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The analysis of plutonium production factors has been carried out by using two methodical approaches: assessment of chromosomal aberrations level in routine and G-banded metaphases and molecular-cytogenetic investigation of aneugenic/clastogenic damages in cytokinesis-block binuclear lymphocytes by FISH with centromere specific DNA probes. The obtaining data point out for the first time about both aneugenic and clastogenic influences of incorporated 239Pu with activity range from 0.37 to 6.95 kBq. Correlation analysis of chromosome aberrations with cytome abnormalities allowed finding significant connection between number parameters of metaphase and interphase approaches. The results of this study support the suggestion that aberrant chromosomes are involved preferable in aneugenic events. The FISH technique in binucleated cytokinesis-blocked lymphocytes allows extending of detecting spectrum of chromosome damages and glance of aneugenic mechanisms. Correlations between metaphase and interphase-FISH results point out a high sensitivity of FISH cytome assay, which could be used as an independent test for detection both clastogenic and aneugenic environment influences.

Association of deletion polymorphism in GSTT1 and GSTM1 genes and polymorphic variant A313G of GSTP1 gene with cirrhosis diseases and 4-year survival rate for the Tomsk region (West Siberia) patients were tested. Homozygous deletion of GSTM1 gene (null genotype) was a protective factor for alcoholic and mixed (HCV, HBV and alcohol) liver cirrhosis development. The patients from the joint group (all etiology forms) as well as having alcoholic and mixed cirrhosis had lower frequency of GSTM1 null genotype (39.2, 39.0, and 34.2%, respectively) in comparison with the control group (64.6%). The GSTM1 null genotype and GSTP1 gene A313G polymorphic variant correlated with the patients' survival rate. The patients survived in comparison with the dead had higher frequency of a GSTM1 null genotype (46.6 vs. 30.2%) and GSTP1 AA genotype (63.1 vs. 40.5%), and lower frequency of GSTP1 AG (A313G) genotype (31.1 vs. 51.2%). A survival rate was 2.5 times higher for patients having GSTP1 AA genotype in comparison with the GG and AG genotype carriers and 2 times higher for patients having GSTM1 null genotype than the gene carriers. A 4-year fatal case probability was 2.3 times higher among the patients having heterozygous AG GSTP1 genotype in comparison with homozygous AA and GG genotype carriers.

Leprosy is an infectious disease caused by the obligate intracellular pathogen Mycobacterium leprae and remains endemic in many parts of the world. Despite several major studies on susceptibility to leprosy, few genomic loci have been replicated independently. We have conducted an association analysis of more than 1,500 individuals from different case-control and family studies, and observed consistent associations between genetic variants in both TLR1 and the HLA-DRB1/DQA1 regions with susceptibility to leprosy (TLR1 I602S, case-control P = 5.7×10−8, OR = 0.31, 95% CI = 0.20–0.48, and HLA-DQA1 rs1071630, case-control P = 4.9×10−14, OR = 0.43, 95% CI = 0.35–0.54). The effect sizes of these associations suggest that TLR1 and HLA-DRB1/DQA1 are major susceptibility genes in susceptibility to leprosy. Further population differentiation analysis shows that the TLR1 locus is extremely differentiated. The protective dysfunctional 602S allele is rare in Africa but expands to become the dominant allele among individuals of European descent. This supports the hypothesis that this locus may be under selection from mycobacteria or other pathogens that are recognized by TLR1 and its co-receptors. These observations provide insight into the long standing host-pathogen relationship between human and mycobacteria and highlight the key role of the TLR pathway in infectious diseases., Author Summary Mycobacterium leprae is an obligate intracellular pathogen that causes leprosy, a disease that shares a long history with the human population but which remains endemic in many parts of the world. Despite the fact that the genome of M. leprae has been sequenced, our understanding of its pathogenesis and interaction with the human host is limited, in part due to the inability to culture the bacterium in vitro. In this gene-centric microarray study, we have genotyped SNPs in over 2,000 genes and identified TLR1 and HLA-DRB1/DQA1 as major leprosy susceptibility genes. Studying the geographical distribution of this hypo-functional TLR1 variant demonstrated extreme population differentiation at this locus. These results suggest that leprosy may have contributed to the evolution of this genomic region, and provide insight into the long history of the host-pathogen relationship between humans and M. leprae.

The authors studied distribution of biochemical markers for HP, GC, EsD, AcP genes, polymorphism of GSTT1 (GST-theta 1), GSTM1 (GST-mu 1), locus WNTR of NOS3 gene (alleles A/B) in chronic dust bronchitis patients and in apparently healthy individuals. Genotypes EsD 1-2 and AcP bb individuals were proved to be most prone to the disease. Endogenous resistent factors for chronic dust bronchitis are genotypes GC 1-1, EsD 1-1, AcP bc.

Study is devoted to "genes for mitochondria"--genes of mitochondrial genome and mitochondrial DNA polymerase gamma gene (POLG1). We compared frequencies of polymorphisms in mitochondrial DNA and in POLG1 between healthy individuals and patients with arterial hypertension, as well as between patients with and without left ventricular hypertrophy. We did not discover significant differences of distribution of C allele of MspI-polymorphism in POLG1 in studied group. We have shown higher prevalence of mitochondrial haplogroup H of mtDNA in patients without left ventricle hypertrophy (OR = 0.42; 95% CI 0.17-0.98; p = 0.043), while compared with patients having this complication. Haplogroup T was more frequently detected in patients with left ventricle hypertrophy (OR = 6.16; 95% CI 1.17-9.74; p = 0.018). This result suggest implication of mitochondrial DNA in hypertension-induced left venticular hypertrophy.

Allele frequencies for 15 STRs (CSF1PO, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11, FGA, Penta D, Penta E, THO1, TPOX, and vWA) in the PowerPlex 16 System (Promega Corporation) were assessed in 386 individuals from five Russian urban populations. No significant between-population differences in frequencies and molecular variance of 15 microsatellites were revealed. For all 15 loci, the combined matching probability is 3.19 x 10(-18) and the power of exclusion is 99.99989%.

Immune mechanisms play a pivotal role in the development of multiple sclerosis (MS). Vitamin D is an important biological immunoregulator acting through receptors of immunocompetent cells. Genotype and haplotype frequencies for VDR polymorphisms in a case-control study of MS have been investigated. Results have shown an association of the VDR T/t variant with the disease (p0.05). This marker was also associated with the number of eosinophils in MS patients (p0.05). Genetic variants B/b and F/f were associated with ESR and IgG levels and a number of CD16+ cells (p0.05). An analysis of VDR haplotype frequencies and an association analysis between MS and VDR haplotypes have also been carried out. We demonstrated that carriers of the Bft haplotype were at higher risk for MS comparing to those with the btT variant. The data obtained suggest that the VDR t allele and the Bft haplotype could increase susceptibility to MS and have the influence on clinical manifestations of the disease.

The gene pool structure of Teleuts was examined and Y-chromosomal haplogroups composition and frequencies were determined. In the gene pool of Teleuts, five haplogroups, C3xM77, N3a, R1b*, R1b3, and R1a1, were identified. Evaluation of the genetic differentiation of the samples examined using analysis of molecular variance (AMOVA) with two marker systems (frequencies of haplogroups and Y-chromosomal microsatellite haplotypes) showed that Bachat Teleuts were equally distant from Southern and Northern Altaians. In Siberian populations, the frequencies and molecular phylogeny of the YSTR haplotypes within Y-chromosomal haplogroup R1a1 were examined. It was demonstrated that Teleuts and Southern Altaians had very close and overlapping profiles of R1a1 haplotypes. Population cluster analysis of the R1a1 YSTR haplotypes showed that Teleuts and Southern Altaians were closer to one another than to all remaining Siberian ethnic groups. Phylogenetic analysis of N3a haplotypes suggested specificity of Teleut haplotypes and their closeness to those of Tomsk Tatars. Teleuts were characterized by extremely high frequency of haplogroup R1b*, distinguished for highly specific profile of YSTR haplotypes and high haplotype diversity. The results of the comparative analysis suggested that the gene pool of Bachat Teleuts was formed on the basis of at least two heterogeneous genetic components, probably associated with ancient Turkic and Samoyedic ethnic components.

The Gagauzes are a small Turkish-speaking ethnic group living mostly in southern Moldova and north- eastern Bulgaria. The origin of the Gagauzes is obscure. They may be descendants of the Turkic nomadic tribes from the Eurasian steppes, as suggested by the ''Steppe'' hypothesis, or have a complex Anatolian-steppe origin, as postu- lated by the ''Seljuk'' or ''Anatolian'' hypothesis. To distinguish these hypotheses, a sample of 89 Y-chromosomes repre- senting two Gagauz populations from the Republic of Moldova was analyzed for 28 binary and seven STR polymor- phisms. In the gene pool of the Gagauzes a total of 15 Y-haplogroups were identified, the most common being I-P37 (20.2%), R-M17 (19.1%), G-M201 (13.5%), R-M269 (12.4%), and E-M78 (11.1%). The present Gagauz populations were compared with other Balkan, Anatolian, and Central Asian populations by means of genetic distances, nonmetric multi- dimentional scaling and analyses of molecular variance. The analyses showed that Gagauzes belong to the Balkan pop- ulations, suggesting that the Gagauz language represents a case of language replacement in southeastern Europe. Interestingly, the detailed study of microsatellite haplotypes revealed some sharing between the Gagauz and Turkish lineages, providing some support of the hypothesis of the ''Seljuk origin'' of the Gagauzes. The faster evolving micro- satellite loci showed that the two Gagauz samples investigated do not represent a homogeneous group. This finding matches the cultural and linguistic heterogeneity of the Gagauzes well, suggesting a crucial role of social factors in shaping the Gagauz Y-chromosome pool and possibly also of effects of genetic drift. Am. J. Hum. Biol. 00:000-000, 2009. ' 2008 Wiley-Liss, Inc. The Gagauzes are a small Turkish-speaking ethnic group living mostly in southern Bessarabia (Moldova Republic, southwestern Ukraine) and southern Dobruja (northeastern Bulgaria, southeastern Romania). The Gagauzes speak the Oghuz version of the Turkic lan- guages, which also includes the Azeri, Turkish, and Turk- meni languages. The Gagauz language is particularly close to the Balkan Turkish dialects spoken in Greece, northeastern Bulgaria, and in the Kumanovo and Bitola areas of Macedonia. The Balkan Turkic languages, includ

Several forms of pathologies, referred to as Yakut hereditary diseases, have been distinguished on the basis of the results of genetic epidemiological studies of Mendelian diseases in the population of the Republic of Sakha (Yakutia): spinocerebellar ataxia type I, myotonic dystrophy, oculopharyngeal muscular dystrophy, hereditary enzymopenic methemoglobinemia, and 3-M syndrome. These diseases are characterized by a high prevalence among Yakuts as compared to their global incidence in the. Data on the molecular nature of mutations in genes responsible for these hereditary diseases are presented.

The ADH1B Arg47His polymorphism has been convincingly associated with alcoholism in numerous studies of several populations in Asia and Europe. In a review of literature from the past 30 years, we have identified studies that report allele frequencies of this polymorphism for 131 population samples from many different parts of the world. The derived ADH1B*47His allele reaches high frequencies only in western and eastern Asia. To pursue this pattern, we report here new frequency data for 37 populations. Most of our data are from South and Southeast Asia and confirm that there is a low frequency of this allele in the region between eastern and western Asia. The distribution suggests that the derived allele increased in frequency independently in western and eastern Asia after humans had spread across Eurasia.

Gene pool structure of Sakha Republic (Yakutia) native population has been studied: we defined composition and frequencies of Y-chromosome haplogroups for Yakuts. Six haplogroups: C3 x M77, C3c, N*, N2, N3a and R1a1 have been revealed in Yakut gene pool. A greater part of Y-chromosome in Yakut population belongs to N3a haplogroup (89%). All investigated Yakut population samples have low values of gene diversity, calculated based on haplogroup frequencies. Gene differentiation of the investigated samples estimated using the analysis of molecular variance (AMOVA) by two marker systems (haplogroup frequencies and microsatellite haplotypes of Y-chromosome) revealed a portion of interpopulation differences amounting to 0.24 and 2.85%, respectively. Frequencies and molecular phylogeny of YSTR-haplotypes were revealed for N3a haplogroup of Y-chromosome. Altogether forty haplotypes were found in Yakuts. Evenks and Yakuts are characterized by overlapping and very specific spectrum of N3a haplotypes, which is not typical for other Siberian ethnic groups. Cluster analysis of populations by N3a YSTR-haplotypes shows Yakut isolation from Turkic-speaking populations in the South Siberia. Genetic diversity generation time for a specific spectrum of Yakut haplotypes was estimated as 4.45 +/- 1.96 thousand years. As opposed to the data on mtDNA, the obtained results give an evidence for significant contribution of a local palaeolithic component into Y-chromosomal Yakut gene pool. Ethnogenetic reconstruction of the present picture of genetic diversity in N3a haplogroup in the territory of Siberia is under consideration.

The clinical-genealogic and molecular-genetic investigation of oculopharyngeal muscular dystrophy (OPMD) in the Republic of Sakha (Yakutia) was performed. It was investigated 33 unrelated Yakut families with 38 patients and 2 russian families with 2 patients and 59 their healthy relatives as well. The high clinical polymorphism of disease was found in patients with OPMD. The mutation in exon 1 of the PABPN1 gene resulting in the expansion of GCG-repeats up to 10 is revealed. Using direct sequencing of the PABPN1 gene in 17 families (16 Yakut, 1 Russian), we identified a type of this mutation as an insertion of 4 GCG-repeats. Frequency of OPMD in the Yakut population is 1:11 680 that is 10-20 times higher comparing to european populations. This is a first report on the patients with OPMD from the Republic of Sakha with diagnosis confirmed by molecular-genetic analysis.

The relationships between serum lipids, blood pressures, anthropometric traits, age, and ischemic changes of the electrocardiogram (ECG) in the North Khanty population were studied. To this end, eight morphophysiological variables--presumably risk factors for ischemic heart disease--have been subjected to a principal components analysis. Two principal components were extracted. The first revealed age dependency of the traits not associated with ischemic changes of myocardium in both sexes. A comparative analysis of the second component has shown that the chosen traits correlated with ischemic heart disease in males but not in females. Interpretation is given of the components obtained.

To date, a wide range of assisted reproductive technologies is available for patients with impaired fertility. In general, the current methods of reproductive medicine are considered safe and do not significantly increase the frequency of birth of children with diseases or congenital malformations. However, the evidence has been accumulating in literature on higher risk of genomic imprinting diseases (Beckwith-Wiedemann and Angelman syndromes) as a result of using assisted reproductive technologies. In most cases examined, the appearance of these syndromes was explained by defective methylation status of imprinted genes. It has been suggested that manipulations with gametes and embryos during the period of total epigenetic modification of their genomes may act as potential risk factors of assisted reproductive technologies. Moreover, overcoming many natural reproductive barriers may contribute to the development of some pathological phenotypes. The review summarizes current views on epigenetic risk factors associated with assisted reproductive technologies.

Y-chromosomal haplogroups composition and frequencies were analyzed in Northern and Southern Altaians. In the gene pool of Altaians a total of 18 Y-chromosomal haplogroups were identified, including C3xM77, C3c, DxM15, E, F*, J2, I1a, I1b, K*, N*, N2, N3a, O3, P*, Q*, R1*, R1a1, and R1b3. The structured nature of the Altaic gene pool is determined by the presence of the Caucasoid and Mongoloid components, along with the ancient genetic substratum, marked by the corresponding Western and Eastern Eurasian haplogroups. Haplogroup R1a1 prevailed in both ethnic groups, accounting for about 53 and 38% of paternal lineages in Southern and Northern Altaians, respectively. This haplogroup is thought to be associated with the eastward expansion of early Indo-Europeans, and marks Caucasoid element in the gene pools of South Siberian populations. Similarly to haplogroup K*, the second frequent haplogroup Q* represents paleo-Asiatic marker, probably associated with the Ket and Samoyedic contributions to the Altaic gene pool. The presence of lineages N2 and N3a can be explained as the contribution of Finno--Ugric tribes, assimilated by ancient Turks. The presence of haplogroups C3xM77, C3c, N*, and 03 reflects the contribution of Central Asian Mongoloid groups. These haplogroups, probably, mark the latest movements of Mongolian migrants from the territory of contemporary Tuva and Mongolia. The data of factor analysis, variance analysis, cluster analysis, and phylogenetic analysis point to substantial genetic differentiation of Northern and Southern Altaians. The differences between Northern and Southern Altaians in the haplogroup composition, as well as in the internal haplotype structure were demonstrated.

The allele and genotype distribution of two alcohol dehydrogenase genes ADH1B (exon 3 polymorphism A/G (47His)), ADH7 (intron 5 polymorphism G/C) and cytochrome P450 2E1 gene (CYP2E1; 5'-flanking region G/C and intron 6 T/A polymorphisms) were examined in Russian (Tomsk, n = 125) healthy population and in coronary atherosclerosis patients (CA, n = 92). The genotype frequencies followed the Hardy-Weinberg equilibrium and the alleles were in linkage equilibrium or gametic equilibrium in the control sample. Only two CYP2E1 gene polymorphisms were in linkage disequilibrium. The frequencies of the derived alleles at ADH1B (*G (+MslI) allele), CYP2E1 (**C2 (+PstI) allele) and CYP2E1 (*C (-Dra I)2 allele) were 8.48 +/- 1.86%; 1.20 +/- 0.69% and 10.00 +/- 1.90%, respectively. The 2ADH7 gene polymorphism showed a high level of heterozygosity; the frequency of the ADH7*C (-Sty I) allele was 44.58 +/- 3.21%. A significantly higher frequency of CYP2E1 (*C2 (+Pst I)) allele has been revealed in the CA group (P = 0.043; OR = 4.23; 95% CI 1.03-20.01). The tendency to significant effect of A1A2 genotype in ADH1B Msl 1 polymorphism was observed for systolic blood pressure in the control group (P = 0.068). The statistically significant two-way interaction effects of ADH7 StyI and CYP2E1 DraI on diastolic blood pressure (P = 0.029) and on the serum high density lipoprotein level (P = 0,042) were also revealed. Association of A1A2 genotype in ADHIB Msl I polymorphism with reduced amount in a serum of a very low density lipoprotein level (P = 0.045) have also been shown. This may result from multifunctional activity of alcohol metabolizing enzymes and their involvement in many metabolic and free radical reactions in the body.

Multiple sclerosis (MS) is a multifactorial and polygenic disorder of the central nervous system, its development being under strong influence of T-helpers type I which produce anti-inflammation cytokines. Interleukin 12 (IL12) plays a key role in such polarization of the immune response. Genotyping for polymorphism of the IL12B gene in the 3'-untranslated region, coding for the p40(IL12B) subunit, has been carried out in 62 patients with MS and 129 healthy controls. The C/C genotype frequency was twice higher in patients as compared to the controls (33.9% and 17.4%, respectively). The allele C in patients was associated with shorter duration of the first remission (p = 0.028) which was 1.79 +/- 0.28 in those with the C allele and 3.27 +/- 0.68 in other patients. Mean rate of relapses per year was also higher (p = 0.079) in patients with the C allele (0.96 +/- 0.11) comparing with the A allele (0.72 +/- 0.11). During the treatment with copaxone, a trend towards increasing of the time before the first relapse was observed in patients with the C allele. An analysis of immunologic indices revealed that they changed in opposite directions depending on the gene variant. The C-allele is suggested to have relation both to liability to MS and to its pathogenesis.

In most cases, the cause of embryo and fetus death remains unclear although the multifactorial causes are suspected. The polymorphic C677T and A1298C variants of the MTHFR gene are associated with an increase in the level of homocysteine, which is risk factor of pregnancy loss. The subject of this study is analysis of genotypes and haplotypes of C677T and A1298C polymorphic variants of MTHFR genes in the groups of spontaneous abortions with the normal karyotype and newborns in the Tomsk population. Between these groups, no statistically significant differences were determined in the allele, genotype, and haplotype distributions of C677T and A1298C polymorphisms of the MTHFR gene. The haplotype frequencies of C677T and A1298C polymorphic variants of MTHFR gene in the Russian populations, which proved to be similar to those in most European populations, are presented.

The compositions and frequencies of Y-chromosome haplogroups identified by genotyping 23 biallelic loci of its nonrecombining region (YAP, 92R7, DYF155S2, 12f2, Tat, M9, M17, M25, M89, M124, M130, M170, M172, M174, M173, M178, M201, M207, M242, M269, P21, P25, and P37) have been determined in a sample of 68 Belarussians. Eleven haplogroups have been found in the Belarussian gene pool (E, F*, G, I, I1b, J2, N3a*, Q*, R1*, R1a1, and R1b3). Haplogroup R1a1 is the most frequent; it includes 46% of all Y chromosomes in this sample. The frequencies of haplogroups I1b and I are 17.6 and 7.3%, respectively. Haplogroup N3a* is the next in frequency. The frequencies of haplogroups E, J2, and R1b3 are 4.4% each; that of R1* is 3%; and those of F*, G, and Q* are 1.5% each.

The sex, age, tribal, and surname compositions of the populations of three villages of Altai Republic, Kulada (Ongudaisk raion), Beshpeltir (Chemal raion), and Kurmach-Baigol (Turochak raion) have been studied. Altaian populations are characterized by a high proportion of persons under 20 years of age (35.3-46.1%); however, there is a tendency towards a narrow base of the sex-age pyramid. The sex ratios in the total populations and in individual age groups are unfavorable. The rural populations studied differ in the spectrum and pattern of surname accumulation. The Kurmach-Baigol population (which consists of Northern Altaians) considerably differs from the Beshpeltir and Kulada populations (which are mostly Southern Altaian) with respect to the calculated parameters characterizing the population structure (random isonymy, migration index, the parameter of tribe diversity, entropy, and the redundancy of surname distribution). Isonymy coefficients of relationship between individual populations have been calculated from the data on tribes (surnames). These coefficients for pairs of populations are the following: for the Beshpeltir and Kulada populations, 0.3035938 (0.0000443 and 0.0000378 for the Altaian and total populations, respectively); for the Beshpeltir and Kurmach-Baigol populations, 0.0026788 (0.0000172 and 0.0000121 for the Altaian and total populations, respectively); and for the Kulada and Kurmach-Baigol populations, 0.0054811 (no common surnames have been found).

The role of A2350G polymorphism in exon 17 of the ACE gene and A1166C - in 3'-UTR of the AGTR1 in the pathogenesis of left ventricular hypertrophy was studied in patients with essential hypertension (EH) and arterial hypertension combined with diabetes mellitus type 2 (AH + DM2). Patients with EH and AH + DM2 did not differ from the control sample of healthy individuals by allele or genotype frequencies. However, an association of both polymorphisms with LVH was detected in EH patients. The frequency of 1166C allele was higher in patients with LVH (33.6% vs 20.7% without LVH). A1166C polymorphism determined the magnitude of left ventricular mass index (LVMI) in EH patients as well (p = 0.007). 2350G allele frequency of the ACE gene was in 1.5, and GG genotype--in 3.5-fold higher in EH patients with LVH, as compared without LVH. LVMI was significantly higher in patients with GG genotype as compared with heterozygotes and AA homozygotes (p = 0.002). Thus the presence of 1166C allele of AGTR1 and 2350G allele of ACE can be considered as predisposing factors for LVH development in EH. In contrast, association of studied polymorphisms with presence or LVH degree was not detected in patients with arterial hypertension combined with DM2. This may indicate another structure of genetic component of predisposition to LVH in different causes.

The Allele and genotype didtributions of the two alcohol dehydrogenase genes ADH1B (polymorphism A/G in exon 3, detected with restrictase MslI) and ADH7 (polymorphism G/C in intron 5, detected with restrictase StyI) was studied in three Russian populations from the Siberian region. The absence of interpopulation and intersexual differences in the allele frequency was determined. The allele ADH1B*G (+MslI, A2) was found in low frequency (3.6-7.5%), the mutant allele ADH7 (-StyI, B2) frequency in total population (n = 339) was 46.02%. The genotype distributions of the ADH1B and ADH7 in these populations were agreed with the Hardy-Weinberg equilibrium and linkage equilibrium. Increased frequency of ADH7 B2 allele was revealed in elder group (after 40 years) in the total sample and in the Tomsk city inhabitants (n = 113) on 11% (P = 0.001) and 9% (P = 0.017) accordingly. ADH7 and ADH1B genes polymorpisms did not show association with antioxidant activity, which was determined from the blood plasma ability to reduce the yield of products interacting with thiobarbituric acid in the lecitin-Fe2+ ions model system. The statistically significant decrease of serum very low density lipoproteins (LPVLD) level (on 9.95%, P = 0.045) and close to statistically significant decrease systolic pressure (on 6.80%, P = 0.068) and serum triglycerides level (on 6.16 of %, P = 0.058) were revealed among the A2 allele ADH1B gene carriers in Tomsk population.

The enzyme methylenetetrahydrofolate reductase (MTHFR) catalyzes synthesis of 5'-methylenehydrofolate, which is the methyl donor for the conversion of homocysteine to methionine. According to the numerous literature data, polymorphic variant of the MTHFR-encoding gene, C677T, is associated with hyperhomocysteinemia, vascular pathologies, neural tube defects, dementia, perinatal mortality, mental disorders, long-term neurodegenerative disorders, lens displacement, arachnodactyly, and venous thromboses. The present study was focused on the analysis of the C677T polymorphism (missence mutation leading to the replacement of cytosine by thymine at position 677) of the MTHFR gene in three indigenous populations of the Republic of Sakha (Yakutia), living in the settlements of Cheriktei, Byadi, and Dyupsya. Comparison of the genotype and allele frequencies revealed no substantial differences between the three Yakut populations, as well as between Yakuts and other Mongoloid ethnic groups.

Y chromosomes from representative sample of Eastern Ukrainians (94 individuals) were analyzed for composition and frequencies of haplogroups, defined by 11 biallelic loci located in non-recombining part of the chromosome (SRY1532, YAP, 92R7, DYF155S2, 12f2, Tat, M9, M17, M25, M89, and M56). In the Ukrainian gene, pool six haplogroups were revealed: E, F (including G and I), J, N3, P, and R1a1. These haplogroups were earlier detected in a study of Y-chromosome diversity on the territory of Europe as a whole. The major haplogroup in the Ukrainian gene pool, haplogroup R1a1 (earlier designated HG3), accounted for about 44% of all Y chromosomes in the sample examined. This haplogroup is thought to mark the migration patterns of the early Indo-Europeans and is associated with the distribution of the Kurgan archaeological culture. The second major haplogroup is haplogroup F (21.3%), which is a combination of the lineages differing by the time of appearance. Haplogroup P found with the frequency of 9.6%, represents the genetic contribution of the population originating from the ancient autochthonous population of Europe. Haplogroups J and E (11.7 and 4.2%, respectively) mark the migration patterns of the Middle-Eastern agriculturists during the Neolithic. The presence of the N3 lineage (9.6%) is likely explained by a contribution of the assimilated Finno-Ugric tribes. The data on the composition and frequencies of Y-chromosome haplogroups in the sample studied substantially supplement the existing picture of the male lineage distribution in the Eastern Slav population.

The review considers the results of genome research on the Russian program Human Genome carried out in the Institute of Medical Genetics (Tomsk) from 1990. The three major fields were molecular cytogenetics and chromosomal disorders, genomics of Mendelian and high-incidence diseases, and ethnogenomics of the North Asian population. Several human genes were cytogenetically mapped, and numerical and structural abnormalities associated with human diseases studied by fluorescence hybridization. Procedures of DNA diagnostics were developed for 15 hereditary diseases. New data were obtained on genetic heterogeneity of idiopathic hypertrophic cardiomyopathy. The genetic bases of multifactorial (atopic bronchial asthma) and infectious (tuberculosis) diseases were analyzed. The North Eurasian population (41 local populations of 21 ethnic groups) was tested for genetic diversity with numerous genetic markers, including Y-chromosomal haplotypes, autosomal microsatellites, and polymorphic Alu insertions.

Genetic relationships among eighth Siberian and Central Asian ethnic groups were examined using autosomal microsatellite loci. Genetic similarity of Buryats and Evenks, as well as close relationships between Tuvinians and Kyrgyzes, most likely resulting from the Altai-Slavic co-ancestry of their gene pools, was demonstrated. Studies of gene flow in these populations demonstrated that, in general, Turkic ethnic groups of Southern Siberia (Altaians and Tuvinians) were the recipients of more intense gene flow compared to Eastern Siberian populations belonging to Altaic family. The local Buryat populations displayed substantial differences in the direction and the level of deviation of the observed gene diversity from the expected one, which was probably caused by the differences in the degree of isolation and/or in effective population sizes.

Analysis of associations between idiopathic disturbances of cardiac conduction (DCC) and polymorphism of mitochondrial genome.A family examination was performed in 431 probands with various DCC and 1347 relatives of the first, second and third degree of kinship (the study group). All the examinees were divided into four subgroups. These included 158 probands with atrioventricular block (AVB) of various degree and their 518 relatives (subgroup 1); 50 probands with a complete right bundle-branch block (BBB) and their 161 relatives (subgroup 2); 108 probands with a complete left BBB and left anterior branch of the His bundle and their 152 relatives (subgroup 3); 115 probands with sick sinus syndrome (SSS) and their 327 relatives (subgroup 4). The control group consisted of 104 probands without clinical ECG manifestations of cardiac diseases and their 321 relatives. All the examinees have undergone ECG, atropin test, echocardioscopy, electrophysiological examination of the heart and mitochondrial DNA (mDNA).Comparison of the incidence of mDNA D-loop restriction sites in the group of patients with idiopathic DCC and controls has found higher frequency of the Hae III 16517 site in the group of the patients (p = 0.0480). By location of the blocks (atrioventricular and intraventricular), the site occurred more frequently in patients with AVB (86.36%). The variant "+" by the site of Hae III 16517 mDNA was found to associate with disturbances of cardiac conduction, more closely in AVB.Variability of mDNA may be an etiological factor of idiopathic DCC pathogenesis.

The gene pool of five ethnic groups of the Central Asian population was characterized using nine human-specific polymorphic insertion/deletion loci (ACE, PLAT, APOA1, PV92, F13B, A25, B65, CD4, Mt-Nuc). It has been shown for the first time that at the CD4 locus, the frequency of Alu(-) is inversely related to the Mongoloid component of the population. For the Central Asian populations, the lowest and highest frequencies of the Alu deletion at locus CD4 were recorded respectively in Dungans (0.04), immigrants from China, and Tajiks (0.15). The coefficient of gene differentiation in the Central Asian populations for all the genes was 2.8%, which indicates a relatively low level of population genetic subdivision in this region. The unity of the gene pool of the Central Asian Caucasoids was shown.

The paper presents the results of analysis of the gene pools of several North Eurasian ethnic groups (Buryats, Evenks, Altaians, Russians, Kyrgyzes, Tuvinians, Tatars, and Ukrainians) examined using a panel of autosomal microsatellite markers (D4S397, D5S393, D7S640, D8S514, D9S161, D10S197, D11S1358, D12S364, and D13S173) mapped on different chromosomes and represented by the (CA)n dinucleotide repeats. In the group of populations examined the proportion of genetic variability at microsatellite loci explained by interpopulation differences was about 2.5%, while genetic differences between the individuals within a population accounted for 97.5% of this variability. Analysis of genetic relationships among the populations revealed substantial differences between the populations belonging to the Indo-European and Altaic linguistic families in gene diversity at microsatellite loci.

The structure of female (mtDNA) and male (Y-chromosome haplotypes) lineages in the Yakut population was examined. To determine mtDNA haplotypes, sequencing of hypervariable segment I and typing of haplotype-specific point substitutions in the other parts of the mtDNA molecule were performed. Y haplogroups were identified through typing of biallelic polymorphisms in the nonrecombining part of the chromosome. Haplotypes within haplogroups were analyzed with seven microsatellite loci. Mitochondrial gene pool of Yakuts is mainly represented by the lineages of eastern Eurasian origin (haplogroups A, B, C, D, G, and F). In Yakuts haplogroups C and D showing the total frequency of almost 80% and consisting of 12 and 10 different haplopypes, respectively, were the most frequent and diverse. The total part of the lineages of western Eurasian origin ("Caucasoid") was about 6% (4 haplotypes, haplogroups H, J, and U). Most of Y chromosomes in the Yakut population (87%) belonged to haplogroup N3 (HG16), delineated by the T-C substitution at the Tat locus. Chromosomes of haplogroup N3 displayed the presence of 19 microsatellite haplotypes, the most frequent of which encompassed 54% chromosomes of this haplogroup. Median network of haplogroup N3 in Yakuts demonstrated distinct "starlike phylogeny". Male lineages of Yakuts were shown to be closest to those of Eastern Evenks.

In 75 male and 46 female subjects of an urban population (93% Russians) and in 38 males and 40 females of a rural population (87% Russians), the antioxidant activity (AOA) of blood plasma was determined from the plasma ability to reduce the yield of products interacting with thiobarbituric acid in the model lecithin-Fe2+ ion system. In the urban population, the loci TF (AvaI in exon5) and ACE (I/D polymorphism of the Alu repeat in intron16) were studied in 130 and 141 subjects, respectively. Of them, 102 and 111 subjects, respectively, were examined for AOA. In the rural population, the corresponding sample sizes were 75 and 76 (73 and 74 subjects were examined for AOA). The polymorphic loci of the urban and rural populations did not differ in the allele frequencies. In both populations Hardy--Weinberg and gametic equilibria were observed. The contributions of the TF and ACE genes to AOA variation in the combined sample from the urban and rural populations were 0.6 and 0.5%, respectively.

Highly repetitive DNA sequences account for more than 50% of the human genome. The L1 and Alu families harbor the most common mammalian long (LINEs) and short (SINEs) interspersed elements. Alu elements are each a dimer of similar, but not identical, fragments of total size about 300 bp, and originate from the 7SL RNA gene. Each element contains a bipartite promoter for RNA polymerase III, a poly(A) tract located between the monomers, a 3'-terminal poly(A) tract, and numerous CpG islands, and is flanked by short direct repeats. Alu repeats comprise more than 10% of the human genome and are capable of retroposition. Possibly, these elements played an important part in genome evolution. Insertion of an Alu element into a functionally important genome region or other Alu-dependent alterations of gene functions cause various hereditary disorders and are probably associated with carcinogenesis. In total, 14 Alu families differing in diagnostic mutations are known. Some of these, which are present in the human genome, are polymorphic and relatively recently inserted into new loci. Alu copies transposed during ethnic divergence of the human population are useful markers for evolutionary genetic studies.

The autosomal gene pool of Yakuts was analyzed with a panel of polymorphic Alu insertions. The observed allele frequencies were typical for other Asian ethnic groups. Genetic differentiation of three Yakut populations was relatively high, 2%. East Siberian ethnic groups were shown to have a common gene pool and to experience no intense gene flow from other populations. Development of the Yakut gene pool was assumed to involve no substantial genetic effect of neighboring populations. The results fit both autochthonous and southern origin hypotheses.

Modern approaches to investigation of hypertension genetics are reviewed. These include genealogical, genetic-epidemiological, bioinformative methods, biological microchip technology. The results of genomic investigation of arterial hypertension are presented. Perspective lines in the research in the field of genetic cardiology are discussed.

Two polymorphisms in theIL4(G/C 3′-UTR) andIL5(C-703T) genes were studied in a sample of families whose probands had atopic bronchial asthma (BA) (66 families, n = 183) and in a group of non-cognate individuals with the severe form of the disease (n = 34). The samples were collected from the Russian population in the city of Tomsk (Russia). Using the transmission/disequilibrium test (TDT), a significant association of allele C-703IL5with BA was established (TDT = 4.923,p= 0.007 ± 0.0007). The analysis of 40 individuals with mild asthma and 49 patients with the severe form of the disease revealed a negative association of genotype GGIL4(OR = 0.39, 95% CI = 0.15−0.99,p= 0.035), and also a trend towards a positive association of the GCIL4genotype (OR = 2.52, 95% CI = 0.98−6.57,p= 0.052) with mild BA. There was a concordance of the clinical classification of BA severity with the ‘genotype’ (McNemar'sχ2test with continuity correction constituted 0.03, d.f. = 1,p= 0.859). These results suggest that polymorphisms in theIL4andIL5genes contribute to the susceptibility to atopic BA and could determine the clinical course of the disease.

Increased frequencies of angiotensin-converting enzyme (ACE) D-allele and ID-genotype among patients with idiopathic atrioventricular blocks and I allele and II genotype among patients with idiopathic intraventricular blocks allow to consider these genotypes risk factors of corresponding disturbances of cardiac conduction. Decreased frequency of ACE I allele and II genotype among patients with idiopathic atrioventricular blocks is indicative of a possible protective role of II genotype against development of this type of cardiac conduction defect. Low frequency of D allele and genotype D prevents derangements of conduction in His-Purkinje system.

The human infectious disease become of the great importance for Health Welfare. The infectious diseases mortality rate reaches one third of total mortality among 51 million patients died annually. The genetic factors seem to be most responsible for potency of human body to withstand to infections, caused by a variety of causative agents. The detection of the coincident factors and understanding the mechanisms of formation of susceptibility and resistance to infectious agents appeared to be important aspects for development of the new methods of prevention and treatment the infectious diseases. In inbred mice the natural resistance to infections, caused by Mycobacterium bovis, Mycobacterium avium, Mycobacterium lepraemurium, Leishmania donovani and Salmonella typhimurium is controlled by gene Nrampl (natural resistance associated macrophage protein gene). The gene codes for integral membrane protein, expressed by phagocytes. Protein is localized in the endosomal/lysosomal compartment of the silent macrophage, being recruited to the membrane of the phagosome containing particles under phagocytosis. This function is to transfer bivalent cations of metals from phagosome inward macrophage, that appears to affect negatively on destiny of microbes consumed. The human homologue of the Nrampl gene, denoted as NRAMP1, is situated on human chromosome 2q35. The gene Nrampl consists of 15 exones of different spread disparted by intrones of various sizes. Several polymorphous variants of the gene are described. The experimental presuppositions to more extensive investigation of the role of the gene NRAMPl in development of human pathology are pointed out.

The following seven polymorphic marker loci of genes responsible for predisposition to coronary atherosclerosis (CAS) were studied: the ACE locus responsible for angiotensin-converting enzyme insertion/deletion polymorphism for the presence or absence of the Alu insertion in the gene; the F13, PLAT, and APOA1 loci, controlling the clotting factor 13, plasminogen-activating tissue factor, and apolipoprotein A, respectively; the MTHFR and AGT polymorphic loci responsible for point mutations in methylenetetrahydrofolate reductase and those in angiotensinogen, respectively, and the NOS3 locus controlling the number of tandem repeats in the nitric oxide synthase gene. These loci are located on different chromosomes and encode products involved into various metabolic pathways leading to CAS. In the populations studied, significant differences between healthy subjects and patients predisposed to cardiovascular diseases were revealed with regard to the above seven markers. The 174M allele (T174M polymorphism in the ACE gene) was significantly associated with coronary atherosclerosis. It was found that specific gene combinations are involved in the CAS development and determine variation in the pathogenetically important quantitative traits.

Variation of Mongoloid-specific restriction sites of mitochondrial genome was analyzed in three territorial groups of Tuvinians. Distribution of mitochondrial DNA haplogroups A, B, C, and D on the territory of the Tuva Republic was estimated. The populations studied did not display distinct differentiation in respect to the mtDNA polymorphism. The specific feature of Tuvinian mitochondrial gene pool was the prevalence of only one haplogroup C (over 40%), mainly represented by two mitotypes. The high frequency of this haplogroup makes Tuvinians similar to more northern Siberian populations. On the other hand, the presence of haplogroup B indicates that Tuvinians have affinity to ethnic groups of Central Asia.

Polymorphism of three rural populations of the Tuva Republic was examined using a set of five autosomal Alu insertions at the ACE, PLAT, PV92, APOA1, and F13B loci. The allele frequency distribution patterns revealed in Tuvinians were typical to Mongoloid populations of Asia and were characterized by relatively high frequency of the Alu-repeat insertion at the PV92 and F13B loci along with relatively low insertion frequency at the APOA1 locus. With respect to the test systems used, Tuvinian populations examined displayed high levels of genetic diversity. The mean expected heterozygosity values in the populations of Kugurtug, Toora-Khem, and Teeli were 0.433, 0.407, and 0.437, respectively. The level of genetic diversity in the pooled Tuvinian sample was 0.432. The coefficient of genetic differentiation in the three populations studied was 1.45 pointing to relatively low level of genetic subdivision of the indigenous Tuvinian populations. However, estimates of genetic differentiation of the Tuvinian gene pool made by use of the Alu-repeat system were higher compared to those performed using classical protein systems, mtDNA, or Y-chromosomal haplotypes. Even though Tuvinian populations were characterized by common gene pool, some features specific to Western Tuvinian population could be distinguished. These features could be associated with higher contribution of the Caucasian component to the gene pool of this population. Phylogenetic analysis demonstrated close genetic relationships between the Tuvinian and Altaic ethnic populations.

The distribution of alleles and haplotypes of three diallellic Y-specific loci (YAP, DYF155S2, and Tat) in the populations of Kyrgyz, Uzbeks and Tajiks was analyzed. In Kyrgyzes and Uzbeks, a relatively high frequency of the DYF155S2 deletion (20 and 12.5%, respectively) and the C allele at the Tat locus (11.2 and 8.3%, respectively) were revealed. In the populations of southern Kyrgyzes and Uzbeks, two chromosomes carrying the YAP+ allele were detected. In both cases the YAP+ allele was found within the YAP+/DYF155S2+/TatT haplotype. The Tajik population was monomorphic in respect to the polymorphisms studied. The Tajiks demonstrated the presence of only the YAP-/DYF155S2+/TatT haplotype. This haplotype appeared to be most frequent in Kyrgyz (78.8%) and Uzbeks (83.3%). The question on the origin and the distribution of Y-chromosome variants in Eurasia are discussed.

Allele and genotype frequencies of the T174M polymorphism of the angiotensinogen gene were for the first time estimated in the West Siberian population. The polymorphism was tested for association with coronary atherosclerosis (CAS) and with several quantitative risk factors in patients with angiographically verified CAS, healthy individuals, and in a population sample nondifferentiated with respect to CAS.

Main points of the new direction genomic medicine and its applications to solution of pulmonological problems are outlined. Information on the molecular epidemiology of cystic fibrosis and bronchial asthma is presented. The frequency of major cystic fibrosis gene mutations and bronchial asthma candidate gene polymorphisms was defined in Siberian populations. The familial case histories of patients with bronchial asthma were used to assess the contribution of interleukine (IL4, IL5, IL9) and nitric oxide synthase (NOS3) genes to susceptibility to bronchial asthma.

The paper discusses relations of new disciplines in medical science, such as genetic cardiology and genomic medicine. It outlines today's achievements and prospects of genomic studies for some groups of cardiovascular diseases: congenital developmental defects of the heart and great vessels, cardiac arrhythmias and cardiomyopathies, and common diseases with complex inheritance, such as atherosclerosis and arterial hypertension. Accumulated knowledge on new candidate genes of these forms of pathology specifies their pathogenesis, makes it possible to outline new gene-specific therapeutical approaches, and serves as a basis for classifying risk groups by specific diseases. On the other hand, studies of the "sphere of influence" (fields of action) of genes that make up a molecular genetic basis of diseases are of fundamental value in defining the physiological role of sequenced human genomic fragments (functional genomics).