Evolutionary origin of mutations in the primate cytochrome P450c21 gene

The CYP21 gene codes for the enzyme cytochrome P450c21 (21-hydroxylase), which is critically involved in the synthesis of glucocorticoids and mineralocorticoids. Standard human haplotypes contain two copies of CYP21--a functional gene and a pseudogene. Inactivation of the functional gene leads to congenital adrenal hyperplasia (CAH). The pseudogene has three main defects: an 8-bp deletion in exon 3, a T insertion in exon 7, and a stop codon in exon 8. To determine the origin of these defects and to shed light on the evolution of the CYP21 gene, we sequenced relevant segments of 10 primate CYP21 genes--three from a chimpanzee, another three from a gorilla, and four from an orangutan. We could show that the 8-bp deletion is present in the chimpanzee and humans, while the other two defects are restricted to humans only. In the gorilla and the orangutan, however, extra CYP21 copies are inactivated by other defects so that the number of functional copies is reduced in each species. Comparison of the sequences has revealed evidence for intraspecific homogenization (concerted evolution) of the CYP21 genes, presumably through an expansion-contraction process effected by relatively frequent unequal but homologous crossing-over.