The south of Tunisia is characterized by marked ethnic diversity, highlighted by the coexistence of native Berbers with Blacks, Jews and Arab-speaking populations. Despite this heterogeneity, genetic anthropology studies investigating the origin of current Southern Tunisians were rarely reported. We examined human leukocyte antigen (HLA) class I (A, B) and class II (DRB1, DQB1) gene profiles of 250 unrelated Southern Tunisians, and compared them with those of Arab-speaking communities, along with Mediterranean and sub-Sahara African populations using genetic distances, neighbor-joining dendrograms, correspondence and haplotype analysis. In total, 137 HLA alleles were detected, which comprised 32 HLA-A, 52 HLA-B, 32 DRB1 and 21 DQB1 alleles. The most frequent alleles were HLA-A∗02:01(18.02%), HLA-B∗50:01 (9.11%), HLA-DRB1∗07:01 (22.06%) and HLA-DQB1∗02:01 (17.21%). All pairs of HLA loci show significant linkage disequilibrium. The four loci depict negative F nd (the normalized deviate of the homozygosity) values indicating an overall trend to balancing selection. Southern Tunisians appear to be closely related to others Tunisian populations including Berbers, North Africans and Iberians. On the contrary, Southern Tunisians were distinct from Palestinian, Lebanese and Jordanian Middle Eastern Arab-speaking population, despite the deep Arab incursions and Arabization that affected Southern Tunisia. In addition, Southern Tunisians were distant from many sub-Saharan communities, evidenced by genetic distance analysis. Collectively, this indicates a limited genetic contribution of Arab invasion and Black caravans on the makeup of Southern Tunisian gene pool.
