Coding versus intron variability: extremely polymorphic HLA-DRB1 exons are flanked by specific composite microsatellites, even in distant populations

Although microsatellite typing is the dominant method in genome research and indirect gene diagnosis, precise relationships of exonic and adjacent simple repeat polymorphisms are not known. We investigated exon 2 sequences of HLA-DRB1 genes and their neighbouring (GT)_n(GA)_m repeats including the intervening single copy spacer. DRB1 is the most polymorphic protein-coding locus in man and all vertebrates investigated. The entire DRB1 variability exists in exon 2. DRB1 genes in different haplotype groups (DR1, DR51, DR52, DR8 and DR53) are accompanied by characteristic modifications of the (GT)_n(GA)_m block (3′ to group-specific single copy spacers). Among more than 520 alleles analysed, > 100 different types of microsatellites were observed. The perfect (GT)_n and (GA)_m blocks vary in length and may be partly ‘degenerated’, mostly in a subgroup-specific manner. Interestingly, the extent of microsatellite diversity varies in given DRB1 alleles. While the microsatellites of the DR7, DR9 alleles and in the DR1 group are virtually invariant, in DR4 and DR13, in particular, simple repeats appear hypervariable with at least 15 or 17 different length alleles, respectively. Comparing Caucasians, Bushmen and South American Indians, the microsatellite variation in identical DRB1 alleles (e.g. DRB1*0102, 03 011, 1302) is smaller than within any of the DR groups in Caucasians. Taken together, extremely polymorphic DRB1 exons evolve in concert with certain variants of an exceptionally well-preserved microsatellite. Received: 8 October 1996