis and in experiments using machine learning. Such a species-specific character is the “character (type) of awnedness” for T. aethiopicum. Our study demonstrates that a combination of automatic phenotyping methods and a model of a mixture of Gaussian distributions can, in principle, lead to an automatic analysis of the allocation of classes in F2 hybrids. It allows, in turn, to detect the presence of genes associated with species-specific traits of wheat plants. Further, the improvement of the applied artificial intelligence (AI) algorithms is required.