DNA analysis of the immunoglobulin IGHG loci in a Mandenka population from eastern Senegal: correlation with Gm haplotypes and hypotheses for the evolution of the Ig CH region

Abstract

This study presents restriction fragment length polymorphism (RFLP) and serological analyses of the immunoglobulin CH loci in a sample of 100 individuals from a Senegalese Mandenka population. The RFLP variability is mostly the result of large DNA insertions or deletions in the non-coding flanking regions of the IGHG genes, and to variable number of tandem repeat-like patterns within their 5'-switch sequences. However, part of the IGHG3 polymorphism also corresponds to a variable number of exons coding for the flexible hinge segment of the IgG3 antibody (the 4-exon and 3-exon forms, and a newly described 2-exon form). This diversity presents relevant associations with Gm haplotypes, suggesting that molecular rearrangements of the G3 hinge are related to the evolution of the Gm polymorphism. Non-significant correlation coefficients are found between Gm haplotypes and A2m alleles in the Mandenka, indicating that these loci may have reached equilibrium through recombination. The effect of recombination on linkage disequilibrium is more generally revealed, across the Ig CH genomic region, by a significant decrease of D' values with increasing physical distances between the loci on the chromosome.

DNA sequence variability of IGHG3 alleles associated to the main G3m haplotypes in human populations

“…Previous studies indicate that G3m 5,10,11,13,14 is found on genes having either 2, 3 or 4 exons coding for the hinge, in contrast to other G3m haplotypes. 17,39 G3m 5,10,11,13,14 is also present at very high frequency in most human population (except, for example, some East Asian, some Amerindian, and many Oceanian populations), although with different linkages to G1m (3 or 1,3 or 1,17) and G2m (23) alleles. 3,4 All these results suggest that G3m 5,10,11,13,14 is an ancestral G3m haplotype.…”

“…Interestingly, G3m 5,6,11,24 and G3m 5,6,10,11,14 (M8) are not monophyletic, in spite of the common presence of G3m (6). Previous studies indicate that their hinge structures are also different (3 and 4 exons, respectively 17 ). G3m 5,6,10,11,14 is probably a relatively recent differentiation of G3m 5,10,11,13,14 (short branch) due to a single punctual mutation (Gln?Glu at position 419) that transformed G3m(13) allotype into G3m(6).…”

“…Indeed, we previously showed that very strong associations exist between IGHG3 hinge lengths, which are composed of 2, 3, or 4 exons, and G3m haplotypes in the Mandenka population. 17 We first checked the putative existence of these associations in 30 Selkups, 30 Lebanese and 13 French (results not shown). We then selected individuals whose IGHG3 genes were known to be associated to specific G3m haplotypes.…”

“…The EZZ sequence (T1) of aTunisian (X03604 37 ) is taken as a reference, and the LAT sequence of another Tunisian (T2) (X16110 38 ) is also included. The G3m haplotype corresponding to each sequence, and the amino acids involved in the observed non-synonymous substitutions are indicated (right and bottom of 17,39 are also shown.…”

Haplotype Evolution and Linkage Disequilibrium: A Simulation Study

“…Haplotypes defined at the molecular level are now being used to address human evolution [1, 2, 3, 4, 5], and an increase in linkage disequilibrium outside of Africa has been cited as evidence for a replacement model of modern human evolution [3]. Particularly interesting regions of the genome have been analyzed through haplotypes: the RH blood groups [6, 7], HLA [8, 9, 10], mitochondrial DNA [11, 12, 13], Y chromosomes [14, 15](see also the review by Mitchell and Hammer [16]), and immunoglobulins [17, 18]. …”