Amel Benammar Elgaaied

Mitochondrial DNA haplogroup H structure in North Africa

BackgroundThe Strait of Gibraltar separating the Iberian Peninsula from North Africa is thought to be a stronger barrier to gene flow for male than for female lineages. However, the recent subdivision of the haplogroup H at mitochondrial DNA (mtDNA) level has revealed greater genetic differentiation among geographic regions than previously detected. The dissection of the mtDNA haplogroup H in North Africa, and its comparison with the Iberian Peninsula and Near-East profiles would help clarify the relative affinities among these regions.ResultsLike the Iberian Peninsula, the dominant mtDNA haplogroup H subgroups in North Africa are H1 (42%) and H3 (13%). The similarity between these regions is stronger in the North-West edge affecting mainly Moroccan Arabs, West Saharans and Mauritanians, and decreases eastwards probably due to gene flow from Near East as attested for the higher frequencies of H4, H5, H7, H8 and H11 subgroups. Moroccan Berbers show stronger affinities with Tunisian and Tunisian Berbers than with Moroccan Arabs. Coalescence ages for H1 (11 ± 2 ky) and H3 (11 ± 4 ky) in North Africa point to the possibility of a late Palaeolithic settlement for these lineages similar to those found for other mtDNA haplogroups. Total and partial mtDNA genomic sequencing unveiled stronger mtDNA differentiation among regions than previously found using HVSI mtDNA based analysis.ConclusionThe subdivision of the mtDNA haplogroup H in North Africa has confirmed that the genetic differentiation found among Western and Eastern populations is mainly due to geographical rather than cultural barriers. It also shows that the historical Arabian role on the region had more a cultural than a demic effect. Whole mtDNA sequencing of identical H haplotypes based on HVSI and RFLP information has unveiled additional mtDNA differences between North African and Iberian Peninsula lineages, pointing to an older mtDNA genetic flow between regions than previously thought. Based on this new information, it seems that the Strait of Gibraltar barrier affected both male and female gene flow in a similar fashion.

Smoking and Polymorphisms in Xenobiotic Metabolism and DNA Repair Genes are Additive Risk Factors Affecting Bladder Cancer in Northern Tunisia

Cancer epidemiology has undergone marked development since the nineteen-fifties. One of the most spectacular and specific contributions was the demonstration of the massive effect of smoking and genetic polymorphisms on the occurrence of bladder cancer. The tobacco carcinogens are metabolized by various xenobiotic metabolizing enzymes, such as the super-families of N-acetyltransferases (NAT) and glutathione S-transferases (GST). DNA repair is essential to an individual’s ability to respond to damage caused by tobacco carcinogens. Alterations in DNA repair genes may affect cancer risk by influencing individual susceptibility to this environmental exposure. Polymorphisms in NAT2, GST and DNA repair genes alter the ability of these enzymes to metabolize carcinogens or to repair alterations caused by this process. We have conducted a case-control study to assess the role of smoking, slow NAT2 variants, GSTM1 and GSTT1 null, and XPC, XPD, XPG nucleotide excision-repair (NER) genotypes in bladder cancer development in North Tunisia. Taken alone, each gene unless NAT2 did not appear to be a factor affecting bladder cancer susceptibility. For the NAT2 slow acetylator genotypes, the NAT2*5/*7 diplotype was found to have a 7-fold increased risk to develop bladder cancer (OR = 7.14; 95% CI: 1.30–51.41). However, in tobacco consumers, we have shown that Null GSTM1, Wild GSTT1, Slow NAT2, XPC (CC) and XPG (CC) are genetic risk factors for the disease. When combined together in susceptible individuals compared to protected individuals these risk factors give an elevated OR (OR = 61). So, we have shown a strong cumulative effect of tobacco and different combinations of studied genetic risk factors which lead to a great susceptibility to bladder cancer.

Genome-Wide and Paternal Diversity Reveal a Recent Origin of Human Populations in North Africa

The geostrategic location of North Africa as a crossroad between three continents and as a stepping-stone outside Africa has evoked anthropological and genetic interest in this region. Numerous studies have described the genetic landscape of the human population in North Africa employing paternal, maternal, and biparental molecular markers. However, information from these markers which have different inheritance patterns has been mostly assessed independently, resulting in an incomplete description of the region. In this study, we analyze uniparental and genome-wide markers examining similarities or contrasts in the results and consequently provide a comprehensive description of the evolutionary history of North Africa populations. Our results show that both males and females in North Africa underwent a similar admixture history with slight differences in the proportions of admixture components. Consequently, genome-wide diversity show similar patterns with admixture tests suggesting North Africans are a mixture of ancestral populations related to current Africans and Eurasians with more affinity towards the out-of-Africa populations than to sub-Saharan Africans. We estimate from the paternal lineages that most North Africans emerged ∼15,000 years ago during the last glacial warming and that population splits started after the desiccation of the Sahara. Although most North Africans share a common admixture history, the Tunisian Berbers show long periods of genetic isolation and appear to have diverged from surrounding populations without subsequent mixture. On the other hand, continuous gene flow from the Middle East made Egyptians genetically closer to Eurasians than to other North Africans. We show that genetic diversity of todays North Africans mostly captures patterns from migrations post Last Glacial Maximum and therefore may be insufficient to inform on the initial population of the region during the Middle Paleolithic period.

Polymorphisms in one-carbon metabolism pathway genes and risk for bladder cancer in a Tunisian population

Cigarette smoking is the most important risk factor for bladder cancer. Moreover, epidemiologic studies have implicated several genetic variations interfering with methyl group metabolisms in susceptibility for a variety of cancers. Examples of these variations can be found in genes of the folate metabolic pathway, which is crucial in the provision of methyl groups for DNA, RNA, and protein methylation, as well as in purine and pyrimidine synthesis. We conducted a case-control study to examine the relationship between the methylenetetrahydrofolate reductase (MTHFR C677 T and MTHFR A1298C), methionine synthase (5-methyltetrahydrofolate-homocysteine methyltransferase, MTR A2756 G), methionine synthase reductase (5-methyltetrahydrofolate-homocysteine methyltransferase reductase, MTRR A66 G and MTRR C524 T), and thymidylate synthase (TYMS 2R-->3R and G/C) genotypes and the risk for bladder cancer in a Tunisian population. The isolated MTHFR 677 *T, MTRR 66 *G and MTRR 524 *T variants did not appear to influence bladder cancer susceptibility. The 3R *C/3R *C genotype for the TYMS gene appears to be a protective factor against bladder cancer development (P=0.0001; OR=0.12; 95% CI=0.03-0.40). However, patients heterozygous for MTHFR A1298C or MTR A2756 G genotypes have 1.62- and 2.13-fold higher risk, respectively, of developing bladder cancer. Moreover, the combined study of MTHFR 1298 *C and MTR 2756 *G variants with either or both MTRR 66GG and TYMS 3R *G/3R *G genotypes suggests a cumulative effect. Finally, this study evidenced that interaction between gene variations involved in folate metabolism and risk of bladder cancer increased dramatically among smokers.

52 additional reference population samples for the 55 AISNP panel

Ancestry inference for a person using a panel of SNPs depends on the variation of frequencies of those SNPs around the world and the amount of reference data available for calculation/comparison. The Kidd Lab panel of 55 AISNPs has been incorporated in commercial kits by both Life Technologies and Illumina for massively parallel sequencing. Therefore, a larger set of reference populations will be useful for researchers using those kits. We have added reference population allele frequencies for 52 population samples to the 73 previously entered so that there are now allele frequencies publicly available in ALFRED and FROG-kb for a total of 125 population samples.

Alu polymorphisms in Jerba Island population (Tunisia): Comparative study in Arab and Berber groups

Jerba Island represents an interesting area because four distinct ethnic groups have been cohabiting there until now: Arabs, Berbers, dark-skinned people of sub-Saharan origin and Jews. Religious and cultural differences seem to have constituted an obstacle to their intermixing. Our aim is to provide further information on the genetic structure of the Arab and Berber groups for whom previous data based on haploid markers confirmed their reproductive isolation. Five polymorphic Alu markers (HS 4.69, Sb 19.3, TPA-25, ACE and APO-A1) were analysed in a sample of 43 Arabs and 48 Berbers of Jerba. The genetic relationships among these groups and several populations from North Africa, sub-Saharan Africa and Europe were analysed using genetic distances based on allele frequencies. The results showed a homogeneous distribution of Alu insertions in the two geographically close groups, reflecting ancient relationships between them. This study also revealed that Arabs from Jerba present close genetic distances to other North African populations, whilst Berbers of Jerba occupy an intermediate position among Mediterranean populations.

MicroRNAs expression in triple negative vs non triple negative breast cancer in Tunisia: interaction with clinical outcome.

Introduction MicroRNAs are small, non coding regulatory molecules containing approximately 21 to 25 nucleotides. They function as controllers of expression at post transcriptional levels of most human protein-coding genes and play an essential role in cell signaling pathways. The objective of the present study is to evaluate the expression profile of the following micro-RNAs: miR-10b, miR-17, miR-21, miR-34a, miR-146a, miR-148a and miR-182, and to determine their possible interaction in triple-negative and non triple-negative primary breast cancers based on clinical outcome. Methods 60 triple-negative and non triple-negative breast cancer cases, along with their corresponding normal samples were investigated in relation to the expression of the seven studied miRNAs using qPCR Syber Green. Results We observed that miR-21, miR-146a and miR-182 were significantly over expressed in triple negative breast cancer. Moreover, miR-10b, miR-21 and miR-182 were significantly associated to lymph node metastases occurrence in triple negative breast carcinoma while only miR-10b was associated with grade III in non triple negative breast cancer cases. Almost all the analyzed microRNAs were strongly associated with patients’ genico-obstetric history in non triple negative breast cancer cases except for miR-34a. All the studied microRNAs were strongly correlated with the use of the contraceptive pills in non triple negative breast cancer groups. The additive effect of hormonal factors in triple negative breast cancer cases showed an association with all the studied miRs except for miR-34 and miR-146a. Conclusion The studied microRNAs are strongly influenced by environmental factors especially with hormonal patients’ history. Moreover, miR-10b, miR-21 and miR-182 could be defined as biomarkers in breast cancer to predict both lymph node metastases and grade III occurrence.

HLA class II polymorphism: protective or risk factors to breast cancer in Tunisia?

HLA system plays a key role in the tumor cells’ escape from immune surveillance. Herein is the first report on the correlation of the susceptibility to breast cancer with HLA class II markers in Tunisia. Molecular typing of HLA-DRB1 and -DQB1 loci was undertaken for 70 Tunisian female patients. Comparison of allele and haplotype distribution between patients and 70 female control subjects reveals a negative association between HLA-DRB1*07-DQB1*02 and the incidence of breast cancer in the Tunisian population. (Pathology Oncology Research Vol 12, No 2, 79–81)

Impact of Metabolism on T-Cell Differentiation and Function and Cross Talk with Tumor Microenvironment

The immune system and metabolism are highly integrated and multilevel interactions between metabolic system and T lymphocyte signaling and fate exist. Accumulating evidence indicates that the regulation of nutrient uptake and utilization in T cells is critically important for the control of their differentiation and manipulating metabolic pathways in these cells can shape their function and survival. This review will discuss some potential cell metabolism pathways involved in shaping T lymphocyte function and differentiation. It will also describe show subsets of T cells have specific metabolic requirements and signaling pathways that contribute to their respective function. Examples showing the apparent similarity between cancer cell metabolism and T cells during activation are illustrated and finally some mechanisms being used by tumor microenvironment to orchestrate T-cell metabolic dysregulation and the subsequent emergence of immune suppression are discussed. We believe that targeting T-cell metabolism may provide an additional opportunity to manipulate T-cell function in the development of novel therapeutics.

Genetic Diversity in Tunisia: A Study Based on the GM Polymorphism of Human Immunoglobulins

The GM polymorphism of human immunoglobulins is analyzed in three Berber populations of southern Tunisia and compared to other GM data. Genetic diversity among Tunisian populations is higher than that among Europeans but does not exhibit any significant geographic or linguistic structure. This result suggests a complex pattern of genetic differentiation.