Publications by authors named "Bruno Cavadas"

30 Publications

  • Page 1 of 1

Dynamics of a Dual SARS-CoV-2 Lineage Co-Infection on a Prolonged Viral Shedding COVID-19 Case: Insights into Clinical Severity and Disease Duration.

Microorganisms 2021 Feb 2;9(2). Epub 2021 Feb 2.

CHUSJ-Centro Hospitalar Universitário S. João, 4200-319 Porto, Portugal.

A few molecularly proven severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases of symptomatic reinfection are currently known worldwide, with a resolved first infection followed by a second infection after a 48 to 142-day intervening period. We report a multiple-component study of a clinically severe and prolonged viral shedding coronavirus disease 2019 (COVID-19) case in a 17-year-old Portuguese female. She had two hospitalizations, a total of 19 RT-PCR tests, mostly positive, and criteria for releasing from home isolation at the end of 97 days. The viral genome was sequenced in seven serial samples and in the diagnostic sample from her infected mother. A human genome-wide array (>900 K) was screened on the seven samples, and in vitro culture was conducted on isolates from three late samples. The patient had co-infection by two SARS-CoV-2 lineages, which were affiliated in distinct clades and diverging by six variants. The 20A lineage was absolute at the diagnosis (shared with the patient's mother), but nine days later, the 20B lineage had 3% frequency, and two months later, the 20B lineage had 100% frequency. The 900 K profiles confirmed the identity of the patient in the serial samples, and they allowed us to infer that she had polygenic risk scores for hospitalization and severe respiratory disease within the normal distributions for a Portuguese population cohort. The early-on dynamic co-infection may have contributed to the severity of COVID-19 in this otherwise healthy young patient, and to her prolonged SARS-CoV-2 shedding profile.
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http://dx.doi.org/10.3390/microorganisms9020300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912897PMC
February 2021

Shedding Light on the African Enigma: In Vitro Testing of Coevolution.

Microorganisms 2021 Jan 25;9(2). Epub 2021 Jan 25.

i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.

The continuous characterization of genome-wide diversity in population and case-cohort samples, allied to the development of new algorithms, are shedding light on host ancestry impact and selection events on various infectious diseases. Especially interesting are the long-standing associations between humans and certain bacteria, such as the case of , which could have been strong drivers of adaptation leading to coevolution. Some evidence on admixed gastric cancer cohorts have been suggested as supporting - coevolution, but reliable experimental data that control both the bacterium and the host ancestries are lacking. Here, we conducted the first in vitro coinfection assays with dual human- and bacterium-matched and -mismatched ancestries, in African and European backgrounds, to evaluate the genome wide gene expression host response to . Our results showed that: (1) the host response to infection was greatly shaped by the human ancestry, with variability on innate immune system and metabolism; (2) African human ancestry showed signs of coevolution with while European ancestry appeared to be maladapted; and (3) mismatched ancestry did not seem to be an important differentiator of gene expression at the initial stages of infection as assayed here.
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http://dx.doi.org/10.3390/microorganisms9020240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912213PMC
January 2021

The Sub-Saharan African information potential to unveil adaptations to infectious diseases.

Hum Mol Genet 2021 Jan 18. Epub 2021 Jan 18.

i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.

Sub-Saharan Africa is the most promising region of the world to conduct high-throughput studies to unveil adaptations to infectious diseases due to several reasons, namely: the longest evolving time-depth in the Homo sapiens phylogenetic tree (at least 2/3 older than any other worldwide region); the continuous burden of infectious diseases (still number one in health/life threat); and the coexistence of populations practising diverse subsistence modes (nomadic or seminomadic hunter-gatherers and agropastoralists, and sedentary agriculturalists, small urban and megacity groups). In this review we will present the most up-to-date results that shed light on three main hypotheses related with this adaptation. One is the hypothesis of coevolution between host and pathogen, given enough time for the establishment of this highly dynamic relationship. The second hypothesis enunciates that the agricultural transition was responsible for the increase of the infectious disease burden, due to the huge expansion of the sedentary human population and the cohabitation with domesticates as main reservoirs of pathogens. The third hypothesis states that the boosting of our immune system against pathogens by past selection may have resulted in maladaptation of the developed hygienic societies, leading to an increase of allergic, inflammatory- and autoimmune disorders. Further work will enlighten the biological mechanisms behind these main adaptations, which can be insightful for translation into diagnosis, prognosis and treatment interventions.
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http://dx.doi.org/10.1093/hmg/ddab001DOI Listing
January 2021

The Sub-Saharan African information potential to unveil adaptations to infectious diseases.

Hum Mol Genet 2021 Jan 12. Epub 2021 Jan 12.

i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.

Sub-Saharan Africa is the most promising region of the world to conduct high-throughput studies to unveil adaptations to infectious diseases due to several reasons, namely: the longest evolving time-depth in the Homo sapiens phylogenetic tree (at least 2/3 older than any other worldwide region); the continuous burden of infectious diseases (still number one in health/life threat); and the coexistence of populations practising diverse subsistence modes (nomadic or seminomadic hunter-gatherers and agropastoralists, and sedentary agriculturalists, small urban and megacity groups). In this review we will present the most up-to-date results that shed light on three main hypotheses related with this adaptation. One is the hypothesis of coevolution between host and pathogen, given enough time for the establishment of this highly dynamic relationship. The second hypothesis enunciates that the agricultural transition was responsible for the increase of the infectious disease burden, due to the huge expansion of the sedentary human population and the cohabitation with domesticates as main reservoirs of pathogens. The third hypothesis states that the boosting of our immune system against pathogens by past selection may have resulted in maladaptation of the developed hygienic societies, leading to an increase of allergic, inflammatory- and autoimmune disorders. Further work will enlighten the biological mechanisms behind these main adaptations, which can be insightful for translation into diagnosis, prognosis and treatment interventions.
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http://dx.doi.org/10.1093/hmg/ddab005DOI Listing
January 2021

Chitinase 3-like-1 and fibronectin in the cargo of extracellular vesicles shed by human macrophages influence pancreatic cancer cellular response to gemcitabine.

Cancer Lett 2021 Mar 16;501:210-223. Epub 2020 Nov 16.

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Portugal; Department of Biological Sciences, FFUP - Faculty of Pharmacy of the University of Porto, Porto, Portugal. Electronic address:

Tumour-associated macrophages have been implicated in pancreatic ductal adenocarcinoma (PDAC) therapy response and Extracellular vesicles (EVs) shed by macrophages might have a role in this process. Here, we demonstrated that large EVs released by anti-inflammatory human macrophages decreased PDAC cellular sensitivity to gemcitabine. Using proteomic analysis, chitinase 3-like-1 (CHI3L1) and fibronectin (FN1) were identified as two of the most abundant proteins in the cargo of macrophages-derived EVs. Overexpression of CHI3L1 and FN1, using recombinant human proteins, induced PDAC cellular resistance to gemcitabine through ERK (extracellular-signal-regulated kinase) activation. Inhibition of CHI3L1 and FN1 by pentoxifylline and pirfenidone, respectively, partially reverted gemcitabine resistance. In PDAC patient samples, CHI3L1 and FN1 were expressed in the stroma, associated with the high presence of macrophages. The Cancer Genome Atlas analysis revealed an association between CHI3L1 and FN1 gene expression, overall survival of PDAC patients, gemcitabine response, and macrophage infiltration. Altogether, our data identifies CHI3L1 and FN1 as potential targets for pharmacological inhibition in PDAC. Further pre-clinical in vivo work is warranted to study the possibility of repurposing pentoxifylline and pirfenidone as adjuvant therapies for PDAC treatment.
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http://dx.doi.org/10.1016/j.canlet.2020.11.013DOI Listing
March 2021

Gastric Microbiome Diversities in Gastric Cancer Patients from Europe and Asia Mimic the Human Population Structure and Are Partly Driven by Microbiome Quantitative Trait Loci.

Microorganisms 2020 Aug 6;8(8). Epub 2020 Aug 6.

i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.

The human gastrointestinal tract harbors approximately 100 trillion microorganisms with different microbial compositions across geographic locations. In this work, we used RNASeq data from stomach samples of non-disease (164 individuals from European ancestry) and gastric cancer patients (137 from Europe and Asia) from public databases. Although these data were intended to characterize the human expression profiles, they allowed for a reliable inference of the microbiome composition, as confirmed from measures such as the genus coverage, richness and evenness. The microbiome diversity (weighted UniFrac distances) in gastric cancer mimics host diversity across the world, with European gastric microbiome profiles clustering together, distinct from Asian ones. Despite the confirmed loss of microbiome diversity from a healthy status to a cancer status, the structured profile was still recognized in the disease condition. In concordance with the parallel host-bacteria population structure, we found 16 human loci (non-synonymous variants) in the European-descendent cohorts that were significantly associated with specific genera abundance. These microbiome quantitative trait loci display heterogeneity between population groups, being mainly linked to the immune system or cellular features that may play a role in enabling microbe colonization and inflammation.
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http://dx.doi.org/10.3390/microorganisms8081196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463948PMC
August 2020

The mitogenome portrait of Umbria in Central Italy as depicted by contemporary inhabitants and pre-Roman remains.

Sci Rep 2020 07 1;10(1):10700. Epub 2020 Jul 1.

Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100, Pavia, Italy.

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.
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http://dx.doi.org/10.1038/s41598-020-67445-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329865PMC
July 2020

Hypoxia and Macrophages Act in Concert Towards a Beneficial Outcome in Colon Cancer.

Cancers (Basel) 2020 Mar 28;12(4). Epub 2020 Mar 28.

i3S-Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal.

In colon cancer, the prognostic value of macrophages is controversial, and it is still unknown how hypoxia modulates macrophage-cancer cell crosstalk. To unravel this, co-cultures of human primary macrophages and colon cancer cells were performed at 20% and 1% O, followed by characterization of both cellular components. Different colon cancer patient cohorts were analyzed for hypoxia and immune markers, and their association with patient overall survival was established. A positive correlation between and in colon cancer patients was identified but, unexpectedly, in cases with higher macrophage infiltration, expression was associated with a better prognosis, in contrast to breast, gastric, and lung cancers. Under hypoxia, co-cultures' secretome indicated a shift towards a pro-inflammatory phenotype. These alterations occurred along with increased macrophage phagocytic activity and decreased SIRPα expression. Cancer cells were more invasive and exhibited higher CD47 expression. We hypothesize that the better prognosis associated with tumors could occur due to macrophagic pro-inflammatory pressure. Indeed, we found that tumors expressed increased levels of , which is positively correlated with . In conclusion, we show that in colon cancer, hypoxia drives macrophages into a pro-inflammatory phenotype, concomitant with increased infiltration of anti-tumor immune cells, favoring better disease outcome.
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http://dx.doi.org/10.3390/cancers12040818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226541PMC
March 2020

A panel of intestinal differentiation markers (CDX2, GPA33, and LI-cadherin) identifies gastric cancer patients with favourable prognosis.

Gastric Cancer 2020 09 25;23(5):811-823. Epub 2020 Mar 25.

IPATIMUP (Institute of Molecular Pathology and Immunology of the University of Porto), Rua Júlio Amaral de Carvalho, 45, 4200-135, Porto, Portugal.

Background: Gastric cancer is the fifth most common cancer and the third cause of global cancer mortality. CDX2 is an intestinal differentiation marker with prognostic value in gastric cancer and transcriptionally regulates the expression of glycoprotein A33 (GPA33) and liver intestine cadherin (LI-cadherin).

Methods: This study evaluated the clinical significance of the combined expression of CDX2 and its targets GPA33 and LI-cadherin in gastric cancer by fluorescence-based multiplex immunohistochemistry together with digital image analysis and chromogenic immunohistochemistry in 329 gastric cancer samples arranged in tissue microarrays. Additionally, publicly available RNA-seq expression data from 354 gastric cancer samples from the TCGA database were used to validate the immunohistochemistry results.

Results: Expression of the three markers (CDX2, GPA33, and LI-cadherin) was strongly correlated, defining an intestinal differentiation panel. Low or negative protein expression of the intestinal differentiation panel identified patients with particularly poor overall survival, irrespective of the methodology used, and was validated in the independent series at the RNA-seq level.

Conclusions: Expression of the intestinal differentiation panel (CDX2, GPA33, and LI-cadherin) defines a set of biomarkers with a strong biological rationale and favourable impact for prognostication of gastric cancer patients.
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http://dx.doi.org/10.1007/s10120-020-01064-6DOI Listing
September 2020

Targets the EPHA2 Receptor Tyrosine Kinase in Gastric Cells Modulating Key Cellular Functions.

Cells 2020 02 24;9(2). Epub 2020 Feb 24.

Ipatimup-Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal.

, a stomach-colonizing Gram-negative bacterium, is the main etiological factor of various gastroduodenal diseases, including gastric adenocarcinoma. By establishing a life-long infection of the gastric mucosa, continuously activates host-signaling pathways, in particular those associated with receptor tyrosine kinases. Using two different gastric epithelial cell lines, we show that targets the receptor tyrosine kinase EPHA2. For long periods of time post-infection, induces EPHA2 protein downregulation without affecting its mRNA levels, an effect preceded by receptor activation via phosphorylation. EPHA2 receptor downregulation occurs via the lysosomal degradation pathway and is independent of the virulence factors CagA, VacA, and T4SS. Using small interfering RNA, we show that EPHA2 knockdown affects cell-cell and cell-matrix adhesion, invasion, and angiogenesis, which are critical cellular processes in early gastric lesions and carcinogenesis mediated by the bacteria. This work contributes to the unraveling of the underlying mechanisms of -host interactions and associated diseases. Additionally, it raises awareness for potential interference between infection and the efficacy of gastric cancer therapies targeting receptors tyrosine kinases, given that infection affects the steady-state levels and dynamics of some receptor tyrosine kinases (RTKs) and their signaling pathways.
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http://dx.doi.org/10.3390/cells9020513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072728PMC
February 2020

Association of Leukotriene A4 Hydrolase with Tuberculosis Susceptibility Using Genomic Data in Portugal.

Microorganisms 2019 Dec 4;7(12). Epub 2019 Dec 4.

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal.

Leukotriene A4 hydrolase (LTA4H) is a key enzyme in the eicosanoid pathway. locus polymorphisms have previously been linked to tuberculosis (TB) susceptibility and disease outcome in a Vietnamese dataset, but further studies suggested that those results were poorly reproducible. We, therefore, compared the full set of variants (113 SNPs) within the gene in a Portuguese dataset of 112 TB patients and 120 controls, using both the frequency of SNPs and haplotypes, in order to assess their association with TB susceptibility. Although we obtained no significant differences between the TB patients and the control group, linkage analysis showed that an extensively typed polymorphism, , was associated with 21 other SNPs, all displaying evidence of association to lower LTA4H expression. While the derived alleles of these SNPs showed a moderately higher frequency in the TB group, differences were not significant. In contrast to Asian populations, where these SNPs are much more frequent, the low frequencies of candidate SNPs in Europeans render them less pertinent in a public health context. Consequently, the typing of specific polymorphisms as a strategy to establish preventive measures and differential TB drug treatments is important but needs to take into consideration that haplotypic background and structure can be substantially different in distinct geographic regions.
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http://dx.doi.org/10.3390/microorganisms7120650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956305PMC
December 2019

Human Genomic Diversity Where the Mediterranean Joins the Atlantic.

Mol Biol Evol 2020 04;37(4):1041-1055

Departamento de Biodiversidad, Ecología y Evolución, Facultad de Biología, Universidad Complutense, Madrid, Spain.

Throughout the past few years, a lively debate emerged about the timing and magnitude of the human migrations between the Iberian Peninsula and the Maghreb. Several pieces of evidence, including archaeological, anthropological, historical, and genetic data, have pointed to a complex and intermingled evolutionary history in the western Mediterranean area. To study to what extent connections across the Strait of Gibraltar and surrounding areas have shaped the present-day genomic diversity of its populations, we have performed a screening of 2.5 million single-nucleotide polymorphisms in 142 samples from southern Spain, southern Portugal, and Morocco. We built comprehensive data sets of the studied area and we implemented multistep bioinformatic approaches to assess population structure, demographic histories, and admixture dynamics. Both local and global ancestry inference showed an internal substructure in the Iberian Peninsula, mainly linked to a differential African ancestry. Western Iberia, from southern Portugal to Galicia, constituted an independent cluster within Iberia characterized by an enriched African genomic input. Migration time modeling showed recent historic dates for the admixture events occurring both in Iberia and in the North of Africa. However, an integrative vision of both paleogenomic and modern DNA data allowed us to detect chronological transitions and population turnovers that could be the result of transcontinental migrations dating back from Neolithic times. The present contribution aimed to fill the gaps in the modern human genomic record of a key geographic area, where the Mediterranean and the Atlantic come together.
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http://dx.doi.org/10.1093/molbev/msz288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086172PMC
April 2020

A different view on fine-scale population structure in Western African populations.

Hum Genet 2020 Jan 19;139(1):45-59. Epub 2019 Oct 19.

GIGA-R Medical Genomics-BIO3, University of Liege, Avenue de l'Hôpital 11, 4000, Liege, Belgium.

Due to its long genetic evolutionary history, Africans exhibit more genetic variation than any other population in the world. Their genetic diversity further lends itself to subdivisions of Africans into groups of individuals with a genetic similarity of varying degrees of granularity. It remains challenging to detect fine-scale structure in a computationally efficient and meaningful way. In this paper, we present a proof-of-concept of a novel fine-scale population structure detection tool with Western African samples. These samples consist of 1396 individuals from 25 ethnic groups (two groups are African American descendants). The strategy is based on a recently developed tool called IPCAPS. IPCAPS, or Iterative Pruning to CApture Population Structure, is a genetic divisive clustering strategy that enhances iterative pruning PCA, is robust to outliers and does not require a priori computation of haplotypes. Our strategy identified in total 12 groups and 6 groups were revealed as fine-scale structure detected in the samples from Cameroon, Gambia, Mali, Southwest USA, and Barbados. Our finding helped to explain evolutionary processes in the analyzed West African samples and raise awareness for fine-scale structure resolution when conducting genome-wide association and interaction studies.
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http://dx.doi.org/10.1007/s00439-019-02069-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942040PMC
January 2020

Profiling of lung microbiota discloses differences in adenocarcinoma and squamous cell carcinoma.

Sci Rep 2019 09 6;9(1):12838. Epub 2019 Sep 6.

Instituto de Investigação e Inovação em Saúde, Universidade do Porto (I3S), Porto, Portugal.

The lung is a complex ecosystem of host cells and microbes often disrupted in pathological conditions. Although bacteria have been hypothesized as agents of carcinogenesis, little is known about microbiota profile of the most prevalent cancer subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC). To characterize lung cancer (LC) microbiota a first a screening was performed through a pooled sequencing approach of 16S ribosomal RNA gene (V3-V6) using a total of 103 bronchoalveaolar lavage fluid samples. Then, identified taxa were used to inspect 1009 cases from The Cancer Genome Atlas and to annotate tumor unmapped RNAseq reads. Microbial diversity was analyzed per cancer subtype, history of cigarette smoking and airflow obstruction, among other clinical data. We show that LC microbiota is enriched in Proteobacteria and more diverse in SCC than ADC, particularly in males and heavier smokers. High frequencies of Proteobacteria were found to discriminate a major cluster, further subdivided into well-defined communities' associated with either ADC or SCC. Here, a SCC subcluster differing from other cases by a worse survival was correlated with several Enterobacteriaceae. Overall, this study provides first evidence for a correlation between lung microbiota and cancer subtype and for its influence on patient life expectancy.
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http://dx.doi.org/10.1038/s41598-019-49195-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731246PMC
September 2019

Expression and Clinical Relevance of SOX9 in Gastric Cancer.

Dis Markers 2019 2;2019:8267021. Epub 2019 Jun 2.

i3S-Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal.

Gastric cancer is one of the most frequent tumours and the third leading cause of cancer-related death worldwide. The investigation of new biomarkers that can predict patient outcome more accurately and allow better treatment and follow-up decisions is of crucial importance. SOX9 (sex-determining region Y (SRY)-box 9) is a regulator of cell fate decisions in embryogenesis and adulthood. Here, we sought to ascertain the relevance of SOX9 transcription factor as a prognostic marker in gastric cancer. SOX9 expression was analyzed by immunohistochemistry in 333 gastric adenocarcinoma cases, and its association with clinicopathological and follow-up data was evaluated. SOX9 nuclear expression was absent in 17% of gastric cancer cases and predicted worse disease-free survival ( = 0.03). SOX9 expression was associated with lower risk of relapse in Cox univariable analysis (HR = 0.58; 95% CI = 0.35-0.97; = 0.04). The prognostic value of SOX9 was more pronounced in tumours with expansive growth ( = 0.01) or with venous invasion ( = 0.02). Two validation cohorts from the Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) confirmed that low SOX9 expression was significantly associated with poor patient outcome. In conclusion, we have identified SOX9 as a biomarker of disease relapse in gastric cancer patients. Further experiments are needed to elucidate its biological relevance at the cellular level.
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http://dx.doi.org/10.1155/2019/8267021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589301PMC
December 2019

Genome-Wide Characterization of Arabian Peninsula Populations: Shedding Light on the History of a Fundamental Bridge between Continents.

Mol Biol Evol 2019 03;36(3):575-586

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.

The Arabian Peninsula (AP) was an important crossroad between Africa, Asia, and Europe, being the cradle of the structure defining these main human population groups, and a continuing path for their admixture. The screening of 741,000 variants in 420 Arabians and 80 Iranians allowed us to quantify the dominant sub-Saharan African admixture in the west of the peninsula, whereas South Asian and Levantine/European influence was stronger in the east, leading to a rift between western and eastern sides of the Peninsula. Dating of the admixture events indicated that Indian Ocean slave trade and Islamization periods were important moments in the genetic makeup of the region. The western-eastern axis was also observable in terms of positive selection of diversity conferring lactose tolerance, with the West AP developing local adaptation and the East AP acquiring the derived allele selected in European populations and existing in South Asia. African selected malaria resistance through the DARC gene was enriched in all Arabian genomes, especially in the western part. Clear European influences associated with skin and eye color were equally frequent across the Peninsula.
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http://dx.doi.org/10.1093/molbev/msz005DOI Listing
March 2019

Afadin Downregulation by Induces Epithelial to Mesenchymal Transition in Gastric Cells.

Front Microbiol 2018 9;9:2712. Epub 2018 Nov 9.

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.

Afadin is a cytoplasmic protein of the adherens junctions, which regulates the formation and stabilization of both the adherens and the tight junctions. Aberrant expression of Afadin has been shown in cancer and its loss has been associated with epithelial-to-mesenchymal transition (EMT). EMT is characterized by the change from an epithelial to a mesenchymal phenotype, with modifications on the expression of adhesion molecules and acquisition of a migratory and invasive cell behavior. While it is known that disrupts the tight and the adherens junctions and induces EMT, the effect of the bacteria on Afadin is still unknown. The aim of this study was to disclose the effect of on Afadin and its impact in the induction of an EMT phenotype in gastric cells. Using two different cell lines, we observed that infection decreased Afadin protein levels, independently of CagA, T4SS, and VacA virulence factors. infection of cell lines recapitulated several EMT features, displacing and downregulating multiple proteins from cell-cell junctions, and increasing the expression of ZEB1, Vimentin, Slug, N-cadherin, and Snail. Silencing of Afadin by RNAi promoted delocalization of junctional proteins from the cell-cell contacts, increased paracellular permeability, and decreased transepithelial electrical resistance, all compatible with impaired junctional integrity. Afadin silencing also led to increased expression of the EMT marker Snail, and to the formation of actin stress fibers, together with increased cell motility and invasion. Finally, and in line with our data, the gastric mucosa of individuals infected with showed decrease/loss of Afadin membrane staining at cell-cell contacts significantly more frequently than uninfected individuals. In conclusion, Afadin is downregulated by infection and , and its downregulation leads to the emergence of EMT and to the acquisition of an aggressive phenotype in gastric cells, which can contribute to gastric carcinogenesis.
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http://dx.doi.org/10.3389/fmicb.2018.02712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237830PMC
November 2018

Population genetics-informed meta-analysis in seven genes associated with risk to dengue fever disease.

Infect Genet Evol 2018 08 17;62:60-72. Epub 2018 Apr 17.

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200-135 Porto, Portugal; Faculdade de Medicina da Universidade do Porto, Portugal. Electronic address:

Population genetics theory predicted that rare frequent markers would be the main contributors for heritability of complex diseases, but meta-analyses of genome-wide association studies are revealing otherwise common markers, present in all population groups, as the identified candidate genes. In this work, we applied a population-genetics informed meta-analysis to 10 markers located in seven genes said to be associated with dengue fever disease. Seven markers (in PLCE1, CD32, CD209, OAS1 and OAS3 genes) have high-frequency and the other three (in MICB and TNFA genes) have intermediate frequency. Most of these markers have high discriminatory power between population groups, but their frequencies follow the rules of genetic drift, and seem to have not been under strong selective pressure. There was a good agreement in directional consistency across trans-ethnic association signals, in East Asian and Latin American cohorts, with heterogeneity generated by randomness between studies and especially by low sample sizes. This led to confirm the following significant associations: with DF, odds ratio of 0.67 for TNFA-rs1800629-A; with DHF, 0.82 for CD32-rs1801274-G; with DSS, 0.55 for OAS3-rs2285933-G, 0.80 for PLCE1-rs2274223-G and 1.32 for MICB-rs3132468-C. The overall genetic risks confirmed sub-Saharan African populations and descendants as the best protected against the severer forms of the disease, while Southeast and Northeast Asians are the least protected ones. European and close neighbours are the best protected against dengue fever, while, again, Southeast and Northeast Asians are the least protected ones. These risk scores provide important predictive information for the largely naïve European and North American regions, as well as for Africa where misdiagnosis with other hemorrhagic diseases is of concern.
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http://dx.doi.org/10.1016/j.meegid.2018.04.018DOI Listing
August 2018

Genomic and transcriptomic characterization of the mitochondrial-rich oncocytic phenotype on a thyroid carcinoma background.

Mitochondrion 2019 05 6;46:123-133. Epub 2018 Apr 6.

Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal; Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal; Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal. Electronic address:

We conducted the first systematic omics study of the oncocytic phenotype in 488 papillary thyroid carcinomas (PTC) from The Cancer Genome Atlas. Oncocytic phenotype is secondary to PTC, being unrelated to several pathologic scores. The nuclear genome had low impact on this phenotype (except in specific copy number variation), which was mostly driven by the significant accumulation of mitochondrial DNA non-synonymous and frameshift mutations at high heteroplasmy levels. Energy and mitochondrial-related pathways were significantly enriched in oncocytic tumors that also displayed increased levels of expression for genes involved in autophagy and fusion of mitochondria. Our in vitro tests confirmed that autophagy is increased and functional while mitophagy is decreased in these tumors.
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http://dx.doi.org/10.1016/j.mito.2018.04.001DOI Listing
May 2019

Characterization of microbiota in male infertility cases uncovers differences in seminal hyperviscosity and oligoasthenoteratozoospermia possibly correlated with increased prevalence of infectious bacteria.

Am J Reprod Immunol 2018 06 3;79(6):e12838. Epub 2018 Mar 3.

Instituto de Investigação e Inovação em Saúde, Universidade do Porto (I3S), Porto, Portugal.

Problem: Sexually transmitted diseases and other infections of male genitourinary tract are thought to negatively impact reproductive health, affecting semen quality. Despite a possible link between bacteria and infertility, few studies attempted to characterize seminal microbiota in healthy and diseased subjects.

Methods Of The Study: A high-throughput sequencing of 16S ribosomal RNA gene was performed in a cohort of infertility-related cases (N = 89) and controls (N = 29) using a pooled sample approach.

Results: A global characterization of microbiota was obtained at low cost, without compromising the identification of bacterial taxa. This strategy allowed us to detect changes in the microbiota of infertility-related phenotypes, such as an increment of Proteobacteria in seminal hyperviscosity, and to separate this later group from oligoasthenoteratozoospermia based in bacterial (family/genus) abundances.

Conclusion: We provide data for a likely contribution of bacteria into seminal hyperviscosity and oligoasthenoteratozoospermia, partially correlated with an increment of Neisseria, Klebsiella, and Pseudomonas pathogens and a reduction in Lactobacillus probiotic agent.
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http://dx.doi.org/10.1111/aji.12838DOI Listing
June 2018

Joint ancestry and association test indicate two distinct pathogenic pathways involved in classical dengue fever and dengue shock syndrome.

PLoS Negl Trop Dis 2018 02 15;12(2):e0006202. Epub 2018 Feb 15.

Functional Genetics of Infectious Diseases Unit, Institut Pasteur, Paris, France.

Ethnic diversity has been long considered as one of the factors explaining why the severe forms of dengue are more prevalent in Southeast Asia than anywhere else. Here we take advantage of the admixed profile of Southeast Asians to perform coupled association-admixture analyses in Thai cohorts. For dengue shock syndrome (DSS), the significant haplotypes are located in genes coding for phospholipase C members (PLCB4 added to previously reported PLCE1), related to inflammation of blood vessels. For dengue fever (DF), we found evidence of significant association with CHST10, AHRR, PPP2R5E and GRIP1 genes, which participate in the xenobiotic metabolism signaling pathway. We conducted functional analyses for PPP2R5E, revealing by immunofluorescence imaging that the coded protein co-localizes with both DENV1 and DENV2 NS5 proteins. Interestingly, only DENV2-NS5 migrated to the nucleus, and a deletion of the predicted top-linking motif in NS5 abolished the nuclear transfer. These observations support the existence of differences between serotypes in their cellular dynamics, which may contribute to differential infection outcome risk. The contribution of the identified genes to the genetic risk render Southeast and Northeast Asian populations more susceptible to both phenotypes, while African populations are best protected against DSS and intermediately protected against DF, and Europeans the best protected against DF but the most susceptible against DSS.
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http://dx.doi.org/10.1371/journal.pntd.0006202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813895PMC
February 2018

CRABP1, C1QL1 and LCN2 are biomarkers of differentiated thyroid carcinoma, and predict extrathyroidal extension.

BMC Cancer 2018 01 10;18(1):68. Epub 2018 Jan 10.

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.

Background: The prognostic variability of thyroid carcinomas has led to the search for accurate biomarkers at the molecular level. Follicular thyroid carcinoma (FTC) is a typical example of differentiated thyroid carcinomas (DTC) in which challenges are faced in the differential diagnosis.

Methods: We used high-throughput paired-end RNA sequencing technology to study four cases of FTC with different degree of capsular invasion: two minimally invasive (mFTC) and two widely invasive FTC (wFTC). We searched by genes differentially expressed between mFTC and wFTC, in an attempt to find biomarkers of thyroid cancer diagnosis and/or progression. Selected biomarkers were validated by real-time quantitative PCR in 137 frozen thyroid samples and in an independent dataset (TCGA), evaluating the diagnostic and the prognostic performance of the candidate biomarkers.

Results: We identified 17 genes significantly differentially expressed between mFTC and wFTC. C1QL1, LCN2, CRABP1 and CILP were differentially expressed in DTC in comparison with normal thyroid tissues. LCN2 and CRABP1 were also differentially expressed in DTC when compared with follicular thyroid adenoma. Additionally, overexpression of LCN2 and C1QL1 were found to be independent predictors of extrathyroidal extension in DTC.

Conclusions: We conclude that the underexpression of CRABP1 and the overexpression of LCN2 may be useful diagnostic biomarkers in thyroid tumours with questionable malignity, and the overexpression of LCN2 and C1QL1 may be useful for prognostic purposes.
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http://dx.doi.org/10.1186/s12885-017-3948-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763897PMC
January 2018

NIS expression in thyroid tumors, relation with prognosis clinicopathological and molecular features.

Endocr Connect 2018 Jan;7(1):78-90

Instituto de Investigação e Inovação em Saúde (i3S)Porto, Portugal

Thyroid cancer therapy is based on surgery followed by radioiodine treatment. The incorporation of radioiodine by cancer cells is mediated by sodium iodide symporter (NIS) (codified by the gene), that is functional only when targeted to the cell membrane. We aimed to evaluate if NIS expression in thyroid primary tumors would be helpful in predicting tumor behavior, response to therapy and prognosis. NIS expression was addressed by qPCR and immunohistochemistry. In order to validate our data, we also studied expression on 378 primary papillary thyroid carcinomas from The Cancer Genome Atlas (TCGA) database. In our series, expression was lower in carcinomas with vascular invasion and with extrathyroidal extension and in those harboring V600E mutation. Analysis of expression from TCGA database confirmed our results. Furthermore, it showed that larger tumors, with locoregional recurrences and/or distant metastases or harboring , and/or promoter (p) mutations presented significantly less expression. Regarding immunohistochemistry, 12/211 of the cases demonstrated NIS in the membrane of tumor cells, those cases showed variable outcomes concerning therapy success, prognosis and all but one were wild type for , and p mutations. mRNA lower expression is associated with features of aggressiveness and with key genetic alterations involving , and p. Mutations in these genes seem to decrease protein expression and its targeting to the cell membrane. mRNA expression is more informative than NIS immunohistochemical expression regarding tumor aggressiveness and prognostic features.
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http://dx.doi.org/10.1530/EC-17-0302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754505PMC
January 2018

TERT, BRAF, and NRAS in Primary Thyroid Cancer and Metastatic Disease.

J Clin Endocrinol Metab 2017 06;102(6):1898-1907

i3S Instituto de Investigação e Inovação em Saúde, Porto 4200-135, Portugal.

Context: Little is known about the frequency of key mutations in thyroid cancer metastases and its relationship with the primary tumor genotype.

Objectives: To evaluate the frequency of TERT promoter (TERTp), BRAF, and NRAS mutations in metastatic thyroid carcinomas, analyzing primary thyroid tumors, lymph node metastases (LNMs), and distant metastases.

Design And Patients: Mutation analysis was performed in 437 tissue samples from 204 patients, mainly with papillary thyroid carcinomas (PTCs; n = 180), including 196 LNMs and 56 distant metastases. All the distant metastases included corresponded to radioiodine-refractory metastatic tissue.

Results: We found the following mutation frequency in primary PTCs, LNMs, and distant metastases, respectively: TERTp: 12.9%, 10.5%, and 52.4%; BRAF: 44.6%, 41.7%, and 23.8%; and NRAS: 1.2%, 1.3%, and 14.3%. There was a significant concordance between the primary tumor genotype and the corresponding LNM for all the genes, in particular BRAF-mutated PTC. The overall concordance between primary tumors and respective distant metastases was low. In the group of patients with PTCs, we found a high frequency of TERTp mutations and a low frequency of BRAF mutations in distant metastases, in comparison with the paired primary tumors. When present in distant metastases, BRAF mutations frequently coexisted with TERTp mutations.

Conclusions: When the genotype of primary tumors is compared with the genotype of LNMs, the concordance is high for all the genes studied. On the other hand, distant metastases show an enrichment in TERTp mutations and a decrease in BRAF mutations. TERTp mutations may play a role in distant metastases.
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http://dx.doi.org/10.1210/jc.2016-2785DOI Listing
June 2017

OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans.

PLoS Pathog 2017 02 27;13(2):e1006220. Epub 2017 Feb 27.

Virology Department, PAHO/WHO Collaborating Center for the Study of Dengue and its Vector, Pedro Kourí Institute of Tropical Medicine (IPK),Havana, Cuba.

Ethnic groups can display differential genetic susceptibility to infectious diseases. The arthropod-born viral dengue disease is one such disease, with empirical and limited genetic evidence showing that African ancestry may be protective against the haemorrhagic phenotype. Global ancestry analysis based on high-throughput genotyping in admixed populations can be used to test this hypothesis, while admixture mapping can map candidate protective genes. A Cuban dengue fever cohort was genotyped using a 2.5 million SNP chip. Global ancestry was ascertained through ADMIXTURE and used in a fine-matched corrected association study, while local ancestry was inferred by the RFMix algorithm. The expression of candidate genes was evaluated by RT-PCR in a Cuban dengue patient cohort and gene set enrichment analysis was performed in a Thai dengue transcriptome. OSBPL10 and RXRA candidate genes were identified, with most significant SNPs placed in inferred weak enhancers, promoters and lncRNAs. OSBPL10 had significantly lower expression in Africans than Europeans, while for RXRA several SNPs may differentially regulate its transcription between Africans and Europeans. Their expression was confirmed to change through dengue disease progression in Cuban patients and to vary with disease severity in a Thai transcriptome dataset. These genes interact in the LXR/RXR activation pathway that integrates lipid metabolism and immune functions, being a key player in dengue virus entrance into cells, its replication therein and in cytokine production. Knockdown of OSBPL10 expression in THP-1 cells by two shRNAs followed by DENV2 infection tests led to a significant reduction in DENV replication, being a direct functional proof that the lower OSBPL10 expression profile in Africans protects this ancestry against dengue disease.
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http://dx.doi.org/10.1371/journal.ppat.1006220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344536PMC
February 2017

Erratum to: Quantifying the legacy of the Chinese Neolithic on the maternal genetic heritage of Taiwan and Island Southeast Asia.

Hum Genet 2016 May;135(5):587

IPATIMUP (Institute of Molecular Pathology and Immunology of the University of Porto), Rua Dr. Roberto Frias s/n, 4200-465, Porto, Portugal.

In the original article, one of the co-authors' (Ken Khong Eng) given name has been published incorrectly. The correct given name should be Ken Khong. The original article has been corrected.
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http://dx.doi.org/10.1007/s00439-016-1653-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969906PMC
May 2016

Quantifying the legacy of the Chinese Neolithic on the maternal genetic heritage of Taiwan and Island Southeast Asia.

Hum Genet 2016 Apr 13;135(4):363-376. Epub 2016 Feb 13.

IPATIMUP (Institute of Molecular Pathology and Immunology of the University of Porto), Rua Dr. Roberto Frias s/n, 4200-465, Porto, Portugal.

There has been a long-standing debate concerning the extent to which the spread of Neolithic ceramics and Malay-Polynesian languages in Island Southeast Asia (ISEA) were coupled to an agriculturally driven demic dispersal out of Taiwan 4000 years ago (4 ka). We previously addressed this question using founder analysis of mitochondrial DNA (mtDNA) control-region sequences to identify major lineage clusters most likely to have dispersed from Taiwan into ISEA, proposing that the dispersal had a relatively minor impact on the extant genetic structure of ISEA, and that the role of agriculture in the expansion of the Austronesian languages was therefore likely to have been correspondingly minor. Here we test these conclusions by sequencing whole mtDNAs from across Taiwan and ISEA, using their higher chronological precision to resolve the overall proportion that participated in the "out-of-Taiwan" mid-Holocene dispersal as opposed to earlier, postglacial expansions in the Early Holocene. We show that, in total, about 20% of mtDNA lineages in the modern ISEA pool result from the "out-of-Taiwan" dispersal, with most of the remainder signifying earlier processes, mainly due to sea-level rises after the Last Glacial Maximum. Notably, we show that every one of these founder clusters previously entered Taiwan from China, 6-7 ka, where rice-farming originated, and remained distinct from the indigenous Taiwanese population until after the subsequent dispersal into ISEA.
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http://dx.doi.org/10.1007/s00439-016-1640-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4796337PMC
April 2016

Resolving the ancestry of Austronesian-speaking populations.

Hum Genet 2016 Mar 18;135(3):309-26. Epub 2016 Jan 18.

Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.

There are two very different interpretations of the prehistory of Island Southeast Asia (ISEA), with genetic evidence invoked in support of both. The "out-of-Taiwan" model proposes a major Late Holocene expansion of Neolithic Austronesian speakers from Taiwan. An alternative, proposing that Late Glacial/postglacial sea-level rises triggered largely autochthonous dispersals, accounts for some otherwise enigmatic genetic patterns, but fails to explain the Austronesian language dispersal. Combining mitochondrial DNA (mtDNA), Y-chromosome and genome-wide data, we performed the most comprehensive analysis of the region to date, obtaining highly consistent results across all three systems and allowing us to reconcile the models. We infer a primarily common ancestry for Taiwan/ISEA populations established before the Neolithic, but also detected clear signals of two minor Late Holocene migrations, probably representing Neolithic input from both Mainland Southeast Asia and South China, via Taiwan. This latter may therefore have mediated the Austronesian language dispersal, implying small-scale migration and language shift rather than large-scale expansion.
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http://dx.doi.org/10.1007/s00439-015-1620-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757630PMC
March 2016

Fine Time Scaling of Purifying Selection on Human Nonsynonymous mtDNA Mutations Based on the Worldwide Population Tree and Mother-Child Pairs.

Hum Mutat 2015 Nov 25;36(11):1100-11. Epub 2015 Aug 25.

Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, 4200-135, Portugal.

A high-resolution mtDNA phylogenetic tree allowed us to look backward in time to investigate purifying selection. Purifying selection was very strong in the last 2,500 years, continuously eliminating pathogenic mutations back until the end of the Younger Dryas (∼11,000 years ago), when a large population expansion likely relaxed selection pressure. This was preceded by a phase of stable selection until another relaxation occurred in the out-of-Africa migration. Demography and selection are closely related: expansions led to relaxation of selection and higher pathogenicity mutations significantly decreased the growth of descendants. The only detectible positive selection was the recurrence of highly pathogenic nonsynonymous mutations (m.3394T>C-m.3397A>G-m.3398T>C) at interior branches of the tree, preventing the formation of a dinucleotide STR (TATATA) in the MT-ND1 gene. At the most recent time scale in 124 mother-children transmissions, purifying selection was detectable through the loss of mtDNA variants with high predicted pathogenicity. A few haplogroup-defining sites were also heteroplasmic, agreeing with a significant propensity in 349 positions in the phylogenetic tree to revert back to the ancestral variant. This nonrandom mutation property explains the observation of heteroplasmic mutations at some haplogroup-defining sites in sequencing datasets, which may not indicate poor quality as has been claimed.
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http://dx.doi.org/10.1002/humu.22849DOI Listing
November 2015

Genetic stratigraphy of key demographic events in Arabia.

PLoS One 2015 4;10(3):e0118625. Epub 2015 Mar 4.

Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal; Faculdade de Medicina da Universidade do Porto, Porto, Portugal.

At the crossroads between Africa and Eurasia, Arabia is necessarily a melting pot, its peoples enriched by successive gene flow over the generations. Estimating the timing and impact of these multiple migrations are important steps in reconstructing the key demographic events in the human history. However, current methods based on genome-wide information identify admixture events inefficiently, tending to estimate only the more recent ages, as here in the case of admixture events across the Red Sea (~8-37 generations for African input into Arabia, and 30-90 generations for "back-to-Africa" migrations). An mtDNA-based founder analysis, corroborated by detailed analysis of the whole-mtDNA genome, affords an alternative means by which to identify, date and quantify multiple migration events at greater time depths, across the full range of modern human history, albeit for the maternal line of descent only. In Arabia, this approach enables us to infer several major pulses of dispersal between the Near East and Arabia, most likely via the Gulf corridor. Although some relict lineages survive in Arabia from the time of the out-of-Africa dispersal, 60 ka, the major episodes in the peopling of the Peninsula took place from north to south in the Late Glacial and, to a lesser extent, the immediate post-glacial/Neolithic. Exchanges across the Red Sea were mainly due to the Arab slave trade and maritime dominance (from ~2.5 ka to very recent times), but had already begun by the early Holocene, fuelled by the establishment of maritime networks since ~8 ka. The main "back-to-Africa" migrations, again undetected by genome-wide dating analyses, occurred in the Late Glacial period for introductions into eastern Africa, whilst the Neolithic was more significant for migrations towards North Africa.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118625PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349752PMC
December 2015