Projecting Ancient Ancestry in Modern-Day Arabians and Iranians: A Key Role of the Past Exposed Arabo-Persian Gulf on Human Migrations

The Arabian Peninsula is strategic for investigations centered on the early structuring of modern humans in the wake of the out-of-Africa migration. Despite its poor climatic conditions for the recovery of ancient human DNA evidence, the availability of both genomic data from neighboring ancient specimens and informative statistical tools allow modeling the ancestry of local modern populations. We applied this approach to a data set of 741,000 variants screened in 291 Arabians and 78 Iranians, and obtained insightful evidence. The west-east axis was a strong forcer of population structure in the Peninsula, and, more importantly, there were clear continuums throughout time linking western Arabia with the Levant, and eastern Arabia with Iran and the Caucasus. Eastern Arabians also displayed the highest levels of the basal Eurasian lineage of all tested modern-day populations, a signal that was maintained even after correcting for a possible bias due to a recent sub-Saharan African input in their genomes. Not surprisingly, eastern Arabians were also the ones with highest similarity with Iberomaurusians, who were, so far, the best proxy for the basal Eurasians amongst the known ancient specimens. The basal Eurasian lineage is the signature of ancient non-Africans who diverged from the common European-eastern Asian pool before 50,000 years ago, prior to the later interbred with Neanderthals. Our results appear to indicate that the exposed basin of the Arabo-Persian Gulf was the possible home of basal Eurasians, a scenario to be further investigated by searching ancient Arabian human specimens.This work was financed by FEDER-Fundo Europeu de Desenvolvimento Regional funds through COMPETE 2020-Operacional Programme for Competitiveness and Internationalization (POCI), Portugal 2020, by Portuguese funds through FCT-Fundação para a Ciência e a Tecnologia, Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Biomedical anthropological study in Arabian Peninsula based on high-throughput genomics” (POCI-01-0145-FEDER-016609), the Italian Ministry of Education, University and Research project Dipartimenti di Eccellenza Program (2018–2022)—Department of Biology and Biotechnology “L. Spallanzani,” University of Pavia (to A.T.). V.F. has a postdoc grant through FCT (SFRH/BPD/114927/2016). i3S is financed by FEDER-COMPETE 2020, Portugal 2020 and by Portuguese funds through FCT in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274). Authors would like to thank Dr Francesco Bertolini for facilitating the research of A.R. in the last stage of the article preparation

The Phylogeny of the Four Pan-American MtDNA Haplogroups: Implications for Evolutionary and Disease Studies

Only a limited number of complete mitochondrial genome sequences belonging to Native American haplogroups were available until recently, which left America as the continent with the least amount of information about sequence variation of entire mitochondrial DNAs. In this study, a comprehensive overview of all available complete mitochondrial DNA (mtDNA) genomes of the four pan-American haplogroups A2, B2, C1, and D1 is provided by revising the information scattered throughout GenBank and the literature, and adding 14 novel mtDNA sequences. The phylogenies of haplogroups A2, B2, C1, and D1 reveal a large number of sub-haplogroups but suggest that the ancestral Beringian population(s) contributed only six (successful) founder haplotypes to these haplogroups. The derived clades are overall starlike with coalescence times ranging from 18,000 to 21,000 years (with one exception) using the conventional calibration. The average of about 19,000 years somewhat contrasts with the corresponding lower age of about 13,500 years that was recently proposed by employing a different calibration and estimation approach. Our estimate indicates a human entry and spread of the pan-American haplogroups into the Americas right after the peak of the Last Glacial Maximum and comfortably agrees with the undisputed ages of the earliest Paleoindians in South America. In addition, the phylogenetic approach also indicates that the pathogenic status proposed for various mtDNA mutations, which actually define branches of Native American haplogroups, was based on insufficient grounds

Uniparental Genetic Heritage of Belarusians: Encounter of Rare Middle Eastern Matrilineages with a Central European Mitochondrial DNA Pool

Ethnic Belarusians make up more than 80% of the nine and half million people inhabiting the Republic of Belarus. Belarusians together with Ukrainians and Russians represent the East Slavic linguistic group, largest both in numbers and territory, inhabiting East Europe alongside Baltic-, Finno-Permic- and Turkic-speaking people. Till date, only a limited number of low resolution genetic studies have been performed on this population. Therefore, with the phylogeographic analysis of 565 Y-chromosomes and 267 mitochondrial DNAs from six well covered geographic sub-regions of Belarus we strove to complement the existing genetic profile of eastern Europeans. Our results reveal that around 80% of the paternal Belarusian gene pool is composed of R1a, I2a and N1c Y-chromosome haplogroups – a profile which is very similar to the two other eastern European populations – Ukrainians and Russians. The maternal Belarusian gene pool encompasses a full range of West Eurasian haplogroups and agrees well with the genetic structure of central-east European populations. Our data attest that latitudinal gradients characterize the variation of the uniparentally transmitted gene pools of modern Belarusians. In particular, the Y-chromosome reflects movements of people in central-east Europe, starting probably as early as the beginning of the Holocene. Furthermore, the matrilineal legacy of Belarusians retains two rare mitochondrial DNA haplogroups, N1a3 and N3, whose phylogeographies were explored in detail after de novo sequencing of 20 and 13 complete mitogenomes, respectively, from all over Eurasia. Our phylogeographic analyses reveal that two mitochondrial DNA lineages, N3 and N1a3, both of Middle Eastern origin, might mark distinct events of matrilineal gene flow to Europe: during the mid-Holocene period and around the Pleistocene-Holocene transition, respectively

Association of the mtDNA m.4171C>A/MT-ND1 mutation with both optic neuropathy and bilateral brainstem lesions

Background: An increasing number of mitochondrial DNA (mtDNA) mutations, mainly in complex I genes, have been associated with variably overlapping phenotypes of Leber’s hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (MELAS) and Leigh syndrome (LS). We here describe the first case in which the m.4171C>A/MT-ND1 mutation, previously reported only in association with LHON, leads also to a Leigh-like phenotype. Case presentation: A 16-year-old male suffered subacute visual loss and recurrent vomiting and vertigo associated with bilateral brainstem lesions affecting the vestibular nuclei. His mother and one sister also presented subacute visual loss compatible with LHON. Sequencing of the entire mtDNA revealed the homoplasmic m.4171C>A/MT-ND1 mutation, previously associated with pure LHON, on a haplogroup H background. Three additional non-synonymous homoplasmic transitions affecting ND2 (m.4705T>C/MT-ND2 and m.5263C>T/MT-ND2) and ND6 (m.14180T>C/MT-ND6) subunits, well recognized as polymorphisms in other mtDNA haplogroups but never found on the haplogroup H background, were also present. Conclusion: This case widens the phenotypic expression of the rare m.4171C>A/MT-ND1 LHON mutation, which may also lead to Leigh-like brainstem lesions, and indicates that the co-occurrence of other ND non-synonymous variants, found outside of their usual mtDNA backgrounds, may have increased the pathogenic potential of the primary LHON mutation

Mutation Rate Switch inside Eurasian Mitochondrial Haplogroups: Impact of Selection and Consequences for Dating Settlement in Europe

R-lineage mitochondrial DNA represents over 90% of the European population and is significantly present all around the planet (North Africa, Asia, Oceania, and America). This lineage played a major role in migration “out of Africa” and colonization in Europe. In order to determine an accurate dating of the R lineage and its sublineages, we analyzed 1173 individuals and complete mtDNA sequences from Mitomap. This analysis revealed a new coalescence age for R at 54.500 years, as well as several limitations of standard dating methods, likely to lead to false interpretations. These findings highlight the association of a striking under-accumulation of synonymous mutations, an over-accumulation of non-synonymous mutations, and the phenotypic effect on haplogroup J. Consequently, haplogroup J is apparently not a Neolithic group but an older haplogroup (Paleolithic) that was subjected to an underestimated selective force. These findings also indicated an under-accumulation of synonymous and non-synonymous mutations localized on coding and non-coding (HVS1) sequences for haplogroup R0, which contains the major haplogroups H and V. These new dates are likely to impact the present colonization model for Europe and confirm the late glacial resettlement scenario

Genetic Continuity in the Franco-Cantabrian Region: New Clues from Autochthonous Mitogenomes

Background: The Late Glacial Maximum (LGM),,20 thousand years ago (kya), is thought to have forced the people inhabiting vast areas of northern and central Europe to retreat to southern regions characterized by milder climatic conditions. Archaeological records indicate that Franco-Cantabria might have been the major source for the re-peopling of Europe at the beginning of the Holocene (11.5 kya). However, genetic evidence is still scarce and has been the focus of an intense debate. Methods/Principal Findings: Based on a survey of more than 345,000 partial control region sequences and the analysis of 53 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 genetic continuity in this region and long-term episodes of isolation. This, in turn, could at least in part explain the unique linguistic and cultural features of the Basque region

Mitochondrial Haplogroup H1 in North Africa: An Early Holocene Arrival from Iberia

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

Three-Dimensional Printing Bioceramic Scaffolds Using Direct-Ink-Writing for Craniomaxillofacial Bone Regeneration

Defects characterized as large osseous voids in bone, in certain circumstances, are difficult to treat, requiring extensive treatments which lead to an increased financial burden, pain, and prolonged hospital stays. Grafts exist to aid in bone tissue regeneration (BTR), among which ceramic-based grafts have become increasingly popular due to their biocompatibility and resorbability. BTR using bioceramic materials such as β-tricalcium phosphate has seen tremendous progress and has been extensively used in the fabrication of biomimetic scaffolds through the three-dimensional printing (3DP) workflow. 3DP has hence revolutionized BTR by offering unparalleled potential for the creation of complex, patient, and anatomic location-specific structures. More importantly, it has enabled the production of biomimetic scaffolds with porous structures that mimic the natural extracellular matrix while allowing for cell growth-a critical factor in determining the overall success of the BTR modality. While the concept of 3DP bioceramic bone tissue scaffolds for human applications is nascent, numerous studies have highlighted its potential in restoring both form and function of critically sized defects in a wide variety of translational models. In this review, we summarize these recent advancements and present a review of the engineering principles and methodologies that are vital for using 3DP technology for craniomaxillofacial reconstructive applications. Moreover, we highlight future advances in the field of dynamic 3D printed constructs via shape-memory effect, and comment on pharmacological manipulation and bioactive molecules required to treat a wider range of boney defects

BeppoSAX Detection and Follow-up of GRB980425

We present BeppoSAX GRBM and WFC light curves of GRB980425 and NFI follow-up data taken in 1998 April, May, and November. The first NFI observation has detected within the 8' radius error box of the GRB an X-ray source positionally consistent with the supernova SN 1998bw, exploded within a day of GRB980425, and a fainter X-ray source, not consistent with the position of the supernova. The former source is detected in the following NFI pointings and exhibits a decline of a factor of two in six months. If it is associated with SN 1998bw, this is the first detection of hard X-ray emission from a Type I supernova. The latter source exhibits only marginally significant variability. Based on these data, it is not possible to select either source as a firm candidate for the GRB counterpart.Comment: 2 pages, 1 PostScript figure, submitted to A&AS, Proc. of the Conference "Gamma-Ray Bursts in the Afterglow Era", held in Rome, 1998 November 3-6. Results concerning 'Source 2' have been update

OPA1-related dominant optic atrophy is not strongly influenced by mitochondrial DNA background

<p>Abstract</p> <p>Background</p> <p>Leber's hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) are the most frequent forms of hereditary optic neuropathies. LHON is associated with mitochondrial DNA (mtDNA) mutations whereas ADOA is mainly due to mutations in the OPA1 gene that encodes a mitochondrial protein involved in the mitochondrial inner membrane remodeling. A striking influence of mtDNA haplogroup J on LHON expression has been demonstrated and it has been recently suggested that this haplogroup could also influence ADOA expression. In this study, we have tested the influence of mtDNA backgrounds on OPA1 mutations.</p> <p>Methods</p> <p>To define the relationships between OPA1 mutations and mtDNA backgrounds, we determined the haplogroup affiliation of 41 French patients affected by OPA1-related ADOA by control-region sequencing and RFLP survey of their mtDNAs.</p> <p>Results</p> <p>The comparison between patient and reference populations did not revealed any significant difference.</p> <p>Conclusion</p> <p>Our results argue against a strong influence of mtDNA background on ADOA expression. These data allow to conclude that OPA1 could be considered as a "severe mutation", directly responsible of the optic atrophy, whereas OPA1-negative ADOA and LHON mutations need an external factor(s) to express the pathology (i.e. synergistic interaction with mitochondrial background).</p