Within the cluster of North African
Within the cluster of North African populations the Sousse population sample is somewhat different from the other six populations. One has to analyze more in depth the reasons of this isolation that has been shown by other genetic studies (Fadhlaoui-Zid et al., 2015). It seems that the particular genetic structure of Sousse would be more related to the high level of admixture of this population rather than to lack of genetic flow. Indeed, this city is from an ancient foundation by Phoenicians 1100 years BC, Interestingly, it is one of the rare Punic towns that escaped destruction by Romans during the Punic wars. The presence of the Phoenician Y chromosome at a frequency of about 10% in Sousse (Fadhlaoui-Zid et al., 2012; Fadhlaoui-Zid et al., 2015) confirms the continuity of this population since its foundation. Moreover its location on the sea and its economic role leading to commercial and human exchanges would explain the MG262 observed at haplotypic level. Indeed, if analysis of haplotype distribution gives information about population relationships, study of linkage disequilibrium might be related to the time of settlement of the population and to its level of admixture. LD profiles in the 22q11.2 location that contains the COMT gene showed a variation that depends on both the region of the gene and the population geographical origin (Mukherjee et al., 2010). High LD was demonstrated in the 5′ and 3′ regions but not in the coding region. The 3 studied SNPs (rs2020917, rs4818, rs4680) belong to the high LD regions in the Europeans, Asians (South West Asia and East Asia) and Native Americans populations (Mukherjee et al., 2010). In this study we also have found the same results but we have used a different strategy based on a small number of SNPs well distributed over the entire gene. In this region we found high levels of LD in North African populations too, the two pairs (rs4818-rs4680) and (rs4680-rs9332377) displaying the highest LD levels. The two SNPs (rs4818-rs4680) analyzed in this study are located in the coding region of the COMT gene, which is characterized by low haplotype diversity and a low level of LD except for the Eurasian populations (Mukherjee et al., 2010) and for the populations of North Africa as shown in this study. This could be probably due to less ancient origin and/or to high level of admixture. However, one cannot exclude drift and selection effects that might accompany population settlement history, including adaptation to geographical latitude. Those effects seem to be associated with COMT activity, itself related to COMT genetic polymorphisms. The levels of COMT activity vary not only between individuals but also between the tissues of the same person. Val158Met seems to be the most important SNP showing an impact on COMT function. The co-dominance of these alleles explains the tri-modal distribution (Low/Medium/High) of the COMT activity. There are studies that have shown that the enzymatic activity of COMT has decreased during evolution because of occurrence of such non-synonymous SNPs (Chen et al., 2004). Moreover, the influence of COMT activity on Dopamine metabolism suggested that we can classify individuals according to their genotypes into warrior or worrier (Stein et al., 2006). This impact on behavior might have been under selective pressures during prehistory. Indeed, there is a significant correlation between rs4680 polymorphism and population with agricultural economy lifestyle associated with the (A: ) allele vs. hunter-gatherer lifestyle associated with the (G: ) allele (Piffer, 2013). In this study, the activity of the 14 described haplotypes in human populations in the 1000 genomes project and the North African data set, has been predicted according to a classification of the pharmacogenomics database PharmGKB (https://www.pharmgkb.org/haplotype/PA165947990), based on studies (Nackley et al., 2006; Bitsios and Roussos, 2011) The (CCAC) haplotype predicted with average enzymatic activity due to the presence of the pattern (rs4818-rs4680: CA) is found in the majority of populations, especially in the European, North African and South-West Asian populations. On the other hand, the (CCGC) haplotype which is expected to sto result in low enzymatic activity and is characterized by the presence of the pattern (rs4818-rs4680: CG) has the highest frequencies in the populations of Africa and East Asia while the lowest frequencies have been observed in Europeans populations, South-West Asians and North Africans. In the present work, the predicted activities in North African populations have not been confirmed at functional level. This should be of great interest, since the COMT gene is one of the genes encoding drug metabolizing enzymes (DME) which makes it a candidate gene in pharmacogenomics. Hence, association studies of COMT polymorphism/activity with psychiatric diseases and with response to treatment could be of great interest.