Polymorphism of HLA-DR beta chains in DR4, -7, and -9 haplotypes: implications for the mechanisms of allelic variation.

We have isolated and sequenced cDNA clones corresponding to the DR beta 1 and DR beta 2 loci from two homozygous B-cell lines typed as DR7 (Burkhart) and DR9 (ISK). These nucleotide sequences were compared to beta 1 and beta 2 chains of other DR haplotypes. The first-domain sequences of beta 2 chains are identical in DR4 and DR7 haplotypes. In addition, there is strong sequence homology within the 3' untranslated regions of beta 1 genes from DR4, -7, and -9 haplotypes, thus confirming the close evolutionary relationship among these three haplotypes. In contrast, the first-domain sequences of beta 1 molecules from these haplotypes are very different from each other and do not reflect the DR4, -7, -9 family relationship. Two explanations for the differences in degree of diversity between beta 1 and beta 2 chains are suggested. The differences may be a consequence of selection pressures; this implies functional differences for products of the beta 1 and beta 2 loci. Alternatively, closely linked segments of the human class II region may differ in their underlying rates of variation, independent of selection pressures, and this may in part account for the extraordinary diversity found in the beta 1 first domain.