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The Central Siberian Plateau was the last geographic area in Eurasia to become habitable by modern humans after the Last Glacial Maximum (LGM). Through a comprehensive dataset of mitochondrial DNA (mtDNA) genomes retained in the remnats of earlier ("Old") Siberians, primarily the Ket, Tofalar, and Todzhi, we explored genetic links between the Yenisei-Sayan region and Northeast Eurasia (best represented by the Yukaghir) over the last 10,000 years. We generated 218 new complete mtDNA sequences and placed them into compound phylogenies with 7 newly obtained and 70 published ancient mitochondrial genomes. We have considerably extended the mtDNA sequence diversity (at the entire mtDNA genome level) of autochthonous Siberians, which remain poorly sampled, and these new data may have a broad impact on the study of human migration. We compared present-day mtDNA diversity in these groups with complete mitochondrial genomes from ancient samples from the region and placed the samples into combined genealogical trees. The resulting components were used to clarify the origins and expansion history of mtDNA lineages that evolved in the refugia of south-central Siberia and beyond, as well as multiple phases of connection between this region and distant parts of Eurasia. [ABSTRACT FROM AUTHOR]

Background: We have described the diversity of complete mtDNA sequences from 'relic' groups of the Russian Far East, primarily the Nivkhi (who speak a language isolate with no clear relatedness to any others) and Oroki of Sakhalin, as well as the sedentary Koryak from Kamchatka and the Udegey of Primorye. Previous studies have shown that most of their traditional territory was dramatically reshaped by the expansion of Tungusic-speaking groups. Results: Overall, 285 complete mitochondrial sequences were selected for phylogenetic analyses of published, revised and new mitogenomes. To highlight the likely role of Neolithic expansions in shaping the phylogeographical landscape of the Russian Far East, we focus on the major East Eurasian maternal lineages (Y1a, G1b, D4m2, D4e5, M7a2, and N9b) that are restricted to the coastal area. To obtain more insight into autochthonous populations, we removed from the phylogeographic analysis the G2a, G3a2, M8a1, M9a1, and C4b1 lineages, also found within our samples, likely resulting from admixture between the expanding proto-Tungus and the indigenous Paleoasiatic groups with whom they assimilated. Phylogenetic analysis reveals that unlike the relatively diverse lineage spectrum observed in the Amur estuary and northwestern Sakhalin, the present-day subpopulation on the northeastern coast of the island is relatively homogenous: a sole Y1a sublineage, conspicuous for its nodal mutation at m.16189 T > C!, includes different haplotypes. Sharing of the Y1a-m.16189 T > C! sublineages and haplotypes among the Nivkhi, Ulchi and sedentary Koryak is also evident. Aside from Y1a, the entire tree approach expands our understanding of the evolutionary history of haplogroups G1, D4m, N9b, and M7a2. Specifically, we identified the novel haplogroup N9b1 in Primorye, which implies a link between a component of the Udegey ancestry and the Hokkaido Jomon. Conclusions: Through a comprehensive dataset of mitochondrial genomes retained in autochthonous populations along the coast between Primorye and the Bering Strait, we considerably extended the sequence diversity of these populations to provide new features based on the number and timing of founding lineages. We emphasize the value of integrating genealogical information with genetic data for reconstructing the population history of indigenous groups dramatically impacted by twentieth century resettlement and social upheavals. [ABSTRACT FROM AUTHOR]

The patterns of prehistoric migrations across the Bering Land Bridge are far from being completely understood: there still exists a significant gap in our knowledge of the population history of former Beringia. Here, through comprehensive survey of mitochondrial DNA genomes retained in 'relic' populations, the Maritime Chukchi, Siberian Eskimos, and Commander Aleuts, we explore genetic contribution of prehistoric Siberians/Asians to northwestern Native Americans. Overall, 201 complete mitochondrial sequences (52 new and 149 published) were selected in the reconstruction of trees encompassing mtDNA lineages that are restricted to Coastal Chukotka and Alaska, the Canadian Arctic, Greenland, and the Aleutian chain. Phylogeography of the resulting mtDNA genomes (mitogenomes) considerably extends the range and intrinsic diversity of haplogroups (eg, A2a, A2b, D2a, and D4b1a2a1) that emerged and diversified in postglacial central Beringia, defining independent origins of Neo-Eskimos versus Paleo-Eskimos, Aleuts, and Tlingit (Na-Dene). Specifically, Neo-Eskimos, ancestral to modern Inuit, not only appear to be of the High Arctic origin but also to harbor Altai/Sayan-related ancestry. The occurrence of the haplogroup D2a1b haplotypes in Chukotka (Sireniki) introduces the possibility that the traces of Paleo-Eskimos have not been fully erased by spread of the Neo-Eskimos or their descendants. Our findings are consistent with the recurrent gene flow model of multiple streams of expansions to northern North America from northeastern Eurasia in late Pleistocene-early Holocene. [ABSTRACT FROM AUTHOR]

To fill remaining gaps in mitochondrial DNA diversity in the least surveyed eastern and western flanks of Siberia, 391 mtDNA samples (144 Tubalar from Altai, 87 Even from northeastern Siberia, and 160 Ulchi from the Russian Far East) were characterized via high-resolution restriction fragment length polymorphism/single nucleotide polymorphisms analysis. The subhaplogroup structure was extended through complete sequencing of 67 mtDNA samples selected from these and other related native Siberians. Specifically, we have focused on the evolutionary histories of the derivatives of M and N haplogroups, putatively reflecting different phases of settling Siberia by early modern humans. Population history and phylogeography of the resulting mtDNA genomes, combined with those from previously published data sets, revealed a wide range of tribal- and region-specific mtDNA haplotypes that emerged or diversified in Siberia before or after the last glacial maximum, ∼18 kya. Spatial distribution and ages of the 'east' and 'west' Eurasian mtDNA haploclusters suggest that anatomically modern humans that originally colonized Altai derived from macrohaplogroup N and came from Southwest Asia around 38,000 years ago. The derivatives of macrohaplogroup M, which largely emerged or diversified within the Russian Far East, came along with subsequent migrations to West Siberia millennia later. The last glacial maximum played a critical role in the timing and character of the settlement of the Siberian subcontinent. Am J Phys Anthropol, 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

In search of the ancestors of Native American mitochondrial DNA (mtDNA) haplogroups, we analyzed the mtDNA of 531 individuals from nine indigenous populations in Siberia. All mtDNAs were subjected to high-resolution RFLP analysis, sequencing of the control-region hypervariable segment I (HVS-I), and surveyed for additional polymorphic markers in the coding region. Furthermore, the mtDNAs selected according to haplogroup/subhaplogroup status were completely sequenced. Phylogenetic analyses of the resulting data, combined with those from previously published Siberian arctic and sub-arctic populations, revealed that remnants of the ancient Siberian gene pool are still evident in Siberian populations, suggesting that the founding haplotypes of the Native American A-D branches originated in different parts of Siberia. Thus, lineage A complete sequences revealed in the Mansi of the Lower Ob and the Ket of the Lower Yenisei belong to A1, suggesting that A1 mtDNAs occasionally found in the remnants of hunting-gathering populations of northwestern and northern Siberia belonged to a common gene pool of the Siberian progenitors of Paleoindians. Moreover, lineage B1, which is the most closely related to the American B2, occurred in the Tubalar and Tuvan inhabiting the territory between the upper reaches of the Ob River in the west, to the Upper Yenisei region in the east. Finally, the sequence variants of haplogroups C and D, which are most similar to Native American C1 and D1, were detected in the Ulchi of the Lower Amur. Overall, our data suggest that the immediate ancestors of the Siberian/Beringian migrants who gave rise to ancient (pre-Clovis) Paleoindians have a common origin with aboriginal people of the area now designated the Altai-Sayan Upland, as well as the Lower Amur/Sea of Okhotsk region. [ABSTRACT FROM AUTHOR]

Human mtDNA shows striking regional variation, traditionally attributed to genetic drift. However, it is not easy to account for the fact that only two mtDNA lineages (M and N) left Africa to colonize Eurasia and that lineages A, C, D, and G show a 5-fold enrichment from central Asia to Siberia. As an alternative to drift, natural selection might have enriched for certain mtDNA lineages as people migrated north into colder climates. To test this hypothesis we analyzed 104 complete mtDNA sequences from all global regions and lineages. African mtDNA variation did not significantly deviate from the standard neutral model, but European, Asian, and Siberian plus Native American variations did. Analysis of amino acid substitution mutations (nonsynonymous, Ka) versus neutral mutations (synonymous, Ks) (ka/ks) for all 13 mtDNA proteincoding genes revealed that the ATP6 gene had the highest amino acid sequence variation of any human mtDNA gene, even though ATP6 is one of the more conserved mtDNA proteins. Comparison of the ka/ks ratios for each mtDNA gene from the tropical, temperate, and arctic zones revealed that ATP6 was highly variable in the mtDNAs from the arctic zone, cytochrome b was particularly variable in the temperate zone, and cytochrome oxidase I was notably more variable in the tropics. Moreover, multiple amino acid changes found in ATP6, cytochrome b, and cytochrome oxidase I appeared to be functionally significant. From these analyses we conclude that selection may have played a role in shaping human regional mtDNA variation and that one of the selective influences was climate. [ABSTRACT FROM AUTHOR]

Gene frequencies of eight Siberian populations (Mansi, Tuva, Todja, Tofalar, Buryat, Okhotsk Evenki, Ulchi, and Negidal) were determined for the three most polymorphic HLA class II loci (DRB1, DQA1, and DQB1) by a combination of single-stranded conformational polymorphism typing and DNA sequencing. The number of alleles per population ranged from 16 to 25, from seven to eight, and from nine to 14 for the DRB1, DQA1, and DQB1 loci, respectively. The alleles at the three loci occurred in 66 different combinations (haplotypes), most of which appeared to be of ancient origin, but some may have arisen within the Siberian populations. Phylogenetic analysis of the frequency data suggests that the HLA genes of Asian and indigenous American populations stem from a single pool distinct from the gene pools of European and African populations. The Asian populations separate into two clusters, one of which encompasses nearly all the Siberian populations and all the indigenous American populations tested, while the other consists of Central, Eastern, and Southeastern Asian populations. The position of the Tuva people appears to be near the node from which the two clusters diverge. The divergence time of the two clusters is estimated to be 21,000–24,000 years BP. Three different branches of the native Siberian peoples seem to have contributed founders for the indigenous American ethnic groups. [ABSTRACT FROM AUTHOR]

Leber's hereditary optic neuropathy (LHON) is a maternally transmitted form of blindness caused by mitochondrial DNA (mtDNA) mutations. Approximately 90% of LHON cases are caused by 3460A, 11778A, or 14484C mtDNA mutations. These are designated "primary" mutations because they impart a high risk for LHON expression. Although the 11778A and 14484C mutations unequivocally predispose carriers to LHON, they are preferentially associated with mtDNA haplogroup J, one of nine Western Eurasian mtDNA lineages, suggesting a synergistic and deleterious interaction between these LHON mutations and haplogroup J polymorphism(s). We report here the characterization of a new primary LHON mutation in the mtDNA ND4L gene at nucleotide pair 10663. The homoplasmic 10663C mutation has been found in three independent LHON patients who lack a known primary mutation and all of which belong to haplogroup J. This mutation has not been found in a large number of haplotype-matched or non-haplogroup-J control mtDNAs. Phylogenetic analysis with primarily complete mtDNA sequence data demonstrates that the 10663C mutation has arisen at least three independent times in haplogroup J, indicating that it is not a rare lineage-specific polymorphism. Analysis of complex I function in patient lymphoblasts and transmitochondrial cybrids has revealed a partial complex I defect similar in magnitude to the 14484C mutation. Thus, the 10663C mutation appears to be a new primary LHON mutation that is pathogenic when co-occurring with haplogroup J. These results strongly support a role for haplogroup J in the expression of certain LHON mutations. [ABSTRACT FROM AUTHOR]

Leber's hereditary optic neuropathy (LHON) is characterized by maternally transmitted, bilateral, central vision loss in young adults. It is caused by mutations in the mitochondrial DNA (mtDNA) encoded genes that contribute polypeptides to NADH dehydrogenase or complex I. Four mtDNA variants, the nucleotide pair (np) 3460A, 11778A, 14484C, and 14459A mutations, are known as "primary" LHON mutations and are found in most, but not all, of the LHON families reported to date. Here, we report the extensive genetic and biochemical analysis of five Russian families from the Novosibirsk region of Siberia manifesting maternally transmitted optic atrophy consistent with LHON. Three of the five families harbor known LHON primary mutations. Complete sequence analysis of proband mtDNA in the other two families has revealed novel complex I mutations at nps 3635A and 4640C, respectively. These mutations are homoplasmic and have not been reported in the literature. Biochemical analysis of complex I in patient lymphoblasts and transmitochondrial cybrids demonstrated a respiration defect with complex-I-linked substrates, although the specific activity of complex I was not reduced. Overall, our data suggests that the spectrum of mtDNA mutations associated with LHON in Russia is similar to that in Europe and North America and that the np 3635A and 4640C mutations may be additional mtDNA complex I mutations contributing to LHON expression. [ABSTRACT FROM AUTHOR]

Presents information on a study which analyzed the mitochondrial DNA (mtDNA) variation in Koryaks and Itel'men populations from different parts of the Kamchatka peninsula. Methodology; mtDNA haplogroups in Kamchatkan populations; Haplotype distribution in eastern Siberians; Genetic diversity of Siberian populations.

Our data first represent the variety of Leber's hereditary optic neuropathy (LHON) mutations in Western Siberia. LHON is a disorder caused by pathogenic mutations in the mitochondrial DNA (mtDNA), inherited maternally and presents mainly in young adults, predominantly males. Clinically, LHON manifests itself as painless central vision loss, resulting in early onset of disability. The epidemiology of LHON has not been fully investigated yet. In this study, we report 44 genetically unrelated families with LHON manifestation. We performed whole mtDNA genome sequencing and provided genealogical and molecular genetic data on mutations and haplogroup background of LHON patients. Known "primary" pathogenic mtDNA mutations (MITOMAP) were found in 32 families: m.11778G>A represents 53.10% (17/32), m.3460G>A—21.90% (7/32), m.14484T>C–18.75% (6/32), and rare m.10663T>C and m.3635G>A represent 6.25% (2/32). We describe potentially pathogenic m.4659G>A in one subject without known pathogenic mutations, and potentially pathogenic m.6261G>A, m.8412T>C, m.8551T>C, m.9444C>T, m.9921G>A, and m.15077G>A in families with known pathogenic mutations confirmed. We suppose these mutations could contribute to the pathogenesis of optic neuropathy development. Our results indicate that haplogroup affiliation and mutational spectrum of the Western Siberian LHON cohort substantially deviate from those of European populations. [ABSTRACT FROM AUTHOR]