Insights into the Middle Eastern paternal genetic pool in Tunisia: high prevalence of T-M70 haplogroup in an Arab population

To obtain refreshed insights into the paternal lineages of Tunisian populations, Y-chromosome diversity was assessed in two populations belonging to an Arab genealogical lineage, Kairouan and Wesletia, as well as in four Tunisian Andalusian populations, Testour, Slouguia, Qalaat-El-Andalous and El Alia. The Arabs from Kairouan revealed 73.47% of E-M81 and close affinities with Berber groups, indicating they are likely arabized Berbers, clearly differentiated from the Arabs from Wesletia, who harbored the highest frequency (71.8%) of the Middle Eastern component ever observed in North Africa. In the Tunisian Andalusians, the North African component largely prevailed, followed by the Middle Eastern contribution. Global comparative analysis highlighted the heterogeneity of Tunisian populations, among which, as a whole, dominated a set of lineages ascribed to be of autochthonous Berber origin (71.67%), beside a component of essentially Middle Eastern extraction (18.35%), and signatures of Sub-Saharan (5.2%), European (3.45%) and Asiatic (1.33%) contributions. The remarkable frequency of T-M70 in Wesletia (17.4%) prompted to refine its phylogeographic analysis, allowing to confirm its Middle Eastern origin, though signs of local evolution in Northern Africa were also detected. Evidence was clear on the ancient introduction of T lineages into the region, probably since Neolithic times associated to spread of agriculture.This work was partially financed by FEDER-Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020-Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT-Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Inovação in the framework of the projects “Institute for Research and Innovation in Health Sciences (i3S)” (POCI-01-0145-FEDER007274). IPATIMUP integrates the i3S research unit. VG is supported by FCT under the program contract provided in Decree-Law no.57/2016 of August 29

The effect of tobacco, XPC, ERCC2 and ERCC5 genetic variants in bladder cancer development

<p>Abstract</p> <p>Background</p> <p>In this work, we have conducted a case-control study in order to assess the effect of tobacco and three genetic polymorphisms in <it>XPC, ERCC2 and ERCC5 </it>genes (rs2228001, rs13181 and rs17655) in bladder cancer development in Tunisia. We have also tried to evaluate whether these variants affect the bladder tumor stage and grade.</p> <p>Methods</p> <p>The patients group was constituted of 193 newly diagnosed cases of bladder tumors. The controls group was constituted of non-related healthy subjects. The rs2228001, rs13181 and rs17655 polymorphisms were genotyped using a polymerase chain reaction-restriction fragment length polymorphism technique.</p> <p>Results</p> <p>Our data have reported that non smoker and light smoker patients (1-19PY) are protected against bladder cancer development. Moreover, light smokers have less risk for developing advanced tumors stage. When we investigated the effect of genetic polymorphisms in bladder cancer development we have found that ERCC2 and ERCC5 variants were not implicated in the bladder cancer occurrence. However, the mutated homozygous genotype for XPC gene was associated with 2.09-fold increased risk of developing bladder cancer compared to the control carrying the wild genotype (p = 0.03, OR = 2.09, CI 95% 1.09-3.99). Finally, we have found that the XPC, ERCC2 and ERCC5 variants don't affect the tumors stage and grade.</p> <p>Conclusion</p> <p>These results suggest that the mutated homozygous genotype for XPC gene was associated with increased risk of developing bladder. However we have found no association between rs2228001, rs13181 and rs17655 polymorphisms and tumors stage and grade.</p

Hereditary breast cancer in Middle Eastern and North African (MENA) populations: identification of novel, recurrent and founder BRCA1 mutations in the Tunisian population

Germ-line mutations in BRCA1 breast cancer susceptibility gene account for a large proportion of hereditary breast cancer families and show considerable ethnic and geographical variations. The contribution of BRCA1 mutations to hereditary breast cancer has not yet been thoroughly investigated in Middle Eastern and North African populations. In this study, 16 Tunisian high-risk breast cancer families were screened for germline mutations in the entire BRCA1 coding region and exon–intron boundaries using direct sequencing. Six families were found to carry BRCA1 mutations with a prevalence of 37.5%. Four different deleterious mutations were detected. Three truncating mutations were previously described: c.798_799delTT (916 delTT), c.3331_3334delCAAG (3450 delCAAG), c.5266dupC (5382 insC) and one splice site mutation which seems to be specific to the Tunisian population: c.212 + 2insG (IVS5 + 2insG). We also identified 15 variants of unknown clinical significance. The c.798_799delTT mutation occurred at an 18% frequency and was shared by three apparently unrelated families. Analyzing five microsatellite markers in and flanking the BRCA1 locus showed a common haplotype associated with this mutation. This suggests that the c.798_799delTT mutation is a Tunisian founder mutation. Our findings indicate that the Tunisian population has a spectrum of prevalent BRCA1 mutations, some of which appear as recurrent and founding mutations

Usefulness of COMT gene polymorphisms in North African populations

The COMT gene encodes for catechol-O-methyl-transferase, an enzyme playing a major role in regulation of synaptic catecholamine neurotransmitters. Investigating 4 markers of the COMT gene (rs2020917, rs4818, rs4680, rs9332377) in 6 Tunisian populations and a pool of Libyans. Our objective was to determine the distribution of allelic, genotypic and haplotypic frequencies by comparison to other populations of the 1000 genomes project and 59 populations from the Kidd Lab dataset. The allelic frequencies established for these SNPs in the North African populations are similar to those of Europeans and South Asians. Linkage disequilibrium between these SNPs and haplotypes frequencies are different between populations whose clustering in principal components analysis (PCA) according to their geographic origin was more significant using haplotypic frequencies. COMT activity prediction by haplotypes genotyping could be limited to rs4818-rs4680 micro-haplotypes. The Low activity haplotype (CG) displays the highest frequency in African populations (55%), in the 59 Kidd Lab populations we found also that Sub-Saharan Africans, Native Americans, and some East Asian and Pacific Island populations all have frequencies in the 50-81% range for (CG) where as its lowest frequency was found in Europeans (10%), this results have been also confirmed for Southwest Asians. North Africans and South Asians with intermediate frequencies have approximately similar values (20% and 25%). Europeans show the highest frequencies of haplotypes with predicted High and Medium activity in contrast to Africans. North Africans and South Asians present similar results for all the category of the COMT activity prediction by haplotypes genotyping. The high level of genetic diversity of COMT haplotypes, not only allows distinction between populations according to their history settlement, origin and ethnicity, it constitutes a basis for studies of association of the COMT gene polymorphism with pathologies, drugs response and for forensic investigation in North African populations.This work was partially supported by the Tunisian Ministry of Higher Education and Scientific Research as well as by the University of Tunis El Manar . Special thanks go to the thousands of individuals around the world who volunteered to give blood and saliva samples to made this study possible.Scopu

Telomere length measurement in tumor and non‐tumor cells as a valuable prognostic for tumor progression

Telomere shortening has been supposed to be implicated in both aging and various human diseases es- pecially carcinogenesis process. This phenomenon can lead to a chromosomal instability, contributing to a cell immortalization and tumor induction. In our study, we analyzed the role of telomere shortening in cancer progression, in Tunisian patients with digestive cancer. We measured the absolute telomere length in tumoral vs healthy adjacent tissues of each patient by using a q-RT PCR method and we investigated the relationship between telomere length and various sociodemographic and clinical parameters such as age, sex, tumor stage. In this pathological situation, we observed that, starting from 60 years of age, the telomere length increases in healthy mucosa and that in both healthy and cancer tissues, patients un- der 60 years have shorter telomeres, suggesting the telomere lengthening becomes more active with age. Finally, a positive correlation between normal and cancer tissues in both non-metastatic and metastatic stages, indicates telomere length in cancer tissue depends essentially on tumor stages. Our data allow us to suggest that telomere length depends on sex and age in healthy tissue while shortening and length- ening fluctuates considerably according to the tumor stage

Y-chromosomal STR haplotypes in three ethnic groups and one cosmopolitan population from Tunisia

The 11 Y-chromosomal short tandem repeats (STRs) included in the Promega Corporation PowerPlex Y System (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385, DYS437, DYS438 and DYS439) were typed in three ethnic groups ("Andalusians", Berber and Arab) and one cosmopolitan population (Tunis) from Tunisia, summing up 247 individuals, and 139 different haplotypes. Focusing the analysis on the seven Y-STRs of the YHRD Minimal Haplotype Core (DYS385 excepted), "Andalusians" showed no differences from the Cosmopolitan and the Arab samples previously published (our Arab sample presented an extremely low haplotype diversity), but were different from the Berbers. The Berbers from Tunisia were not different from those from Morocco.This work was partially supported by the Tunisian Ministry of Higher Education, Scientific Research and Technology. We are very grateful to the Tunisian Ministry of Health for their help in the sampling. Fundação para a Ciência e a Tecnologia granted the research project (POCTI/ANT/45139/2002), the Ph.D. grant of A.G. (SFRH/BD/16518/2004) and partially supports IPATIMUP through Programa Operacional Ciência, Tecnologia e Inovação (POCTI), Quadro Comunitário de Apoio III. Researchers mobility was supported by the cultural technical and scientific agreement between Portugal and Tunisia through GRICES (Gabinete de Relações Internacionais da Ciência e do Ensino Superior)

The Orientalisation of North Africa: New hints from the study of autosomal STRs in an Arab population

Background: Recent genomic analyses suggest that the current North African gene pool was mainly influenced by population flow coming from the East that altered the genetic structure of autochthonous Berber populations. Such genetic flow has not been extensively addressed yet using North African populations of Middle-eastern origin as reference. Aim: To discern the Middle-eastern component in the genetic background of Tunisian Arabs and evaluate the extent of gene flow from the Middle East into North African autochthonous Berber populations. Subjects and methods: This study has examined 113 Tunisians of well-known Arabian origin from Kairouan region, using 15 autosomal Short Tandem Repeats (STRs) loci. Results: No deviations from Hardy-Weinberg equilibrium were observed and all loci presented high levels of heterozygosity. Principal coordinate and STRUCTURE analyses were consistent in clustering together North African and Middle Eastern populations, likely reflecting the recent gene flow from the East dating back to the Arab conquest period. This demographic migration and the Arabisation process that submerged the original Berber language and customs seems to have be accompanied by substantial gene flow and genetic admixture. Conclusion: This study represents an additional step to obtain a comprehensive understanding of the complex demographic history of North African populations

Immunolocalization of BRCA1 protein in tumor breast tissue: prescreening of BRCA1 mutation in Tunisian patients with hereditary breast cancer?

BRCA1 is a tumor suppressor gene which is inactivated by mutation in familial breast and ovarian cancers. Over 300 different disease causing germ-line mutations have been described; 60% are unique to an individual family. This diversity and the large size of the gene lead us to search for a prescreening method for BRCA1 mutations. Since BRCA1 is a nuclear protein in normal cells, but reported by some authors to be cytoplasmic in breast tumor cells of patients with BRCA1 mutation, we evaluated immunohistochemistry as a prescreening technique to identify BRCA1 mutations in patients with familial presentation of breast cancer. Using a monoclonal antibody against the carboxy-terminal region of BRCA1, we performed immunohistochemistry on 18 tumor samples from patients with hereditary breast cancer. Cytoplasmic staining of BRCA1 was observed in 10 cases. Of the 18 tumors, 12 (66%) showed either BRCA mutation or BRCA1 accumulation or both, indicating that BRCA1 function might be lost in breast tumor cells not only through mutation, but also via abnormal cytoplasmic location. The immunohistochemical test used in this study would not be efficient as a pre-screening method of deleterious mutations, but it appeared useful to investigate tumor physiology