A common mutation in the hominoid class I A-locus IFN-responsive element results in the loss of enhancer activity

Despite the observed coordinate expression of HLA-A and -B antigens in somatic tissues, there is growing evidence that the A and B class I genes are differentially regulated at the transcriptional level. Previous studies indicate that this may be related to locus-specific structural differences in certain enhancer elements. We have recently examined the 5' proximal regulatory regions of the A and B homologs in the higher non-human primates and found pronounced differences between the loci. Sequence analysis shows the B-promoters are more homogeneous, whereas the A-locus promoters are divergent among the various species examined. The differences in A- and B-promoters is exemplified by the regulatory element referred to as the IFN-responsive element (IRE). While the B-locus IRE is conserved among all primates examined, the A-locus IRE are divergent and reveal different sequences in the human/chimpanzee, gorilla and orang-utan. In reporter gene bioassays, the B-locus IRE exhibited an enhancer activity in response to induction with IFN-beta and IFN-gamma. In contrast, all the variants of the A-locus IRE found in hominoid primates were unresponsive to IFN. One base substitution shared by all the primate IREs proved to be inactivating. These results provide a molecular basis of how duplicated gene loci encoding structurally and functionally similar antigen-presenting molecules may become differentially responsive to physiological stimulus.