Increased Frequencies of the ‒174G and ‒572C IL6 Alleles in Populations of Indigenous Peoples of Siberia Compared to Russians.

Abstract-The study of immune response and inflammation gene polymorphisms in a genogeographic context is relevant in the study of human populations. Here, in the indigenous populations of Siberia the frequencies of polymorphic variants ‒174G/C (rs1800795) and ‒572C/G (rs1800796) of the IL6 gene encoding the proinflammatory cytokine IL-6 were determined. For the first time, it was shown that the frequencies of the ‒174G and ‒572C alleles, which determine increased inflammatory response and are also associated with several diseases were statistically significantly higher in ethnic groups of Buryats, Teleuts, Yakuts, Dolgans and Tuvinians than in Russians living in Siberia. These values were in the intermediate position between those in the European and East-Asian groups. We hypothesize an adaptive role of these IL6 genetic variants in human settlement from Africa to the Eurasian continent. However, due to the departure from the traditional way of life and the increasing anthropogenic environmental pollution, the risk of diseases whose pathogenesis is based on inflammation in indigenous Siberian populations is likely increased.

[Increased Frequencies of the -174G and -572C IL6 Alleles in Populations of Indigenous Peoples of Siberia Compared to Russians].

The study of immune response and inflammation gene polymorphisms in a genogeographic context is relevant in the study of human populations. Here, in the indigenous populations of Siberia the frequencies of polymorphic variants -174G/C (rs1800795) and -572C/G (rs1800796) of the IL6 gene encoding the proinflammatory cytokine IL-6 were determined. For the first time, it was shown that the frequencies of the -174G and -572C alleles, which determine increased inflammatory response and are also associated with several diseases were statistically significantly higher in ethnic groups of Buryats, Teleuts, Yakuts, Dolgans and Tuvinians than in Russians living in Siberia. These values were in the intermediate position between those in the European and East-Asian groups. We hypothesize an adaptive role of these IL6 genetic variants in human settlement from Africa to the Eurasian continent. However, due to the departure from the traditional way of life and the increasing anthropogenic environmental pollution, the risk of diseases whose pathogenesis is based on inflammation in indigenous Siberian populations is likely increased.

TCF7L2 gene polymorphism in populations of f ive Siberian ethnic groups.

Investigation of the frequencies of functionally signif icant gene variants in the context of medical biology and gene geography is a relevant issue for studying the genetic structure of human populations. The transition from a traditional to an urbanized lifestyle leads to a higher incidence of civilizational diseases associated with metabolic disorders, including type 2 diabetes mellitus. The goal of the present paper is to analyze the frequencies of functionally signif icant gene alleles in the metabolic prof iles of indigenous Siberian peoples to identify the gene pool resilience, evaluate the susceptibility of various ethnic groups to metabolic disorders under changing environmental conditions, and predict the epidemiological situation that may occur in the near future. The study was performed in the monoethnic samples of eastern and western Buryats, Teleuts, Dolgans, and two territorial groups of Yakuts. A real-time PCR was used to determine the frequencies of single nucleotide polymorphisms (SNPs) G103894T, rs12255372, and C53341T, rs7903146 in the TCF7L2 gene. The results obtained were compared to the frequencies identif ied for Russians from Eastern Siberia and the values available in the literature. The frequencies of the polymorphic variants studied in the samples from the indigenous Siberian peoples place them in between Caucasian and East Asian populations, following the geographic gradient of polymorphism distribution. A signif icantly lower occurrence of type 2 diabetes risk alleles TCF7L2 (103894T) and TCF7L2 (53341T) in the samples of indigenous Siberian peoples compared to Russians was observed, which agrees with their lower susceptibility to metabolic disorders compared to the newcomer Caucasian population. Taking into account urbanization, a reduced growth in type 2 diabetes incidence may be predicted in indigenous Siberian peoples, i. e. Buryats, Yakuts, Dolgans, and Teleuts, compared to the newcomer Caucasian population. A further study of population structure with respect to different metabolic prof ile genes is required to better understand the molecular genetic foundations of the adaptive potential of indigenous Siberian peoples.

[N-aсetyltransferase (NAT2) gene polymorphism and gene network analysis]. / Polimorfizm variantov gena N-atsetiltransferazy 2 (NAT2) i analiz gennoi seti.

To search for new targets of therapy, it is necessary to reconstruct the gene network of the disease, and identify the interaction of genes, proteins, and drug compounds. Using the online bioinformatics tools we have analyzed the current data set related to the metabolism of xenobiotics, mediated by the N-acetyltransferase 2 (NAT2) gene. The study of allelic polymorphism of the NAT2 gene has a prognostic value, allowing to determine the risk of a number of oncological diseases, the degree of increased risk due to smoking and exposure to chemical carcinogens, including drugs. The aim of this study was to determine the frequencies of two important "slow" variants of the NAT2 gene (NAT2*5, rs1801280 and NAT2*7, rs1799931), which significantly affected the rate of xenobiotic acetylation among the indigenous Nenets population of Northern Siberia. The obtained frequencies of polymorphic variants among the Nenets occupy an intermediate value between those for Europeans and Asians, which might indicate specific features of adaptation. We present a model of the distribution of two polymorphic variants of the NAT2 gene involved in the biotransformation of xenobiotics to study the characteristics of their metabolism in the indigenous inhabitants of Yamal.

[Analysis of the genetic and demographic structure of populations from Aginskii Buryat district contrasting in habitation conditions].

Genetic and demographic characteristics of populations from two settlements from the Aginskii Buryat district of Trans-Baikal krai (Alkhanai and Orlovskii) were studied. It was demonstrated that the mononational Buryat settlement of Alkhanai, located in the agrarian Dul'durginskii region of the district far from large settlements and transport highways, is characterized by a large prereproductive volume (45%) and by a small share of individuals from the elderly age group (16.4%). A shift in age characteristics in the Buryat group (36.6 and 22.4%, respectively) was detected in the urban settlement of Orlovskii with a population of mixed ethnic composition, located in a densely populated industrialized part of the district. A modified sex ratio was also demonstrated in Alkhanai as opposed to the Buryat part of the Orlovskii population (sex indices were 0.94 and 0.99). Analysis of population mixture was conducted; marriage structure and migrations were described. The endogamy index of the Alkhanai locality was 0.41; in the group of Buryats from Orlovskii, 0.09. A decrease in the amount of pregnancies and births and a larger distribution of family planning practice among Buryats from Orlovskii were detected. The average amount of births of living children per woman in Alkhanai was 5.11; in Buryats from Orlovskii, 3.90. The selection pressure was estimated as low by means of the Crow index (I(tot) 0.28-0.48). In all described groups, a component that characterizes differential fertility (I(f)) exceeds the child mortality component (I(m)).

A private allele ubiquitous in the Americas.

The three-wave migration hypothesis of Greenberg et al. has permeated the genetic literature on the peopling of the Americas. Greenberg et al. proposed that Na-Dene, Aleut-Eskimo and Amerind are language phyla which represent separate migrations from Asia to the Americas. We show that a unique allele at autosomal microsatellite locus D9S1120 is present in all sampled North and South American populations, including the Na-Dene and Aleut-Eskimo, and in related Western Beringian groups, at an average frequency of 31.7%. This allele was not observed in any sampled putative Asian source populations or in other worldwide populations. Neither selection nor admixture explains the distribution of this regionally specific marker. The simplest explanation for the ubiquity of this allele across the Americas is that the same founding population contributed a large fraction of ancestry to all modern Native American populations.

[Genetic variability of hepatitis B virus isolates among population of Shuryskarsky area of Yamal-Nenets autonomous region].

UNLABELLED: The purpose of this work was to determine occurrence of serological markers of hepatites B and to describe subtypes of a superficial antigen and genotypes of hepatitis B virus (HBV) isolates among indigenous population of Yamal-Nenets Autonomous Region (YNAR), Russia. METHODS: We investigated 657 serum samples from inhabitants of Shuryskarsky area of YNAR. ELISA method was used to define the hepatitis B markers: HBsAg, anti-HBs (total) and anti-HBc (IgG and IgM). The HBsAg-positive samples were PCR-tested for the presence of HBV DNA. Genotyping of isolates was by sequencing of the Pre-Sl/Pre-82/S region of HBV genome and phylogenetic analysis. Definition of HBsAg subtypes was executed by two methods: ELISA with subtype-specific monoclonal antibodies and S-gene nucleotide sequence analysis. RESULTS: The following occurrence of hepatitis B markers was observed: HBsAg - 3.2%, anti-HBs (total) - 36.2%, anti-HBc IgG - 30.3%, anti-HBc IgM - 1.6%. Frequency of carrying even one of the markers in the observed population was 47.5%. HBV DNA was found in 17 HBsAg-positive samples. Pre-SI, Pre-S2 and S regions sequences were determined for all HBV DNA-positive samples. The phylogenetic analysis showed an accessory of all investigated HBV isolates to genotype D. HBsAg subtypes distribution appeared the following: ayw2 - 23.5%, ayw3 - 70.6%, adw2 - 5.9%. Results of definition of the subtype ELISA method and by the analysis of S gene nucleotide sequences have coincided in 10/11 (90.1%) cases. CONCLUSIONS: The indigenous population of Shuryskarsky area of YNAR belongs to groups with average HBV carrying. Absolute domination of genotype D (subtypes ayw2, ayw3 and adw2) was revealed. High percentage of concurrence of HBsAg subtypes detected by the ELISA method and method of the analysis of S gene primary structure (90%) was observed. Sequencing of HBV S-gene is preferable to define HBsAg subtypes.

[The effect of marriage migration on the genetic structure of the Taimyr Nganasan population: genealogical analysis inferred from MtDNA markers].

The marriage structure of Nganasans during the time period from 1796 to 1991 and genealogy of carriers of mitochondrial DNA haplotypes was studied in a sample of 280 individuals. It was shown that, from the beginning of its formation to the late 1970s, the population exhibited high endogamy (1976, 83.8%; 1926, 88.4%; 1976, 74.3%). The main source of traditional marriage migration (preferentially female) was populations of Entsy and, indirectly, Nentsy. Intense assimilation of Nganasans by the immigrant population, and to a lesser extent, by Dolgans, in the second half of the 20th century resulted in a reduction of endogamy index in Avam Nganasans to 42.5% by 1991. Assimilation by the immigrants was predominantly paternal, promoting preservation of the historically formed genetic diversity of the Nganasan mitochondrial gene pool. Genealogical analysis of mtDNA haplotypes showed that a relatively high total frequency of Western Eurasian mtDNA haplogroups (20.4%) in the Mongoloid (according to anthropological type) Nganasan population is explained not only by the common ethnic origin with Entsy and Nentsy, but also by direct marriage migration from the Entsy population and indirect marriage migration, from the Nentsy population. This migration led to accumulation of Entsy-Nentsy maternal lineages in the genealogy of Avam Nganasans (38.9% of the total number). Of all mtDNA haplotypes, 28.6% were introduced to Avam Nganasans by female Entsy and Nentsy, whereas the total frequency of these haplotypes was 0.204. Genetic diversity of mitochondrial DNA haplotypes was 0.935.

Strong changes in lipoproteins and autoantibodies of blood serum of the Tundra Nency population as a result of environmental radiation on the territory they inhabit.

As a result of large-scale nuclear tests on the Novaya Zemlya test site (1955-62) the Tundra Nentsy population of Yamal-Nentsy autonomous region (YNAR) fell under the constant influence of incorporated radioactive isotopes (137Cs and 90Sr). Therefore, it is very important to analyze a possible spectrum of diseases of Tundra Nentsy population.

[Polymorphism of the serotonin system genes in some Finno-Ugric populations]. / Polimorfizm riada genov serotoninovoi sistemy v nekotorykh populiatsiiakh finno-ugorskikh narodov.

Polymorphic sites in the genes encoding monoamine oxidase A (MAO-A), serotonin transporter (hSERT) and 5-HT2A receptor were typed in Khant and Komi ethnic groups with the purpose of revealing possible interpopulation differences in genotype and allele frequencies. No statistically significant differences in the hSERT and 5-HT2A gene frequencies were detected. At the same time, the populations examined had statistically significantly different MAO-A genotype and allele frequencies. These results obtained indicate the prevalence of the site gain alleles of the EcoRV and Fnu4HI RFLP loci at the MAO-A gene in Komis and the of the corresponding site loss alleles in Khants.

Determination of HBsAg subtypes in Western Siberian part of Russia.

A set of monoclonal antibodies with specificity for hepatitis B surface antigen (HBsAg) was used for subtyping this antigen in sera from indigenous natives, blood donors, and drug users in Western Siberia with a modified commercial enzyme immunoassay kit for HBsAg detection. Three subtypes of HBsAg in a ratio of 36 (78%) ayw2:8 ayw3varB (18%):2 (4%) adw2 were found in 46 (100%) HBsAg-positive sera of different aboriginal populations of Western Siberia: the Tundra Nenets, Northern Khanty, Southern Altaians, and Kazakhs. Four subtypes of HBsAg in a ratio of 81 (57%) ayw2:58 (15 ayw3varA and 43 ayw3varB; 44%):2 (1%) adw2 were detected in 141 (100%) samples of blood donors from ten cities of Western Siberia. Three subtypes of HBsAg in a ratio of 34 ayw3:(both variants, 33 ayw3varA and 1 ayw3varB; 97.1%):1 (2.9%) ayw2 were found in blood of 35 injection drug users in Novosibirsk.

[Assessment of the status of biological health of the population of tundra Nentsy inhabiting northwestern Siberia from data on analysis of autoantibodies and lipoproteins from blood donors]. / Otsenka sostoianiia biologicheskogo zdorov'ia populiatsii tundrovykh nentsev Iamalo-Nenetskogo avtonomnogo okruga po dannym analiza autoantitel i lipoproteidov krovi donorov.

As a result of large-scale nuclear explosion on Novaya Zemlya test site (1955-62) the Tundra Nentsy population of Yamal-Nentsy autonomous region (YNAR) fell under constant influence of incorporated radioactive isotopes (137Cs and 90Sr). Therefore, it is very important to analyze a possible spectrum of diseases of Tundra Nentsy population. We have developed recently a new method for determination of concentrations of all main fraction and subfraction of lipoproteins (LP, 30 parameters) in human sera using small-angle X-ray scattering, and a general mathematical model to describe LP composition in human blood. The analysis of the 30 parameters characterizing fine spectrum of LPs in 374 YNAR natives showed that only approximately 10% of the donors are normal, while the indices for approximately 90% of the test subjects fall into the range of different pathologies (3-8% incidence in normal population, according to epidemiological studies). Moreover, we found that approximately 41% of European and approximately 56% of Tundra Nentsy have high level of autoantibodies to DNA and cardiolopine like the same for autoimmune diseases patients.

[Hepatitis B markers in southern Altai inhabitants of the village of Mendur-Sokkon (the Republic of Altai). HBsAg subtyping in hepatitis B virus isolates with monoclonal antibodies]. / Markery virusnogo gepatita B u iuzhnykh altaitsev pos. Mendur-Sokkon (respublika Altai). Subtipirovanie HBsAg izoliatov BGB s pomoshch'iu monoklonal'nykh antitel.

Blood samples taken from 231 native inhabitants of the village of Mendur-Sokkon located in the Republic of Altai (South-Western Siberia, Russia) were tested for the presence of virus hepatitis B (HBV) markers. 31 samples (13.4%) were found to contain HBsAg, 111 samples (48.05%) were found to contain total anti-HBc antibodies, 123 samples (53.24%) were found to contain anti-HBs antibodies and 15 blood samples (6.49%), anti-HBc antibodies without anti-HBs antibodies and HBsAg. The age-dependent distribution of the occurrence of HBV markers among the aboriginal population of the South Altal remained unchanged (69.9 +/- 7.9%) for the last 50 years. The vertical and horizontal routes of HBV transmissions were noted. The data obtained in this study are indicative of a highly endemic character of HBV of the territory of Mendur-Sokkon. HBsAg-positive blood samples were taken for HBsAg subtyping with the use of a panel of monoclonal antibodies. Two subtypes of HBsAg were detected: ayw1-2 and ayw3varB with the occurrence of 92.6% and 7.4%, i.e. distributed in the ratio 25/2.

Genetic polymorphisms of CYP1A1, GSTM1 and P53 genes in a unique Siberian population of Tundra Nentsi and its pharmacogenetic importance.

Complete data on the polymorphisms of CYP1A1, GSTM1 and p53 genes in Tundra Nentsi population, with known genealogical history are essential for the analysis of the "cancer susceptibility gene markers" distribution among different Oriental populations. The cytochrome P4501A subfamily is known to be responsible for the metabolic activation of aromatic compounds occurring in the products of gas mixture combustion, the main environmental pollutants in the north of western Siberia. Recently a close correlation was reported between development of some types of cancer and polymorphisms of human CYP1A1, GSTM1 and p53 genes. The frequency of the CYP1A1 Vol allele in the healthy part of the Tundra Nentsi population differs from those previously reported for Japanese and is more than 1.5 times higher. It is necessary to underline that homozygote Val genotype was present in 26% of non-healthy Tundra Nentsi, the incidence being 2.7-times higher in comparison with healthy population. GSTM1 gene deletion is present in 40% of Orientals and in 39% of Tundra Nentsi. Moreover, the share of individuals with null genotype among a group with chromosomal abnormalities and cancer was 63%, or 1.5 fold higher. Thus the prevalence of two polymorphic genes CYP1A1 and GSTM1 responsible for the biotransformation of polycyclic aromatic hydrocarbons was too high in the non-healthy group.

[The spectrum of human chromosomal aberrations detected by routine and differential (GTG) staining]. / Spektr khromosomnykh aberratsii cheloveka pri rutinnom i differentsial'nom (GTG) okrashivaniiakh.

As a result of sample cytogenetic studies of 23 persons living on the territory of Yamal-Nentsy Autonomous District and chronically exposed to the small doses of radiation the data on the frequency and spectrum of chromosome aberrations, detected by the routine and differential (GTG) staining were obtained. Comparative efficiency of these methods was determined. The absence of significant differences for the spectrum and frequencies of chromosome aberrations revealed by both methods was shown.

[Pedigree analysis in evaluating gene frequency in aboriginal populations of Siberia]. / Analiz rodoslovnykh pri otsenke chastot allelei v populiatsiiakh korennykh zhitelei Sibiri.

Procedure is described to estimate allele frequencies in indigenous populations of Siberia using phenotype data not only for "pure-blood" representatives of the ethnic groups examined, but also for the descendants of mixed marriages. Implementation of the method requires reconstruction of the data on relatives for the sample examined. Inclusion of the data on descendants of mixed marriages into the analysis increases the sample information content and decreases variance of the estimates obtained. The advantages of the method are illustrated using an example of Tundra Nentsy, for whom it was shown that variance of estimates at the analysis of the blood groups allele frequencies can be diminished approximately by a factor of 1.5.

BamHI-SacI RFLP and Gm analysis of the immunoglobulin IGHG genes in the Northern Selkups (west Siberia): new haplotypes with deletion, duplication and triplication.

Gm immunoglobulin allotypes have been studied in 1157 individuals of seven Northern Selkup populations, which account for 80% of the entire population of this west Siberian tribe. This study confirms that the northern Selkup populations are a Caucasoid-Mongoloid hybrid. Restriction fragment length polymorphism (RFLP) analysis of the IGHG genes using double BamHI-SacI digests, performed on 475 DNA samples, allowed us to describe nine new BamHI-SacI haplotypes (BS47 to BS55), eight of them being characterized by IGHG gene deletion or duplication: G1 (BS49) or G4 (BS55) deletion, G4 duplication (BS51), GP-G2-G4 multigene deletion (BS50), duplication (BS48, BS53 and BS54) or triplication (BS52). A new rare Gm haplotype 15,16*;1,17;23 has been found associated with BS52. The BS51 haplotype characterized by a duplicated G4 gene (additional 7.85 kb G4 band identifying a new G4*C5 allele) was always found associated with the Gm 5*;3;23 haplotype. A high RFLP diversity has been observed for the Northern-Mongoloid haplotype Gm 15,16*;1,17;.. which was found (1) with the BS27 haplotype characterized by a 3-exon hinge G3 gene, (2) with two different GP-G2-G4 multigene duplications, BS53 and BS54 haplotypes, which differ by the size of the duplicated G4 genes, and (3) with the BS55 haplotype characterized by a G4 deletion. In the Northern Selkups, haplotypes with duplicated genes were observed at a higher frequency (24%) than haplotypes with deleted genes (6%).

[Polymorphism of restriction sites of a control region of mitochondrial DNA in populations of Russian Old Believers and migrant slavic inhabitants of northern Siberia]. / Polimorfizm restriktsionnykh saitov kontrol'nogo raiona mitokhondrial'noi v populiatsiiakh Russkikh staroverov i prishlogo slavianskogo naseleniia severa Sibiri.

Restriction fragment length polymorphism (RFLP) was studied in restriction sites AvaII, BamHI, EcoRV, KpnI, HaeIII, and RsaI of the mitochondrial DNA (mtDNA) D-loop in populations of Old Believers (Starovery) and in Slavic migrants in northern Siberia. Frequencies of rare variants of all polymorphic sites studied were estimated. The results were compared with the published data on mtDNA polymorphism sites studied were estimated. The results were compared with the published data on mtDNA polymorphism in Russian populations of central and southern Russia and in other Eastern Slavic, Caucasoid, and Mongolian populations. Significance of interpopulation differences with respect to distributions of variants of polymorphism sites was estimated with the use of the chi2 test. The comparison did not reveal significant differences between any groups of Eastern Slavs, including Old Believers. However, they significantly differed from both Mongols and Europeans (P < 0.05). To date, stable estimates of the polymorphism level in most of the restriction sites have been obtained for the Russian population. Regarding the distribution of the restriction-site variants of mtDNA, Russians significantly differ from the total European population, as well as from Mongols. In the populations of Old Believers, the effect of isolation on the diversity of the mitochondrial genome was demonstrated.

[Characteristics of the gene pool of Russian Old Believers in Siberia based on polymorphism of blood groups, isoenzymes, and blood proteins]. / Osobennosti genofonda Russkikh staroverov Sibiri na osnove izucheniia polimorfizma grupp krovi, izofermentov i syvorotochnykh belkov.

The frequency distributions of A1A2B0, Rhesus, MNSs, P, Duffy, Kell, Hp, Tf, AcP, PGM1 alleles, and haplotypes were studied in Siberian populations of Old Believers (Burnyi village, Krasnoyarskii krai, and Isetskii raion, Tyumenskaya oblast) and in ethnic Russians from Tyumenskaya oblast. Features characteristic of the genetic structure of these groups were revealed. The Siberian groups of Russians were shown to be genetically removed from European Russian populations (Tverskaya and Vologodskaya oblasts). The Burnyi population of Old Believers was significantly removed from the other groups of Russians due to peculiarities in the sample.