Lotfi Cherni

Female gene pools of Berber and Arab neighboring communities in central Tunisia: microstructure of mtDNA variation in North Africa.

North African populations are considered genetically closer to Eurasians than to sub-Saharans. However, they display a considerably high mtDNA heterogeneity among them, namely in the frequencies of the U6, East African, and sub-Saharan haplogroups. In this study, we describe and compare the female gene pools of two neighboring Tunisian populations, Kesra (Berber) and Zriba (non-Berber), which have contrasting historical backgrounds. Both populations presented lower diversity values than those observed for other North African populations, and they were the only populations not showing significant negative Fus Fs values. Kesra displayed a much higher proportion of typical sub-Saharan haplotypes (49%, including 4.2% of M1 haplogroup) than Zriba (8%). With respect to U6 sequences, frequencies were low (2% in Kesra and 8% in Zriba), and all belonged to the subhaplogroup U6a. An analysis of these data in the context of North Africa reveals that the emerging picture is complex, because Zriba would match the profile of a Berber Moroccan population, whereas Kesra, which shows twice the frequency of sub-Saharan lineages normally observed in northern coastal populations, would match a western Saharan population except for the low U6 frequency. The North African patchy mtDNA landscape has no parallel in other regions of the world and increasing the number of sampled populations has not been accompanied by any substantial increase in our understanding of its phylogeography. Available data up to now rely on sampling small, scattered populations, although they are carefully characterized in terms of their ethnic, linguistic, and historical backgrounds. It is therefore doubtful that this picture truly represents the complex historical demography of the region rather than being just the result of the type of samplings performed so far.

Internal Diversification of Mitochondrial Haplogroup R0a Reveals Post-Last Glacial Maximum Demographic Expansions in South Arabia

Widespread interest in the first successful Out of Africa dispersal of modern humans ∼60-80 thousand years ago via a southern migration route has overshadowed the study of later periods of South Arabian prehistory. In this work, we show that the post-Last Glacial Maximum period of the past 20,000 years, during which climatic conditions were becoming more hospitable, has been a significant time in the formation of the extant genetic composition and population structure of this region. This conclusion is supported by the internal diversification displayed in the highly resolved phylogenetic tree of 89 whole mitochondrial genomes (71 being newly presented here) for haplogroup R0a-the most frequent and widespread haplogroup in Arabia. Additionally, two geographically specific clades (R0a1a1a and R0a2f1) have been identified in non-Arabic speaking peoples such as the Soqotri and Mahri living in the southern part of the Arabian Peninsula where a past refugium was identified by independent archaeological studies. Estimates of time to the most recent common ancestor of these lineages match the earliest archaeological evidence for seafaring activity in the peninsula in the sixth millennium BC.

Population history of the Red Sea—genetic exchanges between the Arabian Peninsula and East Africa signaled in the mitochondrial DNA HV1 haplogroup

Archaeological studies have revealed cultural connections between the two sides of the Red Sea dating to prehistory. The issue has still not been properly addressed, however, by archaeogenetics. We focus our attention here on the mitochondrial haplogroup HV1 that is present in both the Arabian Peninsula and East Africa. The internal variation of 38 complete mitochondrial DNA sequences (20 of them presented here for the first time) affiliated into this haplogroup testify to its emergence during the late glacial maximum, most probably in the Near East, with subsequent dispersion via population expansions when climatic conditions improved. Detailed phylogeography of HV1 sequences shows that more recent demographic upheavals likely contributed to their spread from West Arabia to East Africa, a finding concordant with archaeological records suggesting intensive maritime trade in the Red Sea from the sixth millennium BC onwards. Closer genetic exchanges are apparent between the Horn of Africa and Yemen, while Egyptian HV1 haplotypes seem to be more similar to the Near Eastern ones.

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.

Ancient Local Evolution of African mtDNA Haplogroups in Tunisian Berber Populations

Abstract Our objective is to highlight the age of sub-Saharan gene flows in North Africa and particularly in Tunisia. Therefore we analyzed in a broad phylogeographic context sub-Saharan mtDNA haplogroups of Tunisian Berber populations considered representative of ancient settlement. More than 2,000 sequences were collected from the literature, and networks were constructed. The results show that the most ancient haplogroup is L3*, which would have been introduced to North Africa from eastern sub-Saharan populations around 20,000 years ago. Our results also point to a less ancient western sub-Saharan gene flow to Tunisia, including haplogroups L2a and L3b. This conclusion points to an ancient African gene flow to Tunisia before 20,000 BP. These findings parallel the more recent findings of both archaeology and linguistics on the prehistory of Africa. The present work suggests that sub-Saharan contributions to North Africa have experienced several complex population processes after the occupation of the region by anatomically modern humans. Our results reveal that Berber speakers have a foundational biogeographic root in Africa and that deep African lineages have continued to evolve in supra-Saharan Africa.

Genetic variation in Tunisia in the context of human diversity worldwide.

ABSTRACT Objectives North Africa has a complex demographic history of migrations from within Africa, Europe, and the Middle East. However, population genetic studies, especially for autosomal genetic markers, are few relative to other world regions. We examined autosomal markers for eight Tunisian and Libyan populations in order to place them in a global context. Materials and Methods Data were collected by TaqMan on 399 autosomal single nucleotide polymorphisms on 331 individuals from Tunisia and Libya. These data were combined with data on the same SNPs previously typed on 2585 individuals from 57 populations from around the world. Where meaningful, close by SNPs were combined into multiallelic haplotypes. Data were evaluated by clustering, principal components, and population tree analyses. For a subset of 102 SNPs, data from the literature on seven additional North African populations were included in analyses. Results Average heterozygosity of the North African populations is high relative to our global samples, consistent with a complex demographic history. The Tunisian and Libyan samples form a discrete cluster in the global and regional views and can be separated from sub‐Sahara, Middle East, and Europe. Within Tunisia the Nebeur and Smar are outlier groups. Across North Africa, pervasive East‐West geographical patterns were not found. Discussion Known historical migrations and invasions did not displace or homogenize the genetic variation in the region but rather enriched it. Even a small region like Tunisia contains considerable genetic diversity. Future studies across North Africa have the potential to increase our understanding of the historical demographic factors influencing the region. Am J Phys Anthropol 161:62–71, 2016.

Evaluating a subset of ancestry informative SNPs for discriminating among Southwest Asian and circum-Mediterranean populations

Many different published sets of single nucleotide polymorphisms (SNPs) and/or insertion-deletion polymorphisms (InDels) can serve as ancestry informative markers (AIMs) to distinguish among continental regions of the world. For a focus on Southwest Asian ancestry we chose to start with the Kidd Lab panel of 55 ancestry-informative SNPs (AISNPs) because it already provided good global reference data (FROG-kb: frog.med.yale.edu) in a set of 73 population samples distinguishing at least 8 biogeographic clusters of populations. This panel serves as a good first tier ancestry panel. We are now interested in identifying region-specific second tier panels for more refined distinction among populations within each of the global regions. We have begun studying the global region centered on Southwest Asia and the region encompassing the Mediterranean Sea. We have incorporated 10 populations from North Africa, Turkey and Iran and included 31 of the original 73 populations and eleven 1000 Genomes Phase3 populations for a total of 3129 individuals from 52 populations, all typed for the 55 AISNPs. We have then identified the subset of the 55 AISNPs that are most informative for this region of the world using Heatmap, Fst, and Informativeness analyses to eliminate those SNPs essentially redundant or providing no information among populations in this region, reducing the number of SNPs to 32. STRUCTURE and PCA analyses show the remaining 32 SNPs identify the North African cluster and appropriately include the Turkish and Iranian samples with the Southwest Asian cluster. These markers provide the basis for building an improved, optimized panel of AISNPs that provides additional information on differences among populations in this part of the world. The data have also allowed an examination of the accuracy of the ancestry inference based on 32 SNPs for the newly studied populations from this region. The likelihood ratio approach to ancestry inference embodied in FROG-kb provides highly significant population assignments within one order of magnitude for each individual in the Turkish, Iranian, and Tunisian populations.

Assessing human genetic diversity in Tunisian Berber populations by Alu insertion polymorphisms

Background: The most recent Alu insertions reveal different series of characteristics such as stability that make them particularly suitable genetic markers for human biological studies. Aim: Six human-specific Alu insertion polymorphisms were typed in two Tunisian Berber populations with the aim of analysing the genetic diversity of these two communities and the genetic relationships between this region of North Africa and other populations. Subjects and methods: Forty-seven Berbers from Sejnane and 33 from Takrouna were sampled. Alu insertion polymorphism was analysed using PCR with loci specific primers. Results: A similar level of gene diversity was detected in Sejnane and Takrouna populations. PC results revealed genetic affinities between these two populations and some Eurasian populations (Germany, Genova and Syria). In contrast, there is a differentiation between these two Berber communities and North African and Iberian populations. Conclusion: The results of this study confirm the heterogeneity of Berbers in North Africa, which suggests their diverse origins. In the case of Sejnane and Takrouna populations, these results are in line with an ancient Euro Mediterranean background that has already been studied by archaeologists, particularly for the population of Sejnane.

Reconciling evidence from ancient and contemporary genomes: a major source for the European Neolithic within Mediterranean Europe

Important gaps remain in our understanding of the spread of farming into Europe, due partly to apparent contradictions between studies of contemporary genetic variation and ancient DNA. It seems clear that farming was introduced into central, northern, and eastern Europe from the south by pioneer colonization. It is often argued that these dispersals originated in the Near East, where the potential source genetic pool resembles that of the early European farmers, but clear ancient DNA evidence from Mediterranean Europe is lacking, and there are suggestions that Mediterranean Europe may have resembled the Near East more than the rest of Europe in the Mesolithic. Here, we test this proposal by dating mitogenome founder lineages from the Near East in different regions of Europe. We find that whereas the lineages date mainly to the Neolithic in central Europe and Iberia, they largely date to the Late Glacial period in central/eastern Mediterranean Europe. This supports a scenario in which the genetic pool of Mediterranean Europe was partly a result of Late Glacial expansions from a Near Eastern refuge, and that this formed an important source pool for subsequent Neolithic expansions into the rest of Europe.