Association of the CTLA4 promoter region (-1661G allele) with type 1 diabetes in the South Moroccan population.

The contribution of the candidate gene CTLA4 to type 1 diabetes is not well established. Although several polymorphisms have been repeatedly associated to the disease, several studies have not confirmed the association. The joint analysis of three SNPs in the CTLA4 promoter region (-1722, -1661, and -319), one SNP in the first exon (+49), and one dinucleotide repeat in the 3' untranslated region, in a case-control study in a North African population, shows a strong association of the CTLA4 region with the disease. The -1661G allele showed a significant association with an odds ratio of 2.13. Moreover, the internal structure of the dinucleotide repeat has been deeply analyzed. The present results reveal the importance of polymorphisms in the CTLA4 promoter region, their probable role in gene expression and, ultimately, their relation to the etiology of type 1 diabetes. Previous contradictory association studies might be due to the effect of linkage disequilibrium between the polymorphism analyzed and the alteration within the CTLA4 region. This alteration may be different depending on the genetic background of the population. The present work stresses the need to perform exhaustive analysis of the promoter region polymorphisms in order to detect association with the disease.

TNFA-TNFB haplotypes modify susceptibility to type I diabetes mellitus independently of HLA class II in a Moroccan population.

The contribution of single nucleotide polymorphisms in tumor necrosis factors (TNF) alpha and beta to autoimmune diseases, and to type 1 diabetes mellitus (T1DM) in particular, is not well established, and may be confounded by linkage disequilibrium to class II HLA genes. At least two polymorphisms seem to have functional relevance in the respective genes: TNFA-307 and TNFB+252. We have typed these two polymporphisms in samples of Moroccan T1DM patients and controls for which class II HLA genes had already been typed. Tumor necrosis factors and compound TNF-class II HLA haplotypes were inferred; it was the first time that such a design had been implemented. Independent of linkage disequilibrium with class II HLA, TNF haplotype TNFA-307*2 - TNFB+252*2 showed a significant protective effect (OR = 0.031), partly exacerbated by partial linkage to protective class II haplotypes. Such effect could be detected because Morocco shows the highest frequency of the TNFA-307*2 allele yet reported. This highlights the possible population differences in alleles contributing to autoimmune diseases.

Human mitochondrial DNA sequence variation in the Moroccan population of the Souss area.

BACKGROUND: Various populations have contributed to the present-day gene pool of Morocco, including the autochthonous Berber population, Phoenicians, Sephardic Jews, Bedouin Arabs and sub-Saharan Africans. OBJECTIVE: The primary objective of the study was to complete a genetic description of the Berber-speaking population in the Souss region of southern Morocco, based on mitochondrial DNA (mtDNA) sequence analysis. SUBJECTS AND METHODS: The first hypervariable segment of the mtDNA control region was sequenced in a sample of 50 individuals from the Souss Valley, and the results compared with the extensive body of data available on mtDNA sequence variation in Europe and sub-Saharan Africa. RESULTS: Thirty-four different sequences were found: an estimated 68% of the sequences occurred throughout Europe, West Asia and North Africa, 26% originated in sub-Saharan Africa, and 6% belonged to the North African specific haplogroup U6. The Souss Valley mtDNA sequences indicated the presence of two populations which expanded at different times: the West Eurasian sequences in the Souss sample had a smaller average number of pairwise differences than pairs of sub-Saharan sequences. CONCLUSION: Detailed knowledge of the possible geographic origin of each sequence facilitated an interpretation of both internal diversity parameters and between-population relationships. The sub-Saharan admixture in the Souss Valley matched the south-north cline of sub-Saharan influence in North Africa, also evident in the genetic distances of North African populations to Europeans and sub-Saharan Africans.

P-Element repression in Drosophila melanogaster by a naturally occurring defective telomeric P copy.

In Drosophila melanogaster, hybrid dysgenesis occurs in progeny from crosses between females lacking P elements and males carrying P elements scattered throughout the genome. We have genetically isolated a naturally occurring P insertion at cytological location 1A, from a Tunisian population. The Nasr'Allah-P(1A) element [NA-P(1A)] has a deletion of the first 871 bp including the P promoter. It is flanked at the 3' end by telomeric associated sequences and at the 5' end by a HeT-A element sequence. The NA-P(1A) element strongly represses dysgenic sterility and P transposition. However, when testing P-promoter repression, NA-P(1A) was unable to repress a germinally expressed P-lacZ construct bearing no 5'-homology with it. Conversely, a second P-lacZ construct, in which the fusion with lacZ takes place in exon 3 of P, was successfully repressed by NA-P(1A). This suggests that NA-P(1A) repression involves a homology-dependent component.

Y chromosome STR haplotypes in four populations from northwest Africa.

The eight short tandem repeat (STR) polymorphic systems mapping on the male-specific region of the human Y chromosome, DYS19, DYS388, DYS389I, DYS389II, DYS390, DYS391, DYS392 and DYS393, were typed in four populations from northwest (NW) Africa (Moroccan Arabs, southern Moroccan Berbers, Saharawis and Mozabites). Allele frequency distributions showed statistically significant differences for all loci among all the populations except for DYS19. Complete typing was obtained for 185 chromosomes, which showed 74 different haplotypes. The two most frequent haplotypes were found in 16.2% and 15.1% of the individuals, although the latter was almost exclusively found in the Mozabites. Locus and haplotype informativeness were measured by means of the gene diversity (D). The haplotype diversity ranged from 0.856 (Mozabites) to 0.967 (southern Moroccan Berbers). For some loci, allele frequencies in NW Africans were clearly different from those in Europeans. The most common NW African haplotype was found only in one individual out of a total of 494 Europeans typed for the whole STR set. Thus, NW African and European Y chromosomes are clearly differentiated.

HLA class II DNA polymorphism in a Moroccan population from the Souss, Agadir area.

HLA DRB1, DQA1 and DQB1 polymorphisms were analyzed by PCR-SSO typing in a sample of the Moroccan population from Souss. Uneven allelic frequency distributions are observed at each locus, with particularly high frequencies for DRB1*0701, DRB1*0301, DQA1*0501, DQA1*0201, and DQB1*0201. Only three haplotypes (DRB1*0701-DQA1*0201-DQB1*0201, DRB1*0301-DQA1*0501-DQB1*0201 and DRB1*11-DQA1*0501-DQB1*0301) account for nearly 50% of the total gene frequencies. A genetic distance analysis reveals that the Moroccan population is close to the Spanish and the Algerians, who live in geographically neighboring areas. However, the Souss population is also characterized by a lower level of genetic diversity compared to other African and European populations from the Mediterranean area. This may be the result of a rapid genetic drift due to their likely geographical and/or cultural isolation.

Distribution of HLA class II alleles and haplotypes in insulin-dependent Moroccan diabetics.

HLA class II polymorphism in Moroccan IDDM patients has not been investigated so far. In this study, HLA-DRB1, -DQA1, and -DQB1 allele and haplotype frequencies were analyzed in 125 unrelated Moroccan IDDM patients and 93 unrelated healthy controls, all originating from the Souss region and mostly of Berber origin. Some common features with other Caucasian groups were observed, in particular, a predisposing effect of the DRB1*03-DQA1*0501-DQB1*0201 and DRB1*04-DQA1*0301-DQB1*0302 alleles or allelic combinations. The Moroccan IDDM group also presented with more specific characteristics. Among DRB1*04 subtypes, DRB1*0405 was associated with susceptibility to and DRB1*0406 with protection from the disease. The haplotype and the relative predispositional effect (RPE) analyses indicated that the DRB1*08-DQA1*0401-DQB1*0402 haplotype was also associated with susceptibility to IDDM. Interestingly, the DRB1*09-DQA1*0301-DQB1*0201 haplotype, completely absent from the control group and very rare in North African populations, was observed in 7.2% of the Moroccan diabetics. Conversely, the DRB1*07-DQA1*0201-DQB1*0201 and DRB1*15-DQA1*0102-DQB1*0602 haplotypes were associated with protection from IDDM. Finally, we observed an age-dependent genetic heterogeneity of IDDM, the frequencies of predisposing alleles being higher and those of protective alleles lower in childhood- than in adult-onset diabetics. Our data on Moroccan diabetics, together with data on European and Northern Mediterranean patients, suggest a gradient of various HLA class II predisposing and protective markers that link these populations.

Localization of P elements, copy number regulation, and cytotype determination in Drosophila melanogaster.

Seventeen highly-inbred lines of Drosophila melanogaster extracted from an M' strain (in the P/M system of hybrid dysgenesis) were studied for their cytotype and the number and chromosomal location of complete and defective P elements. While most lines were of M cytotype, three presented a P cytotype (the condition that represses P-element activity) and one was intermediate between M and P. All lines were found to possess KP elements and only eight to bear full-sized P elements. Only the lines with full-sized P elements showed detectable changes in their P-insertion pattern over generations; their rates of gain and of loss of P-element sites were equal to 0.12 and 0.09 per genome, per generation, respectively. There was no correlation between these two rates within lines, suggesting independent transpositions and excisions in the inbred genomes. The results of both Southern blot analysis and in situ hybridization of probes made from left and right sides of the P element strongly suggested the presence of a putative complete P element in region 1A of the X chromosome in the three lines with a P cytotype; the absence of P copy in this 1A region in lines with an M cytotype, favours the hypothesis that the P element inserted in 1A could play a major role in the P-cytotype determination. Insertion of a defective 2 kb P element was also observed in region 93F in 9 of the 13 M lines. The regulation of the P-element copy number in our lines appeared not to be associated with the ratio of full-length and defective P elements.