The nature of introns 4-7 largely reflects the lineage specificity of HLA-A alleles.

For most HLA-A alleles the phylogeny of the 3' non-coding regions has not yet been studied systematically. In this study, we have determined the sequences of introns 4-7 in 50 HLA-A variants, and have computed nucleotide substitution rates and phylogenetic relationships. The A2/A28, A9, and A10 groups were characterized by clear lineage specificity. For the A19 group, lineage specificity was weaker. A*3001 clustered together with the alleles of the A1/A3/A11/A36 serological family, but not with the A19 group alleles. Reduced lineage specificity was also observed for the alleles of the A1/A3/A11/A36groups. The 3' intron sequences of A*8001 were clearly distinct from all other alleles studied. In several cases two allelic groups shared identical intron sequences, whereby the patterns varied with the introns. A similar situation has been previously described for the 5' introns. Since recombination is the major mechanism of HLA diversification, the intronic lineage specificity corresponds to the comparatively lower recombination rate of the HLA-A 3' exons. The low level of recombination within the 3' region of HLA-A is supported by the low CpG content with a maximum of 3.0% in this region compared with up to 10.7% in the 5' region. Apart from phylogenetic studies of HLA diversity and diversification, the sequence data obtained in our study may prove valuable for the development of a haplotype-specific sequencing strategy for the HLA-A3' exons and for the explanation of recombination events in newly described HLA class I alleles.