Polymorphism of human Ia antigens: gene conversion between two DR beta loci results in a new HLA-D/DR specificity

The polymorphic HLA-DR beta-chains are encoded within the human major histocompatibility complex (MHC) by multiple loci resulting from gene duplications. Certain DR haplotypes can be grouped into families based on shared structural factors. We have studied the molecular basis of HLA-DR polymorphism within such a group which includes the haplotypes DR3, DR5 and DRw6. Molecular mapping of the DR beta-chain region allows true allelic comparisons of the two expressed DR beta-chain loci, DR beta I and DR beta III. At the more polymorphic locus, DR beta I, the allelic differences are clustered and may result from gene conversion events over very short distances. The gene encoding the HLA-DR3/Dw3 specificity has been generated by a gene conversion involving the DR beta I and the DR beta III loci of the HLA-DRw6/Dw18 haplotype, as recipient and donor gene, respectively. Based on which allele is found at DR beta III, the less polymorphic locus, two groups of haplotypes can be defined: DRw52a and DRw52b. The generation of HLA-DR polymorphism within the DRw52 supertypic group can thus be accounted for by a succession of gene duplication, divergence and gene conversion.