A human immunoglobulinIGHG3 allele (Gmb0, b1, c3, c5, u) with anIGHG4 converted region and three hinge exons

Abstract

The five human IGHG genes consist of three constant domain exons plus one of or four hinge exon(s), the quadruplicated hinge region being characteristic of the IGHG3 gene. Besides this structural difference, the IGHG genes are polymorphic, as demonstrated by the restriction fragment length polymorphism and, at the protein level, by the Gm allotypic antigenic determinants. In this paper, we report the sequence of the G3m(b0, b1, c3, c5,u) IGHG3 allele, typical of the Black African populations and of populations with Negroid admixture, found in a homozygous Tunisian designated as LAT. We demonstrate that this G3 allele contains only three hinge exons instead of four (the probable result of an unequal crossing over) and that IGHG3 genes with triplicated hinge exons (and therefore encoding shorter gamma 3 chains) are present in healthy individuals from different populations. Moreover, we show that the LAT G3m (b0, b1, c3, c5, u) coding sequence results from the conversion, in the CH3 exon, of the G3m (b0, b1, b3, b4, b5, u, v) allele, the most frequent IGHG3 gene in the Negroid populations, by the homologous region of a IGHG4 gene. The structural features of the LAT IGHG3 allele, which are the lack of one hinge exon and its conversion by the IGHG4 gene, demonstrate that both crossing-over and gene conversion events occur in the evolution of the human IGHG genes.

Evolution of the porcine (Sus scrofa domestica) immunoglobulin kappa locus through germline gene conversion

“…The pattern of variation may be due to evolution through non-crossover homologous recombination events, namely gene conversion. Evidence for germline gene conversion was also observed in the human IGKV (Bentley and Rabbitts 1983) and mouse IGHV (Cohen and Givol 1983) genes and in the human IGHC genes (Flanagan et al 1984; Lefranc et al 1986; Huck et al 1989). IG gene conversion is generally presented as a mechanism of somatic antibody diversification, especially in chickens and rabbits which utilize a diverse array of pseudogenes as templates for functional IG gene assembly during B cell development to diversify limited functional germline repertoires (recently reviewed by Kurosawa and Ohta (2011)).…”

Human IgG2 Can Form Covalent Dimers

“…A sequence comparison of the human IgG hinges is shown in Table I. The hinge of human IgG3 is unusual in that it is encoded on four separate exons (20) although hinges containing only two and three exons have been reported (22,23). Unlike the other ␥ hinge regions, the ␥2 hinge contains four Cys residues.…”

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

“…Although the long branch differentiating this haplotype suggests a long divergence time from G3m 5,10,11,13,14 , the absence of variability among Mandenka and Tunisian suggests a recent diffusion of this haplotype within Africa. Huck et al 38 have interpreted the G3m 5,6,11,24 sequence as a gene conversion between a G3m 5,10,11,13,14 sequence and a IGHG4 gene, due to shared substitutions between G3m 5,6,11,24 and IGHG4 genes. According to this hypothesis, we expect a high molecular divergence of this haplotype even in the case of a recent differentiation, which is compatible with our results.…”