Short tandem repeat (STR) haplotypes in HLA: an integrated 50-kb STR/linkage disequilibrium/gene map between the RING3 and HLA-B genes and identification of STR haplotype diversification in the class III region

We present a dense STR/linkage disequilibrium(LD)/gene map between the RING 3 and HLA-B loci, reference allelic sizes on the most prevalent HLA haploty pes and their allelic frequencies in pedigree founders. This resource will facilitate LD, evolution and gene mapping studies, including comparisons of HLA and STR haplotypes and identification of HLA recombinants. The map was constructed by testing novel and previously reported STRs using a panel of 885 individuals in 211 families and 60 DNA samples from cell lines and bon e marrow donors homozygous in the HLA-A, -B and -DR loci selected from over 15 000 entries into the registry of Swedish bone marrow donors. We have al so analysed the variability of STR alleles/haplotypes on the most prevalent HLA haplotypes to identify STRs useful for fine mapping of disease genes i n the region previously implicated in susceptibility to many disorders. The analysis of 40 HLA-A*01, B*0801, DRB1*03011, DQB1*0207 haplotypes in homoz ygous donors showed a surprising stability in 23 STRs between the class II recombination hot spot and HLA-B, with the average of 1.9% (16/838) variant alleles. However, 40% variant alleles were found at the D6S2670 locus in i ntron 19 of the tenascin-X gene both in the families and homozygous donors. The nucleotide sequence analysis of this STR showed a complex polymorphism consisting of tetra- (CTTT)(8-18) and penta-nucleotide (CTTTT)(1-2) repeat s, separated by an intervening non-polymorphic sequence of 42 bp. The HLA-A 1, B*0801, DRBI*03011, DQBI*0201 haplotypes had five (CTTT)(14-18)/(CTTTT)( 2) variants with a predominant (CTTT)(16) allele, implicating the tetranucl eotide component as the source of this ancestral haplotype diversification, which may be due to the location of D6S2670 in the region of the highest G C content in the human MHC.