GENE CONVERSIONS AND UNEQUAL CROSSOVERS BETWEEN CYP21 (STEROID 21-HYDROXYLASE GENE) AND CYP21P INVOLVE DIFFERENT MECHANISMS

Most cases of congenital adrenal hyperplasia, the inherited inability to synthesize cortisol, are caused by mutations in the steroid 21-hydr oxylase gene (CYP21). Steroid 21-hydroxylase deficiency is unusual amo ng genetic diseases in that approximate to 95% of the mutant alleles h ave apparently been generated by recombination between a normally acti ve gene (CYP21) and a linked pseudogene (CYP21P), Approximately 20% of mutant alleles carry DNA deletions of 30 kb that have presumably been generated by unequal meiotic crossing-over, whereas 75% carry one or more mutations in CYP21 that are normally found in the CYP21P pseudoge ne, These latter mutations are termed ''gene conversions,'' although t he mechanism by which they are generated is not well understood. To as sess the frequency at which these different recombination events occur , we have used PCR to detect de novo deletions and gene conversions in matched sperm and peripheral blood leukocyte DNA samples from normal individuals, Deletions with breakpoints in a 100-bp region in intron 2 and exon 3 were detected in sperm, DNA samples with frequencies of ap proximate to 1 in 10(5)-10(6) genomes but were never detected in the m atching leukocyte DNA Gene conversions in the same region occur in app roximate to 1 in 10(3)-10(5) genomes in both sperm and leukocyte DNA, These data suggest that whereas deletions occur exclusively in meiosis , gene conversions occur during both meiosis and mitosis, or perhaps o nly during mitosis. Thus, gene conversions must occur by a mechanism d istinct from unequal crossing-over.