Nonrandom allelic variation in the regulatory complex of HLA class I genes

Recently, we have demonstrated that the HLA class I regulatory complex (CRC) is conserved in a locus-specific manner with limited allelic variation. In this study, we have analyzed the CRC sequences of the alleles that showed variation from a total of 22 well-characterized, HLA-homozygous B-LCLs, using PCR amplification of genomic DNA and direct sequencing. We compared the sequences of these alleles with their respective locus consensus sequence at kappa B1, kappa B2, the IRS, the putative NRE, and the HLA counterpart of the H-2RII region, the R x R beta-binding site. The palindromic kappa B1 sequence, an active enhancer, was found to be conserved in all HLA-A and -B alleles and in one HLA-C allele. The sequences of the kappa B2 site showed locus-specific divergence with almost no allelic variation. The IRS is strictly locus specific and HLA-B and -C have identical sequences in this region. Variation in the putative NRE sequence and RII-kappa B2 junctional sequence was apparently generated by gene conversion between B and C loci. Each locus had two sequence patterns at the putative RII site. Overall, sequence analysis of variant alleles demonstrated that there is limited variation in a nonrandom fashion. These results may provide a structural basis for locus and allele-specific modulation of these genes.