Sana Hsouna

Consanguinity, endogamy, and genetic disorders in Tunisia

Consanguinity refers to marriages between individuals who share at least one common ancestor. In clinical genetics, a consanguineous marriage is defined as a union between two individuals who are related as second cousins or closer, with the inbreeding coefficient (F) equal or higher than 0.0156 (Bittles2001). However, reports on consanguinity rates may sometimes include marriages between third cousins or more distantly related individuals (Hamamy2011). It is estimate that more than 690 million people in the world are consan- guineous (Bittles and Black 2010 ). Middle East, Northern Africa, and South Asia are regions that have historically and culturally had a high rate of consanguineous unions (Al- Awadi et al. 1985; Al-Gazali et al.1997; Jaber et al.1997;Bittles et al.2002; Bener and Alali2006). Recent studieshave shown that 20 % to 50 % of marriages in Arab countries are between relatives (Tadmouri et al. 2009;Bittles2011; Hamamy et al.2011). The rate was 68 % inEgypt (Mokhtar and Abdel-Fattah2001), 51-58 % in Jordan

Phylogeny and genetic structure of Tunisians and their position within Mediterranean populations

Abstract Tunisia is located at the crossroads of Europe, the Middle East and Sub-Saharan Africa. This position might lead to numerous waves of migrations, contributing to the current genetic landscape of Tunisians. In this study, we analyzed 815 mitochondrial DNA (mtDNA) sequences from Tunisia in order to characterize the mitochondrial DNA genetic structure of this region, to construct the processes for its composition and to compare it to other Mediterranean populations. To that end, additional 4206 mtDNA sequences were compiled from previous studies performed in African (1237), Near Eastern (231) and European (2738) populations. Both phylogenetic and statistical analyses were performed. This study confirmed the mosaic genetic structure of the Tunisian population with the predominance of the Eurasian lineages, followed by the Sub-Saharan and North African lineages. Among Tunisians, the highest haplogroup and haplotype diversity were observed in particular in the Capital Tunis. No significant differentiation was observed between both geographical (Northern versus Southern Tunisia) and different ethnic groups in Tunisia. Our results highlight the presence of outliers and most frequent unique sequences in Tunisia (10.2%) compared to 45 Mediterranean populations. Phylogenetic analysis showed that the majority of Tunisian localities were closer to North Africans and Near Eastern populations than to Europeans. The exception was found for Berbers from Jerba which are clustered with Sardinians and Valencians.

Contribution of CDKAL1 rs7756992 and IGF2BP2 rs4402960 polymorphisms in type 2 diabetes, diabetic complications, obesity risk and hypertension in the Tunisian population 在突尼斯人群中，CDKAL1 rs7756992与IGF2BP2 rs4402960的多态性对2型糖尿病、糖尿病并发症、肥胖风险以及高血压的影响

The insulin‐like growth factor 2 mRNA‐binding protein 2 (IGF2BP2) and the cyclin‐dependent kinase 5 regulatory subunit‐associated protein 1‐like 1 (CDKAL1) identified through genome‐wide association (GWA) studies have been shown to be associated with Type 2 diabetes in various ethnic groups. In this study, we investigated the association of the rs7756992 of CDKAL1 and the rs4402960 of IGF2BP2 with Type 2 diabetes, diabetic complications (nephropathy, retinopathy and cardiovascular disease), obesity and hypertension in a Tunisian population.

Association study of mitochondrial DNA polymorphisms with type 2 diabetes in Tunisian population

Abstract Mitochondrial DNA (mtDNA) variation may play an important role in the pathogenesis of type 2 diabetes (T2Ds). In this study, we aimed to explore whether mtDNA variants contribute to the susceptibility to T2Ds in a Tunisian population. The hypervariable region 1 (HVS1) of the mtDNA of 64 T2Ds patients and 77 healthy controls was amplified and sequenced. Statistical analysis was performed using the STATA program. Analysis of the total screened variants (N = 88) from the HVS1 region showed no significant difference in the distribution of all polymorphisms between T2Ds and controls, except for the variant G16390A which was more frequent in T2Ds (15.9%) than in controls (5.4%) (p = 0.04). The association of G16390A was not detected after multivariate regression analysis. Similarly, analysis of the distribution of mitochondrial haplogroups within our dataset showed 18 distinct major haplogroups with no significant difference between T2Ds and controls. Except, the weakly association found for the G16390A variant, our results showed that none of the tested polymorphisms from the HVS1 region have a major role in T2Ds pathogenesis in the studied Tunisian population even when taking into account the population stratification.

Estimation of Recent and Ancient Inbreeding in a Small Endogamous Tunisian Community Through Genomic Runs of Homozygosity.

Runs of homozygosity (ROHs) are extended genomic regions of homozygous genotypes that record populations’ mating patterns in the past. We performed microarray genotyping on 15 individuals from a small isolated Tunisian community. We estimated the individual and population genome‐wide level of homozygosity from data on ROH above 0.5 Mb in length. We found a high average number of ROH per individual (48.2). The smallest ROH category (0.5–1.49 Mb) represents 0.93% of the whole genome, while medium‐size (1.5‐4.99 Mb) and long‐size ROH (≥5 Mb) cover 1.18% and 0.95%, respectively. We found that genealogical individual inbreeding coefficients (Fped) based on three‐ to four‐generation pedigrees are not reliable indicators of the current proportion of genome‐wide homozygosity inferred from ROH (FROH) either for 0.5 or 1.5 Mb ROH length thresholds, while identity‐by‐descent sharing is a function of shared coancestry. This study emphasizes the effect of reproductive isolation and a prolonged practice of consanguinity that limits the genetic heterogeneity. It also provides evidence of both recent and ancient parental relatedness contribution to the current level of genome‐wide homozygosity in the studied population. These findings may be useful for evaluation of long‐term effects of inbreeding on human health and for future applications of ROHs in identifying recessive susceptibility genes.

Evidence for Association of the E23K Variant of KCNJ11 Gene with Type 2 Diabetes in Tunisian Population: Population-Based Study and Meta-Analysis

Aims. Genetic association studies have reported the E23K variant of KCNJ11 gene to be associated with Type 2 diabetes. In Arab populations, only four studies have investigated the role of this variant. We aimed to replicate and validate the association between the E23K variant and Type 2 diabetes in Tunisian and Arab populations. Methods. We have performed a case-control association study including 250 Tunisian patients with Type 2 diabetes and 267 controls. Allelic association has also been evaluated by 2 meta-analyses including all population-based studies among Tunisians and Arabs (2 and 5 populations, resp.). Results. A significant association between the E23K variant and Type 2 diabetes was found (OR = 1.6, 95% CI = 1.14–2.27, and P = 0.007). Furthermore, our meta-analysis has confirmed the significant role of the E23K variant in susceptibility of Type 2 diabetes in Tunisian and Arab populations (OR = 1.29, 95% CI = 1.15–1.46, and P < 10−3 and OR = 1.33, 95% CI = 1.13–1.56, and P = 0.001, resp.). Conclusion. Both case-control and meta-analyses results revealed the significant association between the E23K variant of KCNJ11 and Type 2 diabetes among Tunisians and Arabs.

Differential impact of consanguineous marriages on autosomal recessive diseases in Tunisia.

Consanguinity is common in Tunisia. However, little information exists on its impact on recessive disorders. In this study, we evaluate the impact of consanguineous marriages on the occurrence of some specific autosomal recessive disorders and consider how other factors, such as population substructure and mutation frequency, may be of equal importance in disease prevalence.

On the origin of Iberomaurusians: new data based on ancient mitochondrial DNA and phylogenetic analysis of Afalou and Taforalt populations

Abstract The Western North African population was characterized by the presence of Iberomaurusian civilization at the Epiplaeolithic period (around 20,000 years before present (YBP) to 10,000 YBP). The origin of this population is still not clear: they may come from Europe, Near East, sub-Saharan Africa or they could have evolved in situ in North Africa. With the aim to contribute to a better knowledge of the settlement of North Africa we analysed the mitochondrial DNA extracted from Iberomaurusian skeletons exhumed from the archaeological site of Afalou (AFA) (15,000–11,000 YBP) in Algeria and from the archaeological site of Taforalt (TAF) (23,000–10,800 YBP) in Morocco. Then, we carried out a phylogenetic analysis relating these Iberomaurusians to 61 current Mediterranean populations. The genetic structure of TAF and AFA specimens contains only North African and Eurasian maternal lineages. These finding demonstrate the presence of these haplotypes in North Africa from at least 20,000 YBP. The very low contribution of a Sub-Saharan African haplotype in the Iberomaurusian samples is confirmed. We also highlighted the existence of genetic flows between Southern and Northern coast of the Mediterranean.

Study of the T16189C variant and mitochondrial lineages in Tunisian and overall Mediterranean region.

Abstract The mitochondrial DNA (mtDNA) variant T16189C has been investigated in several metabolic diseases. In this study, we aimed to estimate the frequency of the T16189C variant in Tunisian and other Mediterranean populations and to evaluate the impact of this variant on the phylogeny of Mediterranean populations. Blood sample of 240 unrelated Tunisian subjects were recruited from several Tunisian localities. The hypervariable region 1 of the mtDNA were amplified and sequenced. Additional sequences (N = 4921) from Mediterranean populations were compiled from previous studies. The average frequency of T16189C variant in Tunisia (29%) is similar to that observed in North African and Near Eastern populations. Our findings showed positive correlation of the T16189C variant with Sub-Saharan and North African lineages, while a negative correlation was found with the Eurasian haplogroups, reaching its maximum with the Eurasian haplogroup H. The principal component analyses showed a high internal heterogeneity between Tunisian localities. At the Mediterranean scale, Tunisians are closer to North African (Algerian and Moroccan) and Near Eastern populations (Syrians and Palestinians) than to Europeans.

History of settlement of villages from Central Tunisia by studying families sharing a common founder Glycogenosis type III mutation

Abstract Glycogen storage disease type III (GSD III; Cori disease; Forbes disease) is an autosomal recessive inherited metabolic disorder resulting from deficient glycogen debrancher enzyme activity in liver and muscle. In this study, we focused on a single AGL gene mutation p.W1327X in 16 Tunisian patients from rural area surrounding the region of Mahdia in Central Tunisia. This constitutes the largest pool of patients with this mutation ever described. This study was performed to trace the history of the patients’ ancestries in a single region. After extraction of genomic DNA, exon 31 of AGL gene was sequenced. The patients were investigated for the hypervariable segment 1 of mitochondrial DNA and 17 Y-STR markers. We found that the p.W1327X mutation was a founder mutation in Tunisia Analysis of maternal lineages shows an admixture of autochthonous North African, sub-Saharan and a predominance of Eurasian haplogroups. Heterogeneity of maternal haplogroups indicates an ancient settlement. However, paternal gene flow was highly homogeneous and originates from the Near East. We hypothesize that the p.W1327X mutation was introduced into the Tunisian population probably by a recent migration event; then the mutation was fixed in a small region due to the high rate of consanguineous marriages and genetic drift. The screening for this mutation should be performed in priority for GSD III molecular diagnosis, for patients from the region of Mahdia and those from regions sharing the same settlement history.