[Mitochondrial genome and human mitochondrial diseases].

Today there are described more than 400 point mutations and more than hundred of structural rearrangements of mitochondrial DNA associated with characteristic neuromuscular and other mitochondrial syndromes, from lethal in the neonatal period of life to the disease with late onset. The defects of oxidative phosphorylation are the main reasons of mitochondrial disease development. Phenotypic diversity and phenomenon of heteroplasmy are the hallmark of mitochondrial human diseases. It is necessary to assess the amount of mutant mtDNA accurately, since the level of heteroplasmy largely determines the phenotypic manifestation. In spite of better understanding of the processes of phenotypic expression, currently there are no adequate treatments for mitochondrial diseases.

[Role of natural selection in evolution of mitochondrial haplogroups from Northeastern Eurasia].

The role of natural selection in the evolution of human populations from Northeastern Eurasia was studied. Selection for the regions-specific haplogroup C was demonstrated.

[The genetic history of long-term Russian resident populations of polar northeastern Siberia based on mitochondrial DNA variability].

The mtDNA variation has been studied in representatives of the Russkoe Ust'e (n = 30), Kolyma (n = 31), and Markovo (n = 26) ethnic subgroups originating from Russian military men, hunters, and fishers who married local Yukaghir women and settled at the Arctic Ocean coast and on the Anadyr' River more than 350 years ago. The mtDNA haplotypes characteristic of indigenous Siberian peoples have been demonstrated to form the basis of the mitochondrial gene pool of long-term Russian resident populations of the region. Only one of 30 identified haplotypes belonging to 11 haplogroups (H2a) is characteristic of European populations. The C and D haplogroups are the most diverse. The analysis has revealed the characteristics of the population structure of the long-term Russian resident populations and allowed them to be interpreted in terms of recent historical and environmental processes.

[Analysis of the mitochondrial DNA diversity in Yukaghirs in the evolutionary context].

Based on the mtDNA first hypervariable segment sequence variation data, statistical analysis of the diversity in Yukaghirs in comparison with the other indigenous populations of Siberia, was carried out. The level of the Yukaghir mtDNA gene diversity (GD) constituted 0.920, which was only slightly different from the corresponding estimate for the other Siberian populations. Integral estimates of the genetic structure of Siberian populations (k, S, theta(s), and pi) are presented. Phylogenetic analysis, performed using the neighbor-joining method, showed that the Siberian populations clustered irrespectively to their language affiliation. Negative F(s) values found in Yukaghirs pointed to the possible influence of adaptive selection.

[Spectrum of pathogenic mtDNA mutations in Leber hereditary optic neuropathy families from Siberia].

The results of clinical, genealogical and molecular investigation of eighteen families with Leber hereditary optic neuropathy (LHON), identified on the territory of Siberia during the period from 1997 to 2005, are presented. Comprehensive analysis of mitochondrial genome variations in probands and their matrilineal relatives revealed the presence of relatively frequent (G11778A, G3460A, and T14484C), as well as rare and new mutations with the established or presumptive pathological effect (T10663C, G363A, C4640T, and A14619G). The G11778A mutation was detected in nine pedigrees (50%), mostly in the families of ethnic Russians. In eight of these families G11778A was found in preferred association with the coding-region substitutions, typical of western Eurasian mtDNA lineage (haplogroup) TJ. On the contrary, the G3460A mutation was detected in the three families belonging to the indigenous Siberian populations (Tuvinians, Altaians, and Buryats). It was associated with clearly different haplotypes of eastern Eurasian haplogroups, C3, D5, and D8. Unexpectedly, the G3460A de novo mutation was found in a large Tuvinian pedigree. At the same time, in eleven out of fourteen families of Caucasoid origin pathogenic mutations in the ND genes were associated with the T4216C and C1542A coding-region mutations, marking the root motif of haplogoup TJ. It is suggested that phylogenetically ancient mutations could have provided their carriers with the adaptive advantages upon the development of Central and Northern Europe at the end of the last glaciation (10 000 to 9 000 years ago), thereby, contributing to the preservation of weekly pathogenic LHON mutations, appearing at specific genetic background.

[Genetic history of Aleuts of the Komandor islands from results of analyzing variability of class II HLA genes]. / Geneticheskaia istoriia aleutov komandorskikh ostrovov po rezul'tatam analiza izmenchivosti HLA-genov II klassa.

Variability of the HLA class II genes (alleles of the DRB1, DQA1, and DQB1 loci) was investigated in a sample of Aleuts of the Commanders (n = 31), whose ancestors inhabited the Commander Islands for many thousand years. Among 19 haplotypes revealed in Aleuts of the Commanders, at most eight were inherited from the native inhabitants of the Commander Islands. Five of these haplotypes (DRB1*0401-DQA1*0301-DQB1*0301, DRB1*1401-DQA1*0101-DQB1*0503, DRB1*0802-DQA1*0401-DQB1*0402, DRB1*1101-DQA1*0501-DQB1*0301, and DRB1*1201-DQA1*0501-DQB1*0301) were typical of Beringian Mongoloids, i.e., Coastal Chukchi and Koryaks, as well as Siberian and Alaskan Eskimos. Genetic contribution of the immigrants to the genetic pool of proper Aleuts constituted about 52%. Phylogenetic analysis based on Transberingian distribution of the DRB1 allele frequencies favored the hypothesis on the common origin of Paleo-Aleuts, Paleo-Eskimos, and the Indians from the northwestern North America, whose direct ancestors survived in Beringian/southwestern Alaskan coastal refugia during the late Ice Age.

[Mitochondrial DNA variation in Kets and Nganasans and the early peoples of Northern Eurasia]. / Izmenchivost' mitokhondrial'noi DNK u ketov i nganasan v sviazi s pervonachal'nym zaseleniem Severnoi Evrazii.

Mitochondrial DNA (mtDNA) variation was studied in 38 Kets and 24 Nganasans, the indigenous inhabitants of the north of the Yenisey River Basin and the Taimyr Peninsula. The results were compared with the analogous data obtained for 59 Kondinski and 39 Sos'vinski Mansi. As a whole, mitochondrial gene pool of Mansi, Nganasans, and Kets was characterized by unique combination of European-specific (H, H2, H3, H8, U2, U4, U5, U7, J2, and W) and Asian-specific (A, C, D, and Z) mtDNA haplogroups. Specific features of the haplogroup geographical distribution along with the results of phylogenetic reconstruction favor the hypothesis of the genetic trace left in Eastern Cis-Urals and the adjacent Siberian territories by early migrations from the Near East.

[The mitochondrial genome and human mitochondrial diseases]. / Mitokhondrial'nyi genom i mitokhondrial'nye bolezni cheloveka.

To date, more than 100 point mutations and several hundreds of structural rearrangements of mitochondrial DNA (mtDNA) are known too be connected with characteristic neuromuscular and other mitochondrial syndromes varying form those causing death at the neonatal stage to diseases with late ages of onset. The immediate cause of mitochondrial disorders is a defective oxidative phosphorylation. Wide phenotypic variation and the heteroplasmy phenomenon, which some authors include in mutation load, are characteristic of human mitochondrial diseases. As the numbers of cases identified and pedigrees described increase, data on the genotype--phenotype interaction and the structure and frequency of pathogenic and conditionally pathogenic mtDNA mutations in human populations are rapidly accumulated. The data on the genetics and epidemiology of mitochondrial diseases are not only important for differential diagnosis and genetic counseling. Since both neutral and mildly pathogenic mutations of mtDNA are progressively accumulated in maternal phyletic lines, molecular analysis of these mutations permits not only reconstruction of the genealogical tree of modern humans, but also estimation of the role that these mutations play in natural selection.

Glyceraldehyde-3-phosphate dehydrogenase is responsible for intranuclear localization of some oligonucleotides.

Nuclear accumulation of ODNs has been associated with their binding to a series of nuclear proteins. These interactions could be responsible for the sequence-independent effects of ODNs as well as for their sequence-specific interactions and their intracellular distribution. Investigation of interaction of ODNs with these proteins may shed light on the mechanisms of cellular uptake and nuclear accumulation of oligonucleotides.