THE NATURE OF POLYMORPHISM OF THE HLA-DRB INTRON SEQUENCES IS LINEAGE-SPECIFIC

The sequence database of HLA-DRB genes is mainly derived from mRNA ana lysis or has focused exclusively on the polymorphism of the 2nd exon. Little is known about the non-coding sequences of the different DRB al leles which represent about 94% of the genes. In this study we have de termined the sequence of the 3' 500 bp intron 1 fragment adjacent to e xon 2 in all serologically defined HLA-DRB genes and their most freque nt allelic subtypes. The intron sequences turned out to be highly poly morphic. Similar to the class I introns, this variability was not cha racterized by random point mutations but by a highly systematic divers ity reflecting the lineage-specific relationship of the HLA-DR alleles . With a few exceptions in DRB115, 13 and 08 as well as DRB4 and 5, t he variability mirrors the serological diversity. As well as deliverin g insight into the genetic relationship between the different DRB alle les, these sequences will provide an extremely valuable basis for deve loping advanced DRB sequencing strategies for clinical purposes.