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Cloning and complete sequence of an HLA-A2 gene: analysis of two HLA-A alleles at the nucleotide level.

The gene for the HLA-A2 antigen has been cloned from the human lymphoblastoid cell line 721. Comparison of this sequence with the published sequence for HLA-A3 permits the examination of two alleles at the extremely polymorphic HLA-A locus. A high degree of sequence conservation was seen in both coding and noncoding DNA, 97.2% and 94.5%, respectively. Interestingly, the 3' untranslated region was the most conserved, with 99.5% homology. The polymorphism of the HLA-A antigens results from a high proportion of amino acid substitutions relative to the total nucleotide changes in exons 2 and 3. Unlike the clustered differences seen in this region on comparison of two H-2K alleles of mouse, nucleotide substitutions between the HLA-A2 and A3 alleles are evenly distributed. Substitutions at silent sites and within introns were used to calculate an intra-allelic divergence time of at least 10 to 15 million years for these two HLA-A alleles.