CHARACTERIZATION OF 3 SEPARATED EXONS IN THE HLA CLASS-II DR REGION OF THE HUMAN MAJOR HISTOCOMPATIBILITY COMPLEX

The human major histocompatibility complex, HLA, is a highly polymorph ic gene region which includes the DRA and DRB genes. The number of DRB genes differs between haplotypes. The DR4 haplotype seems to be one o f the most complex with five DRB loci, DRB1, DRB4, DRB7, DRB8, and DRB 9, in addition to the single DRA locus. We determined the nucleotide s equences of three separated DRB exons located between the DRB4 locus a nd the DRA locus in the DR4 haplotype, two DRB signal-peptide exons (S 1 and S3) and one DRB first-domain exon (locus designation DRB9). Sequ ence comparisons suggest the following order of events for the origin of these exons: DRB9 seems to be the oldest exon and has previously be en detected in multiple HLA haplotypes. DRB9 is more divergent than th e three other known DRB pseudogenes, all of which have been found in a pes. This suggests that DRB9 arose prior to the hominoid divergence. A n L1 repeat has been inserted 3' to DRB9. Subsequently, a LTR of the E RV9 retrovirus-like family was inserted into the L1 repeat. Such LTRs have recently been observed in some of the other DRB genes. The pseudo genes DRB7 and DRB8 (containing only exons 3-6) arose after DRB9. Fina lly, the separated signal peptide exons S1. and S3 were formed. The mo lecular characterization of these separated DRB exons and insertion el ements further clarifies the complex evolutionary history of the HLA-D R region. These selectively neutral exons may serve as useful markers for tracing the phylogeny of HLA haplotypes.