GENERATION OF THE HLA-B35, HLA-B5, HLA-B16, AND HLA-B15 GROUPS OF ALLELES STUDIED BY INTRON-1 AND INTRON-2 SEQUENCE-ANALYSIS

HLA-B is the most polymorphic of the major histocompatibility complex classical class I loci. This polymorphism is mainly in exons 2 and 3, which code for the molecule's alpha 1 and alpha 2 domains and include the antigenic peptide binding site. Recent studies have indicated that not only exons but also the intron 2 region may be involved in the ge neration of certain HLA-B alleles such as B3906 and B*1522. To study the degree of intron 2 participation and the mechanisms that generate polymorphism at the HLA-B locus, intron 1 and 2 sequences from the HLA -B35, -B5, -B16 and -B15 groups of alleles were obtained. A group-spec ific intronic polymorphism was found: namely, B5301 shows intron 1 an d 2 sequences identical to those found in all B35 alleles studied. On the other hand, B5101 and B*52012 show the same intron 1 and 2 sequen ces and their intron 1 is the same as that found in the B35 group. Thi s suggests that B5 and B35 groups of alleles may have arisen from a co mmon ancestor. All known B16 alleles show the same introns 1 and 2, wi th the exception of B39061 and B*39062, and all B15 alleles also bear the same introns 1 and 2, with the exception of B1522. Variability a t intron 1 is more restricted than at intron 2, and the use of intron 1 for HLA-B allele phylogenetic analysis is better for grouping allele s of a postulated common origin. In conclusion, there is a remarkable conservation of intronic sequences within related HLA-B alleles, which probably reflects a common origin and perhaps a selective force avoid ing DNA changes. Intronic sequences are also potentially useful to des ign DNA typing strategies.