Mt. Tusieluna et Pc. White, GENE CONVERSIONS AND UNEQUAL CROSSOVERS BETWEEN CYP21 (STEROID 21-HYDROXYLASE GENE) AND CYP21P INVOLVE DIFFERENT MECHANISMS, Proceedings of the National Academy of Sciences of the United Statesof America, 92(23), 1995, pp. 10796-10800
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.