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 B-1, kappa B-2, the IRS, the putative NRE, and the HLA counterpart of the H-2RII region, the R X R beta-binding site. The palindromic kappa B-1 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 B-2 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 B-2 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.