Gene dosage and gene expression in the HLA region: evidence from deletion variants

Among variants selected in a human cell line for nonexpression of a single gene product in the HLA complex, most are single-gene variants, but several have been isolated that are cis-acting and abolish expression of a series of closely linked genes. The two most plausible mechanisms by which such variants could arise are mitotic crossing-over and chromosome deletion. In two HLA variants the presence of a visible chromosome deletion, a 50% reduction in activity of glyoxalase I (a closely linked marker), or both provided evidence for deletional origins. In a third variant these changes were not demonstrable. All three variants showed reductions in amount of cell surface HLA antigens: 40% for the Ia antigens (HLA-DR) and 20-25% for HLA-ABC antigens. The reductions in cell surface antigen in deletion variants have an important implication: in the case of the HLA-A, -B, and -C heterodimer, which consists of a subunit coded for within the major histocompatibility complex and another subunit (beta(2)-microglobulin) coded for on a different chromosome, it is the gene of the major histocompatibility complex that is limiting. The nonmutant haplotype includes A2; binding of an A2 monoclonal antibody in two of the mutants was found to be approximately equal to that in the wild-type cells. Thus, loss of one copy of HLA-ABC genes does not lead to gene dosage compensation-i.e., increased activity by the remaining ABC alleles. The results with the two types of antibodies support a deletional mechanism and are inconsistent with mitotic crossing-over. Of interest with respect to the potential use of deletion variants for purposes of mapping is the fact that each of these variants has distinctive breakpoints. The absence of mitotic crossing-over in 1.2 x 10(7) cells selected suggests that the event is rare in this autosomal region, if it occurs at all.