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Based on current studies, the incidence of Ewing sarcoma (ES) varies significantly by race and ethnicity, with the disease being most common in patients of European ancestry. However, race/ethnicity has generally been self-reported rather than formally evaluated at a population level using DNA evidence. Additionally, mitochondrial dysfunction is a hallmark of ES, yet there have been no reported studies of mitochondrial genetics in ES. Thus, we evaluated both the mitochondrial and nuclear ancestries of 420 pediatric ES patients in the United States using whole-genome sequencing. We found that the mitochondrial DNA (mtDNA) genomes of only six (1.4 %) patients belonged to African L haplogroups, while those of 90 % of the patients belonged to macrohaplogroup R, which includes haplogroup H, the most common maternal lineage in Europe. Compared to the general US population, European haplogroups were significantly enriched in ES patients (p < 2.2e-16) and the African haplogroups are significantly impoverished (p < 4.6e-16). Using the ancestry informative markers defined in a National Genographic study, the vast majority of patients exhibited significant nuclear ancestry originating from the Mediterranean, Northern Europe, and Southwest Asia, including all six patients with African L mtDNAs. Very few had primarily African nuclear ancestry. This is the first genomic epidemiology study to simultaneously interrogate the mitochondrial and nuclear ancestries of ES patients. While supporting previous findings of enriched European ancestry in ES patients, these results also suggest alternative hypotheses for the significant contribution of mitochondrial ancestry in ES patients, as well as the protective role of African ancestry., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Micronesia began to be peopled earlier than other parts of Remote Oceania, but the origins of its inhabitants remain unclear. We generated genome-wide data from 164 ancient and 112 modern individuals. Analysis reveals five migratory streams into Micronesia. Three are East Asian related, one is Polynesian, and a fifth is a Papuan source related to mainland New Guineans that is different from the New Britain-related Papuan source for southwest Pacific populations but is similarly derived from male migrants ~2500 to 2000 years ago. People of the Mariana Archipelago may derive all of their precolonial ancestry from East Asian sources, making them the only Remote Oceanians without Papuan ancestry. Female-inherited mitochondrial DNA was highly differentiated across early Remote Oceanian communities but homogeneous within, implying matrilocal practices whereby women almost never raised their children in communities different from the ones in which they grew up.

Background: We combined an unsupervised learning methodology for analyzing mitogenome sequences with maximum likelihood (ML) phylogenetics to make detailed inferences about the evolution and diversification of mitochondrial DNA (mtDNA) haplogroup U5, which appears at high frequencies in northern Europe., Methods: Haplogroup U5 mitogenome sequences were gathered from GenBank. The hierarchal Bayesian Analysis of Population Structure (hierBAPS) method was used to generate groups of sequences that were then projected onto a rooted maximum likelihood (ML) phylogenetic tree to visualize the pattern of clustering. The haplogroup statuses of the individual sequences were assessed using Haplogrep2., Results: A total of 23 hierBAPS groups were identified, all of which corresponded to subclades defined in Phylotree, v.17. The hierBAPS groups projected onto the ML phylogeny accurately clustered all haplotypes belonging to a specific haplogroup in accordance with Haplogrep2. By incorporating the geographic source of each sequence and subclade age estimates into this framework, inferences about the diversification of U5 mtDNAs were made. Haplogroup U5 has been present in northern Europe since the Mesolithic, and spread in both eastern and western directions, undergoing significant diversification within Scandinavia. A review of historical and archeological evidence attests to some of the population interactions contributing to this pattern., Conclusions: The hierBAPS algorithm accurately grouped mitogenome sequences into subclades in a phylogenetically robust manner. This analysis provided new insights into the phylogeographic structure of haplogroup U5 diversity in northern Europe, revealing a detailed perspective on the diversity of subclades in this region and their distribution in Scandinavian populations., (© 2022. The Author(s).)

Objectives: Mitochondria are critical for the survival of eukaryotic organisms due to their ability to produce cellular energy, which drives virtually all aspects of host biology. However, the effects of mitochondrial DNA (mtDNA) variation in relation to disease etiology and adaptation within contemporary global human populations remains incompletely understood., Methods: To develop a more holistic understanding of the role of mtDNA diversity in human adaptation, health, and disease, we investigated mitochondrial biology and bioenergetics. More specifically, we synthesized details from studies of mitochondrial function and variation in the context of haplogroup background, climatic adaptation, and oxidative disease., Results: The majority of studies show that mtDNA variation arose during modern human dispersal around the world. Some of these variants appear to have been positively selected for their adaptiveness in colder climates, with these sequence changes having implications for tissue-specific function and thermogenic capacity. In addition, many variants modulating energy production are also associated with damaging metabolic byproducts and mitochondrial dysfunction, which, in turn, are implicated in the onset and severity of several different adult mitochondrial diseases. Thus, mtDNA variation that governs bioenergetics, metabolism, and thermoregulation may potentially have adverse consequences for human health, depending on the genetic background and context in which it occurs., Conclusions: Our review suggests that the mitochondrial research field would benefit from independently replicating mtDNA haplogroup-phenotype associations across global populations, incorporating potentially confounding environmental, demographic, and disease covariates into studies of mtDNA variation, and extending association-based studies to include analyses of complete mitogenomes and assays of mitochondrial function., (© 2021 Wiley Periodicals LLC.)

Background: While well known for its Viking past, Norway's population history and the influences that have shaped its genetic diversity are less well understood. This is particularly true with respect to its demography, migration patterns, and dialectal regions, despite there being curated historical records for the past several centuries. In this study, we undertook an analysis of mitochondrial DNA (mtDNA) diversity within the country to elaborate this history from a matrilineal genetic perspective., Methods: We aggregated 1174 partial modern Norwegian mtDNA sequences from the published literature and subjected them to detailed statistical and phylogenetic analysis by dialectal regions and localities. We further contextualized the matrilineal ancestry of modern Norwegians with data from Mesolithic, Iron Age, and historic period populations., Results: Modern Norwegian mtDNAs fell into eight West Eurasian (N, HV, JT, I, U, K, X, W), five East Eurasian (A, F, G, N11, Z), and one African (L2) haplogroups. Pairwise analysis of molecular variance (AMOVA) estimates for all Norwegians indicated they were differentiated from each other at 1.68% (p < 0.001). Norwegians within the same dialectal region also showed genetic similarities to each other, although differences between subpopulations within dialectal regions were also observed. In addition, certain mtDNA lineages in modern Norwegians were also found among prehistoric and historic period populations, suggesting some level of genetic continuity over hundreds to many thousands of years., Conclusions: This analysis of mtDNA diversity provides a detailed picture of the genetic variation within Norway in light of its topography, settlement history, and historical migrations over the past several centuries., (© 2021 The Authors. American Journal of Physical Anthropology published by Wiley Periodicals LLC.)

The strategic location of Pakistan and its presence at the crossroads of Asia has resulted in it playing a central role in both prehistoric and historic human migratory events, thereby linking and facilitating contacts between the inhabitants of the Middle East, Central Asia, China and South Asia. Despite the importance of this region and its inhabitants for our understanding of modern human origins and population dispersals, the nature of mitochondrial DNA (mtDNA) variation among members of the myriad populations of this area has largely been unexplored. Here, we report mtDNA control region sequences in 58 individuals from the Khattak and the Kheshgi, two major Pakhtun tribes residing within the Peshawar Valley of northwestern Pakistan. The results reveal that these ethnic groups are genetically heterogeneous, having 55.7% West Eurasian, 33.9% South Asian and 10.2% East Asian haplogroups. The genetic diversity observed for the Kheshgi was somewhat higher than that of the Khattak. A multidimensional scaling plot based on haplogroup frequencies for the Khattak, Kheshgi and neighboring populations indicates that the Khattak have close affinities with Baluch, Uzbek and Kazak populations but are only distantly related to the Kheshgi and other Pakistani populations. By contrast, the Kheshgi cluster closely with other Pakhtun or Pathan populations of Pakistan, suggesting a possible common maternal gene pool shared amongst them. These mtDNA data allow us to begin reconstructing the origins of the Khattak and Kheshgi and describe their complex interactions with populations from the surrounding regions.

Background: The use of human and viral genetic markers offers a novel way to study human migration in multiethnic populations of Latin America., Objectives: Our goal was to characterize the genetic diversity and geographical origins of JC Polyomavirus (JCPyV) and the genetic ancestry of mitochondrial DNA (mtDNA) in inhabitants from 25 de Mayo, Misiones-Argentina, a small village of largely German ancestry located close to the border with Brazil. We also evaluated the extent of agreement between viral and mtDNA markers for the different ancestry components of this population., Study Design: 68 individuals were analyzed for JCPyV and mtDNA diversity. JCPyV detection and typing was conducted in urine samples by PCR amplification, sequencing and phylogenetic analysis of the VP1 gene. mtDNA ancestry was assessed through HVS1 sequencing, with the resulting haplotypes being classified into haplogroups of Amerindian, European and African origin. The distribution of JCPyV diversity and mtDNA ancestry in the population was statistically evaluated by Fisher exact test and the level of agreement of both markers at the individual level was evaluated by Cohen's kappa coefficient., Results: Our analysis showed that 57.4% of the samples were positive for JCPyV. Of these, the 47.6% were Asian-American Type 2, 33.3% European Type 1 and 19.1% African Type 3 in origin. The mtDNA ancestry of the study participants was 33.3% Amerindian and 66.7% European. There was a significant difference among the distribution of JCPyV diversity and mtDNA ancestry (p = 0.009) and at the individual level there was no correlation between the distribution of the both markers (κ = 0.154, p = 0.297)., Conclusion: The apparent incongruence between JCPyV diversity and mtDNA ancestry may reflect the original settlement process and more recent migration to 25 de Mayo, the latter involving viral spread through migrants from Brazil. Some potential limitations to our interpretations are also discussed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Misiones Province in northeastern Argentina is considered to be a region with a high prevalence of HPV infection and a high mortality rate due to cervical cancer. The reasons for this epidemiological trend are not completely understood. To gain insight into this problem, we explored the relationship between mitochondrial DNA (mtDNA) ancestry, HPV infection, and development of cervical lesions/cancer in women from the city of Posadas in Misiones Province., Methods: Two hundred and sixty-one women, including 92 cases of patients diagnosed with cervical lesions and 169 controls, were analyzed. mtDNA ancestry was assessed through HVS1 sequencing, while the detection and typing of HPV infection was conducted through nested multiplex PCR analysis. Multivariate logistic regression was conducted with the resulting data to estimate the odds ratios (ORs) adjusted by socio-demographic variables., Results: The study participants showed 68.6% Amerindian, 26.1% European and 5.3% African mtDNA ancestry, respectively. Multiple regression analysis showed that women with African mtDNAs were three times more likely to develop a cervical lesion than those with Native American or European mtDNAs [OR of 3.8 (1.2-11.5) for ancestry and OR of 3.5 (1.0-12.0) for L haplogroups], although the associated p values were not significant when tested under more complex multivariate models. HPV infection and the development of cervical lesions/cancer were significant for all tested models, with the highest OR values for HPV16 [OR of 24.2 (9.3-62.7)] and HPV-58 [OR of 19.0 (2.4-147.7)]., Conclusion: HPV infection remains a central risk factor for cervical cancer in the Posadas population. The potential role of African mtDNA ancestry opens a new avenue for future medical association studies in multiethnic populations, and will require further confirmation in large-scale studies.

Aboriginal Australians are one of the more poorly studied populations from the standpoint of human evolution and genetic diversity. Thus, to investigate their genetic diversity, the possible date of their ancestors' arrival and their relationships with neighboring populations, we analyzed mitochondrial DNA (mtDNA) diversity in a large sample of Aboriginal Australians. Selected mtDNA single-nucleotide polymorphisms and the hypervariable segment haplotypes were analyzed in 594 Aboriginal Australians drawn from locations across the continent, chiefly from regions not previously sampled. Most (~78%) samples could be assigned to mtDNA haplogroups indigenous to Australia. The indigenous haplogroups were all ancient (with estimated ages >40 000 years) and geographically widespread across the continent. The most common haplogroup was P (44%) followed by S (23%) and M42a (9%). There was some geographic structure at the haplotype level. The estimated ages of the indigenous haplogroups range from 39 000 to 55 000 years, dates that fit well with the estimated date of colonization of Australia based on archeological evidence (~47 000 years ago). The distribution of mtDNA haplogroups in Australia and New Guinea supports the hypothesis that the ancestors of Aboriginal Australians entered Sahul through at least two entry points. The mtDNA data give no support to the hypothesis of secondary gene flow into Australia during the Holocene, but instead suggest long-term isolation of the continent.

Background: We hypothesized that endothelial cells having distinct mitochondrial genetic backgrounds would show variation in mitochondrial function and oxidative stress markers concordant with known differential cardiovascular disease susceptibilities. To test this hypothesis, mitochondrial bioenergetics were determined in endothelial cells from healthy individuals with African versus European maternal ancestries., Methods and Results: Bioenergetics and mitochondrial DNA (mtDNA) damage were assessed in single-donor human umbilical vein endothelial cells belonging to mtDNA haplogroups H and L, representing West Eurasian and African maternal ancestries, respectively. Human umbilical vein endothelial cells from haplogroup L used less oxygen for ATP production and had increased levels of mtDNA damage compared with those in haplogroup H. Differences in bioenergetic capacity were also observed in that human umbilical vein endothelial cells belonging to haplogroup L had decreased maximal bioenergetic capacities compared with haplogroup H. Analysis of peripheral blood mononuclear cells from age-matched healthy controls with West Eurasian or African maternal ancestries showed that haplogroups sharing an A to G mtDNA mutation at nucleotide pair 10398 had increased mtDNA damage compared with those lacking this mutation. Further study of angiographically proven patients with coronary artery disease and age-matched healthy controls revealed that mtDNA damage was associated with vascular function and remodeling and that age of disease onset was later in individuals from haplogroups lacking the A to G mutation at nucleotide pair 10398., Conclusions: Differences in mitochondrial bioenergetics and mtDNA damage associated with maternal ancestry may contribute to endothelial dysfunction and vascular disease., (© 2016 American Heart Association, Inc.)

Historical discourses about the Caribbean often chronicle West African and European influence to the general neglect of indigenous people's contributions to the contemporary region. Consequently, demographic histories of Caribbean people prior to and after European contact are not well understood. Although archeological evidence suggests that the Lesser Antilles were populated in a series of northward and eastern migratory waves, many questions remain regarding the relationship of the Caribbean migrants to other indigenous people of South and Central America and changes to the demography of indigenous communities post-European contact. To explore these issues, we analyzed mitochondrial DNA and Y-chromosome diversity in 12 unrelated individuals from the First Peoples Community in Arima, Trinidad, and 43 unrelated Garifuna individuals residing in St. Vincent. In this community-sanctioned research, we detected maternal indigenous ancestry in 42% of the participants, with the remainder having haplotypes indicative of African and South Asian maternal ancestry. Analysis of Y-chromosome variation revealed paternal indigenous American ancestry indicated by the presence of haplogroup Q-M3 in 28% of the male participants from both communities, with the remainder possessing either African or European haplogroups. This finding is the first report of indigenous American paternal ancestry among indigenous populations in this region of the Caribbean. Overall, this study illustrates the role of the region's first peoples in shaping the genetic diversity seen in contemporary Caribbean populations.

Mitochondrial DNA (mtDNA) sequence variation can influence the penetrance of complex diseases and climatic adaptation. While studies in geographically defined human populations suggest that mtDNA mutations become fixed when they have conferred metabolic capabilities optimally suited for a specific environment, it has been challenging to definitively assign adaptive functions to specific mtDNA sequence variants in mammals. We investigated whether mtDNA genome variation functionally influences Caenorhabditis elegans wild isolates of distinct mtDNA lineages and geographic origins. We found that, relative to N2 (England) wild-type nematodes, CB4856 wild isolates from a warmer native climate (Hawaii) had a unique p.A12S amino acid substitution in the mtDNA-encoded COX1 core catalytic subunit of mitochondrial complex IV (CIV). Relative to N2, CB4856 worms grown at 20°C had significantly increased CIV enzyme activity, mitochondrial matrix oxidant burden, and sensitivity to oxidative stress but had significantly reduced lifespan and mitochondrial membrane potential. Interestingly, mitochondrial membrane potential was significantly increased in CB4856 grown at its native temperature of 25°C. A transmitochondrial cybrid worm strain, chpIR (M, CB4856>N2), was bred as homoplasmic for the CB4856 mtDNA genome in the N2 nuclear background. The cybrid strain also displayed significantly increased CIV activity, demonstrating that this difference results from the mtDNA-encoded p.A12S variant. However, chpIR (M, CB4856>N2) worms had significantly reduced median and maximal lifespan relative to CB4856, which may relate to their nuclear-mtDNA genome mismatch. Overall, these data suggest that C. elegans wild isolates of varying geographic origins may adapt to environmental challenges through mtDNA variation to modulate critical aspects of mitochondrial energy metabolism., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Dysfunctional bioenergetics has emerged as a key feature in many chronic pathologies such as diabetes and cardiovascular disease. This has led to the mitochondrial paradigm in which it has been proposed that mtDNA sequence variation contributes to disease susceptibility. In the present study we show a novel animal model of mtDNA polymorphisms, the MNX (mitochondrial-nuclear exchange) mouse, in which the mtDNA from the C3H/HeN mouse has been inserted on to the C57/BL6 nuclear background and vice versa to test this concept. Our data show a major contribution of the C57/BL6 mtDNA to the susceptibility to the pathological stress of cardiac volume overload which is independent of the nuclear background. Mitochondria harbouring the C57/BL6J mtDNA generate more ROS (reactive oxygen species) and have a higher mitochondrial membrane potential relative to those with C3H/HeN mtDNA, independent of nuclear background. We propose this is the primary mechanism associated with increased bioenergetic dysfunction in response to volume overload. In summary, these studies support the 'mitochondrial paradigm' for the development of disease susceptibility, and show that the mtDNA modulates cellular bioenergetics, mitochondrial ROS generation and susceptibility to cardiac stress.

The Genographic Project is an international effort aimed at charting human migratory history. The project is nonprofit and nonmedical, and, through its Legacy Fund, supports locally led efforts to preserve indigenous and traditional cultures. Although the first phase of the project was focused on uniparentally inherited markers on the Y-chromosome and mitochondrial DNA (mtDNA), the current phase focuses on markers from across the entire genome to obtain a more complete understanding of human genetic variation. Although many commercial arrays exist for genome-wide single-nucleotide polymorphism (SNP) genotyping, they were designed for medical genetic studies and contain medically related markers that are inappropriate for global population genetic studies. GenoChip, the Genographic Project's new genotyping array, was designed to resolve these issues and enable higher resolution research into outstanding questions in genetic anthropology. The GenoChip includes ancestry informative markers obtained for over 450 human populations, an ancient human (Saqqaq), and two archaic hominins (Neanderthal and Denisovan) and was designed to identify all known Y-chromosome and mtDNA haplogroups. The chip was carefully vetted to avoid inclusion of medically relevant markers. To demonstrate its capabilities, we compared the FST distributions of GenoChip SNPs to those of two commercial arrays. Although all arrays yielded similarly shaped (inverse J) FST distributions, the GenoChip autosomal and X-chromosomal distributions had the highest mean FST, attesting to its ability to discern subpopulations. The chip performances are illustrated in a principal component analysis for 14 worldwide populations. In summary, the GenoChip is a dedicated genotyping platform for genetic anthropology. With an unprecedented number of approximately 12,000 Y-chromosomal and approximately 3,300 mtDNA SNPs and over 130,000 autosomal and X-chromosomal SNPs without any known health, medical, or phenotypic relevance, the GenoChip is a useful tool for genetic anthropology and population genetics.

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., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Owl monkeys (Aotus spp.) inhabit much of South America yet represent an enigmatic evolutionary branch among primates. While morphological, cytogenetic, and immunological evidence suggest that owl monkey populations have undergone isolation and diversification since their emergence in the New World, problems with adjacent species ranges, and sample provenance have complicated efforts to characterize genetic variation within the genus. As a result, the phylogeographic history of owl monkey species and subspecies remains unclear, and the extent of genetic diversity at the population level is unknown. To explore these issues, we analyzed mitochondrial DNA (mt DNA) variation in a population of wild Azara's owl monkeys (Aotus azarai azarai) living in the Gran Chaco region of Argentina. We sequenced the complete mitochondrial genome from one individual (16,585 base pairs (bp)) and analyzed 1,099 bp of the hypervariable control region (CR) and 696 bp of the cytochrome oxidase II (COII) gene in 117 others. In addition, we sequenced the mitochondrial genome (16,472 bp) of one Nancy Ma's owl monkey (A. nancymaae). Based on the whole mtDNA and COII data, we observed an ancient phylogeographic discontinuity among Aotus species living north, south, and west of the Amazon River that began more than eight million years ago. Our population analyses identified three major CR lineages and detected a high level of haplotypic diversity within A. a. azarai. These data point to a recent expansion of Azara's owl monkeys into the Argentinean Chaco. Overall, we provide a detailed view of owl monkey mtDNA variation at genus, species, and population levels., (Copyright © 2011 Wiley-Liss, Inc.)

Previous population genetics studies in Turkey failed to delineate recent historical and social factors that shaped Anatolian cultural and genetic diversity at the local level. To address this shortcoming, we conducted focused ethnohistorical fieldwork and screened biological samples collected from the Yuksekyer region for mitochondrial, Y chromosome, and autosomal markers and then analyzed the data within an ethnohistorical context. Our results revealed that, at the village level, paternal genetic diversity is structured among settlements, whereas maternal genetic diversity is distributed more homogenously, reflecting the strong patrilineal cultural traditions that transcend larger ethnic and religious structures. Local ancestries and origin myths, rather than ethnic or religious affiliations, delineate the social boundaries and projected identities among the villages. Therefore, we conclude that broad, ethnicity-based sampling is inadequate to capture the genetic signatures of recent social and historical dynamics, which have had a profound influence on contemporary genetic and cultural regional diversity.

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., (Copyright 2010 Wiley-Liss, Inc.)

Background: Population history can be reflected in group genetic ancestry, where genomic variation captured by the mitochondrial DNA (mtDNA) and non-recombining portion of the Y chromosome (NRY) can separate female- and male-specific admixture processes. Genetic ancestry may influence genetic association studies due to differences in individual admixture within recently admixed populations like African Americans., Principal Findings: We evaluated the genetic ancestry of Senegalese as well as European Americans and African Americans from Philadelphia. Senegalese mtDNA consisted of approximately 12% U haplotypes (U6 and U5b1b haplotypes, common in North Africa) while the NRY haplotypes belonged solely to haplogroup E. In Philadelphia, we observed varying degrees of admixture. While African Americans have 9-10% mtDNAs and approximately 31% NRYs of European origin, these results are not mirrored in the mtDNA/NRY pools of European Americans: they have less than 7% mtDNAs and less than 2% NRYs from non-European sources. Additionally, there is <2% Native American contribution to Philadelphian African American ancestry and the admixture from combined mtDNA/NRY estimates is consistent with the admixture derived from autosomal genetic data. To further dissect these estimates, we have analyzed our samples in the context of different demographic groups in the Americas., Conclusions: We found that sex-biased admixture in African-derived populations is present throughout the Americas, with continual influence of European males, while Native American females contribute mainly to populations of the Caribbean and South America. The high non-European female contribution to the pool of European-derived populations is consistently characteristic of Iberian colonization. These data suggest that genomic data correlate well with historical records of colonization in the Americas.

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.

Melanesian populations are known for their diversity, but it has been hard to grasp the pattern of the variation or its underlying dynamic. Using 1,223 mitochondrial DNA (mtDNA) sequences from hypervariable regions 1 and 2 (HVR1 and HVR2) from 32 populations, we found the among-group variation is structured by island, island size, and also by language affiliation. The more isolated inland Papuan-speaking groups on the largest islands have the greatest distinctions, while shore dwelling populations are considerably less diverse (at the same time, within-group haplotype diversity is less in the most isolated groups). Persistent differences between shore and inland groups in effective population sizes and marital migration rates probably cause these differences. We also add 16 whole sequences to the Melanesian mtDNA phylogenies. We identify the likely origins of a number of the haplogroups and ancient branches in specific islands, point to some ancient mtDNA connections between Near Oceania and Australia, and show additional Holocene connections between Island Southeast Asia/Taiwan and Island Melanesia with branches of haplogroup E. Coalescence estimates based on synonymous transitions in the coding region suggest an initial settlement and expansion in the region at approximately 30-50,000 years before present (YBP), and a second important expansion from Island Southeast Asia/Taiwan during the interval approximately 3,500-8,000 YBP. However, there are some important variance components in molecular dating that have been overlooked, and the specific nature of ancestral (maternal) Austronesian influence in this region remains unresolved.

Archaeological evidence supports the inhabitation of the Lake Baikal region since the Paleolithic. Both metric and nonmetric osteological studies suggest that Neolithic Cis-Baikal populations are the ancestors of contemporary inhabitants of the region. To date, ancient DNA data have not been used to corroborate this biological continuity hypothesis. This study presents a temporal snapshot of the Cis-Baikal Neolithic by examining mtDNA diversity in two cemetery populations situated on the Angara River downstream of Lake Baikal. The 800 years separating the use of the two cemeteries is thought to represent a biocultural hiatus in the Cis-Baikal region, one that ended when a new group migrated into the area. To assess the likelihood that genetic continuity exists between these two Neolithic groups, we examined both mtDNA coding region and hypervariable region I (HVI) polymorphisms from skeletal remains excavated from both cemeteries (Lokomotiv and Ust'-Ida). The mtDNA haplogroup distributions of the two cemetery populations differ significantly, suggesting that they were biologically distinct groups. When the biological distance between these Neolithic groups is compared with modern Siberian and other East Eurasian groups, the posthiatus group (Serovo-Glazkovo) generally aligns with contemporary Siberians, while the prehiatus (Kitoi) individuals are significantly different from all but modern Kets and Shorians living in the Yenisey and Ob River basins to the west of Lake Baikal. These results suggest that the Lake Baikal region experienced a significant depopulation event during the sixth millennium BP, and was reoccupied by a new immigrant population some 800 years later., ((c) 2005 Wiley-Liss, Inc.)

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.

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.

A number of important insights into the peopling of the New World have been gained through molecular genetic studies of Siberian and Native American populations. While there is no complete agreement on the interpretation of the mitochondrial DNA (mtDNA) and Y chromosome (NRY) data from these groups, several generalizations can be made. To begin with, the primary migration of ancestral Asians expanded from south-central Siberia into the New World and gave rise to ancestral Amerindians. The initial migration seems to have occurred between 20,000-15,000 calendar years before present (cal BP), i.e., before the emergence of Clovis lithic sites (13,350-12,895 cal BP) in North America. Because an interior route through northern North America was unavailable for human passage until 12,550 cal BP, after the last glacial maximum (LGM), these ancestral groups must have used a coastal route to reach South America by 14,675 cal BP, the date of the Monte Verde site in southern Chile. The initial migration appears to have brought mtDNA haplogroups A-D and NRY haplogroups P-M45a and Q-242/Q-M3 to the New World, with these genetic lineages becoming widespread in the Americas. A second expansion that perhaps coincided with the opening of the ice-free corridor probably brought mtDNA haplogroup X and NRY haplogroups P-M45b, C-M130, and R1a1-M17 to North and Central America. Finally, populations that formerly inhabited Beringia expanded into northern North America after the LGM, and gave rise to Eskimo-Aleuts and Na-Dené Indians., (Copyright 2004 Wiley-Liss, Inc.)

The mitochondrial DNA (mtDNA) variation in 179 Aleuts from five different islands (Atka, Unalaska, Umnak, St. Paul, and St. George) and Anchorage was analyzed to better understand the origins of Aleuts and their role in the peopling of the Americas. Mitochondrial DNA samples were characterized using polymerase chain reaction amplification, restriction fragment length polymorphism analysis, and direct sequencing of the first hypervariable segment (HVS-I) of the control region. This study showed that Aleut mtDNAs belonged to two of the four haplogroups (A and D) common among Native Americans. Haplogroup D occurred at a very high frequency in Aleuts, and this, along with their unique HVS-I sequences, distinguished them from Eskimos, Athapaskan Indians, and other northern Amerindian populations. While sharing several control region sequences (CIR11, CHU14, CIR60, and CIR61) with other circumarctic populations, Aleuts lacked haplogroup A mtDNAs having the 16265G mutation that are specific to Eskimo populations. R-matrix and median network analyses indicated that Aleuts were closest genetically to Chukotkan (Chukchi and Siberian Eskimos) rather than to Native American or Kamchatkan populations (Koryaks and Itel'men). Dating of the Beringian branch of haplogroup A (16192T) suggested that populations ancestral to the Aleuts, Eskimos, and Athapaskan Indians emerged approximately 13,120 years ago, while Aleut-specific A and D sublineages were dated at 6539 +/- 3511 and 6035 +/- 2885 years, respectively. Our findings support the archaeologically based hypothesis that ancestral Aleuts crossed the Bering Land Bridge or Beringian platform and entered the Aleutian Islands from the east, rather than island hopping from Kamchatka into the western Aleutians. Furthermore, the Aleut migration most likely represents a separate event from those responsible for peopling the remainder of the Americas, meaning that the New World was colonized through multiple migrations.

In a previous study of Southeast Asian genetic variation, we characterized mitochondrial DNAs (mtDNAs) from six populations through high-resolution restriction fragment length polymorphism (RFLP) analysis. Our analysis revealed that these Southeast Asian populations were genetically similar to each other, suggesting they had a common origin. However, other patterns of population associations also emerged. Haplotypes from a major founding haplogroup in Papua New Guinea were present in Malaysia; the Vietnamese and Malaysian aborigines (Orang Asli) had high frequencies of haplogroup F, which was also seen in most other Southeast Asian populations; and haplogroup B, defined by the Region V 9-base-pair deletion, was present throughout the region. In addition, the Malaysian and Sabah (Borneo) aborigine populations exhibited a number of unique mtDNA clusters that were not observed in other populations. Unfortunately, it has been difficult to compare these patterns of genetic diversity with those shown in subsequent studies of mtDNA variation in Southeast Asian populations because the latter have typically sequenced the first hypervariable segment (HVS-I) of the control region (CR) sequencing rather than used RFLP haplotyping to characterize the mtDNAs present in them. For this reason, we sequenced the HVS-I of Southeast Asian mtDNAs that had previously been subjected to RFLP analysis, and compared the resulting data with published information from other Southeast Asian and Oceanic groups. Our findings reveal broad patterns of mtDNA haplogroup distribution in Southeast Asia that may reflect different population expansion events in this region over the past 50,000-5,000 years.

The mitochondrial DNA (mt-DNA) variation of in the Walbiri tribe of the Northern Territories, Australia, was characterized by high resolution restriction fragment length polymorphism (HR-RFLP) analysis and control region sequencing. Surveying each mt-DNA for RFLPs with 14 different restriction enzymes detected 24 distinct haplotypes, whereas direct sequencing of the control region hypervariable segment I (HVS-I) of these mt-DNAs revealed 34 distinct sequences. Phylogenetic analysis of the RFLP haplotype and HVS-I sequence data depicted that the Walbiri have ten distinct haplotype groups (haplogroups), or mt-DNA lineages. The majority of the Walbiri RFLP haplotypes lacked polymorphisms common to Asian populations. In fact, most of the Walbiri haplogroups were unique to this population, although a few appeared to be subbranches of larger clusters of mt-DNAs that included other Aboriginal Australian and/or Papua New Guinea haplotypes. The similarity of these haplotypes suggested that Aboriginal Australian and Papua New Guinea populations may have once shared an ancient ancestral population(s), and then rapidly diverged from each other once geographically separated. Overall, the mt-DNA data corroborate the genetic uniqueness of Aboriginal Australian populations.

The mtDNA variation of 74 Khoisan-speaking individuals (Kung and Khwe) from Schmidtsdrift, in the Northern Cape Province of South Africa, was examined by high-resolution RFLP analysis and control region (CR) sequencing. The resulting data were combined with published RFLP haplotype and CR sequence data from sub-Saharan African populations and then were subjected to phylogenetic analysis to deduce the evolutionary relationships among them. More than 77% of the Kung and Khwe mtDNA samples were found to belong to the major mtDNA lineage, macrohaplogroup L* (defined by a HpaI site at nucleotide position 3592), which is prevalent in sub-Saharan African populations. Additional sets of RFLPs subdivided macrohaplogroup L* into two extended haplogroups-L1 and L2-both of which appeared in the Kung and Khwe. Besides revealing the significant substructure of macrohaplogroup L* in African populations, these data showed that the Biaka Pygmies have one of the most ancient RFLP sublineages observed in African mtDNA and, thus, that they could represent one of the oldest human populations. In addition, the Kung exhibited a set of related haplotypes that were positioned closest to the root of the human mtDNA phylogeny, suggesting that they, too, represent one of the most ancient African populations. Comparison of Kung and Khwe CR sequences with those from other African populations confirmed the genetic association of the Kung with other Khoisan-speaking peoples, whereas the Khwe were more closely linked to non-Khoisan-speaking (Bantu) populations. Finally, the overall sequence divergence of 214 African RFLP haplotypes defined in both this and an earlier study was 0.364%, giving an estimated age, for all African mtDNAs, of 125,500-165,500 years before the present, a date that is concordant with all previous estimates derived from mtDNA and other genetic data, for the time of origin of modern humans in Africa.

In this study, we analyzed the mitochondrial DNA (mtDNA) variation in 202 individuals representing one Itel'men and three Koryak populations from different parts of the Kamchatka peninsula. All mtDNAs were subjected to high resolution restriction (RFLP) analysis and control region (CR) sequencing, and the resulting data were combined with those available for other Siberian and east Asian populations and subjected to statistical and phylogenetic analysis. Together, the Koryaks and Itel'men were found to have mtDNAs belonging to three (A, C, and D) of the four major haplotype groups (haplogroups) observed in Siberian and Native American populations (A-D). In addition, they exhibited mtDNAs belonging to haplogroups G, Y, and Z, which were formerly called "Other" mtDNAs. While Kamchatka harbored the highest frequencies of haplogroup G mtDNAs, which were widely distributed in eastern Siberian and adjacent east Asian populations, the distribution of haplogroup Y was restricted within a relatively small area and pointed to the lower Amur River-Sakhalin Island region as its place of origin. In contrast, the pattern of distribution and the origin of haplogroup Z mtDNAs remained unclear. Furthermore, phylogenetic and statistical analyses showed that Koryaks and Itel'men had stronger genetic affinities with eastern Siberian/east Asian populations than to those of the north Pacific Rim. These results were consistent with colonization events associated with the relatively recent immigration to Kamchatka of new tribes from the Siberian mainland region, although remnants of ancient Beringian populations were still evident in the Koryak and Itel'men gene pools.

On the basis of comprehensive RFLP analysis, it has been inferred that approximately 97% of Native American mtDNAs belong to one of four major founding mtDNA lineages, designated haplogroups "A"-"D." It has been proposed that a fifth mtDNA haplogroup (haplogroup X) represents a minor founding lineage in Native Americans. Unlike haplogroups A-D, haplogroup X is also found at low frequencies in modern European populations. To investigate the origins, diversity, and continental relationships of this haplogroup, we performed mtDNA high-resolution RFLP and complete control region (CR) sequence analysis on 22 putative Native American haplogroup X and 14 putative European haplogroup X mtDNAs. The results identified a consensus haplogroup X motif that characterizes our European and Native American samples. Among Native Americans, haplogroup X appears to be essentially restricted to northern Amerindian groups, including the Ojibwa, the Nuu-Chah-Nulth, the Sioux, and the Yakima, although we also observed this haplogroup in the Na-Dene-speaking Navajo. Median network analysis indicated that European and Native American haplogroup X mtDNAs, although distinct, nevertheless are distantly related to each other. Time estimates for the arrival of X in North America are 12,000-36,000 years ago, depending on the number of assumed founders, thus supporting the conclusion that the peoples harboring haplogroup X were among the original founders of Native American populations. To date, haplogroup X has not been unambiguously identified in Asia, raising the possibility that some Native American founders were of Caucasian ancestry.

The mtDNAs of 145 individuals representing the aboriginal populations of Chukotka-the Chukchi and Siberian Eskimos-were subjected to RFLP analysis and control-region sequencing. This analysis showed that the core of the genetic makeup of the Chukchi and Siberian Eskimos consisted of three (A, C, and D) of the four primary mtDNA haplotype groups (haplogroups) (A-D) observed in Native Americans, with haplogroup A being the most prevalent in both Chukotkan populations. Two unique haplotypes belonging to haplogroup G (formerly called "other" mtDNAs) were also observed in a few Chukchi, and these have apparently been acquired through gene flow from adjacent Kamchatka, where haplogroup G is prevalent in the Koryak and Itel'men. In addition, a 16111C-->T transition appears to delineate an "American" enclave of haplogroup A mtDNAs in northeastern Siberia, whereas the 16192C-->T transition demarcates a "northern Pacific Rim" cluster within this haplogroup. Furthermore, the sequence-divergence estimates for haplogroups A, C, and D of Siberian and Native American populations indicate that the earliest inhabitants of Beringia possessed a limited number of founding mtDNA haplotypes and that the first humans expanded into the New World approximately 34,000 years before present (YBP). Subsequent migration 16,000-13,000 YBP apparently brought a restricted number of haplogroup B haplotypes to the Americas. For millennia, Beringia may have been the repository of the respective founding sequences that selectively penetrated into northern North America from western Alaska.

Students of the time of entry of the ancestors of the Amerinds into the New World are divided into two camps, one favoring an "early" entry [more than approximately 30,000 years before the present (YBP)], the other favoring a "late" entry (less than approximately 13,000 YBP). An "intermediate" date is unlikely for geological reasons. The correlation of the appropriate data on mtDNA variation in Amerinds with linguistic, archaeological, and genetic data offers the possibility of establishing a time frame for mtDNA evolution in Amerinds. In this paper, we estimate that the separation of the Chibcha-speaking tribes of Central America from other linguistic groups/nascent tribes began approximately 8000-10,000 YBP. Characterization of the mtDNA of 110 Chibcha speakers with 14 restriction enzymes leads on the basis of their time depth to an estimated mtDNA nucleotide substitution rate for Amerinds of 0.022-0.029% per 10,000 years. As a first application of this rate, we consider the mtDNA variation observed in 18 Amerind tribes widely dispersed throughout the Americas and studied by ourselves with the same techniques, and we estimate that if the Amerinds entered the New World as a single group, that entry occurred approximately 22,000-29,000 YBP. This estimate carries a large but indeterminate error. The mtDNA data are thus at present equivocal with respect to the most likely times of entry of the Amerind into the New World mentioned above but favor the "early" entry hypothesis.

The mtDNA variation of 321 individuals from 17 Native American populations was examined by high-resolution restriction endonuclease analysis. All mtDNAs were amplified from a variety of sources by using PCR. The mtDNA of a subset of 38 of these individuals was also analyzed by D-loop sequencing. The resulting data were combined with previous mtDNA data from five other Native American tribes, as well as with data from a variety of Asian populations, and were used to deduce the phylogenetic relationships between mtDNAs and to estimate sequence divergences. This analysis revealed the presence of four haplotype groups (haplogroups A, B, C, and D) in the Amerind, but only one haplogroup (A) in the Na-Dene, and confirmed the independent origins of the Amerinds and the Na-Dene. Further, each haplogroup appeared to have been founded by a single mtDNA haplotype, a result which is consistent with a hypothesized founder effect. Most of the variation within haplogroups was tribal specific, that is, it occurred as tribal private polymorphisms. These observations suggest that the process of tribalization began early in the history of the Amerinds, with relatively little intertribal genetic exchange occurring subsequently. The sequencing of 341 nucleotides in the mtDNA D-loop revealed that the D-loop sequence variation correlated strongly with the four haplogroups defined by restriction analysis, and it indicated that the D-loop variation, like the haplotype variation, arose predominantly after the migration of the ancestral Amerinds across the Bering land bridge.

The mtDNA variation of 411 individuals from 10 aboriginal Siberian populations was analyzed in an effort to delineate the relationships between Siberian and Native American populations. All mtDNAs were characterized by PCR amplification and restriction analysis, and a subset of them was characterized by control region sequencing. The resulting data were then compiled with previous mtDNA data from Native Americans and Asians and were used for phylogenetic analyses and sequence divergence estimations. Aboriginal Siberian populations exhibited mtDNAs from three (A, C, and D) of the four haplogroups observed in Native Americans. However, none of the Siberian populations showed mtDNAs from the fourth haplogroup, group B. The presence of group B deletion haplotypes in East Asian and Native American populations but their absence in Siberians raises the possibility that haplogroup B could represent a migratory event distinct from the one(s) which brought group A, C, and D mtDNAs to the Americas. Our findings support the hypothesis that the first humans to move from Siberia to the Americas carried with them a limited number of founding mtDNAs and that the initial migration occurred between 17,000-34,000 years before present.

Human mitochondrial DNAs (mtDNAs) from 153 independent samples encompassing seven Asian populations were surveyed for sequence variation using the polymerase chain reaction (PCR), restriction endonuclease analysis and oligonucleotide hybridization. All Asian populations were found to share two ancient AluI/DdeI polymorphisms at nps 10394 and 10397 and to be genetically similar indicating that they share a common ancestry. The greatest mtDNA diversity and the highest frequency of mtDNAs with HpaI/HincII morph 1 were observed in the Vietnamese suggesting a Southern Mongoloid origin of Asians. Remnants of the founding populations of Papua New Guinea (PNG) were found in Malaysia, and a marked frequency cline for the COII/tRNA(Lys) intergenic deletion was observed along coastal Asia. Phylogenetic analysis indicates that both insertion and deletion mutations in the COII/tRNA(Lys) region have occurred more than once.

Mitochondrial DNAs (mtDNAs) from 167 American Indians including 87 Amerind-speakers (Amerinds) and 80 Nadene-speakers (Nadene) were surveyed for sequence variation by detailed restriction analysis. All Native American mtDNAs clustered into one of four distinct lineages, defined by the restriction site variants: HincII site loss at np 13,259, AluI site loss at np 5,176, 9-base pair (9-bp) COII-tRNA(Lys) intergenic deletion and HaeIII site gain at np 663. The HincII np 13,259 and AluI np 5,176 lineages were observed exclusively in Amerinds and were shared by all such tribal groups analyzed, thus demonstrating that North, Central and South American Amerinds originated from a common ancestral genetic stock. The 9-bp deletion and HaeIII np 663 lineages were found in both the Amerinds and Nadene but the Nadene HaeIII np 663 lineage had a unique sublineage defined by an RsaI site loss at np 16,329. The amount of sequence variation accumulated in the Amerind HincII np 13,259 and AluI np 5,176 lineages and that in the Amerind portion of the HaeIII np 663 lineage all gave divergence times in the order of 20,000 years before present. The divergence time for the Nadene portion of the HaeIII np 663 lineage was about 6,000-10,000 years. Hence, the ancestral Nadene migrated from Asia independently and considerably more recently than the progenitors of the Amerinds. The divergence times of both the Amerind and Nadene branches of the COII-tRNA(Lys) deletion lineage were intermediate between the Amerind and Nadene specific lineages, raising the possibility of a third source of mtDNA in American Indians.

Restriction analysis of mitochondrial DNA (mtDNA) of 3065 humans from 62 geographic samples identified 149 haplotypes and 81 polymorphic sites. These data were used to test several aspects of the evolutionary past of the human species. A dendrogram depicting the genetic relatedness of all haplotypes shows that the native African populations have the greatest diversity and, consistent with evidence from a variety of sources, suggests an African origin for our species. The data also indicate that two individuals drawn at random from the entire sample will differ at approximately 0.4% of their mtDNA nucleotide sites, which is somewhat higher than previous estimates. Human mtDNA also exhibits more interpopulation heterogeneity (GST = 0.351 +/- 0.025) than does nuclear DNA (GST = 0.12). Moreover, the virtual absence of intermediate levels of linkage disequilibrium between pairs of sites is consistent with the absence of genetic recombination and places constraints on the rate of mutation. Tests of the selective neutrality of mtDNA variation, including the Ewens-Watterson and Tajima tests, indicate a departure in the direction consistent with purifying selection, but this departure is more likely due to the rapid growth of the human population and the geographic heterogeneity of the variation. The lack of a good fit to neutrality poses problems for the estimation of times of coalescence from human mtDNA data.

The mitochondrial DNA (mtDNA) sequence variation of the South American Ticuna, the Central American Maya, and the North American Pima was analyzed by restriction-endonuclease digestion and oligonucleotide hybridization. The analysis revealed that Amerindian populations have high frequencies of mtDNAs containing the rare Asian RFLP HincII morph 6, a rare HaeIII site gain, and a unique AluI site gain. In addition, the Asian-specific deletion between the cytochrome c oxidase subunit II (COII) and tRNA(Lys) genes was also prevalent in both the Pima and the Maya. These data suggest that Amerindian mtDNAs derived from at least four primary maternal lineages, that new tribal-specific variants accumulated as these mtDNAs became distributed throughout the Americas, and that some genetic variation may have been lost when the progenitors of the Ticuna separated from the North and Central American populations.

Leber's hereditary optic neuropathy is a maternally inherited disease resulting in optic nerve degeneration and cardiac dysrhythmia. A mitochondrial DNA replacement mutation was identified that correlated with this disease in multiple families. This mutation converted a highly conserved arginine to a histidine at codon 340 in the NADH dehydrogenase subunit 4 gene and eliminated an Sfa NI site, thus providing a simple diagnostic test. This finding demonstrated that a nucleotide change in a mitochondrial DNA energy production gene can result in a neurological disease.