Polymorphism of HLA-DR β Chains in DR4, -7, and -9 Haplotypes: Implications for the Mechanisms of Allelic Variation

We have isolated and sequenced cDNA clones corresponding to the DRβ 1 and DRβ 2 loci from two homozygous B-cell lines typed as DR7 (Burkhart) and DR9 (ISK). These nucleotide sequences were compared to β 1 and β 2 chains of other DR haplotypes. The first-domain sequences of β 2 chains are identical in DR4 and DR7 haplotypes. In addition, there is strong sequence homology within the 3′ untranslated regions of β 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 β 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 β 1 and β 2 chains are suggested. The differences may be a consequence of selection pressures; this implies functional differences for products of the β 1 and β 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 β 1 first domain.