The difference in sizes of conserved stretches of DNA sequence within the major histocompatibility complex (MHC) in human individuals constitutes an underappreciated genetic diversity that has many practical implications. We developed a model to describe the variable sizes of stretches of conserved DNA in the MHC using the known frequencies of four different kinds of small (< 0.2 Mb) blocks of relatively conserved DNA sequence: HLA-Cw/B; TNF; complotype; and HLA-DR/DQ. Each of these small blocks is composed of two or more alleles of closely linked loci inherited as one genetic unit. We updated the concept of the conserved extended haplotype (CEH) using HLA allele identification and TNF microsatellites to show that specific combinations of the four blocks form single genetic units (>/= 1.5 Mb) with a total haplotype frequency in the Caucasian population of 0.30. Some CEHs extend to the HLA-A and -DPB1 loci forming fixed genetic units of up to at least 3.2 Mb of DNA. Finally, intermediate fragments of CEHs also exist, which are, nevertheless, larger than any of the four small blocks. This complexity of genetic fixity at various levels should be taken into account in studies of genetic disease association, immune response control, and human diversity. This knowledge could also be used for matching CEHs and their fragments for patients undergoing allotransplantation.

Background: The definition of human MHC class I haplotypes through association of HLA-A, HLA-Cw and HLA-B has been used to analyze ethnicity, population migrations and disease association.

The gamma-aminobutyric acid receptor type B 1 (GABA(B) R1) is located approximately at 200 kb telomeric to HLA-A on chromosome 6. It has 11 single-nucleotide polymorphisms (SNPs). We studied the most common of its SNPs (T1974C) in a panel of 118 normal Caucasians from New England and 161 epileptic patients of Caucasian ancestry residing in USA. The frequency of the polymorphism did not differ between patients and controls. Here, we report that the allele C of this SNP in the GABA(B) R1 gene is in linkage disequilibrium with HLA-A11 (P<0.00001) and to a lesser extent with HLA-A1 (P<0.01).