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%.

Медицинская генетика. 2010. Т. 9. № 5 (95). С. 24-34.

Приведены результаты исследования полиморфизма генов-кандидатов заболеваний сердечно-сосудистой системы: ADRB2 (rs1042713 - A46G и rs1042714 - C79G), NOS3 (rs2070744 - T-786C, rs1799983 - G894T и VNTR), ACE (rs4291 - A-240T и rs4343 - A2350G), AGTR1 (rs5186 - A1166C и T-713G) и GNB3 (rs5442 - G814C и rs5443 - C825T) у представителей четырех этнических групп Сибири (бурят, тувинцев, якутов и пришлого русского населения). Обследованные этнические группы различаются между собой по частотам аллелей большинства изученных маркеров, только для трех из 11 изученных полиморфных вариантов (rs4291 и rs4343 гена АСЕ и rs5443 гена GNB3) не установлено межэтнических различий по частотам аллелей. Русские жители в большей степени отличаются от изученных монголоидных популяций, чем последние различаются между собой. Наибольший вклад в показатель тотальной гетерогенности по частотам аллелей между русскими и этническими группами монголоидной расы вносят полиморфные варианты гена NOS3 (VNTR и rs2070744), rs5186 гена AGTR1, между русскими и тувинцами - также вариант Т-713С гена AGTR1, между русскими и якутами - rs1799983 гена NOS3. Монголоидные популяции Сибири также статистически значимо различаются по частотам аллелей, преимущественно за счет следующих SNP: для бурят и тувинцев - rs1042713 и rs1042714 гена ADRB2; для бурят и якутов - rs1042713 гена ADRB2 и rs1799983 гена NOS3; для тувинцев и якутов - rs2070744 и rs1799983 гена NOS3. Согласно относительным величинам популяционно-специфического индекса FST, рассчитанного для отдельных локусов, к числу расоспецифичных можно отнести 5 из 11 изученных полиморфных вариантов генов-кандидатов заболеваний сердечно-сосудистой системы - rs2070744 и VNTR гена NOS3, вариант T-713G и rs5186 гена AGTR1, rs4291 гена АСЕ.

Среди опухолевой патологии человека рак желудка занимает важное место, оставаясь одной из наиболее распространенных неоплазий в мире. Канцерогенез желудка представляет собой сложный многоступенчатый процесс, в основе которого лежат различные молекулярно-генетические факторы. Одной из характеристик опухолевых клеток являются хромосомные аберрации. Различные хромосомные нарушения встречаются практически на всех этапах развития неоплазий желудка, однако до настоящего времени существуют противоречивые мнения относительно роли хромосомных аберраций в процессе злокачественной трансформации данного органа. Вместе с тем, цитогенетические исследования показывают наличие ассоциаций некоторых хромосомных изменений с патологической картиной, биологическим характером опухоли и прогнозом развития болезни. Развитие современных молекулярно-цитогенетических методов позволяет получать новые данные о спектре хромосомных аберраций в малигнизированной клетке. Выявление роли определенных хромосомных аномалий может стать основой для разработки новых стратегий классификации, скрининга и терапии злокачественных новообразований. Цель настоящего обзора заключается в систематизации данных о роли хромосомных аберраций в развитии рака желудка.

Для сельских и городских населенных пунктов (обследовано 5 административных центров) Республики Саха (Якутия) характерны интенсивные брачные миграции: среди вступивших в брак регистрировались как уроженцы различных улусов республики (от 7 до 30%), так и мигранты из-за пределов Якутии (7–29%). Все обследованные популяции характеризуются широкой географией мест рождения супругов (от 14 до 24 улусов) при отсутствии направленных (преимущественных) миграционных потоков из одного района в другой. Показано высокое распространение гомолокальных браков среди коренных этнических групп (эвенки, эвены, юкагиры) – от 75 до 100%; доля гомолокальных браков среди якутов варьировала от 26 до 68%; для пришлого населения (русские) более характерно заключение гетеролокальных браков (41–95%). В большинстве обследованных популяций выявлена положительная брачная ассортативность по местам рождения женихов и невест (исключением явился Момский улус).

Many new genetic tests for common multifactorial disorders are becoming available to individuals, including direct-to-consumer genotyping services. Typically, studies of public attitudes reveal a high level of interest for individual genotyping. In a Russian urban population, 85% of 2000 respondents answered positively to a question about their own willingness to undergo predictive genetic testing for preventable health conditions. Gender, age and health status significantly influenced response. Multivariate discriminant analyses revealed that wanting to know about probable future diseases, readiness to improve lifestyles and an interest in learning about individual genome characteristics are the most important predictors for wanting to be tested. Along with the high level of interest, highly overestimated expectations were encountered in many studies. With the low predictive abilities of currently available genetic tests for common disorders, proper interpretation of the data and genetic counseling are essential. There is a need for prospective validation of genetic panels for risk assessments, and for efforts to measure the effects of genetic information disclosure and how this information might contribute to lifestyle changes.

Mutations in three genes PSEN1, PSEN2, and APP are known to be a cause of familial forms of Alzheimer’s disease (AD). APOE gene polymorphism is a strong risk genetic factor for AD. We have evaluated allele and genotype frequency distribution of rs11136000 polymorphism in the clusterin (CLU) gene (or apolipoprotein J, APOJ) in the samples from three Russian populations and in AD patients. Genome-wide association studies in samples from several European populations have recently revealed the highly significant association of CLU gene with AD (p = 8.5 × 10−10). We found no differences in allele and genotype frequencies of rs11136000 between the populations from the Moscow, Ural, and Siberia regions. The allele frequencies are close to those in European populations. The genetic association analysis in cohort of AD patients and normal individuals (>500 individuals in each group) revealed no significant association of the rs11136000 polymorphism in CLU gene with Alzheimer’s disease in Russian populations. Although our results showed that the CLU gene polymorphism rs11136000 is likely not a major genetic factor for the common form of Alzheimer’s disease, the data do not rule out the possibility of a modest effect of CLU and interaction between CLU and APOE genotypes in etiology of Alzheimer’s disease.

We tested the association of deletion polymorphism in the GSTT1 and GSTM1 genes for glutathione S-transferases and the A313G single-nucleotide polymorphism in the GSTP1 gene with cirrhosis morbidity and 4-year survival rate among residents of the Tomsk region, West Siberia. The homozygous deletion of the GSTM1 gene (null genotype) proved to be a protective factor against alcoholic and mixed (viral and alcoholic) liver cirrhosis. The frequency of this genotype in patients of the combined group having cirrhosis of any etiology was 39.2%, in patients with alcoholic cirrhosis it was 39.0%, and in patients with mixed cirrhosis it was 34.2%. This genotype was much more frequent among patients of the control group: 64.6%. The GSTM1 null genotype and the GSTP1 A313G polymorphic variant correlated with survival rate. The survivors had a higher GSTM1 null genotype frequency than the dead patients, 46.6 and 30.2%, respectively; a higher frequency of the GSTP1 AA genotype, 63.1 and 40.5%; and a lower frequency of the GSTP1 AG (A313G) genotype (31.1 and 51.2%). The survival rate in patients with the GSTP1 AA genotype was 2.5 times as high as in GG or AG genotype carriers. In patients with the GSTM1 null genotype, the survival rate was twice as high as in patients without the deletion. The 4-year fatal case probability in patients having the heterozygous GSTP1 AG genotype was 2.3 times higher than in patients with the homozygous AA or GG genotypes.

Risks related to occupational exposure of humans to ionizing radiation remains a focus of attention. Of special importance is the poorly understood effect of ionizing radiation on the rate of numerical chromosome aberrations in human somatic cells. The purpose of this study was characterization of a radiation-induced increase in the rate of aneuploidy induced by incorporated plutonium-239 (239Pu) in somatic cells of chemonuclear industry workers. Significant differences in the chromosome 2, 7, 8, 12, and Y aneuploidy rate have been found between subjects with incorporated 239Pu and control subjects have been demonstrated. Chromosome nondisjunction has been found to be the main mechanism of aneuploidy induced by incorporated 239Pu.

The isolation and study of autologous human stem cells remain among the most urgent problems in cell biology and biomedicine to date. Induced pluripotent stem cells can be derived from human somatic cells by the overexpression of a number of genes. In this study we reprogrammed fetal human skin fibroblasts by transduction with retroviral vectors carrying murine Oct4, Sox2, Klf4, and c-Myc cDNAs. As a result, cells with the protein expression and gene transcription pattern characteristic of human embryonic stem cells were derived. These induced pluripotent cells are capable of differentiation in vitro into the ectoderm, mesoderm, and endoderm derivatives.

Polymorphic markers were studied in mitochondrial DNA and the nuclear POLG1 gene, coding for mitochondrial DNA polymerase γ. Their frequencies were compared between healthy individuals and patients with arterial hypertension, as well as between patients with and without left ventricular hypertrophy. The healthy group was found not to be clearly dominated by the C allele of MspI polymorphism in POLG1. Mitochondrial haplogroup H was more frequent (OR = 0.42; 95%CI 0.17–0.98; p = 0.043) in patients without left ventricular hypertrophy than in patients having this complication. Haplogroup T was more often detected in patients with left ventricular hypertrophy (OR = 6.16; 95%CI 1.17–9.74; p = 0.018). This result suggests the implication of mitochondrial DNA in hereditary susceptibility to cardiovascular diseases.

The population dynamics and changes in the sex and age structure of the Shor populations of four rural district municipalities of Tashtagolskii raion of Kemerovo oblast (Kyzyl-Shorskii, Ust-Anzasskii, Ust-Kolzasskii, and Ust-Kabyrzinsskii) with time have been analyzed. The Shor populations have been found to have contained a high proportion of people under 18 years of age during two periods, 1940–1955 and 1970–1975 (38.12–46.38 and 40.98–54.97%, respectively). However, the population reproduction pattern changed into the “reduced” one in all the municipalities studied by the early 2000s. Although there are some regional variations, a common trend towards rural population aging has formed: the man age in the Tashtagolskii raion population has increased by 7.52 and 6.94 years for men and women, respectively, during two generations; the natural sex ratio has been disturbed in both the prereproductive and reproductive populations. The total population size and effective reproductive size have decreased in three out of the four rural subpopulations studied.

The gene pool structure of aboriginal Siberian populations has been described based on the polymorphism of the ZFX gene located on the chromosome X. In the ten populations studied, 49 haplotypes were present, three of them with high frequencies. Comparison of the obtained results with the available data from the HapMap project revealed unique African haplotypes that occurred in the Yoruba with the frequency of 3-7% and were not found in other populations. The genetic differentiation coefficient of the Siberian ethnic groups studied was 0.0486. Correlation analysis using Mantel's test did not detect significant correlations between the genetic distance matrix and the matrices of geographic, linguistic, and anthropological differences, although the correlation with the anthropological matrix was the highest. Phylogenetic analysis proved strong isolation of the African population from the other ethnic groups investigated. The Siberian populations were divided into two separate clusters: the first one included Yakuts, Buryats, and Kets, while the second cluster included Altaians, Tuvinians, and Khanty. Using the principal component analysis, the populations were combined into three groups clearly differing by manifestation of Caucasoid and Mongoloid components. The first group included residents of Europe and one of Khanty populations, the second group included populations of South Siberia and residents of China. Mongoloid populations of East Siberia, the Japanese, and Kets were combined into the third group. Barrier analysis revealed a similar structure of genetic differentiation of Siberian populations. Linkage disequilibrium structure was obtained for six ethnic groups of Siberia. In five of them (except for the Ket population), ten ZFX SNPs formed a single linkage block.

This review discusses the progress of ethnic genetics, the genetics of common diseases, and the concepts of personalized medicine. We show the relationship between the structure of genetic diversity in human populations and the varying frequencies of Mendelian and multifactor diseases. We also examine the population basis of pharmacogenetics and evaluate the effectiveness of pharmacotherapy, along with a review of new achievements and prospects in personalized genomics.

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 x 10(-8), OR = 0.31, 95% CI = 0.20-0.48, and HLA-DQA1 rs1071630, case-control P = 4.9 x 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.

Marriage structure has been analyzed in the populations of the administrative centers of five uluses of the Republic of Sakha (Yakutia). The populations studied differ from one another with respect to ethnic composition, namely in the ratio between the indigenous and immigrant populations (the indigenous populations are larger in three uluses), in the proportions of representatives of indigenous ethnic groups among men and women contracting marriages, and in the frequencies of monoethnic and interethnic marriages. Positive assortative marriage among persons of the same ethnic group has been demonstrated. The total inbreeding estimated by isonymy (Fit) varies from 0 to 0.007576.