Selective Heterozygous Advantage of Carriers of с.-23+1G>A Mutation in GJB2 Gene Causing Autosomal Recessive Deafness 1A.

We present the results of analysis of skin epidermis thickness in individuals with recessive mutation c.-23+1G>A in the GJB2 gene in comparison with individuals without this mutation living in Eastern Siberia (Yakut population). We examined 152 individuals with different genotypes by GJB2 gene mutation c.-23+1G>A. Homozygotes and heterozygotes by c.-23+1G>A have thicker epidermal layer (0.245 mm and 0.269 mm, respectively) in comparison with individuals without this mutation (0.193 mm) (p<0.05). The obtained data support the hypothesis about selective advantage of carriers of mutant GJB2 gene alleles and partly explain extremely high carrier frequency (10.3%) of c.-23+1G>A mutation in the GJB2 gene in Yakut population in Eastern Siberia.

[Analysis of mitochondrial 12S rRNA and tRNA(Ser(UCN)) genes in patients with nonsyndromic sensorineural hearing loss from various regions of Russia].

Mitochondrial DNA (mtDNA) mutations play an important role in etiology of hereditary hearing loss. In various regions of the world, patients suffer from nonsyndromic sensorineural hearing loss initiated by aminoglycoside antibiotics. Mutations that had been shown as pathogenetically important for hearing function disturbance were identified in mitochondrial 12S rRNA and tRNA(Ser(UCN)) genes while pathogenic role of several DNA sequences requires additional studies. This work presents the results of studying the spectrum of mutations and polymorphic variations in mtDNA genes 12S rRNA and tRNA(Ser(UGN)) in 410 patients with nonsyndromal sensoneural hearing impairment/loss from the Volga Ural region, St Petersburg, Yakutia, and Altai and in 520 individuals with normal hearing, which represent several ethnic groups (Russians, Tatars, Bashkirs, Yakuts, Altaians) residing in the Russian Federation. Pathogenetically significant mutation A1555G (12S rRNA) was found in two families (from Yakutia and St Peresburg) with hearing loss, probably caused by treatment with aminoglucosides, and in the population sample of Yakuts with a frequency of 0.83%. Further research is needed to confirm the role in hearing impairment of mutations 961insC, 961insC(n), 961delTinsC(n), T961G, T1095C (12S rRNA) and G7444A, A7445C (tRNA(Ser(UGN revealed in the patients. In addition, in the patients and the population groups, polymorphic mt DNA variants were detected, which are characteristic also of other Eurasian populations both in spectrum and frequency.

[Cochlear implantation in a child with congenital sensorineural deafness due to 35 DELG mutation in GJB2 (connexin 26) gene].

This paper reports the first case of cochlear implantation performed in this country in a child with congenital non-syndromic sensorineural loss of hearing having hereditary etiology and attributable to autosomal-recessive 35 delG mutation in locus DFNB1 (13q.11-q12) of GJB2 (connexin 26) gene.

Genetic polymorphism of CYP1A1 and CYP2D6 in the Tundra Nentsi population of Siberia.

The purpose of this study was to establish the frequencies of CYP1A1 and CYP2D6 polymorphic genotypes in the Tundra Nentsi population, which is a small indigenous northern people living in Siberia and belonging to the Northern Mongoloid race. The frequencies of Ile/Ile, Ile/Val, and Val/Val genotypes in the Tundra Nentsi population, as determined by means of the allele-specific PCR, were 50.8%, 39.2%, and 10%, respectively. Thus, the Val allele frequency in Tundra Nentsi appeared to be as high (29.5%) as in the Japanese population (25%) reported elsewhere. Those frequencies in the reference group of Siberian Caucasians were in good agreement with the data reported elsewhere for other Caucasians, although the Val allele frequency observed in Siberia inhabitants (5.7%) was somewhat higher than those frequencies obtained for other Caucasian populations. By means of PCR followed by specific-site digestion with MvaI endonuclease, we analysed the frequencies of CYP2D6B allele in the Tundra Nentsi population. The frequencies of 2D6wt/2D6wt and 2D6wt/B in the group of 120 Nentsi were 84.2% and 15.8%, respectively, with no subject possessing the 2D6B/2D6B genotype. The group of Siberian Caucasians represented those frequencies as 67.7%, 27.1%, and 5.2%, respectively. In total, the frequency of CYP2D6B allele in the Tundra Nentsi population was half that in Caucasians (8.3% vs. 19%). Taken together, our data indicate that the frequencies of CYP2D6B and Val allele of CYP1A1 in Tundra Nentsi population are different from those obtained for Caucasians. We also found similarities in the CYP1A1 mutation frequencies in the Tundra Nentsi and Japanese populations.

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.

[Negative correlation between heterozygosity and potential fertility in the Eveny population of Iakutiia]. / Otritsatel'naia sviaz' mezhdu geterozigotnost'iu i potentsial'noi plodovitost'iu v populiatsii évenov Iakutii.

The relationship between heterozygosity of 9 polymorphic loci and fertility of women surviving beyond the menopause was studied in the North-Siberian tribe Eveny. The number of pregnancies negatively correlated with the individual heterozygosity (r = -0.2913 + 0.1302, P less than 0.05). Drastic fertility reduction in heterozygous women was observed for G1M, ACP and HP loci.

[Genetic and ecologic study of aboriginal inhabitants of the Siberian northeast. III. Demographic structure of three modern population links of Yakutia]. / Geneticheskoe i ékologicheskoe izuchenie korennykh zhitelei severo-vostoka Sibiri. III. Demograficheskaia struktura trekh sovremennykh populiatsii zvenov iakutii.

Demographic data of genetic interest were studied in three separate populations of Tungus-speaking Evens. They are characterized as expanding populations, rather as a result of migration and admixture, than due to natural increase. The mean and variance of livebirths per female, whose reproduction was completed, were 7.23 and 13.07, respectively. The Crow's index of the opportunity for selection (It) and its components (Im and If) were found to be 0.62, 0.30 and 0.25, respectively. The values of Im and If appeared to be essentially lower than those previously found in other northern populations.

[Genetic and ecological study of aboriginal populations of northeastern Siberia. II. Polymorphic blood systems, immunoglobulin allotypes and other genetic markers in asian eskimos. Genetic structure of Bering sea eskimos]. / Geneticheskoe i ékologicheskoe izuchenie korennykh zhitelei severo-vostoka Sibiri. Soobshchenie II. Polimorfnye sistemy krovi, allotipy immunoglobulinov i drugie geneticheskie markery u aziatskikh éskimosov. Geneticheskaia struktura éskimosov Beringova moria.

Blood groups, immunoglobulin allotypes, serum proteins and red cell enzymes were tested in four populations of Asiatic Eskimos. 12 of 16 gene loci studied were found to be polymorphic. Analysis of covariance and variance matrices for gene frequencies of 8 Bering Sea populations revealed major aspects of regional genetic structure. Regression of average heterozygosity on genetic distance from centroid permitted us to interpret it in the light of counterbalancing action of systematic and non-systematic pressure. Analysis of R matrix containing gene frequencies for both Eskimo and Chukchi populations revealed two different clusters - more heterogeneous Eskimo cluster and less heterogeneous Chukchi cluster. Good fit was observed between regional genetic structure, history and geography.

[Population structure of the forest Nentsi. V. F-statistics, genetic distances and the average heterozygosity (compared to the Nganasani)]. / Populiatsionnaia struktura lesnykh nentsev. Soobshchenie V. F-statistika, geneticheskie distantsii i sredniaia geterozigotnost' (v sopostavlenii s nganasanami).

Aspects of population structure within two of the least disintegrated "anthropological isolates" in north-western (forest Nentsi) and north-central (Nganasani) Siberia were analysed on the basis of 14 polymorphic loci. The mean FIS values were found to be 0.008 in the forest Nentsi and -0.038 in the Nganasani. The negative FIS in the latter may be due to avoidance of close inbreeding. This is not the case with the Forest Nentsi who prefer matings of the uncle-niece and first cousin's type. The mean RST(FST) values of 0.026 for the forest Nentsi and 0.009 for less heterogeneous Nganasani fall within the range of values found in subdivided human groups with a similar pattern of material culture and economy. Analysis of covariance and variance matrices containing gene frequencies for seven forest Nentsi and three Nganasani subdivisions indicate that the population structure of both groups is the product of the counterbalancing action of genetic drift and migration. Pairwise genetic and geographic distance matrices between subpopulations within both groups are highly correlated, allowing us to ascribe more than 90 percent of variation among subdivisions of the Nganasani and almost 70 percent in the forest Nentsi to the effects of geographic barriers, namely distance. Mean locus heterozygosity was found to be higher in the forest Nentsi (0.332) than in the Nganasani (0.286) reflecting pronounced difference in their histories.

[Genetic-demographic analysis of the population of native inhabitants of the Samburg tundra]. / Genetiko-demograficheskii analiz populiatsii korennykh zhitelei Samburgskoi tundry.

Genetic-demographic parameters (Tundra Nentsi, Forest Nentsi, and Komi) of the population of native inhabitants of the Samburg Tundra (population size, age and sex structure, sex ratio) are presented. The size of the portion of the population of reproductive age (35.5% of the total), family size (3.04), and the predominance of the portion of the population under reproductive allow us to classify this population as growing. Results of analysis of marriage structure, mixing, and migration processes in the group of Tundra Nentsi are presented. It is shown, that the gene contribution of Tundra Nentsi themselves into the population is 74%. The index of endogamy is 42.4%. The inbreeding coefficient in the population is 0.003. It is demonstrated that the average number and variance of births for Tundra Nentsi women who have passed their reproductive years are 7.55 and 11.07, respectively. Crow's index of total selection (Itot) and its components (Im, I(f)) were 0.75, 0.47, and 0.19, respectively.

[The gene pool of native inhabitants of the Samburg tundra]. / Genofond korennykh zhitelei Samburgskoi tundry.

This study continues a series of investigations of the gene pool of native Siberian ethnic groups. In a population of Tundra Nentsi (Northern Samoyeds) and a group of Komi-Zyryans (Finno-Ugrian) (Samburg settlement, Tyumenskaya oblast, Yamalo-Nenetskii Autonomous okrug), gene markers of the following genetic systems were studied: blood groups (ABO, MNSs, Rhesus, Kell, Duffy, and P), erythrocyte acid phosphatase (AcP), phosphoglucomutase 1 (PGM 1), haptoglobin (Hp), and transferrin (Tf). The population of Samburg Tundra Nentsi was shown to have a close genetic relationship with the "core" of the Forest Nentsi population. In Northern Samoyeds, three carriers of the rare allele K (blood group Kell) were found for the first time. It is suggested that this allele was transferred into the population of Tundra Nentsi from Komi. Samburg Tundra Nentsi are found to have the maximum frequency of the allele PGM 1 (Posphoglucomutase 1) among aboriginal populations of northern Asia. Analysis of original data and the literature revealed a significant genetic distance between the Komi and Northern Samoyed populations. It was shown that Samburg Komi occupy an intermediate position between the clusters of Nenets populations and Finno-Ugrians (Komi) living in Komi Republic.

[A genetic-demographic study of the South Altaian population of the Mendur-Sokkon village (Altai Republic)]. / Genetiko-demograficheskii analiz populiatsii iuzhnykh altatsev pos. Mendur-Sokkon (Respublika Altai).

The main demographic parameters of the population of South Altaians from the Mendur-Sokkon village, Ust'-Kanskii raion, Altai Republic, were studied. This population was classified as a growing one because the population's reproductive size was large (37%), the prereproductive part constituted the majority of the population (52%), and the average number of surviving children per spouse was 2.6. The population studied began to mix with other ethnic groups (mostly Russians and Kazakhs) only recently; therefore, the proportion of interethnic hybrids was only 5%. The tribal structure of the Mendur-Sokkon population was typical of all South Altaians and characterized by stringent observance of exogamous regulations. An ethnically pure core was preserved in the population. The degree of endogamy was 0.36; however, the population mostly exchanged marriage migrants within the Ust'-Kanskii raion. A study of postreproductive females revealed that the average number of surviving children and pregnancies per female was 4.9 and 5.3, respectively; these values were lower than those in indigenous northern Siberian populations studied earlier. The high value of the Crow's index of total selection (Itot = 0.63) was mainly accounted for by the differential fecundity component, I(f) = 0.40, whereas the prereproductive mortality component (Im = 0.16) was considerably lower than in northern Siberian populations (Nganasans, Forest and Tundra Nentsi, Evens, Asian Eskimos, etc.) and closer to the values characteristic of urban human populations.

[Genetic and ecological study of aboriginal inhabitants of the Siberian northeast. IV. Genotype and genetic structure of three modern populations of Yakutia]. / Geneticheskoe i ékologichekoe izuchenie korennykh zhitelei severo- vostoka Siberi. IV. Genotip i geneticheskaia struktura trekh sovremennykh populiatsii zvenov iakutii.

Three separate and reproductively isolated populations living at present in boreal forest and tundra area in Eastern Siberia were studied. Blood groups (AB0, MNSs, Rhesus, Duffy, P. Diego), immunoglobulin allotypes--G1m (z, a, x, f), G3m (b, b0, b1, b3, s, t), Hp, Tf, PGM1, AcP, 6-PGD were tested in blood samples obtained from total 570 individuals. Analysis of covariance and variance matrices containing gene frequencies of the Nganasans, Reindeer Chukchi, the Yugaghir and the Evens has revealed major aspects of regional genetic structure which is in good accordance with regional history and geography.

[Polymorphism of CYP1A1 and CYP2D6 genes in tundra nentses and European populations of western Siberia]. / Izuchenie polimorfizma genov CYP1A1 i CYP2D6 v populiatsiiakh tundrovykh nentsev i evropeoidov zapadnoi Sibiri.

Data on the first examination of the CYP1A1 and CYP2D6 genes' polymorphism in the populations of Tundra Nentsis (Yamalo-Nenetskii Autonomous District) and migrant population of Western Siberia (Novosibirsk oblast and Altaiskii krai) are presented. The frequency of the 2D6*4 mutant allele in Tundra Nentsis, characterized by a two-component Caucasoid and Mongoloid origin, was shown to be intermediate in Caucasoid and Mongoloid populations. The frequencies of the 2D6*4 and 1A1Val* mutant alleles across migrant inhabitants of Western Siberia (Caucasoid populations) were similar to that reported for the Caucasoid populations overall. Distribution of the CYP1A1 genotypes (Ile/Ile, Ile/Val*, and Val*/Val*) in Tundra Nentsis was similar to that found in Mongoloid groups. However, the frequency of the 1A1Val* allele in Tundra Nentsis was 1.5 times higher than that in the Southern Mongoloid populations (Chinese, Koreans, and Japanese).

[Genetic analysis of the South Altaian population of the Mendur-Sokkon village, Altai Republic]. / Geneticheskii analiz struktury populiatsii iuzhnykh altaitsev pos. Mendur-Sokkon (Respublika Altai).

This study was a continuation of complex research on the gene pool of indigenous Siberian populations conducted at the Institute of Cytology and Genetics, Siberian Division, Russian Academy of Sciences. In the population of South Altaians from the Mendur-Sokkon village, Ust'-Kanskii raion, Altai Republic, polymorphism for the following genetic markers was studied: blood groups ABO, MNSs, Rhesus, Kell, Duffy, and P; erythrocyte acid phosphatase (AcP); phosphoglucomutase 1 (PGM1); haptoglobin (Hp); and transferrin (Tf). The genetic position of South Altaians relative to the populations of the European part of Russia, Siberia, and the Urals was estimated. It was demonstrated that the gene pool of the South Altaian population of Mendur-Sokkon possessed both Caucasoid and Mongoloid genetic characteristics, with the latter prevailing. Genetically, this population is most closely related to Mongols and Nentsis. The genetic distance between South and North Altaians was large; this agreed with earlier genetic data and confirmed anthropological and ethnographic evidence indicating that these two groups had different backgrounds and were at different stages of ethnogenesis.

[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.

[Frequency of encountering markers of viral hepatitis A, B, and C in the aboriginal inhabitants of the northwest region of Siberia]. / Chastota vstrechaemosti markerov virusnykh gepatitiv A, B, C u korennogo naseleniia severa zapadnoi sibiri.

A minor population of Nenets living near the village of Samburg in the Purov District, Tyumen region was screened for serological markers of virus hepatitides A, B, and C (VHA, HVB, and HVC, respectively). Commercial kits manufactured by VectorBest JSC, Russia, were used. All the tested sera contained antiHVA IgG; IgM antibodies to VHA were detected in none of the tested sera, anti-HVC IgG were found in 1 (0.93%) serum, antiHBc IgG in 11 (10.2%), and HBsAg was detected in 2 (1.85%) serum samples. The sera positive by antiHBc IgG and HBsAg were tested for DNA by the polymerase chain reaction. HVB DNA was found in two HBsAg-positive sera with the HBsAg subtype determined as "non ad".

[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.

Haplotype Diversity and Reconstruction of Ancestral Haplotype Associated with the c.35delG Mutation in the GJB2 (Cx26) Gene among the Volgo-Ural Populations of Russia.

The mutations in theGJB2(Сх26) gene make the biggest contribution to hereditary hearing loss. The spectrum and prevalence of theGJB2gene mutations are specific to populations of different ethnic origins. For severalGJB2 mutations, their origin from appropriate ancestral founder chromosome was shown, approximate estimations of "age" obtained, and presumable regions of their origin outlined. This work presents the results of the carrier frequencies' analysis of the major (for European countries) mutation c.35delG (GJB2gene) among 2,308 healthy individuals from 18 Eurasian populations of different ethnic origins: Bashkirs, Tatars, Chuvashs, Udmurts, Komi-Permyaks, Mordvins, and Russians (the Volga-Ural region of Russia); Byelorussians, Ukrainians (Eastern Europe); Abkhazians, Avars, Cherkessians, and Ingushes (Caucasus); Kazakhs, Uzbeks, Uighurs (Central Asia); and Yakuts, and Altaians (Siberia). The prevalence of the c.35delG mutation in the studied ethnic groups may act as additional evidence for a prospective role of the founder effect in the origin and distribution of this mutation in various populations worldwide. The haplotype analysis of chromosomes with the c.35delG mutation in patients with nonsyndromic sensorineural hearing loss (N=112) and in population samples (N =358) permitted the reconstruction of an ancestral haplotype with this mutation, established the common origin of the majority of the studied mutant chromosomes, and provided the estimated time of the c.35delG mutation carriers expansion (11,800 years) on the territory of the Volga-Ural region.

Genetic study of the Evens, an ancient human population of eastern Siberia.

Three territorial subgroups of reindeer breeders, fishermen, and fur hunters living under conditions of partial isolation in remote parts of the Yakut ASSR, have been investigated with respect to polymorphic genetic systems. Analysis of covariance matrices containing allele frequencies in an array of 12 loci for a large sample of Evens, Nganasans, and reindeer Chukchi indicates that the genetic relationships support known phylogenetic, linguistic, and historical events.