Охарактеризован генофонд пяти этнических групп населения Средней Азии с использованием девяти специфичных для человека полиморфных инсерционно-делеционных локусов (ACE, PLAT, APOA1, PV92, F13B, A25, B65, CD4, Mt-Nuc). Впервые показано, что в локусе CD4 частота Alu(-) четко уменьшается с увеличением монголоидного компонента в популяции. Для популяций Средней Азии наименьшая частота делеции Alu-элемента в локусе CD4 выявлена для дунган (0.04), выходцев из Китая, а наибольшая - для таджиков (0.15). Коэффициент генной дифференциации по совокупности генов для популяций Средней Азии составил 2.8%, что свидетельствует об относительно невысоком уровне генетической подразделенности населения изучаемого региона. Показана общность генофондов для среднеазиатских европеоидов.

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.

Исследована структура женских (мтДНК) и мужских (гаплотипы Y-хромосомы) линий в популяции якутов. Гаплотипирование мтДНК осуществляли с помощью секвенирования гипервариабельного сегмента I и типирования гаплотип-специфичных точечных замен в других участках молекулы мтДНК. Гаплогруппы Y-хромосомы выявляли с помощью типирования диаллельных полиморфизмов в нерекомбинантной части хромосомы. Анализ гаплотипов внутри гаплогрупп проводили с помощью семи микросателлитных локусов. Митохондриальный генный пул якутов представлен в основном линиджами восточноевразийского происхождения (гаплогруппы A, B, C, D, G и F). Самыми частыми и наиболее разнообразными гаплогруппами мтДНК у якутов оказались гаплогруппы C и D (с суммарной частотой около 80%), представленные 12 и 10 различными гаплотипами соответственно. Общая доля линиджей западноевразийского происхождения (“европеоидных”) составила около 6% (4 гаплотипа, гаплогруппы H, J, U). Большая часть Y-хромосом в якутской популяции (87%) принадлежит к гаплогруппе N3 (HG16), характеризующейся транзицией T-C в локусе Tat. На хромосомах гаплогруппы N3 обнаружено 19 микросателлитных гаплотипов, наиболее частный из которых охватывает 54% хромосом этой гаплогруппы. Медианная сеть гаплогруппы N3 у якутов демонстрирует ярко выраженную “звездообразную филогению”. Показано, что мужские линии у якутов наиболее близки к таковым у восточных эвенков.

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.

Антиоксидантная активность (АОА), оцениваемая по способности плазмы крови снижать выход продуктов, реагирующих с тиобарбитуровой кислотой в модельной системе “лецитин - ионы Fe 2+”, определена у 75 мужчин и 46 женщин в городской (93% русские) и у 38 мужчин и 40 женщин в сельской популяциях (87% русские). По локусам TF (Aval в 5-м экзоне гена) и АСЕ (I/D-полиморфизм Alu-повтора в 16-м интроне) обследовано в городской популяции 130 и 141 человек соответственно (из них 102 и 111 человек исследованы по АОА). Для сельских жителей соответствующие объемы выборок составили 75 и 76 человек (оценки АОА получены для 73 и 74 человек). Для исследованных полиморфных локусов не выявлено различий в частотах аллелей между городской и сельской популяциями, наблюдаются равновесие Харди-Вайнберга и гаметическое равновесие. Оценки вкладов локусов генов TF и АСЕ в вариацию АОА в общей выборке городской и сельской популяций составили 0.6 и 0.5% соответственно.

Karyotyping of noncultivated cells of 60 first-trimester spontaneous abortions (blighted ovum and missed abortions) was carried out using fluorescence in situ hybridization (FISH) with centromere-specific DNA probes for all chromosomes of the karyotype. Conventional cytogenetic study of these abortions was impossible because of cell culture failures. The algorithm is proposed for molecular cytogenetic FISH analysis of interphase karyotypes. Chromosome abnormalities were found in 32 fetuses (53.3%). In groups of missed abortions and blighted ovum, the frequency of numerical chromosome abnormalities was 50 and 60%, respectively. Both the numerical chromosome abnormalities typical of spontaneous human abortions (autosomal trisomies, sex chromosome aneuploidy, and polyploidy) and a relatively rare type of genomic imbalance unidentifiable by standard cytogenetic analysis (autosomal monosomies 7, 15, 21, and 22 in mosaic state) were observed. The frequency of these type of chromosome abnormalities comprised 19% of all known karyotype abnormalities determined in spontaneously aborted embryos. Note that the level of confined placental mosaicism in embryos with low cell proliferative activity was 25%, which is substantially higher than the corresponding parameter (1–2%) determined by prenatal diagnosis of chromosome abnormalities in developing embryos. The results of interphase FISH analysis of cells with low proliferative activity in vitro suggest that the pathology of early fetal development and missed abortion in humans are associated with a wider spectrum of chromosome abnormalities.

С помощью флуоресцентной гибридизации in situ (FISH) с центромероспецифичными ДНК-зондами на все хромосомы набора проведен анализ кариотипа некультивированных клеток 60 спонтанных абортусов I триместра беременности (анэмбрионии и неразвивающиеся беременности), стандартное цитогенетическое исследование которых оказалось невозможным вследствие дегенерации клеточных культур. Предложен алгоритм молекулярно-цитогенетического анализа кариотипа с использованием интерфазного FISH-анализа. У 32 зародышей (53.3%) выявлены хромосомные аномалии. В группах неразвивающихся беременностей и анэмбрионий частота числовых хромосомных аномалий составила 50 и 60% соответственно. Обнаружены как характерные для спонтанных абортусов человека числовые нарушения хромосом (аутосомные трисомии, анеуплоидия половых хромосом, полиплоидия), так и сравнительно редкий тип геномного дисбаланса, практически не выявляемый стандартным цитогенетическим анализом - моносомии по аутосомам 7, 15, 21 и 22 в мозаичном состоянии. Частота этого типа хромосомных аномалий составила 19% от всех зарегистрированных нарушений кариотипа у спонтанно погибших зародышей. Кроме того, уровень ограниченного плацентарного мозаицизма у эмбрионов с низкой пролиферативной активностью клеток составил 25%, что существенно выше соответствующего показателя (в среднем 1-2%), регистрируемого при пренатальной диагностике хромосомных аномалий у продолжающих развитие зародышей. Результаты интерфазного FISH-анализа кариотипа клеток с низкой пролиферативной активностью in vitro свидетельствуют о более широком спектре хромосомных нарушений, определяющих патологию ранних этапов эмбрионального развития человека и невынашивание беременности.

In the patients with enzymopenic hereditary methemoglobinemia type I, a disease widely distributed on the territory of Yakutia, a search for the mutations in exons 3 and 4 of the DIA1 gene encoding NADH-cytochrome b5 reductase was carried out. It was shown that Yakut patients have none of three missence mutations, Arg57Gln, Leu72Pro, and Val105Met, described in case of this disease in the neighboring populations, Chinese and Japanese, inhabiting the territories south of Yakutia.

Проведен поиск мутаций в 3 и 4 экзонах гена D1A1, кодирующего NADH-цитохром Ь5 редуктазу, у больных с наследственной энзимопенической метгемоглобинемией I типа - заболевании, широко распространенном на территории Якутии. Показано, что в якутской популяции не встречается ни одна из трех миссенс-мутаций - Arg57Gln, Leu72Pro и Val105Met, описанных при данном заболевании в соседних популяциях, проживающих на территориях южнее Якутии, - у китайцев и японцев.

A maximum parsimony tree of 21 complete mitochondrial DNA (mtDNA) sequences belonging to haplogroup X and the survey of the haplogroup-associated polymorphisms in 13,589 mtDNAs from Eurasia and Africa revealed that haplogroup X is subdivided into two major branches, here defined as ""X1"" and ""X2."" The first is restricted to the populations of North and East Africa and the Near East, whereas X2 encompasses all X mtDNAs from Europe, western and Central Asia, Siberia, and the great majority of the Near East, as well as some North African samples. Subhaplogroup X1 diversity indicates an early coalescence time, whereas X2 has apparently undergone a more recent population expansion in Eurasia, most likely around or after the last glacial maximum. It is notable that X2 includes the two complete Native American X sequences that constitute the distinctive X2a clade, a clade that lacks close relatives in the entire Old World, including Siberia. The position of X2a in the phylogenetic tree suggests an early split from the other X2 clades, likely at the very beginning of their expansion and spread from the Near East.

Mutations causing familial hypertrophic cardiomyopathy (HCM) have been described in at least 11 genes encoding cardiac sarcomeric proteins. In this study, three previously unknown deletions have been identified in the human cardiac genes coding for beta-myosin heavy chain (MYH7 on chromosome 14) and myosin-binding protein-C (MYBPC3 on chromosome 11). In family MM, a 3-bp deletion in MYH7 was detected to be associated with loss of glutamic acid in position 927 (DeltaE927) of the myosin rod. In two other families (HH and NP, related by a common founder) a 2-bp loss in codon 453 (exon 16) of MYBPC3 was identified as the presumable cause of a translation reading frame shift. Taken together 15 living mutation carriers were investigated. Six deceased family members (with five cases of premature sudden cardiac death (SCD) in families MM and NP) were either obligate or suspected mutation carriers. In addition to these mutations a 25-bp deletion in intron 32 of MYBPC3 was identified in family MM (five carriers) and in a fourth family (MiR, one HCM patient, three deletion carriers). In agreement with the loss of the regular splicing branch point in the altered intron 32, a splicing deficiency was observed in an exon trapping experiment using MYBPC3 exon 33 as a test substrate. Varying disease profiles assessed using standard clinical, ECG and echocardiographic procedures in conjunction with mutation analysis led to the following conclusions: (1) In family MM the DeltaE927 deletion in MYH7 was assumed to be associated with complete penetrance. Two cases of reported SCD might have been related to this mutation. (2) The two families, HH and NP, distantly related by a common founder, and both suffering from a 2-bp deletion in exon 16 of MYBPC3 differed in their average phenotypes. In family NP, four cases of cardiac death were documented, whereas no cardiac-related death was reported from family HH. These results support the notion that mutations in HCM genes may directly determine disease penetrance and severity; however, a contribution of additional, unidentified factors (genes) to the HCM phenotype can-at least in some cases-not be excluded. (3) The deletion in intron 32 of MYBPC3 was seen in two families, but in both its relation to disease was not unequivocal. In addition, this deletion was observed in 16 of 229 unrelated healthy individuals of the population of the South Indian states of Kerala and Tamil Nadu. It was not seen in 270 Caucasians from Russia and western Europe. Hence, it is considered to represent a regional genetic polymorphism restricted to southern India. The association of the deletion with altered splicing in transfected cells suggests that this deletion may create a ""modifying gene"", which is per se not or only rarely causing HCM, but which may enhance the phenotype of a mutation responsible for disease.

Two polymorphisms in the IL4 (G/C 3'-UTR) and IL5 (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-703 IL5 with 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 GG IL4 (OR = 0.39, 95% CI = 0.15-0.99, p = 0.035), and also a trend towards a positive association of the GC IL4 genotype (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's chi(2) test with continuity correction constituted 0.03, d.f. = 1, p = 0.859). These results suggest that polymorphisms in the IL4 and IL5 genes contribute to the susceptibility to atopic BA and could determine the clinical course of the disease.

Two tribal groups from southern India--the Chenchus and Koyas--were analyzed for variation in mitochondrial DNA (mtDNA), the Y chromosome, and one autosomal locus and were compared with six caste groups from different parts of India, as well as with western and central Asians. In mtDNA phylogenetic analyses, the Chenchus and Koyas coalesce at Indian-specific branches of haplogroups M and N that cover populations of different social rank from all over the subcontinent. Coalescence times suggest early late Pleistocene settlement of southern Asia and suggest that there has not been total replacement of these settlers by later migrations. H, L, and R2 are the major Indian Y-chromosomal haplogroups that occur both in castes and in tribal populations and are rarely found outside the subcontinent. Haplogroup R1a, previously associated with the putative Indo-Aryan invasion, was found at its highest frequency in Punjab but also at a relatively high frequency (26%) in the Chenchu tribe. This finding, together with the higher R1a-associated short tandem repeat diversity in India and Iran compared with Europe and central Asia, suggests that southern and western Asia might be the source of this haplogroup. Haplotype frequencies of the MX1 locus of chromosome 21 distinguish Koyas and Chenchus, along with Indian caste groups, from European and eastern Asian populations. Taken together, these results show that Indian tribal and caste populations derive largely from the same genetic heritage of Pleistocene southern and western Asians and have received limited gene flow from external regions since the Holocene. The phylogeography of the primal mtDNA and Y-chromosome founders suggests that these southern Asian Pleistocene coastal settlers from Africa would have provided the inocula for the subsequent differentiation of the distinctive eastern and western Eurasian gene pools.

Разработанные в настоящее время технологии сделали доступной пренатальную диагностику многих врожденных пороков развития и наследственных заболеваний. Более того, новые диагностические методы создали реальную возможность предупреждать рождение детей с грубой патологией невральной трубки, сердца, почек, скелета и др. Техника оперативного лечения врожденных пороков развития разрабатывается в течение последних 15 лет в эксперименте и клинике.