Molecular analysis of HLA-B35 alleles and their relationship to HLA-B15 alleles.

The HLA-B35 serotype is one of the largest allelic groups of HLA class I molecules and includes four isotypes. Of the four, the B35 variant isoform is relatively rare and is the most acidic form. DNA sequencing of the rare isoforms revealed three alleles, B1522, B3511, and B3517. A phylogenetic tree of HLA-B15- and HLA-B35-related alleles for the exon 2 and 3 nucleotide sequences showed that exon 2 of B1522 clusters with B35 alleles whereas exon 3 clusters with B15 alleles. Branches of the tree suggest that the serodeterminants of B35, B62, B63, and B70 may reside in the alpha 1 domain, encoded by exon 2. The B1520 and B1522 genes, which type as B62 and B35, respectively, are hybrid molecules alternatively using exon 2 and exon 3 sequences of B3501 and B1501. A comparison of intron 2 sequences for B3501, B1501 and B*1522 suggests that the recombination site may have been in the region at the 3' end of intron 2. Despite being flanked by two highly polymorphic exons (exons 2 and 3), intron 2 is relatively well conserved in the B-locus, and it is characterized by seven to eight tandem repeats of the CGGGG pentanucleotide. A high degree of sequence homology and repetitive sequences are essential for a significant frequency of recombination. In this report, we reveal more about the complex evolutionary history of the HLA-B alleles.