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Narcolepsy type 1 (NT1) is due to selective loss of hypocretin (hcrt)-producing-neurons. Hcrt is a neuropeptide regulating the sleep/wake cycle, as well as feeding behavior. A subset of NT1 patients become overweight/obese, with a dysmetabolic phenotype. We hypothesized that mitochondrial DNA (mtDNA) sequence variation might contribute to the metabolic features in NT1 and we undertook an exploratory survey of mtDNA haplogroups in a cohort of well-characterized patients. We studied 246 NT1 Italian patients, fully defined for their metabolic features, including obesity, hypertension, low HDL, hypertriglyceridemia and hyperglycemia. For haplogroup assignment, the mtDNA control region was sequenced in combination with an assessment of diagnostic markers in the coding region. NT1 patients displayed the same mtDNA haplogroups (H, HV, J, K, T, U) frequency as those reported in the general Italian population. The majority of NT1 patients (64%) were overweight: amongst these, 35% were obese, 48% had low HDL cholesterol levels, and 31% had hypertriglyceridemia. We identified an association between haplogroups J, K and hypertriglyceridemia (P = 0.03, 61.5% and 61.5%, respectively vs. 31.3% of the whole sample) and after correction for age and sex, we observed a reduction of these associations (OR = 3.65, 95%CI = 0.76-17.5, p = 0.106 and 1.73, 0.52-5.69, p = 0.368, respectively). The low HDL level showed a trend for association with haplogroup J (P = 0.09, 83.3% vs. 47.4% of the whole sample) and after correction we observed an OR = 6.73, 95%CI = 0.65-69.9, p = 0.110. Our study provides the first indication that mtDNA haplogroups J and K can modulate metabolic features of NT1 patients, linking mtDNA variation to the dysmetabolic phenotype in NT1.

The barn swallow (Hirundo rustica) poses a number of fascinating scientific questions, including the taxonomic status of postulated subspecies. Here, we obtained and assessed the sequence variation of 411 complete mitogenomes, mainly from the European H. r. rustica, but other subspecies as well. In almost every case, we observed subspecies-specific haplogroups, which we employed together with estimated radiation times to postulate a model for the geographical and temporal worldwide spread of the species. The female barn swallow carrying the Hirundo rustica ancestral mitogenome left Africa (or its vicinity) around 280 thousand years ago (kya), and her descendants expanded first into Eurasia and then, at least 51 kya, into the Americas, from where a relatively recent (

Background Recent genome studies of modern and ancient samples have proposed that Native Americans derive from a subset of the Eurasian gene pool carried to America by an ancestral Beringian population, from which two well-differentiated components originated and subsequently mixed in different proportion during their spread in the Americas. To assess the timing, places of origin and extent of admixture between these components, we performed an analysis of the Y-chromosome haplogroup Q, which is the only Pan-American haplogroup and accounts for virtually all Native American Y chromosomes in Mesoamerica and South America. Results Our analyses of 1.5 Mb of 152 Y chromosomes, 34 re-sequenced in this work, support a “coastal and inland routes scenario” for the first entrance of modern humans in North America. We show a major phase of male population growth in the Americas after 15 thousand years ago (kya), followed by a period of constant population size from 8 to 3 kya, after which a secondary sign of growth was registered. The estimated dates of the first expansion in Mesoamerica and the Isthmo-Colombian Area, mainly revealed by haplogroup Q-Z780, suggest an entrance in South America prior to 15 kya. During the global constant population size phase, local South American hints of growth were registered by different Q-M848 sub-clades. These expansion events, which started during the Holocene with the improvement of climatic conditions, can be ascribed to multiple cultural changes rather than a steady population growth and a single cohesive culture diffusion as it occurred in Europe. Conclusions We established and dated a detailed haplogroup Q phylogeny that provides new insights into the geographic distribution of its Eurasian and American branches in modern and ancient samples. Electronic supplementary material The online version of this article (10.1186/s12915-018-0622-4) contains supplementary material, which is available to authorized users.

Umbria is located in Central Italy and took the name from its ancient inhabitants, the Umbri, whose origins are still debated. Here, we investigated the mitochondrial DNA (mtDNA) variation of 545 present-day Umbrians (with 198 entire mitogenomes) and 28 pre-Roman individuals (obtaining 19 ancient mtDNAs) excavated from the necropolis of Plestia. We found a rather homogeneous distribution of western Eurasian lineages across the region, with few notable exceptions. Contemporary inhabitants of the eastern part, delimited by the Tiber River and the Apennine Mountains, manifest a peculiar mitochondrial proximity to central-eastern Europeans, mainly due to haplogroups U4 and U5a, and an overrepresentation of J (30%) similar to the pre-Roman remains, also excavated in East Umbria. Local genetic continuities are further attested to by six terminal branches (H1e1, J1c3, J2b1, U2e2a, U8b1b1 and K1a4a) shared between ancient and modern mitogenomes. Eventually, we identified multiple inputs from various population sources that likely shaped the mitochondrial gene pool of ancient Umbri over time, since early Neolithic, including gene flows with central-eastern Europe. This diachronic mtDNA portrait of Umbria fits well with the genome-wide population structure identified on the entire peninsula and with historical sources that list the Umbri among the most ancient Italic populations. We are grateful to Soprintendenza Archeologia, Belle Arti e Paesaggio dell’Umbria, to Istituto Comprensivo Statale Foligno 5 (Perugia) and to all the volunteers who generously participated in this survey and made this research possible. We thank our colleagues Prof. Fausto Panara and Dr. Livia Lucentini with whom we have been discussing the feasibility and the first steps of this project, and Prof. Cristina Cereda, Dr. Gaetano Grieco, Dr. Marialuisa Valente, Dr. Nicole Huber and Jannika Oeke for technical support. We would like to thank the two anonymous reviewers for their suggestions and thoughtful comments. This research received support from: the Italian Ministry of Education, University and Research projects FIR2012 RBFR126B8I (to AO and AA), PRIN2017 20174BTC4R (to AA); Dipartimenti di Eccellenza Program (2018–2022)—Department of Biology and Biotechnology “L. Spallanzani,” University of Pavia (to AA, AO, OS and AT) and Department of Biology, University of Florence (to DC); the Fondazione Cariplo (project no. 2018–2045 to AA, AO and AT); the Fon-dazione Carifol (2008 to AA) and the Tiroler Wissenschaftsfonds (TWF) (UNI-404/1998) (to MB).

In the last 40 years, despite its small size, mtDNA has provided an immense amount of valuable information concerning the origin of human populations. This success is due to a number of particular features that have allowed mtDNA data to be much more readily acquired and assessed relative to its nuclear counterpart. As examples, the mtDNA perspectives on three temporally and geographically distant migratory events are reviewed: the “Out of Africa Exit,” the first peopling of the Americas, and the settlement of Sardinia. Even though we have entered the era of genomics and archeogenomics, mtDNA analyses are going to remain a major complement to nuclear genome studies, which still lack the genealogical resolution provided by nonrecombining mtDNA and face difficulties in making full use of the information present in haplotypes, something that instead large-scale surveys of entire mitogenomes do extremely well.

There is growing evidence that the sequence variation of mitochondrial DNA (mtDNA), which clusters in population- and/or geographic-specific haplogroups, may result in functional effects that, in turn, become relevant in disease predisposition or protection, interaction with environmental factors and ultimately in modulating longevity. To unravel functional differences between mtDNA haplogroups we here employed transmitochondrial cytoplasmic hybrid cells (cybrids) grown in galactose medium, a culture condition that forces oxidative phosphorylation, and in the presence of rotenone, the classic inhibitor of respiratory Complex I. Under this experimental paradigm we assessed functional parameters such as cell viability and respiration, ATP synthesis, reactive oxygen species production and mtDNA copy number. Our analyses show that haplogroup J1, which is common in western Eurasian populations, is the most sensitive to rotenone, whereas K1 mitogenomes orchestrate the best compensation, possibly because of the haplogroup-specific missense variants impinging on Complex I function. Remarkably, haplogroups J1 and K1 fit the genetic associations previously established with Leber's hereditary optic neuropathy (LHON) for J1, as a penetrance enhancer, and with Parkinson's disease (PD) for K1, as a protective background. Our findings provide functional evidences supporting previous well-established genetic associations of specific haplogroups with two neurodegenerative pathologies, LHON and PD. Our experimental paradigm is instrumental to highlighting the subtle functional differences characterizing mtDNA haplogroups, which will be increasingly needed to dissect the role of mtDNA genetic variation in health, disease and longevity.

Recent and compelling archaeological evidence attests to human presence ∼14.5 ka at multiple sites in South America and a very early exploitation of extreme high-altitude Andean environments. Considering that, according to genetic evidence, human entry into North America from Beringia most likely occurred ∼16 ka, these archeological findings would imply an extremely rapid spread along the double continent. To shed light on this issue from a genetic perspective, we first completely sequenced 217 novel modern mitogenomes of Native American ancestry from the northwestern area of South America (Ecuador and Peru); we then evaluated them phylogenetically together with other available mitogenomes (430 samples, both modern and ancient) from the same geographic area and, finally, with all closely related mitogenomes from the entire double continent. We detected a large number (N = 48) of novel subhaplogroups, often branching into further subclades, belonging to two classes: those that arose in South America early after its peopling and those that instead originated in North or Central America and reached South America with the first settlers. Coalescence age estimates for these subhaplogroups provide time boundaries indicating that early Paleo-Indians probably moved from North America to the area corresponding to modern Ecuador and Peru over the short time frame of ∼1.5 ka comprised between 16.0 and 14.6 ka This study received support from the University of Pavia strategic theme “Towards a governance model for international migration: An interdisciplinary and diachronic perspective” (MIGRAT-IN-G) (to A.O., A.A., O.S., and A.T.), and the Italian Ministry of Education, University and Research: Progetti Futuro in Ricerca 2012 (RBFR126B8I) (to A.O. and A.A.) and Progetti Ricerca Interesse Nazionale 2012 (to A.A, O.S., and A.T.) SI

Surveys of mitochondrial DNA (mtDNA) variation have shown that worldwide domestic cattle are characterized by just a few major haplogroups. Two, T and I, are common and characterize Bos taurus and Bos indicus, respectively, while the other three, P, Q and R, are rare and are found only in taurine breeds. Haplogroup P is typical of extinct European aurochs, while intriguingly modern P mtDNAs have only been found in northeast Asian cattle. These Asian P mtDNAs are extremely rare with the exception of the Japanese Shorthorn breed, where they reach a frequency of 45.9%. To shed light on the origin of this haplogroup in northeast Asian cattle, we completely sequenced 14 Japanese Shorthorn mitogenomes belonging to haplogroup P. Phylogenetic and Bayesian analyses revealed: (1) a post-glacial expansion of aurochs carrying haplogroup P from Europe to Asia; (2) that all Asian P mtDNAs belong to a single sub-haplogroup (P1a), so far never detected in either European or Asian aurochs remains, which was incorporated into domestic cattle of continental northeastern Asia possibly ~ 3700 years ago; and (3) that haplogroup P1a mtDNAs found in the Japanese Shorthorn breed probably reached Japan about 650 years ago from Mongolia/Russia, in agreement with historical evidence.

Many anthropological, linguistic, genetic and genomic analyses have been carried out to evaluate the potential impact that evolutionary forces had in shaping the present-day Sardinian gene pool, the main outlier in the genetic landscape of Europe. However, due to the homogenizing effect of internal movements, which have intensified over the past fifty years, only partial information has been obtained about the main demographic events. To overcome this limitation, we analyzed the male-specific region of the Y chromosome in three population samples obtained by reallocating a large number of Sardinian subjects to the place of origin of their monophyletic surnames, which are paternally transmitted through generations in most of the populations, much like the Y chromosome. Three Y-chromosome founding lineages, G2-L91, I2-M26 and R1b-V88, were identified as strongly contributing to the definition of the outlying position of Sardinians in the European genetic context and marking a significant differentiation within the island. The present distribution of these lineages does not always mirror that detected in ancient DNAs. Our results show that the analysis of the Y-chromosome gene pool coupled with a sampling method based on the origin of the family name, is an efficient approach to unravelling past heterogeneity, often hidden by recent movements, in the gene pool of modern populations. Furthermore, the reconstruction and comparison of past genetic isolates represent a starting point to better assess the genetic information deriving from the increasing number of available ancient DNA samples.

Due to its central and strategic position in Europe and in the Mediterranean Basin, the Italian Peninsula played a pivotal role in the first peopling of the European continent and has been a crossroad of peoples and cultures since then.This study aims to gain more information on the genetic structure of modern Italian populations and to shed light on the migration/expansion events that led to their formation.High resolution Y-chromosome variation analysis in 817 unrelated males from 10 informative areas of Italy was performed. Haplogroup frequencies and microsatellite haplotypes were used, together with available data from the literature, to evaluate Mediterranean and European inputs and date their arrivals.Fifty-three distinct Y-chromosome lineages were identified. Their distribution is in general agreement with geography, southern populations being more differentiated than northern ones.A complex genetic structure reflecting the multifaceted peopling pattern of the Peninsula emerged: southern populations show high similarity with those from the Middle East and Southern Balkans, while those from Northern Italy are close to populations of North-Western Europe and the Northern Balkans. Interestingly, the population of Volterra, an ancient town of Etruscan origin in Tuscany, displays a unique Y-chromosomal genetic structure.

Sardinians are "outliers" in the European genetic landscape and, according to paleogenomic nuclear data, the closest to early European Neolithic farmers. To learn more about their genetic ancestry, we analyzed 3,491 modern and 21 ancient mitogenomes from Sardinia. We observed that 78.4% of modern mitogenomes cluster into 89 haplogroups that most likely arose in situ. For each Sardinian-specific haplogroup (SSH), we also identified the upstream node in the phylogeny, from which non-Sardinian mitogenomes radiate. This provided minimum and maximum time estimates for the presence of each SSH on the island. In agreement with demographic evidence, almost all SSHs coalesce in the post-Nuragic, Nuragic and Neolithic-Copper Age periods. For some rare SSHs, however, we could not dismiss the possibility that they might have been on the island prior to the Neolithic, a scenario that would be in agreement with archeological evidence of a Mesolithic occupation of Sardinia., This study received support from the University of Pavia strategic theme “Towards a governance model for international migration: an interdisciplinary and diachronic perspective” (MIGRAT-IN-G) (to A.O., A.A., O.S., A.T.), the British Academy Research Development Award n. 53097 (to R.S.), the Italian Ministry of Education, University and Research: Progetti Futuro in Ricerca 2012 (RBFR126B8I) (to A.O. and A.A.) and Progetti Ricerca Interesse Nazionale 2012 (to A.A., O.S. and A.T.). The sequencing data reported in the study were supported by the National Human Genome Research Institute grants HG005581, HG005552, HG006513, HG007022, and HG007089; the National Heart Lung and Blood Institute grant HL117626; the Intramural Research Program of the NIH, National Institute on Aging, with contracts N01-AG-1-2109 and HHSN271201100005C; the Sardinian Autonomous Region (L.R. no. 7/2009) grant cRP3-154. P.S. was supported by FCT, ESF and POPH through the FCT Investigator Programme (IF/01641/2013). P.S. and E.C.-S. acknowledge FCT IP and ERDF (COMPETE2020 – POCI) for the CBMA programme UID/BIA/04050/2013 (POCI-01-0145-FEDER-007569). T.R. was supported by an FCT grant (SFRH/BPD/108126/2015). M.P., P.S. and M.B.R. acknowledge FCT support through project PTDC/EPH-ARQ/4164/2014 partially funded by FEDER funds (COMPETE 2020 project 016899). M.B.R. received support from a Leverhulme Doctoral Scholarship programme. C.P. was supported by the Baden Württemberg Foundation and the Max Planck Society. The sequence data for the modern (N = 2,136) and ancient (N = 21) Sardinian mitogenomes are available in GenBank with accession numbers KY408145−KY410236, KY399164−KY399207, and KY399143−KY399163, info:eu-repo/semantics/publishedVersion

Important gaps remain in our understanding of the spread of farming into Europe, due partly to apparent contradictions between studies of contemporary genetic variation and ancient DNA. It seems clear that farming was introduced into central, northern, and eastern Europe from the south by pioneer colonization. It is often argued that these dispersals originated in the Near East, where the potential source genetic pool resembles that of the early European farmers, but clear ancient DNA evidence from Mediterranean Europe is lacking, and there are suggestions that Mediterranean Europe may have resembled the Near East more than the rest of Europe in the Mesolithic. Here, we test this proposal by dating mitogenome founder lineages from the Near East in different regions of Europe. We find that whereas the lineages date mainly to the Neolithic in central Europe and Iberia, they largely date to the Late Glacial period in central/eastern Mediterranean Europe. This supports a scenario in which the genetic pool of Mediterranean Europe was partly a result of Late Glacial expansions from a Near Eastern refuge, and that this formed an important source pool for subsequent Neolithic expansions into the rest of Europe., FCT, the Portuguese Foundation for Science and Technology, supported this work through the research project PTDC/CS–ANT/ 113832/2009 and personal grants to J.B.P. (SFRH/BD/45657/2008) and M.D.C. (SFRH/BD/48372/2008). P.S. is supported by FCT, ESF, POPH, and the FCT Investigator Programme (IF/01641/2013) and acknowledges FCT I.P. and ERDF (through COMPETE2020- POCI) for CBMA’s strategic programme UID/BIA/04050/2013 (POCI-01-0145-FEDER-007569). AT received support by the University of Pavia strategic theme ‘Towards a governance model for international migration: an interdisciplinary and diachronic perspective (MIGRAT.IN.G)’ and the Italian Ministry of Education, University and Research: Progetti Ricerca Interesse Nazionale 2012. M.B.R. received support from The Leverhulme Trust (research project grant no. F/10 105/D) and M.P. from the Newton International Fellowship scheme. This work was financed by FEDER-Fundo Europeu de Desenvolvimento Regional funds through COMPETE 2020-Operational Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through FCT/Ministério da Ciência, Tecnologia e Inovação in the framework of the project ‘Institute for Research and Innovation in Health Sciences’ (POCI-01-0145-FEDER-007274).

In the last 40 years, the Asian tiger mosquito Aedes albopictus, indigenous to East Asia, has colonized every continent except Antarctica. Its spread is a major public health concern, given that this species is a competent vector for numerous arboviruses, including those causing dengue, chikungunya, West Nile, and the recently emerged Zika fever. To acquire more information on the ancestral source(s) of adventive populations and the overall diffusion process from its native range, we analyzed the mitogenome variation of 27 individuals from representative populations of Asia, the Americas, and Europe. Phylogenetic analyses revealed five haplogroups in Asia, but population surveys appear to indicate that only three of these (A1a1, A1a2, and A1b) were involved in the recent worldwide spread. We also found out that a derived lineage (A1a1a1) within A1a1, which is now common in Italy, most likely arose in North America from an ancestral Japanese source. These different genetic sources now coexist in many of the recently colonized areas, thus probably creating novel genomic combinations which might be one of the causes of the apparently growing ability of A. albopictus to expand its geographical range.

"Article number: 25472", Rare mitochondrial lineages with relict distributions can sometimes be disproportionately informative about deep events in human prehistory. We have studied one such lineage, haplogroup R0a, which uniquely is most frequent in Arabia and the Horn of Africa, but is distributed much more widely, from Europe to India. We conclude that: (1) the lineage ancestral to R0a is more ancient than previously thought, with a relict distribution across the Mediterranean/Southwest Asia; (2) R0a has a much deeper presence in Arabia than previously thought, highlighting the role of at least one Pleistocene glacial refugium, perhaps on the Red Sea plains; (3) the main episode of dispersal into Eastern Africa, at least concerning maternal lineages, was at the end of the Late Glacial, due to major expansions from one or more refugia in Arabia; (4) there was likely a minor Late Glacial/early postglacial dispersal from Arabia through the Levant and into Europe, possibly alongside other lineages from a Levantine refugium; and (5) the presence of R0a in Southwest Arabia in the Holocene at the nexus of a trading network that developed after ~3 ka between Africa and the Indian Ocean led to some gene flow even further afield, into Iran, Pakistan and India., This work was supported by the University of Pavia strategic theme “Towards a governance model for international migration: an interdisciplinary and diachronic perspective” (MIGRAT-IN-G), the Italian Ministry of Education, University and Research: Progetti Futuro in Ricerca 2012 (RBFR126B8I) (to A.A. and A.O.) and Progetti Ricerca Interesse Nazionale 2012 (to A.A., F.C., A.T. and O.S.), a Leverhulme Doctoral Scholarship award to M.B.R., a Newton International Fellowship to M.P., the intramural funding program of the Medical University Innsbruck for young scientists MUI-START, Project 2013042025 (to M.B.), an EMBO short-term fellowship (ASTF 70- 2014/Award) and a University of Huddersfield University Research Fellowship award to F.G. P.S. is supported by FCT, European Social Fund, Programa Operacional Potencial Humano and the FCT Investigator Programme (IF/01641/2013) and acknowledges FCT I.P. for CBMA’s strategic funding UID/BIA/04050/2013.

It is now widely agreed that the Native American founders originated from a Beringian source population ∼15-18 thousand years ago (kya) and rapidly populated all of the New World, probably mainly following the Pacific coastal route. However, details about the migration into the Americas and the routes pursued on the continent still remain unresolved, despite numerous genetic, archaeological, and linguistic investigations. To examine the pioneering peopling phase of the South American continent, we screened literature and mtDNA databases and identified two novel mitochondrial DNA (mtDNA) clades, here named D1g and D1j, within the pan-American haplogroup D1. They both show overall rare occurrences but local high frequencies, and are essentially restricted to populations from the Southern Cone of South America (Chile and Argentina). We selected and completely sequenced 43 D1g and D1j mtDNA genomes applying highest quality standards. Molecular and phylogeographic analyses revealed extensive variation within each of the two clades and possibly distinct dispersal patterns. Their age estimates agree with the dating of the earliest archaeological sites in South America and indicate that the Paleo-Indian spread along the entire longitude of the American double continent might have taken even

Archaeological and genetic evidence concerning the time and mode of wild horse (Equus ferus) domestication is still debated. High levels of genetic diversity in horse mtDNA have been detected when analyzing the control region; recurrent mutations, however, tend to blur the structure of the phylogenetic tree. Here, we brought the horse mtDNA phylogeny to the highest level of molecular resolution by analyzing 83 mitochondrial genomes from modern horses across Asia, Europe, the Middle East, and the Americas. Our data reveal 18 major haplogroups (A-R) with radiation times that are mostly confined to the Neolithic and later periods and place the root of the phylogeny corresponding to the Ancestral Mare Mitogenome at ~130-160 thousand years ago. All haplogroups were detected in modern horses from Asia, but F was only found in E. przewalskii--the only remaining wild horse. Therefore, a wide range of matrilineal lineages from the extinct E. ferus underwent domestication in the Eurasian steppes during the Eneolithic period and were transmitted to modern E. caballus breeds. Importantly, now that the major horse haplogroups have been defined, each with diagnostic mutational motifs (in both the coding and control regions), these haplotypes could be easily used to (i) classify well-preserved ancient remains, (ii) (re)assess the haplogroup variation of modern breeds, including Thoroughbreds, and (iii) evaluate the possible role of mtDNA backgrounds in racehorse performance. This research received support from the Italian Ministry of Education, University and Research: Fondo per gli Investimenti della Ricerca di Base (FIRB) Futuro in Ricerca 2008 (to A.A. and A.O.), Progetti Ricerca Interesse Nazionale 2008 (to E.G.) and 2009 (to A.A., O.S., and A.T.); L'ORÉAL Italia per le Donne e la Scienza (to A.O.), Fundação para a Ciência e Tecnologia (FCT), Grant SFRH/BPD/64233/2009 (to P.S.); Consorzio Interuniversitario di Biotecnologie (to M. Santagostino); Fondazione Alma Mater Ticinensis (O.S. and A.T.); and Progetto Ricerca e INNOVAzione nelle attività di miglioramento GENetico animale (INNOVAGEN), Italian Ministry of Agriculture (M. Silvestrelli). Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP) is an Associate Laboratory of the Portuguese Ministry of Science, Technology, and Higher Education and is partially supported by FCT.

The Turin Shroud is traditionally considered to be the burial cloth in which the body of Jesus Christ was wrapped after his death approximately 2000 years ago. Here, we report the main findings from the analysis of genomic DNA extracted from dust particles vacuumed from parts of the body image and the lateral edge used for radiocarbon dating. Several plant taxa native to the Mediterranean area were identified as well as species with a primary center of origin in Asia, the Middle East or the Americas but introduced in a historical interval later than the Medieval period. Regarding human mitogenome lineages, our analyses detected sequences from multiple subjects of different ethnic origins, which clustered into a number of Western Eurasian haplogroups, including some known to be typical of Western Europe, the Near East, the Arabian Peninsula and the Indian sub-continent. Such diversity does not exclude a Medieval origin in Europe but it would be also compatible with the historic path followed by the Turin Shroud during its presumed journey from the Near East. Furthermore, the results raise the possibility of an Indian manufacture of the linen cloth.

To define the matrilineal relationships between Bulgarians and other European populations, we have evaluated the mitochondrial DNA (mtDNA) variation in a sample of 855 Bulgarian subjects from the mtDNA perspective. The molecular survey was performed by sequencing ∼750 bp of the control region, which resulted in 557 different haplotypes, and by a subsequent restriction fragment length polymorphism analysis to confirm haplogroup/subhaplogroup affiliation. The classification was carried out according to the most updated criteria as reported by van Oven and Kayser (Hum Mutat 30:386-394, 2009), allowing the identification of 45 mitochondrial clades. The observed pattern of mtDNA variation indicates that the Bulgarian mitochondrial pool is geographically homogeneous across the country, and that is characterized by an overall extremely high frequency of western Eurasian lineages. In the principal component analysis, Bulgarians locate in an intermediate position between Eastern European and Mediterranean populations, which is in agreement with historical events. Thus, while the Mediterranean legacy could be attributed to the Thracians, indigenous people that firstly inhabited the Balkans, the Eastern contribution is likely due to the Proto-Bulgarians originating from the Middle East and to the Slavs migrating from northeast Europe.

Contains fulltext : 52562.pdf (Publisher’s version ) (Closed access) Leber hereditary optic neuropathy (LHON) is due primarily to one of three common point mutations of mitochondrial DNA (mtDNA), but the incomplete penetrance implicates additional genetic or environmental factors in the pathophysiology of the disorder. Both the 11778G-->A and 14484T-->C LHON mutations are preferentially found on a specific mtDNA genetic background, but 3460G-->A is not. However, there is no clear evidence that any background influences clinical penetrance in any of these mutations. By studying 3,613 subjects from 159 LHON-affected pedigrees, we show that the risk of visual failure is greater when the 11778G-->A or 14484T-->C mutations are present in specific subgroups of haplogroup J (J2 for 11778G-->A and J1 for 14484T-->C) and when the 3460G-->A mutation is present in haplogroup K. By contrast, the risk of visual failure is significantly less when 11778G-->A occurs in haplogroup H. Substitutions on MTCYB provide an explanation for these findings, which demonstrate that common genetic variants have a marked effect on the expression of an ostensibly monogenic mtDNA disorder.

Background Distinct, partly competing, “waves” have been proposed to explain human migration in(to) today’s Island Southeast Asia and Australia based on genetic (and other) evidence. The paucity of high quality and high resolution data has impeded insights so far. In this study, one of the first in a forensic environment, we used the Ion Torrent Personal Genome Machine (PGM) for generating complete mitogenome sequences via stand-alone massively parallel sequencing and describe a standard data validation practice. Results In this first representative investigation on the mitochondrial DNA (mtDNA) variation of East Timor (Timor-Leste) population including >300 individuals, we put special emphasis on the reconstruction of the initial settlement, in particular on the previously poorly resolved haplogroup P1, an indigenous lineage of the Southwest Pacific region. Our results suggest a colonization of southern Sahul (Australia) >37 kya, limited subsequent exchange, and a parallel incubation of initial settlers in northern Sahul (New Guinea) followed by westward migrations

Background\ud \ud Genetic studies support the scenario that Bos taurus domestication occurred in the Near East during the Neolithic transition about 10 thousand years (ky) ago, with the likely exception of a minor secondary event in Italy. However, despite the proven effectiveness of whole mitochondrial genome data in providing valuable information concerning the origin of taurine cattle, until now no population surveys have been carried out at the level of mitogenomes in local breeds from the Near East or surrounding areas. Egypt is in close geographic and cultural proximity to the Near East, in particular the Nile Delta region, and was one of the first neighboring areas to adopt the Neolithic package. Thus, a survey of mitogenome variation of autochthonous taurine breeds from the Nile Delta region might provide new insights on the early spread of cattle rearing outside the Near East.\ud \ud \ud Methodology\ud Using Illumina high-throughput sequencing we characterized the mitogenomes from two cattle breeds, Menofi (N = 17) and Domiaty (N = 14), from the Nile Delta region. Phylogenetic and Bayesian analyses were subsequently performed.\ud \ud \ud Conclusions\ud Phylogenetic analyses of the 31 mitogenomes confirmed the prevalence of haplogroup T1, similar to most African cattle breeds, but showed also high frequencies for haplogroups T2, T3 and Q1, and an extremely high haplotype diversity, while Bayesian skyline plots pointed to a main episode of population growth ~12.5 ky ago. Comparisons of Nile Delta mitogenomes with those from other geographic areas revealed that (i) most Egyptian mtDNAs are probably direct local derivatives from the founder domestic herds which first arrived from the Near East and the extent of gene flow from and towards the Nile Delta region was limited after the initial founding event(s); (ii) haplogroup Q1 was among these founders, thus proving that it underwent domestication in the Near East together with the founders of the T clades.

The variation at 28 Y-chromosome biallelic markers was analysed in 256 males (90 Croats, 81 Serbs and 85 Bosniacs) from Bosnia-Herzegovina. An important shared feature between the three ethnic groups is the high frequency of the "Palaeolithic" European-specific haplogroup (Hg) I, a likely signature of a Balkan population re-expansion after the Last Glacial Maximum. This haplogroup is almost completely represented by the sub-haplogroup I-P37 whose frequency is, however, higher in the Croats (approximately 71%) than in Bosniacs (approximately 44%) and Serbs (approximately 31%). Other rather frequent haplogroups are E (approximately 15%) and J (approximately 7%), which are considered to have arrived from the Middle East in Neolithic and post-Neolithic times, and R-M17 (approximately 14%), which probably marked several arrivals, at different times, from eastern Eurasia. Hg E, almost exclusively represented by its subclade E-M78, is more common in the Serbs (approximately 20%) than in Bosniacs (approximately 13%) and Croats (approximately 9%), and Hg J, observed in only one Croat, encompasses approximately 9% of the Serbs and approximately 12% of the Bosniacs, where it shows its highest diversification. By contrast, Hg R-M17 displays similar frequencies in all three groups. On the whole, the three main groups of Bosnia-Herzegovina, in spite of some quantitative differences, share a large fraction of the same ancient gene pool distinctive for the Balkan area.

The southwestern and Central Asian corridor has played a pivotal role in the history of humankind, witnessing numerous waves of migration of different peoples at different times. To evaluate the effects of these population movements on the current genetic landscape of the Iranian plateau, the Indus Valley, and Central Asia, we have analyzed 910 mitochondrial DNAs (mtDNAs) from 23 populations of the region. This study has allowed a refinement of the phylogenetic relationships of some lineages and the identification of new haplogroups in the southwestern and Central Asian mtDNA tree. Both lineage geographical distribution and spatial analysis of molecular variance showed that populations located west of the Indus Valley mainly harbor mtDNAs of western Eurasian origin, whereas those inhabiting the Indo-Gangetic region and Central Asia present substantial proportions of lineages that can be allocated to three different genetic components of western Eurasian, eastern Eurasian, and south Asian origin. In addition to the overall composite picture of lineage clusters of different origin, we observed a number of deep-rooting lineages, whose relative clustering and coalescent ages suggest an autochthonous origin in the southwestern Asian corridor during the Pleistocene. The comparison with Y-chromosome data revealed a highly complex genetic and demographic history of the region, which includes sexually asymmetrical mating patterns, founder effects, and female-specific traces of the East African slave trade.

A novel mitochondrial DNA (mtDNA) transition (3733G-->A) inducing the E143 K amino acid change at a very conserved site of the NADH dehydrogenase subunit 1 (ND1) was identified in a family with six maternally related individuals with Leber's hereditary optic neuropathy (LHON) and in an unrelated sporadic case, all negative for known mutations and presenting with the canonical phenotype. The transition was not detected in 1,082 control mtDNAs and was heteroplasmic in several individuals from both pedigrees. In addition, the mtDNAs of the two families were found to belong to different haplogroups (H and X), thus confirming that the 3733G-->A mutation occurred twice independently. Phosphorus magnetic resonance spectroscopy disclosed an in vivo brain and skeletal muscle energy metabolism deficit in the four examined patients. Muscle biopsy from two patients showed slight mitochondrial proliferation with abnormal mitochondria. Biochemical investigations in platelets showed partially insensitive complex 1 to rotenone inhibition. We conclude that the 3733G-->A transition is a novel cause of LHON and, after those at positions 3460 and 4171, is the third ND1 mutation to be identified in multiple unrelated families. This finding shows that, in addition to ND6, the ND1 subunit gene is also a mutational hot spot for LHON.

Analyses of mtDNA and Y-chromosome variation were performed in a sample of Iraqis, a scarcely investigated population of the "Fertile Crescent." A total of 216 mtDNAs were screened for the diagnostic RFLP markers of the main Eurasian and African haplogroups. A subset of these samples, whose HVS-I sequences were previously obtained, was also examined by high-resolution restriction analysis. The Y-chromosome variation was investigated in 139 subjects by using 17 biallelic markers and the 49a,f/Taq I system. For both uniparental systems, the large majority of the haplogroups observed in the Iraqi population are those (H, J, T, and U for the mtDNA, and J(xM172) and J-M172 for the Y chromosome) considered to have originated in the Middle East and to have later spread all over Western Eurasia. However, about 9% of the mtDNAs and 30% of the Y-chromosomes most likely represent arrivals from distant geographic regions. The different proportion of long-range genetic input observed for the mtDNA and the Y chromosome appears to indicate that events of gene flow to this area might have involved mainly males rather than females.

The possibility that some combinations of mtDNA polymorphisms, previously associated with Leber's hereditary optic neuropathy (LHON), may affect mitochondrial respiratory function was tested in osteosarcoma-derived transmitochondrial cytoplasmic hybrids (cybrids). In this cellular system, in the presence of the same nuclear background, different exogenous mtDNAs are used to repopulate a parental cell line previously devoid of its original mtDNA. No detectable differences in multiple parameters exploring respiratory function were observed when mtDNAs belonging to European haplogroups X, H, T and J were used. Different possible explanations for the previously established association between haplogroup J and LHON 11778/ND4 and 14484/ND6 pathogenic mutations are discussed, including the unconventional proposal that mtDNA haplogroup J may exert a protective rather than detrimental effect.

We have analyzed the maternally inherited mitochondrial DNA from each of nine geographically separated Jewish groups, eight non-Jewish host populations, and an Israeli Arab/Palestinian population, and we have compared the differences found in Jews and non-Jews with those found using Y-chromosome data that were obtained, in most cases, from the same population samples. The results suggest that most Jewish communities were founded by relatively few women, that the founding process was independent in different geographic areas, and that subsequent genetic input from surrounding populations was limited on the female side. In sharp contrast to this, the paternally inherited Y chromosome shows diversity similar to that of neighboring populations and shows no evidence of founder effects. These sex-specific differences demonstrate an important role for culture in shaping patterns of genetic variation and are likely to have significant epidemiological implications for studies involving these populations. We illustrate this by presenting data from a panel of X-chromosome microsatellites, which indicates that, in the case of the Georgian Jews, the female-specific founder event appears to have resulted in elevated levels of linkage disequilibrium.

Forty-seven mtDNAs collected in the Dominican Republic and belonging to the African-specific haplogroup L2 were studied by high-resolution RFLP and control-region sequence analyses. Four sets of diagnostic markers that subdivide L2 into four clades (L2a–L2d) were identified, and a survey of published African data sets appears to indicate that these clades encompass all L2 mtDNAs and harbor very different geographic/ethnic distributions. One mtDNA from each of the four clades was completely sequenced by means of a new sequencing protocol that minimizes time and expense. The phylogeny of the L2 complete sequences showed that the two mtDNAs from L2b and L2d seem disproportionately derived, compared with those from L2a and L2c. This result is not consistent with a simple model of neutral evolution with a uniform molecular clock. The pattern of nonsynonymous versus synonymous substitutions hints at a role for selection in the evolution of human mtDNA. Regardless of whether selection is shaping the evolution of modern human mtDNAs, the population screening of L2 mtDNAs for the mutations identified by our complete sequence study should allow the identification of marker motifs of younger age with more restricted geographic distributions, thus providing new clues about African prehistory and the origin and relationships of African ethnic groups.

Founder analysis is a method for analysis of nonrecombining DNA sequence data, with the aim of identification and dating of migrations into new territory. The method picks out founder sequence types in potential source populations and dates lineage clusters deriving from them in the settlement zone of interest. Here, using mtDNA, we apply the approach to the colonization of Europe, to estimate the proportion of modern lineages whose ancestors arrived during each major phase of settlement. To estimate the Palaeolithic and Neolithic contributions to European mtDNA diversity more accurately than was previously achievable, we have now extended the Near Eastern, European, and northern-Caucasus databases to 1,234, 2, 804, and 208 samples, respectively. Both back-migration into the source population and recurrent mutation in the source and derived populations represent major obstacles to this approach. We have developed phylogenetic criteria to take account of both these factors, and we suggest a way to account for multiple dispersals of common sequence types. We conclude that (i) there has been substantial back-migration into the Near East, (ii) the majority of extant mtDNA lineages entered Europe in several waves during the Upper Palaeolithic, (iii) there was a founder effect or bottleneck associated with the Last Glacial Maximum, 20,000 years ago, from which derives the largest fraction of surviving lineages, and (iv) the immigrant Neolithic component is likely to comprise less than one-quarter of the mtDNA pool of modern Europeans.

Recent progress in the phylogenetic resolution of the Y-chromosome phylogeny permits the male demographic dynamics and migratory events that occurred in Central and Southern America after the initial human spread into the Americas to be investigated at the regional level. To delve further into this issue, we examined more than 400 Native American Y chromosomes (collected in the region ranging from Mexico to South America) belonging to haplogroup Q – virtually the only branch of the Y phylogeny observed in modern-day Amerindians of Central and South America – together with 27 from Mongolia and Kamchatka. Two main founding lineages, Q1a3a1a-M3 and Q1a3a1-L54(xM3), were detected along with novel sub-clades of younger age and more restricted geographic distributions. The first was also observed in Far East Asia while no Q1a3a1-L54(xM3) Y chromosome was found in Asia except the southern Siberian-specific sub-clade Q1a3a1c-L330. Our data not only confirm a southern Siberian origin of ancestral populations that gave rise to Paleo-Indians and the differentiation of both Native American Q founding lineages in Beringia, but support their concomitant arrival in Mesoamerica, where Mexico acted as recipient for the first wave of migration, followed by a rapid southward migration, along the Pacific coast, into the Andean region. Although Q1a3a1a-M3 and Q1a3a1-L54(xM3) display overlapping general distributions, they show different patterns of evolution in the Mexican plateau and the Andean area, which can be explained by local differentiations due to demographic events triggered by the introduction of agriculture and associated with the flourishing of the Great Empires.

The current human mitochondrial (mtDNA) phylogeny does not equally represent all human populations but is biased in favour of representatives originally from north and central Europe. This especially affects the phylogeny of some uncommon West Eurasian haplogroups, including I and W, whose southern European and Near Eastern components are very poorly represented, suggesting that extensive hidden phylogenetic substructure remains to be uncovered. This study expanded and re-analysed the available datasets of I and W complete mtDNA genomes, reaching a comprehensive 419 mitogenomes, and searched for precise correlations between the ages and geographical distributions of their numerous newly identified subclades with events of human dispersal which contributed to the genetic formation of modern Europeans. Our results showed that haplogroups I (within N1a1b) and W originated in the Near East during the Last Glacial Maximum or pre-warming period (the period of gradual warming between the end of the LGM, ∼19 ky ago, and the beginning of the first main warming phase, ∼15 ky ago) and, like the much more common haplogroups J and T, may have been involved in Late Glacial expansions starting from the Near East. Thus our data contribute to a better definition of the Late and postglacial re-peopling of Europe, providing further evidence for the scenario that major population expansions started after the Last Glacial Maximum but before Neolithic times, but also evidencing traces of diffusion events in several I and W subclades dating to the European Neolithic and restricted to Europe.

In this study we evaluated migration models to the Americas by using the information contained in native mitochondrial genomes (mitogenomes) from North America. Molecular and phylogeographic analyses of B2a mitogenomes, which are absent in Eskimo–Aleut and northern Na-Dene speakers, revealed that this haplogroup arose in North America ∼11–13 ka from one of the founder Paleo-Indian B2 mitogenomes. In contrast, haplogroup A2a, which is typical of Eskimo–Aleuts and Na-Dene, but also present in the easternmost Siberian groups, originated only 4–7 ka in Alaska, led to the first Paleo-Eskimo settlement of northern Canada and Greenland, and contributed to the formation of the Na-Dene gene pool. However, mitogenomes also show that Amerindians from northern North America, without any distinction between Na-Dene and non–Na-Dene, were heavily affected by an additional and distinctive Beringian genetic input. In conclusion, most mtDNA variation (along the double-continent) stems from the first wave from Beringia, which followed the Pacific coastal route. This was accompanied or followed by a second inland migratory event, marked by haplogroups X2a and C4c, which affected all Amerindian groups of Northern North America. Much later, the ancestral A2a carriers spread from Alaska, undertaking both a westward migration to Asia and an eastward expansion into the circumpolar regions of Canada. Thus, the first American founders left the greatest genetic mark but the original maternal makeup of North American Natives was subsequently reshaped by additional streams of gene flow and local population dynamics, making a three-wave view too simplistic.

To better define the structure and origin of the Bulgarian paternal gene pool, we have examined the Y-chromosome variation in 808 Bulgarian males. The analysis was performed by high-resolution genotyping of biallelic markers and by analyzing the STR variation within the most informative haplogroups. We found that the Y-chromosome gene pool in modern Bulgarians is primarily represented by Western Eurasian haplogroups with ∼ 40% belonging to haplogroups E-V13 and I-M423, and 20% to R-M17. Haplogroups common in the Middle East (J and G) and in South Western Asia (R-L23*) occur at frequencies of 19% and 5%, respectively. Haplogroups C, N and Q, distinctive for Altaic and Central Asian Turkic-speaking populations, occur at the negligible frequency of only 1.5%. Principal Component analyses group Bulgarians with European populations, apart from Central Asian Turkic-speaking groups and South Western Asia populations. Within the country, the genetic variation is structured in Western, Central and Eastern Bulgaria indicating that the Balkan Mountains have been permeable to human movements. The lineage analysis provided the following interesting results: (i) R-L23* is present in Eastern Bulgaria since the post glacial period; (ii) haplogroup E-V13 has a Mesolithic age in Bulgaria from where it expanded after the arrival of farming; (iii) haplogroup J-M241 probably reflects the Neolithic westward expansion of farmers from the earliest sites along the Black Sea. On the whole, in light of the most recent historical studies, which indicate a substantial proto-Bulgarian input to the contemporary Bulgarian people, our data suggest that a common paternal ancestry between the proto-Bulgarians and the Altaic and Central Asian Turkic-speaking populations either did not exist or was negligible.

Background: The Late Glacial Maximum (LGM), ∼20 thousand years ago (kya), is thought to have forced the peopleinhabiting vast areas of northern and central Europe to retreat to southern regions characterized by milder climaticconditions. Archaeological records indicate that Franco-Cantabria might have been the major source for the re-peopling ofEurope at the beginning of the Holocene (11.5 kya). However, genetic evidence is still scarce and has been the focus of anintense debate.Methods/Principal Findings:Based on a survey of more than 345,000 partial control region sequences and the analysis of53 mitochondrial DNA (mtDNA) genomes, we identified an mtDNA lineage, HV4a1a, which most likely arose in the Franco-Cantabrian area about 5.4 kya and remained confined to northern Iberia.Conclusions/Significance:The HV4a1a lineage and several of its younger branches reveal for the first time geneticcontinuity in this region and long-term episodes of isolation. This, in turn, could at least in part explain the unique linguisticand cultural features of the Basque region. This research study received support from the Fundación de Investigación Médica Mutua Madrileña (to AS), the Ministerio de Ciencia e Innovación(SAF2008-02971) (to AS), the Progetti Ricerca Interesse Nazionale 2009 (Italian Ministry of the University) (to AA and AT), the FIRB-Futuro in Ricerca (Italian Ministry of the University) (to AA and AO), the Fondazione Alma Mater Ticinensis (to AT) SI

Knowledge of high resolution Y-chromosome haplogroup diversification within Iran provides important geographic context regarding the spread and compartmentalization of male lineages in the Middle East and southwestern Asia. At present, the Iranian population is characterized by an extraordinary mix of different ethnic groups speaking a variety of Indo-Iranian, Semitic and Turkic languages. Despite these features, only few studies have investigated the multiethnic components of the Iranian gene pool. In this survey 938 Iranian male DNAs belonging to 15 ethnic groups from 14 Iranian provinces were analyzed for 84 Y-chromosome biallelic markers and 10 STRs. The results show an autochthonous but non-homogeneous ancient background mainly composed by J2a sub-clades with different external contributions. The phylogeography of the main haplogroups allowed identifying post-glacial and Neolithic expansions toward western Eurasia but also recent movements towards the Iranian region from western Eurasia (R1b-L23), Central Asia (Q-M25), Asia Minor (J2a-M92) and southern Mesopotamia (J1-Page08). In spite of the presence of important geographic barriers (Zagros and Alborz mountain ranges, and the Dasht-e Kavir and Dash-e Lut deserts) which may have limited gene flow, AMOVA analysis revealed that language, in addition to geography, has played an important role in shaping the nowadays Iranian gene pool. Overall, this study provides a portrait of the Y-chromosomal variation in Iran, useful for depicting a more comprehensive history of the peoples of this area as well as for reconstructing ancient migration routes. In addition, our results evidence the important role of the Iranian plateau as source and recipient of gene flow between culturally and genetically distinct populations.

Human populations, along with those of many other species, are thought to have contracted into a number of refuge areas at the height of the last Ice Age. European populations are believed to be, to a large extent, the descendants of the inhabitants of these refugia, and some extant mtDNA lineages can be traced to refugia in Franco-Cantabria (haplogroups H1, H3, V, and U5b1), the Italian Peninsula (U5b3), and the East European Plain (U4 and U5a). Parts of the Near East, such as the Levant, were also continuously inhabited throughout the Last Glacial Maximum, but unlike western and eastern Europe, no archaeological or genetic evidence for Late Glacial expansions into Europe from the Near East has hitherto been discovered. Here we report, on the basis of an enlarged whole-genome mitochondrial database, that a substantial, perhaps predominant, signal from mitochondrial haplogroups J and T, previously thought to have spread primarily from the Near East into Europe with the Neolithic population, may in fact reflect dispersals during the Late Glacial period, ∼19-12 thousand years (ka) ago. M.P. was supported by Marie Curie Early Stage Training “Advanced Genetic Analysis in the Postgenomic Era” (European Union MEST-CT-2004-504318) and by a Newton International Fellowship. This research was also supported by the Italian Ministry of Education, University, and Research: Progetti FIRB-Futuro in Ricerca 2008 (to A.A. and A.O.), and Progetti Ricerca Interesse Nazionale 2009 (to A.A., O.S. and A.T.); Fondazione Alma Mater Ticinensis (to A.T. and O.S.); the European Commission, Directorate-General for Research (FP7 Ecogene grant number 205419, to R.V.); the European Union Regional Development Fund (through the Centre of Excellence in Genomics, to R.V.); the Estonian Ministry of Education and Research (Basic Research grant numbers SF 0270177As08, to R.V., and SF 0270177Bs08, to E.M.); the Estonian Science Foundation (grant number 7858, to E.M.); and the FCT (Portuguese Foundation for Science and Technology), through research project PTDC/CS-ANT/113832/2009 and personal grants to J.B.P. (SFRH/BD/45657/2008) and P.S. (SFRH/BPD/64233/2009). P.S. also received support from the DeLaszlo Foundation. N.A.-Z. was supported by the Institute of International Education fellowship. IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology, and Higher Education (FCT) and is partially supported by FCT.

BACKGROUND: Most genetic studies on modern cattle have established a common origin for all taurine breeds in the Near East, during the Neolithic transition about 10 thousand years (ka) ago. Yet, the possibility of independent and/or secondary domestication events is still debated and is fostered by the finding of rare mitochondrial DNA (mtDNA) haplogroups like P, Q and R. Haplogroup T1, because of its geographic distribution, has been the subject of several investigations pointing to a possible independent domestication event in Africa and suggesting a genetic contribution of African cattle to the formation of Iberian and Creole cattle. Whole mitochondrial genome sequence analysis, with its proven effectiveness in improving the resolution of phylogeographic studies, is the most appropriate tool to investigate the origin and structure of haplogroup T1. METHODOLOGY: A survey of >2200 bovine mtDNA control regions representing 28 breeds (15 European, 10 African, 3 American) identified 281 subjects belonging to haplogroup T1. Fifty-four were selected for whole mtDNA genome sequencing, and combined with ten T1 complete sequences from previous studies into the most detailed T1 phylogenetic tree available to date. CONCLUSIONS: Phylogenetic analysis of the 64 T1 mitochondrial complete genomes revealed six distinct sub-haplogroups (T1a-T1f). Our data support the overall scenario of a Near Eastern origin of the T1 sub-haplogroups from as much as eight founding T1 haplotypes. However, the possibility that one sub-haplogroup (T1d) arose in North Africa, in domesticated stocks, shortly after their arrival from the Near East, can not be ruled out. Finally, the previously identified "African-derived American" (AA) haplotype turned out to be a sub-clade of T1c (T1c1a1). This haplotype was found here for the first time in Africa (Egypt), indicating that it probably originated in North Africa, reached the Iberian Peninsula and sailed to America, with the first European settlers.

International audience; BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disorder, which in over 90% of cases is due to one of three primary mitochondrial DNA (mtDNA) point mutations (m.11778G>A, m.3460G>A and m.14484T>C, respectively in MT-ND4, MT-ND1 and MT-ND6 genes). However, the spectrum of mtDNA mutations causing the remaining 10% of cases is only partially and often poorly defined. METHODOLOGY/PRINCIPAL FINDINGS: In order to improve such a list of pathological variants, we completely sequenced the mitochondrial genomes of suspected LHON patients from Italy, France and Germany, lacking the three primary common mutations. Phylogenetic and conservation analyses were performed. Sixteen mitochondrial genomes were found to harbor at least one of the following nine rare LHON pathogenic mutations in genes MT-ND1 (m.3700G>A/p.A132T, m.3733G>A-C/p.E143K-Q, m.4171C>A/p.L289M), MT-ND4L (m.10663T>C/p.V65A) and MT-ND6 (m.14459G>A/p.A72V, m.14495A>G/p.M64I, m.14482C>A/p.L60S, and m.14568C>T/p.G36S). Phylogenetic analyses revealed that these substitutions were due to independent events on different haplogroups, whereas interspecies comparisons showed that they affected conserved amino acid residues or domains in the ND subunit genes of complex I. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that these nine substitutions are all primary LHON mutations. Therefore, despite their relative low frequency, they should be routinely tested for in all LHON patients lacking the three common mutations. Moreover, our sequence analysis confirms the major role of haplogroups J1c and J2b (over 35% in our probands versus 6% in the general population of Western Europe) and other putative synergistic mtDNA variants in LHON expression.

With analyses of entire mitogenomes, studies of Native American mitochondrial DNA (mtDNA) variation have entered the final phase of phylogenetic refinement: the dissection of the founding haplogroups into clades that arose in America during and after human arrival and spread. Ages and geographic distributions of these clades could provide novel clues on the colonization processes of the different regions of the double continent. As for the Southern Cone of South America, this approach has recently allowed the identification of two local clades (D1g and D1j) whose age estimates agree with the dating of the earliest archaeological sites in South America, indicating that Paleo-Indians might have reached that region from Beringia in less than 2000 years. In this study, we sequenced 46 mitogenomes belonging to two additional clades, termed B2i2 (former B2l) and C1b13, which were recently identified on the basis of mtDNA control-region data and whose geographical distributions appear to be restricted to Chile and Argentina. We confirm that their mutational motifs most likely arose in the Southern Cone region. However, the age estimate for B2i2 and C1b13 (11–13,000 years) appears to be younger than those of other local clades. The difference could reflect the different evolutionary origins of the distinct South American-specific sub-haplogroups, with some being already present, at different times and locations, at the very front of the expansion wave in South America, and others originating later in situ, when the tribalization process had already begun. A delayed origin of a few thousand years in one of the locally derived populations, possibly in the central part of Chile, would have limited the geographical and ethnic diffusion of B2i2 and explain the present-day occurrence that appears to be mainly confined to the Tehuelche and Araucanian-speaking groups. SI

Mitochondrial DNAs (mtDNAs) of 54 Tibetans residing at altitudes ranging from 3,000–4,500 m were amplified by polymerase chain reaction (PCR), examined by high-resolution restriction endonuclease analysis, and compared with those previously described in 10 other Asian and Siberian populations. This comparison revealed that more than 50% of Asian mtDNAs belong to a unique mtDNA lineage which is found only among Mongoloids, suggesting that this lineage most likely originated in Asia at an early stage of the human colonization of that continent. Within the Tibetan mtDNAs, sets of additional linked polymorphic sites defined seven minor lineages of related mtDNA haplotypes (haplogroups). The frequency and distribution of these haplogroups in modern Asian populations are supportive of previous genetic evidence that Tibetans, although located in southern Asia, share common ancestral origins with northern Mongoloid populations. This analysis of Tibetan mtDNAs also suggests that mtDNA mutations are unlikely to play a major role in the adaptation of Tibetans to high altitudes. © 1994 Wiley-Liss, Inc.

Recent analyses of mitochondrial genomes from Native Americans have brought the overall number of recognized maternal founding lineages from just four to a current count of 15. However, because of their relative low frequency, almost nothing is known for some of these lineages. This leaves a considerable void in understanding the events that led to the colonization of the Americas following the Last Glacial Maximum (LGM). In this study, we identified and completely sequenced 14 mitochondrial DNAs belonging to one extremely rare Native American lineage known as haplogroup C4c. Its age and geographical distribution raise the possibility that C4c marked the Paleo-Indian group(s) that entered North America from Beringia through the ice-free corridor between the Laurentide and Cordilleran ice sheets. The similarities in ages andgeographical distributions for C4c and the previously analyzed X2a lineage provide support to the scenario of a dual origin for Paleo-Indians. Taking into account that C4c is deeply rooted in the Asian portion of the mtDNA phylogeny and is indubitably of Asian origin, the finding that C4c and X2a are characterized by parallel genetic histories definitively dismisses the controversial hypothesis of an Atlantic glacial entry route into North America.

We report a sampling strategy based on Mendelian Breeding Units (MBUs), representing an interbreeding group of individuals sharing a common gene pool. The identification of MBUs is crucial for case-control experimental design in association studies. The aim of this work was to evaluate the possible existence of bias in terms of genetic variability and haplogroup frequencies in the MBU sample, due to severe sample selection. In order to reach this goal, the MBU sampling strategy was compared to a standard selection of individuals according to their surname and place of birth. We analysed mitochondrial DNA variation (first hypervariable segment and coding region) in unrelated healthy subjects from two different areas of Sardinia: the area around the town of Cabras and the western Campidano area. No statistically significant differences were observed when the two sampling methods were compared, indicating that the stringent sample selection needed to establish a MBU does not alter original genetic variability and haplogroup distribution. Therefore, the MBU sampling strategy can be considered a useful tool in association studies of complex traits.

Pan-American mitochondrial DNA (mtDNA) haplogroup C1 has been recently subdivided into three branches, two of which (C1b and C1c) are characterized by ages and geographical distributions that are indicative of an early arrival from Beringia with Paleo-Indians. In contrast, the estimated ages of C1d—the third subset of C1—looked too young to fit the above scenario. To define the origin of this enigmatic C1 branch, we completely sequenced 63 C1d mitochondrial genomes from a wide range of geographically diverse, mixed, and indigenous American populations. The revised phylogeny not only brings the age of C1d within the range of that of its two sister clades, but reveals that there were two C1d founder genomes for Paleo-Indians. Thus, the recognized maternal founding lineages of Native Americans are at least 15, indicating that the overall number of Beringian or Asian founder mitochondrial genomes will probably increase extensively when all Native American haplogroups reach the same level of phylogenetic and genomic resolution as obtained here for C1d. Fil: Perego, Ugo A.. Soreson Molecular Genealogy Foundation; Estados Unidos. Università di Pavia. Dipartimento di Genetica e Microbiologia; Italia Fil: Angerhofer, Norman. Soreson Molecular Genealogy Foundation; Estados Unidos Fil: Pala, Maria. Università di Pavia. Dipartimento di Genetica e Microbiologia; Italia Fil: Olivieri, Anna. Università di Pavia. Dipartimento di Genetica e Microbiologia; Italia Fil: Lancioni, Hovirag. Universita Di Perugia; Italia Fil: Kashani, Baharak Hooshiar. Università di Pavia. Dipartimento di Genetica e Microbiologia; Italia Fil: Carossa, Valeria. Università di Pavia. Dipartimento di Genetica e Microbiologia; Italia Fil: Ekins, Jayne E.. Soreson Molecular Genealogy Foundation; Estados Unidos Fil: Gómez Carballa, Alberto. Universidad de Santiago de Compostela; España Fil: Huber, Gabriela. Universidad de Innsbruck; Austria Fil: Zimmermann, Bettina. Universidad de Innsbruck; Austria Fil: Corach, Daniel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Babudri, Nora. Universita Di Perugia; Italia Fil: Panara, Fausto. Universita Di Perugia; Italia Fil: Myres, Natalie M.. Soreson Molecular Genealogy Foundation; Estados Unidos Fil: Parson, Walther. Universidad de Innsbruck; Austria Fil: Semino, Ornella. Università di Pavia. Dipartimento di Genetica e Microbiologia; Italia Fil: Salas, Antonio. Universidad de Santiago de Compostela; España Fil: Woodward, Scott R.. Soreson Molecular Genealogy Foundation; Estados Unidos Fil: Achilli, Alessandro. Università di Pavia. Dipartimento di Genetica e Microbiologia; Italia. Universita Di Perugia; Italia Fil: Torroni, Antonio. Università di Pavia. Dipartimento di Genetica e Microbiologia; Italia

The Tuareg of the Fezzan region (Libya) are characterized by an extremely high frequency (61%) of haplogroup H1, a mitochondrial DNA (mtDNA) haplogroup that is common in all Western European populations. To define how and when H1 spread from Europe to North Africa up to the Central Sahara, in Fezzan, we investigated the complete mitochondrial genomes of eleven Libyan Tuareg belonging to H1. Coalescence time estimates suggest an arrival of the European H1 mtDNAs at about 8,000–9,000 years ago, while phylogenetic analyses reveal three novel H1 branches, termed H1v, H1w and H1x, which appear to be specific for North African populations, but whose frequencies can be extremely different even in relatively close Tuareg villages. Overall, these findings support the scenario of an arrival of haplogroup H1 in North Africa from Iberia at the beginning of the Holocene, as a consequence of the improvement in climate conditions after the Younger Dryas cold snap, followed by in situ formation of local H1 sub-haplogroups. This process of autochthonous differentiation continues in the Libyan Tuareg who, probably due to isolation and recent founder events, are characterized by village-specific maternal mtDNA lineages.

BackgroundAlzheimer's Disease (AD) is the most common neurodegenerative disease and the leading cause of dementia among senile subjects. It has been proposed that AD can be caused by defects in mitochondrial oxidative phosphorylation. Given the fundamental contribution of the mitochondrial genome (mtDNA) for the respiratory chain, there have been a number of studies investigating the association between mtDNA inherited variants and multifactorial diseases, however no general consensus has been reached yet on the correlation between mtDNA haplogroups and AD.Methodology/principal findingsWe applied for the first time a high resolution analysis (sequencing of displacement loop and restriction analysis of specific markers in the coding region of mtDNA) to investigate the possible association between mtDNA-inherited sequence variation and AD in 936 AD patients and 776 cognitively assessed normal controls from central and northern Italy. Among over 40 mtDNA sub-haplogroups analysed, we found that sub-haplogroup H5 is a risk factor for AD (OR=1.85, 95% CI:1.04-3.23) in particular for females (OR=2.19, 95% CI:1.06-4.51) and independently from the APOE genotype. Multivariate logistic regression revealed an interaction between H5 and age. When the whole sample is considered, the H5a subgroup of molecules, harboring the 4336 transition in the tRNAGln gene, already associated to AD in early studies, was about threefold more represented in AD patients than in controls (2.0% vs 0.8%; p=0.031), and it might account for the increased frequency of H5 in AD patients (4.2% vs 2.3%). The complete re-sequencing of the 56 mtDNAs belonging to H5 revealed that AD patients showed a trend towards a higher number (p=0.052) of sporadic mutations in tRNA and rRNA genes when compared with controls.ConclusionsOur results indicate that high resolution analysis of inherited mtDNA sequence variation can help in identifying both ancient polymorphisms defining sub-haplogroups and the accumulation of sporadic mutations associated with complex traits such as AD.

There are extensive data indicating that some glacial refuge zones of southern Europe (Franco-Cantabria, Balkans, and Ukraine) were major genetic sources for the human recolonization of the continent at the beginning of the Holocene. Intriguingly, there is no genetic evidence that the refuge area located in the Italian Peninsula contributed to this process. Here we show, through phylogeographic analyses of mitochondrial DNA (mtDNA) variation performed at the highest level of molecular resolution (52 entire mitochondrial genomes), that the most likely homeland for U5b3-a haplogroup present at a very low frequency across Europe-was the Italian Peninsula. In contrast to mtDNA haplogroups that expanded from other refugia, the Holocene expansion of haplogroup U5b3 toward the North was restricted by the Alps and occurred only along the Mediterranean coasts, mainly toward nearby Provence (southern France). From there, approximately 7,000-9,000 years ago, a subclade of this haplogroup moved to Sardinia, possibly as a result of the obsidian trade that linked the two regions, leaving a distinctive signature in the modern people of the island. This scenario strikingly matches the age, distribution, and postulated geographic source of a Sardinian Y chromosome haplogroup (I2a2-M26), a paradigmatic case in the European context of a founder event marking both female and male lineages.

Background Central Asia and the Indian subcontinent represent an area considered as a source and a reservoir for human genetic diversity, with many markers taking root here, most of which are the ancestral state of eastern and western haplogroups, while others are local. Between these two regions, Terai (Nepal) is a pivotal passageway allowing, in different times, multiple population interactions, although because of its highly malarial environment, it was scarcely inhabited until a few decades ago, when malaria was eradicated. One of the oldest and the largest indigenous people of Terai is represented by the malaria resistant Tharus, whose gene pool could still retain traces of ancient complex interactions. Until now, however, investigations on their genetic structure have been scarce mainly identifying East Asian signatures. Results High-resolution analyses of mitochondrial-DNA (including 34 complete sequences) and Y-chromosome (67 SNPs and 12 STRs) variations carried out in 173 Tharus (two groups from Central and one from Eastern Terai), and 104 Indians (Hindus from Terai and New Delhi and tribals from Andhra Pradesh) allowed the identification of three principal components: East Asian, West Eurasian and Indian, the last including both local and inter-regional sub-components, at least for the Y chromosome. Conclusion Although remarkable quantitative and qualitative differences appear among the various population groups and also between sexes within the same group, many mitochondrial-DNA and Y-chromosome lineages are shared or derived from ancient Indian haplogroups, thus revealing a deep shared ancestry between Tharus and Indians. Interestingly, the local Y-chromosome Indian component observed in the Andhra-Pradesh tribals is present in all Tharu groups, whereas the inter-regional component strongly prevails in the two Hindu samples and other Nepalese populations. The complete sequencing of mtDNAs from unresolved haplogroups also provided informative markers that greatly improved the mtDNA phylogeny and allowed the identification of ancient relationships between Tharus and Malaysia, the Andaman Islands and Japan as well as between India and North and East Africa. Overall, this study gives a paradigmatic example of the importance of genetic isolates in revealing variants not easily detectable in the general population.

A Neolithic domestication of taurine cattle in the Fertile Crescent from local aurochsen (Bos primigenius) is generally accepted, but a genetic contribution from European aurochsen has been proposed. Here we performed a survey of a large number of taurine cattle mitochondrial DNA (mtDNA) control regions from numerous European breeds confirming the overall clustering within haplogroups (T1, T2 and T3) of Near Eastern ancestry, but also identifying eight mtDNAs (1.3%) that did not fit in haplogroup T. Sequencing of the entire mitochondrial genome showed that four mtDNAs formed a novel branch (haplogroup R) which, after the deep bifurcation that gave rise to the taurine and zebuine lineages, constitutes the earliest known split in the mtDNA phylogeny of B. primigenius. The remaining four mtDNAs were members of the recently discovered haplogroup Q. Phylogeographic data indicate that R mtDNAs were derived from female European aurochsen, possibly in the Italian Peninsula, and sporadically included in domestic herds. In contrast, the available data suggest that Q mtDNAs and T subclades were involved in the same Neolithic event of domestication in the Near East. Thus, the existence of novel (and rare) taurine haplogroups highlights a multifaceted genetic legacy from distinct B. primigenius populations. Taking into account that the maternally transmitted mtDNA tends to underestimate the extent of gene flow from European aurochsen, the detection of the R mtDNAs in autochthonous breeds, some of which are endangered, identifies an unexpected reservoir of genetic variation that should be carefully preserved.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disease due to mitochondrial DNA (mtDNA) point mutations in complex I subunit genes, whose incomplete penetrance has been attributed to both genetic and environmental factors. Indeed, the mtDNA background defined as haplogroup J is known to increase the penetrance of the 11778/ND4 and 14484/ND6 mutations. Recently it was also documented that the professional exposure to n-hexane might act as an exogenous trigger for LHON. Therefore, we here investigate the effect of the n-hexane neurotoxic metabolite 2,5-hexanedione (2,5-HD) on cell viability and mitochondrial function of different cell models (cybrids and fibroblasts) carrying the LHON mutations on different mtDNA haplogroups. The viability of control and LHON cybrids and fibroblasts, whose mtDNAs were completely sequenced, was assessed using the MTT assay. Mitochondrial ATP synthesis rate driven by complex I substrates was determined with the luciferine/luciferase method. Incubation with 2,5-HD caused the maximal loss of viability in control and LHON cells. The toxic effect of this compound was similar in control cells irrespective of the mtDNA background. On the contrary, sensitivity to 2,5-HD induced cell death was greatly increased in LHON cells carrying the 11778/ND4 or the 14484/ND6 mutation on haplogroup J, whereas the 11778/ND4 mutation in association with haplogroups U and H significantly improved cell survival. The 11778/ND4 mutation on haplogroup U was also more resistant to inhibition of complex I dependent ATP synthesis by 2,5-HD. In conclusion, this study shows that mtDNA haplogroups modulate the response of LHON cells to 2,5-HD. In particular, haplogroup J makes cells more sensitive to its toxic effect. This is the first evidence that an mtDNA background plays a role by interacting with an environmental factor and that 2,5-HD may be a risk element for visual loss in LHON. This proof of principle has broad implications for other neurodegenerative disorders such as Parkinson's disease.

The mitochondrial DNA variation of 295 Berber-speakers from Morocco (Asni, Bouhria and Figuig) and the Egyptian oasis of Siwa was evaluated by sequencing a portion of the control region (including HVS-I and part of HVS-II) and surveying haplogroup-specific coding region markers. Our findings show that the Berber mitochondrial pool is characterized by an overall high frequency of Western Eurasian haplogroups, a somehow lower frequency of sub-Saharan L lineages, and a significant (but differential) presence of North African haplogroups U6 and M1, thus occupying an intermediate position between European and sub-Saharan populations in PCA analysis. A clear and significant genetic differentiation between the Berbers from Maghreb and Egyptian Berbers was also observed. The first are related to European populations as shown by haplogroup H1 and V frequencies, whereas the latter share more affinities with East African and Nile Valley populations as indicated by the high frequency of M1 and the presence of L0a1, L3i, L4*, and L4b2 lineages. Moreover, haplogroup U6 was not observed in Siwa. We conclude that the origins and maternal diversity of Berber populations are old and complex, and these communities bear genetic characteristics resulting from various events of gene flow with surrounding and migrating populations.