New insights into the genetic history of Tunisians: data from Alu insertion and apolipoprotein E gene polymorphisms.

BACKGROUND: Among polymorphisms of non-transcribed DNA sequences and functional genes, those of Alu insertions and that of the APOE gene have been widely used to clarify the degree of genetic relationships between human populations. AIM: APOE gene and eight Alu insertion polymorphisms were investigated in Tunisians and compared with data from neighbour populations in order to gain new insights into the genetic position of Tunisia in the Mediterranean region. SUBJECTS AND METHODS: A total of 121 individuals from the North and Centre-South regions were sampled. RESULTS: No significant genetic differences were found between Tunisians and North Africans when samples representative of wide areas were considered. APOE gene variation seemed slightly less powerful than the Alu polymorphisms in detecting North-South Mediterranean differences. CONCLUSION: North African populations show a substantial degree of genetic homogeneity, which may reflect the similarity of their origins, mainly when samples from large geographical areas are compared. The relative genetic homogeneity of the whole Mediterranean region probably reflects a common origin and/or remarkable levels of gene flow. However, this gene flow has not yet erased the differentiation between the two Mediterranean shores, as revealed by Alu insertion polymorphisms.

Genetic differentiation of Yemeni people according to rhesus and Gm polymorphisms.

For introducing Yemeni population in synthesis of genetic relationships of human populations, analysis of rhesus and Gm polymorphisms have been carried out for a population sample of 210 Yemenites. Rhesus haplotype frequencies were compared to those estimated in an original sample of 171 Tunisians and to available data for other populations. Gm haplotype frequencies were introduced in a wide synthesis of genetic relationships for 67 populations from Africa, Europe, the Near East and India. The genetic profile of Yemeni people would be close to that of a highly diversified ancestral population. The first inhabitants of North Africa, the Berbers and Yemenites have very likely a common origin and were not subject to important genetic drift after their geographic differentiation. While, the divergence between Yemenites and their neighbours of sub-Saharan Africa would have occurred with a founder effect and a long isolation. An important parallelism is observed for the Gm system between genetic and linguistic differentiations.

Genetic heterogeneity study of non-syndromic autosomal recessive sensorineural deafness within the Tunisian population.

The number of loci for non-syndromic autosomal recessive sensorineural (N-SARS) deafness, was estimated within the Tunisian population and compared to that obtained in other populations. 30 deaf couples have been collected from 4 governorates (2,318,900 inhabitants) and 3 villages. Our investigations in these regions show that the percentage of congenitally deaf persons which marry each other is exceptionally low (10-30%). The number of loci for N-SARS deafness in the governorates sample was estimated at 8.3. Results could provide data for genetic counseling and facilitate our research concerning the localization of the different loci for N-SARS deafness present in Tunisian population.

The primary hereditary form of distal renal tubular acidosis: clinical and genetic studies in 60-member kindred.

A distal (type 1) renal tubular acidosis (RTA-1) has been studied in 60 of 69 living members of a large family "HK" and two unrelated small families. The "HK" family, including 28 RTA-1 subjects, presents the first large family with only primary RTA-1 reported to date. The genetic situation in this family confirms the autosomal dominant transmission of the hereditary primary RTA-1 suggested previously on the basis of a few small families. Our data show that, in contrast to the secondary hereditary form, RTA-1 in its primary hereditary form is always complete and often tolerated (asymptomatic). It occurs in non-hypercalciuric families with no clinical variants observed in family members without RTA-1. In our series some clinical abnormalities commonly associated with RTA-1, such as nephrocalcinosis and growth retardation, appeared only in three cases among offspring when both parents were affected. The appearance of such abnormalities, taken as consequences of chronic acidosis in RTA-1, could be favored by the genetic background and/or the homozygosity for the RTA-1 gene. Linkage studies between RTA-1 and 10 genetic markers have been carried out. Results show that only ABO, MNS, GM and RH loci are informative for linkage analysis and none of these loci can be suggested as linked to RTA-1 locus.

Genetic characterization and origin of Tunisian Berbers.

Blood samples from 120 Tunisian Berbers of Gallala village were typed for Gm and Km immunoglobulin allotypes, alpha-1-antitrypsin variants and AB0 blood groups. The results were compared with those of other Berber groups. The combined data, considered in the light of sociological, historical and paleontological data, support the hypothesis that the Berbers are native to North Africa and their ancestors, the first modern man (Homo sapiens) of North Africa, were the founders of the European populations. The ancestors of the Berbers could have been an intermediate population between H. sapiens from Europe and from South Africa.

Restriction fragment length polymorphisms associated with immunoglobulin heavy chain gamma genes in Tunisians.

DNA polymorphisms in the human immunoglobulin gamma (gamma) region have been studied in random Arabo-Berber Tunisians and in a large Tunisian Berber kindred. Haplotypes have then been designated, based on variation in the BamHI restriction fragments containing the C gamma 1, C gamma 2, C gamma 4, and C psi gamma genes. Two new haplotypes, in addition to the four previously described, have been observed. These new haplotypes, designated H5 and H6, were confirmed by family studies. The H5 haplotype was associated with black African Gm haplotypes (Gm1,17;..;5,6,11 and Gm1,17;..;5,11) (Gma,z;..;blc3bo and Gma,z;..;blbo) and probably represents a common haplotype in the black population. The haplotype H6 may be derived from H5. One of 39 random Tunisians was homozygous for a multigene deletion. DNA polymorphisms of the C gamma genes, in conjunction with Gm markers, provide highly variable genetic markers important for the characterization of human populations.

Gene conversion in human immunoglobulin gamma locus shown by unusual location of IgG allotypes.

The constant region of the gamma 1, gamma 2 and gamma 3 heavy chains of the human IgG1, IgG2 and IgG3 immunoglobulins carries antigenic determinants or G1m, G2m and G3m allotypes, which are genetic markers of these subclasses. The exceptional presence on gamma 1 and gamma 2 chains of Gm allotypes usually located on the CH3 domain of gamma 3 shows an unexpected clustering of base changes and subsequent identity of short DNA sequences in the CH3 exon of the non-allelic gamma 1, gamma 2 and gamma 3 genes. Such clusters of substitutions are not easily explained on the classical basis of point mutations. A gene conversion, which substituted a segment of the gamma 1 or gamma 2 gene with the homologous region of the non-allelic gamma 3 gene, is more likely. Other examples of possible conversion involving the gamma genes are described. The conservation or the restoration of short sequences produced by the conversion events might be related to the biological properties of the constant region of the heavy chains.

Immunoglobulin allotypes in patients with nasopharyngeal carcinoma.

Gm phenotypes and the Km(1) allotype were studied in Tunisian patients with nasopharyngeal carcinoma (NPC). A highly significant association was found between the Km(1) allotype and the NPC disease. Two rare Gm haplotypes, Gm(1, 17; 11, 15, 21) and Gm(1, 3, 5, 11), were found to be significantly increased among the NPC patients.

A multigene deletion within the immunoglobulin heavy-chain region.

The immunoglobulin heavy-chain genes are located in a cluster on chromosome 14. The simultaneous absence of the human IgG1, IgG2, IgG4, and IgA1 subclasses was previously reported in a healthy Tunisian Berber and was later shown to be due to a multigene deletion. We now describe a serological and molecular study of a different deletion observed in a healthy Tunisian. Blot hybridization analysis of the proband's DNA using gamma, epsilon, alpha, and mu switch probes showed that the deletion involves a large region of the immunoglobulin heavy-chain gene cluster: C psi epsilon, C alpha 1, C psi gamma, C gamma 2, and C gamma 4. Incidentally, we showed that the restriction enzyme EcoRI alone can be used with the alpha probe to differentiate A2m types. The deletion described, present in a person homozygous for GM-Am haplotypes (Gm1,17;..;5,14,11,13,10 A2m2), is consistent with previous location, by association analysis, of C psi gamma between C alpha 1 and C gamma 2. There is evidence to suggest that deletions may be more common in the Mediterranean region than in North American Caucasians.

Genetic study of Tunisian Berbers. I. Gm, Am and Km immunoglobulin allotypes and ABO blood groups.

The Gm, Am and Km immunoglobulin allotypes and ABO blood groups were studied in three groups of Tunisian Berbers . The results showed that the actual Berbers of Tunisia present certain heterogeneity and their ancestors were probably the first inhabitants of North Africa. Indeed, although their Gm-Am haplotypes are mainly Caucasoid, some of them are typically African. The group of Kesra village, the most Caucasoid, shows frequencies of Gm-Am haplotypes very close to those of South European populations, particularly the Spanish, who are probably of the same origin. The gene frequencies of the ABO groups in the three Berber groups were similar to those recorded in European populations with a relatively high frequency of the O genes typical of the Berbers .

Genetic study of Tunisian Berbers. II. Alpha 1-antitrypsin (Pi) polymorphism: report of a new allele (Pi S Berber).

The alpha 1-antitrypsin (alpha 1-AT) (Pi) polymorphism has been studied in three Berber groups of Tunisia by high-resolution isoelectric focusing. The results showed that actual Tunisian Berbers are mainly Caucasoid. A new variant of alpha 1-AT, tentatively called Pi S Berber, was found in the three Berber groups. On isoelectric focusing this variant was slightly more cathodal than the product of the usual Pi S allele. Family studies showed that the Gm-Pi linkage is probably close when the Pi locus supports the Pi P allele which is responsible for moderate (30%) serum alpha 1-AT deficiency.

Instability of the human immunoglobulin heavy chain constant region locus indicated by different inherited chromosomal deletions.

Previously we reported a gross genetic polymorphism of the human immunoglobulin heavy chain locus manifest by a large internal deletion within the constant region gene segment. We now describe a detailed serological and molecular genetic study of a Tunisian family in which members appear to carry two chromosomes 14 with different DNA deletions. The first is similar to that previously described encompassing three gamma subclass genes, a pseudo-epsilon gene and the alpha 1 subclass gene; the second deletion is less complex involving only the pseudo-epsilon gene and the alpha 1 gene.

HLA A*, B*-BF* and C4 A*, B* allele associations, with special reference to BF*S07, in the Tunisian population.

The HLA A*2, Bw*50-BF*S07-C4 A*2, B*1 linkage group was transmitted unambiguously in four unrelated Tunisian families. In one of these, another allele association, also carrying BF*S07, HLA A*9, Bw*50-BF*S07-C4 A*1, B*1, was encountered. The previously reported linkage disequilibrium between BF*S07 and HLA Bw*50, a subtypic specificity of HLA Bw*21, is confirmed in our study. The C4 A*2, B*1 haplotype, rare in the other populations until now studied, seems more frequent in Tunisia since it has been also found linked to HLA A*11, B*27 and BF*S in one of these families. Other allele associations were unambiguously demonstrated with predominantly the C4 A*3, B*1 haplotype, particularly a rare HLA A*3, B*18-BF*F1-C4 A*3, B*1 linkage group. A silent gene at the C4 A locus was found linked to HLA B*8.

Simultaneous absence of the human IgG1, IgG2, IgG4 and IgA1 subclasses: immunological and immunogenetical considerations.

Simultaneous absence of the IgG1, IgG2, IgG4 and IgA1 immunoglobulins has been unambiguously demonstrated in a healthy 75-year-old woman by testing for allotypes, isoallotypes and for isotypes of these four subclasses. Only IgM, IgD, IgG3, IgA2 and IgE were present. The IgG3 levels were significantly increased. Family investigation showed inheritance of a haplotype Gm-;-;b A2m2. This person is homozygous for an extensive DNA deletion including the C gamma 1, C gamma 2, C gamma 4 and C alpha 1 genes.

Unusual heavy chains of human IgG immunoglobulins: rearrangements of the ch domain exons.

Unusual combinations--unexpected sets, excess of lack--of antigenic determinants, or Gm allotypes, on the constant regions of the heavy chains of the human IgG1 and IgG3 immunoglobulins are accounted for in terms of genetic events (exchanges, duplications and deletions) involving the DNA sequences, or exons, coding for the three CH1-, CH2- and CH3 domains of the gamma 1 and gamma 3 chains. Equal and unequal cross-overs at the level of the introns without damage to the CH exons are postulated.