The Nivkhs are a small ethnic group indigenous of the Russian Far East, living in the Khabarovsk Territory and on Sakhalin Island, descending from the ancient inhabitants of these territories. In the Nivkhs, a specific Sakhalin-Amur anthropological type is prevalent. They are quite isolated, due to long isolation from contacts with other peoples. The gene pool of the Nivkhs and other Far Eastern and Siberian populations was characterized using a genome-wide panel of autosomal single-nucleotide polymorphic markers and Y chromosome haplogroups. Bioinformatic processing of frequencies of autosomal SNPs, Y chromosome haplogroups and YSTR haplotypes showed that the Nivkh gene pool is very different from the other populations’. Analysis of the SNP frequencies using the PCA method divided the Far Eastern populations in full accordance with the territories of their residence into the northern group of the Chukchi and Koryaks and the southern group, including the Nivkhs and Udege. The remoteness of the Nivkhs coincides with their geographic localization, with the Nivkhs and Udege demonstrating the greatest kinship. The Nivkhs have a specific component of their gene pool, which is present with much less frequency in the Udege and Transbaikal Evenks. According to the IBD blocks, the genotypes of the Nivkhs show a very small percentage of coincidence with the Udege, Koryaks, Evenks and Chukchi, the value of which is the lowest compared to the IBD blocks among all other Siberian populations. The Nivkh-specific composition of haplogroups and YSTR haplotypes was shown. In the Nivkhs, the C2a1 haplogroup is divided into three sublines, which have a fairly ancient origin and are associated with the ancestors of modern northern Mongoloids. The Nivkh haplogroup O2a1b1a2a-F238 is found among residents of China and Myanmar. The Q1a1a1-M120 line is represented among the Nivkhs, Koryaks, Evenks and Yukaghirs. Phylogenetic analysis of individual Y chromosomal haplogroups demonstrated the closeness of the Nivkh gene pool with the ancient population of the Amur and Okhotsk regions, the Koryaks, the Tungus peoples and the population of Southeast Asia. The Nivkh gene pool confirms the relative smallness of their ancestral groups without mixing with other populations.

The gene pool of the Koryaks was studied in comparison with other Far Eastern and Siberian peoples using a genome-wide panel of autosomal single-nucleotide polymorphic markers and Y-chromosome markers. The results of analyzing the frequencies of autosomal SNPs using various methods, the similarity in the composition of Y-chromosome haplogroups and YSTR haplotypes indicate that the gene pool of the Koryaks is as close as possible to the Chukchi one and was formed as a result of the unification of several groups whose ancestors had moved from the territory of modern Yakutia and the Amur region. The two dominant Y-chromosome haplogroups of the Koryaks with different sublines of haplotype clusters demonstrate their contacts with the Chukchi, Evens, Yukaghirs, and Eskimos. Analysis of the composition of genetic components and IBD blocks on autosomes indicates the maximum genetic proximity of the Koryaks to the Chukchi. Among the Siberian populations, the Chukchi, Koryaks, and Nivkhs form a cluster separate from the main group of Siberian populations, while the Chukchi and Koryaks are more closely related. Far Eastern populations are divided in full accordance with geographic localization into the northern group (Chukchi and Koryaks) and the southern group, including the Nivkhs and Udege. A more detailed analysis of the component composition of gene pools in some populations reveals components specific to them. The isolation of such components is associated with founder effects and a shift in allele frequencies for these populations. The Koryaks and Chukchi represent one of the most striking examples of long-standing genetic kinship. Their populations demonstrate maximum values of the level of genomic inbreeding FROH > 1.5 (0.0422, 0.0409), which is natural due to their relative isolation.

Pycnodysostosis (PD) is a rare autosomal recessive skeletal dysplasia from impaired bone resorption due to osteoclastic dysfunction. The features of PD are deformity of the skull, maxilla, and phalanges; osteosclerosis; and bone fragility. We describe the case of a patient with complaints of multiple fractures of the lower extremities in the anamnesis and pain in the lower extremities, cervical spine, and shoulder girdle during physical exertion. Genetic testing revealed a novel homozygous variant c.704T>C (p.Leu235Pro) in the CTSK gene. Biallelic pathogenic variants in this gene lead to PD. Thus, the diagnosis in the patient was established by finding a novel likely pathogenic variant in the CTSK gene.

The effects of the demographic history of mankind have led to the fact that the indigenous peoples of Dagestan and Siberia are inferior in terms of genetic diversity to the populations of Europe, which affects the level of identification informativeness of standard forensic autosomal markers in these populations. In our study, we evaluated the effectiveness of two standard sets of autosomal STRs (13 CODIS, 20 CODIS, Combined DNA Index System) for the genetic testing of parent-child relatedness in four highly inbred populations of the Russian Federation and the Russian population, using two types of reference frequencies. The results of the study confirmed the assumption that the level of identification informativity of standard autosomal markers in highly inbred populations of Siberia and Dagestan is lower than in the Russian population. The total information content of markers of the new CODIS standard exceeds the threshold values required in the order of the Ministry of Health and Social Development of the Russian Federation (No. 346n). At the same time, the probability of a false positive result increases with an increase in the inbreeding coefficient in the population.

The effects of the demographic history of mankind have led to the fact that the indigenous peoples of Dagestan and Siberia are inferior in terms of genetic diversity to the populations of Europe, which affects the level of identification informativeness of standard forensic autosomal markers in these populations. In our study, we evaluated the effectiveness of two standard sets of autosomal STRs (13 CODIS, 20 CODIS, Combined DNA Index System) for the genetic examination of parent–child relationship in four highly inbred populations of the Russian Federation and the Russian population, using two types of reference frequencies. The results of the study confirmed the assumption that the level of identification informativity of standard autosomal markers in highly inbred populations of Siberia and Dagestan is lower than in the Russian population. The total information content of markers of the new CODIS standard exceeds the threshold values required in the order of the Ministry of Health and Social Development of the Russian Federation (no. 346n). At the same time, the probability of a false positive result increases with an increase in the inbreeding coefficient in the population.

Pallister-Killian syndrome (PKS) is a rare inherited disease with multiple congenital anomalies, profound intellectual disability, and the presence in the karyotype of sSMC - i(12)(p10). The frequency of PKS may be underestimated due to problems with cytogenetic diagnosis caused by tissue-specific mosaicism and usually a low percentage of peripheral blood cells containing sSMC. Such tissue-specific mosaicism also complicates a detailed analysis of the sSMC, which, along with the assessment of mosaicism in different tissues, is an important part of cytogenetic diagnosis in PKS. Unfortunately, a full-fledged diagnosis in PKS is either practically impossible or complicated. On the one hand, this is due to problems with the biopsy of various tissues (skin biopsy with fibroblast culture is most often used in practice); on the other - a low percentage of dividing peripheral blood cells containing sSMC, which often significantly complicates the analysis of its composition and organization. In the present study, a detailed analysis of sSMC was carried out in a patient with a characteristic clinical picture of PKS. A relatively high percentage of peripheral blood cells with sSMC (50%) made it possible to perform a detailed molecular cytogenetic analysis of de novo sSMC using chromosomal in situ suppression hybridization (CISS-hybridization), multicolor FISH (mFISH), multicolor chromosome banding (MCB), array CGH (aCGH), and quantitative real-time PCR (qPCR), and short tandem repeat (STR) - analysis. As a result, it was found that the sSMC is not a typical PKS derivative of chromosome 12. In contrast to the classical i(12)(p10) for PKS, the patient’s cells contained an acrocentric chromosome consisting of 12p material. Clusters of telomeric repeats were found at the both ends of the sSMC. Furthemore, the results of aCGH and qPCR indicate the presence of interstitial 8.9 Mb duplication at 12p13.1-p12.1 within the sSMC, which leads to different representations of DNA from different segments of 12p within cells containing sSMC. The obtained data raise the question of the instability of the sSMC and, as a consequence, the possible presence of additional rearrangements, which, in traditional cytogenetic analysis of patients with PKS, are usually described as i(12)(p10).

The gene pool of the indigenous population of Siberia is a unique system for studying population and evolutionary genetic processes, analyzing genetic diversity, and reconstructing the genetic history of populations. High ethnic diversity is a feature of Siberia, as one of the regions of the peripheral settlement of modern human. The vast expanses of this region and the small number of aboriginal populations contributed to the formation of significant territorial and genetic subdivision. About 40 indigenous peoples are settled on the territory of the Siberian historical and ethnographic province. Within the framework of this work, a large-scale population study of the gene pool of the indigenous peoples of Siberia was carried out for the first time at the level of high-density biochips. This makes it possible to fill in a significant gap in the genogeographic picture of the Eurasian population. For this, DNA fragments were analyzed, which had been inherited without recombination by each pair of individuals from their recent common ancestor, that is, segments (blocks) identical by descent (IBD). The distribution of IBD blocks in the populations of Siberia is in good agreement with the geographical proximity of the populations and their linguistic affiliation. Among the Siberian populations, the Chukchi, Koryaks, and Nivkhs form a separate cluster from the main Siberian group, with the Chukchi and Koryaks being more closely related. Separate subclusters of Evenks and Yakuts, Kets and Chulyms are formed within the Siberian cluster. Analysis of SNPs that fell into more IBD segments of the analyzed populations made it possible to compile a list of 5358 genes. According to the calculation results, biological processes enriched with these genes are associated with the detection of a chemical stimulus involved in the sensory perception of smell. Enriched for the genes found, molecular pathways are associated with the metabolism of linoleic, arachidonic, tyrosic acids and by olfactory transduction. At the same time, an analysis of the literature data showed that some of the selected genes, which were found in a larger number of IBD blocks in several populations at once, can play a role in genetic adaptation to environmental factors.

Проведена оценка уровня генетического разнообразия, вероятности дискриминации неродственных индивидов (PD, power of discrimination) и исключающей способности (PE, power of exclusion) 43 аутосомных STR (D3S1358, TH01, D12S391, D5S818, TPOX, D13S317, FGA, D22S1045, D18S51, D16S539, D8S1179, CSF1PO, D6S1043, vWA, D21S11, SE33, D10S1248, D1S1656, D19S433, D2S1338, D20S1082, D6S474, D12ATA63, D4S2666, D1S1677, D11S4463, D9S1122, D2S1776, D10S1435, D3S3053, D5S2500, D1S1627, D3S4529, D2S1360, D17S974, D3S1744, D9S2157, D17S1301, D8S1132, Penta D, D21S2050, D7S1517, Penta E) в популяциях аварцев из трех районов Дагестана: Шамильского, Тляратинского, Унцукульского. Полученные результаты показали, что для проведения генетической экспертизы в Дагестане, при выборе референсной группы, необходимо учитывать не только этническую принадлежность индивида, но и географическую локализацию. We assessed the level of genetic diversity, power of discrimination, power of exclusion of 43 autosomal STRs (D3S1358, TH01, D12S391, D5S818, TPOX, D13S317, FGA, D22S1045, D18S51, D16S539 , D8S1179, CSF1PO, D6S1043, vWA, D21S11, SE33, D10S1248, D1S1656, D19S433, D2S1338, D20S1082, D6S474, D12ATA63, D4S2666, D1S1677, D11S4463, D9S1 122, D2S1776, D10S1435, D3S3053, D5S2500, D1S1627, D3S4529, D2S1360, D17S974 , D3S1744, D9S2157, D17S1301, D8S1132, Penta D, D21S2050, D7S1517, Penta E) in Avar populations from three regions of Dagestan: Shamilsky district, Tlyaratinsky district, Untsukulsky district. The results emphasized the need to take into account the geographic origin of the individual, and not just his nationality, when choosing reference data during genetic examination in the populations of Dagestan.

Cystic fibrosis (CF) is a hereditary disease that leads to impaired functioning of chloride channels in cells, and, as a result, to a decrease in the viscoelastic properties of the secretion of all exocrine glands. Cystic fibrosis is the result of mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene, which encodes the CFTR protein. In this study, induced pluripotent stem cells (iPSCs) were obtained from the skin fibroblasts of a patient with a homozygous mutation F508del CFTR (NM_000492.3(CFTR):c.1521_1523del). This deletion is the most common for cystic fibrosis. The resulting iPSC line had a normal karyotype, retained the original genotype, and also demonstrated the presence of pluripotency markers (OCT4, SOX2, NANOG, SSEA4, TRA-1-60) and the ability to differentiate into derivatives of three germ layers.

Популяции коренных этносов Средней Азии представляют значительный интерес для популяционной геномики по причине специфичности их генофондов, развивавшихся в различных генетико-демографических условиях. Данные о сигналах направленного отбора являются важным дополнением к существующим данным о эволюции генофондов и механизмах генетической адаптации населения Евразии. Мы использовали массив генотипов по 1779819 SNP в выборке из 128 человек, включающей 5 популяций населения Средней Азии, для поиска сигналов направленного отбора с помощью тестов на протяженную гомозиготность гаплотипов (nSL, iHS). Обнаружено, что все исследованные популяции сильно отличаются друг от друга по составу генов, которые демонстрируют влияние отбора. Наибольшее число значимых сигналов естественного отбора выявлено в популяциях киргизов и узбеков. Среди локусов генома, несущих наиболее выраженные сигналы направленного отбора в популяциях выделяются гены CUEDC1, ERC1, FAM20C, MRC1. The populations of the indigenous ethnic groups of Central Asia are of considerable interest for population genomics, due to the specificity of their gene pools, which developed under various genetic and demographic conditions. The data on directional selection signals is an important addition to the existing data on the evolution of gene pools and the mechanisms of genetic adaptation of the Eurasian population. We used an array of genotypes for 1779819 SNPs in a sample of 128 people, including 5 populations of the population of Central Asia, to search for directional selection signals using tests for extended haplotype homozygosity (nSL, iHS). For the populations of Central Asia, it was found that all the studied populations differ greatly from each other in the composition of genes that demonstrate the influence of selection. The largest number of significant signals of natural selection was found in the populations of the Kyrgyz and Uzbeks. The CUEDC1, ERC1, FAM20C, and MRC1 genes are among the genome loci that carry the most pronounced signals of directional selection in populations.

Khanty are indigenous Siberian people living on the territory of Western Siberia, mainly on the territory of the Khanty-Mansiysk and Yamalo-Nenets Autonomous Okrugs. The present study is aimed at a comprehensive analysis of the structure of the Khanty gene pool and their comparison with other populations of the indigenous population of Southern and Western Siberia. To address the issues of genetic proximity of the Khanty with other indigenous peoples, we performed genotyping of a wide genomic set of autosomal markers using high-density biochips, as well as an expanded set of SNP and STR markers of the Y-chromosome in various ethnic groups: Khakas, Tuvans, Southern Altaians, Siberian Tatars, Chulyms (Turkic language family) and Kets (Yeniseian language family). The structure of the gene pool of the Khanty and other West Siberian and South Siberian populations was studied using a genome-wide panel of autosomal single nucleotide polymorphic markers and Y-chromosome markers. The results of the analysis of autosomal SNPs frequencies by various methods, the similarities in the composition of the Y-chromosome haplogroups and YSTR haplotypes indicate that the Khanty gene pool is quite specific. When analyzing autosomal SNPs, the Ugrian genetic component completely dominates in both samples (up to 99–100 %). The samples of the Khanty showed the maximum match in IBD blocks with each other, with a sample of the Kets, Chulyms, Tuvans, Tomsk Tatars, Khakas, Kachins, and Southern Altaians. The degree of coincidence of IBD blocks between the Khanty, Kets, and Tomsk Tatars is consistent with the results of the distribution of allele frequencies and common genetic components in these populations. According to the composition of the Y-chromosome haplogroups, the two samples of the Khanty differ significantly from each other. A detailed phylogenetic analysis of various Y-chromosome haplogroups made it possible to describe and clarify the differences in the phylogeny and structure of individual ethnospecific sublines, to determine their relationship, traces of population expansion in the Khanty gene pool. Variants of different haplogroups of the Y-chromosome in the Khanty, Khakas and Tuvans go back to their common ancestral lines. The results of a comparative analysis of male samples indicate a close genetic relationship between the Khanty and Nenets, Komi, Udmurts and Kets. The specificity of haplotypes, the discovery of various terminal SNPs confirms that the Khanty did not come into contact with other ethnic groups for a long time, except for the Nenets, which included many Khanty clans.

Osteogenesis imperfecta (OI) is a group of connective tissue disorders with different types of inheritance. OI is characterized by bone fragility and deformities, frequent fractures, low bone-mineral density, and impaired bone micro-architectonics. We described here a case of a one-year-old Tuvan patient with multiple fractures. The disease manifestation occurred first at 12 weeks of age as a shoulder joint bruise, and during the year, the patient sustained 27 fractures. Genetic testing revealed a novel homozygous mutation, c.259_260insCGGCC (p.T87fs), in the SERPINF1 gene. This insertion leads to an open-reading frameshift, and the mutation is not represented in the databases. Mutations in SERPINF1 lead to type VI OI, the clinical picture of which is similar to the disease phenotype manifestation of the patient. Thus, the patient's diagnosis was established by finding a novel pathogenic variant in the SERPINF1 gene.

Tuvans are one of the most compactly living peoples of Southern Siberia, settled mainly in the territory of Tuva. The gene pool of the Tuvans is quite isolated, due to endogamy and a very low frequency of interethnic marriages. The structure of the gene pool of the Tuvans and other Siberian populations was studied using a genomewide panel of autosomal single nucleotide polymorphic markers and Y-chromosome markers. The results of the analysis of the frequencies of autosomal SNPs by various methods, the similarities in the composition of the Y-chromosome haplogroups and YSTR haplotypes show that the gene pool of the Tuvans is very heterogeneous in terms of the composition of genetic components. It includes the ancient autochthonous Yeniseian component, which dominates among the Chulym Turks and Kets, the East Siberian component, which prevails among the Yakuts and Evenks, and the Far Eastern component, the frequency of which is maximum among the Nivkhs and Udeges. Analysis of the composition of IBD-blocks on autosomes shows the maximum genetic relationship of the Tuvans with the Southern Altaians, Khakas and Shors, who were formed during the settlement of the Turkic groups of populations on the territory of the Altai-Sayan region. A very diverse composition of the Tuvan gene pool is shown for various sublines of Y-chromosomal haplogroups, most of which show strong ethnic specificity. Phylogenetic analysis of individual Y-chromosome haplogroups demonstrates the maximum proximity of the gene pool of the Tuvans with the Altaians, Khakas and Shors. Differences in frequencies of Y-chromosome haplogroups between the Todzhans and Tuvans and a change in the frequencies of haplogroups from south to north associated with the East Asian component were found. The majority of the most frequent Y-chromosome haplogroups in the Tuvans demonstrate the founder effect, the formation age of which is fully consistent with the data on their ethnogenesis.

The indigenous populations of Siberia are of significant interest for population genomics because of the specificity of their gene pools, which developed in various genetic and demographic conditions. Data on directional selection signals is an important addition to the existing data on the evolution of gene pools and the mechanisms of genetic adaptation of the population of Eurasia. We used genotype array of 1 779 819 SNPs in a group of 477 unrelated subjects, including 20 indigenous populations of Siberia, to search for directional selection signals using a test for extended homozygosity of haplotypes (nSL). The present study detected that all studied populations of Siberia strongly differ from each other in the composition of genes that demonstrate the effect of selection. The largest number of significant signals of natural selection was found in the populations of the Khanty, Koryaks, and Chukchi. The genes ADGRB3 , ANO3 , CDH13 , CUEDC1 , and PCDH15 are distinguished among the genomic loci carrying the most pronounced directional selection signals in the northern populations.

The structure of the gene pool of the Chulym Turks, Kets, Khakass, and other South Siberian populations are studied using microarrays and Y-chromosome markers. The results of the analysis of the frequencies of autosomal SNPs using various methods, the similarity in the composition of the Y-chromosome haplogroups, and Y-STR haplotypes indicate that the gene pool of the Chulyms was formed during the resettlement of Turkic groups from the territory of Khakassia and their mixing with the local autochthonous population. Two dominant Y-chromosome haplogroups in the Chulyms and haplotype clusters demonstrate the founder effect; their formation age is fully consistent with the data on their ethnogenesis. Analysis of the composition of the genetic components and IBD blocks demonstrates their genetic affinity with the Kets, Khakass, and Tomsk Tatars. This confirms the information about the formation of their gene pool as a result of the mixing of alien and indigenous populations of the Chulym basin.

Populations of the indigenous ethnic groups of Northern Eurasia are of considerable interest for population genomics, both because they have been relatively poorly studied with the use of modern genomic technologies and owing to the specificity of their gene pools that developed in various genetic-demographic conditions. We used genotype data on 242 179 autosomal SNPs of 876 individuals to search for regions with runs of homozygosity of more than 1 Mb. For Siberian populations, the number of runs of homozygosity and their total length was higher than for other populations of Northern Eurasia.

Wilson's disease is a rare autosomal recessive disorder of copper metabolism. The copper accumulation in the viscera appears due to the functional impairment of copper-transporting ATPase, which is encoded by the ATP7B gene. In this study, PBMCs of a patient with two ATP7B mutations were reprogrammed. The first mutation is a missense mutation p.H1069Q, which is the most frequent mutation in the human population. At the same time, the second one is a frameshift mutation p.Lys1013fs. The generated iPSC line had a normal karyotype, maintained the original genotype, expressed pluripotency markers, and demonstrated the ability to differentiate into derivatives of the three germ layers.