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 g enes are differentially regulated at the transcriptional level. Previo us studies indicate that this may be related to locus-specific structu ral differences in certain enhancer elements, We have recently examine d the 5' proximal regulatory regions of the A and B homologs in the hi gher non-human primates and found pronounced differences between the l oci. Sequence analysis shows the B-promoters are more homogeneous, whe reas the A-locus promoters are divergent among the various species exa mined, The differences in A- and B-promoters is exemplified by the reg ulatory element referred to as the IFN-responsive element (IRE). While the and locus IRE is conserved among all primates examined, the A-loc us IRE are divergent and reveal different sequences in the human/chimp anzee, 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 f ound in hominoid primates were unresponsive to IFN. One base substitut ion shared by all the primate IREs proved to be inactivating. These re sults provide a molecular basis of how duplicated gene loci encoding s tructurally and functionally similar antigen-presenting molecules may become differentially responsive to physiological stimulus.