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Beyond fat suppression (FS), the efficacy of (fat-water separation or Dixon [FWD]) Dixon imaging in gadolinium-enhanced spine imaging has yet to be validated. This study evaluated enhanced opposed-phase (OP) and fat-only (FO) images along with water-only (WO; FS) images against traditional unenhanced techniques and rated the incremental value of in-phase imaging in patients with presumed neoplastic focal spine lesions.A retrospective cohort study of 36 subjects with focal spine lesions imaged with FWD was evaluated qualitatively and quantitatively.Enhanced OP, WO, and FO images were of significant value in detection of osseous lesions, surpassing the lesion conspicuity with conventional techniques both qualitatively and quantitatively, although the impact of in-phase imaging was limited. Water-only imaging performed well for FS.Contrast-enhanced FO, WO, and OP outperform traditional techniques, providing reliable lesion characterization and highest conspicuity. In-phase imaging offered limited impact on the subjective assessment of enhancement. The added value and robustness of FWD, particularly the unique contrast provided by FO imaging, suggests consideration for routine use for postgadolinium spine imaging.

The linguistically distinctive Haida and Tlingit tribes of Southeast Alaska are known for their rich material culture, complex social organization, and elaborate ritual practices. However, much less is known about these tribes from a population genetic perspective. For this reason, we analyzed mtDNA and Y-chromosome variation in Haida and Tlingit populations to elucidate several key issues pertaining to the history of this region. These included the genetic relationships of Haida and Tlingit to other indigenous groups in Alaska and Canada; the relationship between linguistic and genetic data for populations assigned to the Na-Dene linguistic family, specifically, the inclusion of Haida with Athapaskan, Eyak, and Tlingit in the language family; the possible influence of matrilineal clan structure on patterns of genetic variation in Haida and Tlingit populations; and the impact of European entry into the region on the genetic diversity of these indigenous communities. Our analysis indicates that, while sharing a “northern” genetic profile, the Haida and the Tlingit are genetically distinctive from each other. In addition, Tlingit groups themselves differ across their geographic range, in part due to interactions of Tlingit tribes with Athapaskan and Eyak groups to the north. The data also reveal a strong influence of maternal clan identity on mtDNA variation in these groups, as well as the significant influence of non-native males on Y-chromosome diversity. These results yield new details about the histories of the Haida and Tlingit tribes in this region.

Recently, the observation of a high-frequency private allele, the 9-repeat allele at microsatellite D9S1120, in all sampled Native American and Western Beringian populations has been interpreted as evidence that all modern Native Americans descend primarily from a single founding population. However, this inference assumed that all copies of the 9-repeat allele were identical by descent and that the geographic distribution of this allele had not been influenced by natural selection. To investigate whether these assumptions are satisfied, we genotyped 34 single nucleotide polymorphisms across approximately 500 kilobases (kb) around D9S1120 in 21 Native American and Western Beringian populations and 54 other worldwide populations. All chromosomes with the 9-repeat allele share the same haplotypic background in the vicinity of D9S1120, suggesting that all sampled copies of the 9-repeat allele are identical by descent. Ninety-one percent of these chromosomes share the same 76.26 kb haplotype, which we call the "American Modal Haplotype" (AMH). Three observations lead us to conclude that the high frequency and widespread distribution of the 9-repeat allele are unlikely to be the result of positive selection: 1) aside from its association with the 9-repeat allele, the AMH does not have a high frequency in the Americas, 2) the AMH is not unusually long for its frequency compared with other haplotypes in the Americas, and 3) in Latin American mestizo populations, the proportion of Native American ancestry at D9S1120 is not unusual compared with that observed at other genomewide microsatellites. Using a new method for estimating the time to the most recent common ancestor (MRCA) of all sampled copies of an allele on the basis of an estimate of the length of the genealogy descended from the MRCA, we calculate the mean time to the MRCA of the 9-repeat allele to be between 7,325 and 39,900 years, depending on the demographic model used. The results support the hypothesis that all modern Native Americans and Western Beringians trace a large portion of their ancestry to a single founding population that may have been isolated from other Asian populations prior to expanding into the Americas.

The Altaian Kazakhs, a Turkic speaking group, now reside in the southern part of the Altai Republic in south-central Russia. According to historical accounts, they are one of several ethnic and geographical subdivisions of the Kazakh nomadic group that migrated from China and Western Mongolia into the Altai region during the 19th Century. However, their population history of the Altaian Kazakhs and the genetic relationships with other Kazakh groups and neighboring Turkic-speaking populations is not well understood. To begin elucidating their genetic history, we analyzed the mtDNAs from 237 Altaian Kazakhs through a combination of SNP analysis and HVS1 sequencing. This analysis revealed that their mtDNA gene pool was comprised of roughly equal proportions of East (A-G, M7, M13, Y and Z) and West (H, HV, pre-HV, R, IK, JT, X, U) Eurasian haplogroups, with the haplotypic diversity within haplogroups C, D, H, and U being particularly high. This pattern of diversity likely reflects the complex interactions of the Kazakhs with other Turkic groups, Mongolians, and indigenous Altaians. Overall, these data have important implications for Kazakh population history, the genetic prehistory of the Altai-Sayan region, and the phylogeography of major mitochondrial lineages in Eurasia.

In 1653, the Patriarch Nikon modified liturgical practices to bring the Russian Orthodox Church in line with those of the Eastern (Greek) Orthodox Church, from which it had split 200 years earlier. The Old Believers (staroveri) rejected these changes and continued to worship using the earlier practices. These actions resulted in their persecution by the Russian Orthodox Church, which forced them into exile across Siberia. Given their history, we investigate whether populations of Old Believers have diverged genetically from other Slavic populations as a result of their isolation. We also examine whether the three Old Believer populations analyzed in this study are part of a single gene pool (founder population) or are instead derived from heterogeneous sources. As part of this analysis, we survey the mitochondrial DNAs (mtDNAs) of 189 Russian Old Believer individuals from three populations in Siberia and 201 ethnic Russians from different parts of Siberia for phylogenetically informative mutations in the coding and noncoding regions. Our results indicate that the Old Believers have not significantly diverged genetically from other Slavic populations over the 200-300 years of their isolation in Siberia. However, they do show some unique patterns of mtDNA variation relative to other Slavic groups, such as a high frequency of subhaplogroup U4, a surprisingly low frequency of haplogroup H, and low frequencies of the rare East Eurasian subhaplogroup D5.

We report the de novo occurrence of a heteroplasmic 12706T-->C (12705C) ND5 mutation associated with the clinical expression of fatal Leigh syndrome. Phylogenetic analysis of several cases having the 12706C mutation confirmed that this mutation occurred independently in distinctive mtDNA backgrounds. In each of these cases, the low level of heteroplasmy and the association of the mutation with a deleterious phenotype indicated that the 12706C had a primary role in the expression of LS/MELAS in its carriers. Secondary structure analysis of the ND5 protein further supported the deleterious role of the 12706C mutation, as it was found to affect a functionally significant transmembrane domain that is likely responsible for the proton-translocation function of complex I.

The three-wave migration hypothesis of Greenberg et al . has permeated the genetic literature on the peopling of the Americas. Greenberg et al . proposed that Na-Dene, Aleut-Eskimo and Amerind are language phyla which represent separate migrations from Asia to the Americas. We show that a unique allele at autosomal microsatellite locus D9S1120 is present in all sampled North and South American populations, including the Na-Dene and Aleut-Eskimo, and in related Western Beringian groups, at an average frequency of 31.7%. This allele was not observed in any sampled putative Asian source populations or in other worldwide populations. Neither selection nor admixture explains the distribution of this regionally specific marker. The simplest explanation for the ubiquity of this allele across the Americas is that the same founding population contributed a large fraction of ancestry to all modern Native American populations.

Recent studies suggest that certain mutations with phylogeographic importance as haplogroup markers may also influence the phenotypic expression of particular mitochondrial disorders. One such disorder, Leber's hereditary optic neuropathy (LHON), demonstrates a clear expression bias in mtDNAs belonging to haplogroup J, a West Eurasian maternal lineage defined by polymorphic markers that have been called 'secondary' disease mutations. In this report, we present evidence for a de novo heteroplasmic COX2 mutation associated with a LHON clinical phenotype. This particular mutation-at nucleotide position 7,598-occurs in West Eurasian haplogroup H, the most common maternal lineage among individuals of European descent, whereas previous studies have detected this mutation only in East Eurasian haplogroup E. A review of the available mtDNA sequence data indicates that the COX2 7598 mutation occurs as a homoplasic event at the tips of these phylogenetic branches, suggesting that it could be a variant that is rapidly eliminated by selection. This finding points to the potential background influence of polymorphisms on the expression of mild deleterious mutations such as LHON mtDNA defects and further highlights the difficulties in distinguishing deleterious mtDNA changes from neutral polymorphisms and their significance in the development of mitochondriopathies.

The marriage structure of Nganasans during the time period from 1796 to 1991 and genealogy of carriers of mitochondrial DNA haplotypes was studied in a sample of 280 individuals. It was shown that, from the beginning of its formation to the late 1970s, the population exhibited high endogamy (1976, 83.8%; 1926, 88.4%; 1976, 74.3%). The main source of traditional marriage migration (preferentially female) was populations of Entsy and, indirectly, Nentsy. Intense assimilation of Nganasans by the immigrant population, and to a lesser extent, by Dolgans, in the second half of the 20th century resulted in a reduction of endogamy index in Avam Nganasans to 42.5% by 1991. Assimilation by the immigrants was predominantly paternal, promoting preservation of the historically formed genetic diversity of the Nganasan mitochondrial gene pool. Genealogical analysis of mtDNA haplotypes showed that a relatively high total frequency of Western Eurasian mtDNA haplogroups (20.4%) in the Mongoloid (according to anthropological type) Nganasan population is explained not only by the common ethnic origin with Entsy and Nentsy, but also by direct marriage migration from the Entsy population and indirect marriage migration, from the Nentsy population. This migration led to accumulation of Entsy-Nentsy maternal lineages in the genealogy of Avam Nganasans (38.9 in 2000 of the total number). Of all mtDNA haplotypes, seven (of 21) were introduced to Avam Nganasans by female Entsy and Nentsy, whereas the total frequency of these haplotypes was 0.204. Genetic diversity of mitochondrial DNA haplotypes was 0.935.

Variation in the manifestation age is typical of many mitochondrial diseases. The estimation of penetrance of pathogenic mutations causing such diseases is usually conducted on samples of individuals whose age exceeds the maximum age of the disease manifestation. In the case of rare diseases, samples of sufficient size sometimes cannot be formed. In this study, we propose a method for estimating penetrance involving individuals of any age. The efficiency of the method is demonstrated using Leber hereditary optic neuropathy as an example. It is shown that the method provides an unbiased estimate of penetrance and considerably reduces the error of this estimate in comparison with a sample including individuals whose age exceeds the maximum age of disease manifestation.

The name "Wampanoag" means "Eastern People" or "People of the First Light" in the local dialect of the Algonquian language. Once extensively populating the coastal lands and neighboring islands of the eastern United States, the Wampanoag people now consist of two federally recognized tribes, the Aquinnah and Mashpee, the state-recognized Seaconke Wampanoag tribe, and a number of bands and clans in present-day southern Massachusetts. Because of repeated epidemics and conflicts with English colonists, including King Philip's War of 1675-76, and subsequent colonial laws forbidding tribal identification, the Wampanoag population was largely decimated, decreasing in size from as many as 12,000 individuals in the 16th century to less than 400, as recorded in 1677. To investigate the influence of the historical past on its biological ancestry and native cultural identity, we analyzed genetic variation in the Seaconke Wampanoag tribe. Our results indicate that the majority of their mtDNA haplotypes belongs to West Eurasian and African lineages, thus reflecting the extent of their contacts and interactions with people of European and African descent. On the paternal side, Y-chromosome analysis identified a range of Native American, West Eurasian, and African haplogroups in the population, and also surprisingly revealed the presence of a paternal lineage that appears at its highest frequencies in New Guinea and Melanesia. Comparison of the genetic data with genealogical and historical information allows us to reconstruct the tribal history of the Seaconke Wampanoag back to at least the early 18th century.

Native Americans derive from a small number of Asian founders who likely arrived to the Americas via Beringia. However, additional details about the intial colonization of the Americas remain unclear. To investigate the pioneering phase in the Americas we analyzed a total of 623 complete mtDNAs from the Americas and Asia, including 20 new complete mtDNAs from the Americas and seven from Asia. This sequence data was used to direct high-resolution genotyping from 20 American and 26 Asian populations. Here we describe more genetic diversity within the founder population than was previously reported. The newly resolved phylogenetic structure suggests that ancestors of Native Americans paused when they reached Beringia, during which time New World founder lineages differentiated from their Asian sister-clades. This pause in movement was followed by a swift migration southward that distributed the founder types all the way to South America. The data also suggest more recent bi-directional gene flow between Siberia and the North American Arctic., La lista completa de autores que integran el documento puede consultarse en el archivo., Instituto Multidisciplinario de Biología Celular, Facultad de Ciencias Naturales y Museo

Leber's hereditary optic neuropathy (LHON) is a frequent cause of inherited blindness. A routine screening for common mtDNA mutations constitutes an important first in its diagnosis. However, a substantial number of LHON patients do not harbor known variants, both pointing to the genetic heterogeneity of LHON and bringing into question its genetic diagnosis. We report a familial case that exhibited typical features of LHON but lacked any of the common mutations. Genetic analysis revealed a novel pathogenic defect in the ND6 gene at 14279A that was not detected in any haplogroup-matched controls screened for it, nor has it been previously reported. This mutation causes a substantial conformational change in the secondary structure of the polypeptide matrix coil and may explain the LHON expression. Thus, it expands the spectrum of deleterious changes affecting ND6-encoding subunit and further highlights the functional significance of this gene, providing additional clues to the disease pathogenesis.

BackgroundSakha – an area connecting South and Northeast Siberia – is significant for understanding the history of peopling of Northeast Eurasia and the Americas. Previous studies have shown a genetic contiguity between Siberia and East Asia and the key role of South Siberia in the colonization of Siberia.ResultsWe report the results of a high-resolution phylogenetic analysis of 701 mtDNAs and 318 Y chromosomes from five native populations of Sakha (Yakuts, Evenks, Evens, Yukaghirs and Dolgans) and of the analysis of more than 500,000 autosomal SNPs of 758 individuals from 55 populations, including 40 previously unpublished samples from Siberia. Phylogenetically terminal clades of East Asian mtDNA haplogroups C and D and Y-chromosome haplogroups N1c, N1b and C3, constituting the core of the gene pool of the native populations from Sakha, connect Sakha and South Siberia. Analysis of autosomal SNP data confirms the genetic continuity between Sakha and South Siberia. Maternal lineages D5a2a2, C4a1c, C4a2, C5b1b and the Yakut-specific STR sub-clade of Y-chromosome haplogroup N1c can be linked to a migration of Yakut ancestors, while the paternal lineage C3c was most likely carried to Sakha by the expansion of the Tungusic people. MtDNA haplogroups Z1a1b and Z1a3, present in Yukaghirs, Evens and Dolgans, show traces of different and probably more ancient migration(s). Analysis of both haploid loci and autosomal SNP data revealed only minor genetic components shared between Sakha and the extreme Northeast Siberia. Although the major part of West Eurasian maternal and paternal lineages in Sakha could originate from recent admixture with East Europeans, mtDNA haplogroups H8, H20a and HV1a1a, as well as Y-chromosome haplogroup J, more probably reflect an ancient gene flow from West Eurasia through Central Asia and South Siberia.ConclusionsOur high-resolution phylogenetic dissection of mtDNA and Y-chromosome haplogroups as well as analysis of autosomal SNP data suggests that Sakha was colonized by repeated expansions from South Siberia with minor gene flow from the Lower Amur/Southern Okhotsk region and/or Kamchatka. The minor West Eurasian component in Sakha attests to both recent and ongoing admixture with East Europeans and an ancient gene flow from West Eurasia.

The Saami are regarded as extreme genetic outliers among European populations. In this study, a high-resolution phylogenetic analysis of Saami genetic heritage was undertaken in a comprehensive context, through use of maternally inherited mitochondrial DNA (mtDNA) and paternally inherited Y-chromosomal variation. DNA variants present in the Saami were compared with those found in Europe and Siberia, through use of both new and previously published data from 445 Saami and 17, 096 western Eurasian and Siberian mtDNA samples, as well as 127 Saami and 2, 840 western Eurasian and Siberian Y-chromosome samples. It was shown that the "Saami motif" variant of mtDNA haplogroup U5b is present in a large area outside Scandinavia. A detailed phylogeographic analysis of one of the predominant Saami mtDNA haplogroups, U5b1b, which also includes the lineages of the "Saami motif, " was undertaken in 31 populations. The results indicate that the origin of U5b1b, as for the other predominant Saami haplogroup, V, is most likely in western, rather than eastern, Europe. Furthermore, an additional haplogroup (H1) spread among the Saami was virtually absent in 781 Samoyed and Ob-Ugric Siberians but was present in western and central European populations. The Y-chromosomal variety in the Saami is also consistent with their European ancestry. It suggests that the large genetic separation of the Saami from other Europeans is best explained by assuming that the Saami are descendants of a narrow, distinctive subset of Europeans. In particular, no evidence of a significant directional gene flow from extant aboriginal Siberian populations into the haploid gene pools of the Saami was found.

The Altai region of southern Siberia has played a critical role in the peopling of northern Asia as an entry point into Siberia and a possible homeland for ancestral Native Americans. It has an old and rich history because humans have inhabited this area since the Paleolithic. Today, the Altai region is home to numerous Turkic-speaking ethnic groups, which have been divided into northern and southern clusters based on linguistic, cultural, and anthropological traits. To untangle Altaian genetic histories, we analyzed mtDNA and Y chromosome variation in northern and southern Altaian populations. All mtDNAs were assayed by PCR-RFLP analysis and control region sequencing, and the nonrecombining portion of the Y chromosome was scored for more than 100 biallelic markers and 17 Y-STRs. Based on these data, we noted differences in the origin and population history of Altaian ethnic groups, with northern Altaians appearing more like Yeniseian, Ugric, and Samoyedic speakers to the north, and southern Altaians having greater affinities to other Turkic speaking populations of southern Siberia and Central Asia. Moreover, high-resolution analysis of Y chromosome haplogroup Q has allowed us to reshape the phylogeny of this branch, making connections between populations of the New World and Old World more apparent and demonstrating that southern Altaians and Native Americans share a recent common ancestor. These results greatly enhance our understanding of the peopling of Siberia and the Americas.

Background Mitochondrial genome sequence analysis is critical to the diagnostic evaluation of mitochondrial disease. Existing methodologies differ widely in throughput, complexity, cost efficiency, and sensitivity of heteroplasmy detection. Affymetrix MitoChip v2.0, which uses a sequencing-by-genotyping technology, allows potentially accurate and high-throughput sequencing of the entire human mitochondrial genome to be completed in a cost-effective fashion. However, the relatively low call rate achieved using existing software tools has limited the wide adoption of this platform for either clinical or research applications. Here, we report the design and development of a custom bioinformatics software pipeline that achieves a much improved call rate and accuracy for the Affymetrix MitoChip v2.0 platform. We used this custom pipeline to analyze MitoChip v2.0 data from 24 DNA samples representing a broad range of tissue types (18 whole blood, 3 skeletal muscle, 3 cell lines), mutations (a 5.8 kilobase pair deletion and 6 known heteroplasmic mutations), and haplogroup origins. All results were compared to those obtained by at least one other mitochondrial DNA sequence analysis method, including Sanger sequencing, denaturing HPLC-based heteroduplex analysis, and/or the Illumina Genome Analyzer II next generation sequencing platform. Results An average call rate of 99.75% was achieved across all samples with our custom pipeline. Comparison of calls for 15 samples characterized previously by Sanger sequencing revealed a total of 29 discordant calls, which translates to an estimated 0.012% for the base call error rate. We successfully identified 4 known heteroplasmic mutations and 24 other potential heteroplasmic mutations across 20 samples that passed quality control. Conclusions Affymetrix MitoChip v2.0 analysis using our optimized MitoChip Filtering Protocol (MFP) bioinformatics pipeline now offers the high sensitivity and accuracy needed for reliable, high-throughput and cost-efficient whole mitochondrial genome sequencing. This approach provides a viable alternative of potential utility for both clinical diagnostic and research applications to traditional Sanger and other emerging sequencing technologies for whole mitochondrial genome analysis.