Tracing the origin of HLA-DRB1 alleles by microsatellite polymorphism

We analyzed the origin of allelic diversity at the class II HLA-DRB1 locus, using a complex microsatellite located in intron 2, close to the polymorph ic second exon. A phylogenetic analysis of human, gorilla, and chimpanzee D RB1 sequences indicated that the structure of the microsatellite has evolve d, primarily by point mutations, from a putative ancestral (GT)(x)(GA)(y)-c omplex-dinucleotide repeat. In all contemporary DRB1 allelic lineages, with the exception of the human *04 and the gorilla *08 lineages, the (GA)(y) r epeat is interrupted, often by a G-->C substitution. In general, the length of the 3' (GA)(y) repeat correlates with the allelic lineage and thus evol ves more slowly than a middle (GA)(z) repeat, whose length correlates with specific alleles within the lineage. Comparison of the microsatellite seque nce from 30 human DRB1 alleles showed the longer 5' (GT)(x) to be more vari able than the shorter middle (GA)(z) and 3' (GA)(y) repeats. Analysis of mu ltiple samples with the same exon sequence, derived from different continen ts, showed that the 5' (GT)(x) repeat evolves more rapidly than the middle (GA)(z) and the 3' (GA)(y) repeats, which is consistent with findings of a higher mutation rate for longer tracts. The microsatellite-repeat-length va riation was used to trace the origin of new DRB1 alleles, such as the new * 08 alleles found in the Cayapa people of Ecuador and the Ticuna people of B razil.