Evolution of a highly polymorphic human cytochrome P450 gene cluster: CYP2D6

Abstract

The CYP2D gene cluster on human chromosome 22 containing the functional cytochrome P450 gene CYP2D6 and two or three highly homologous pseudogenes is involved in a clinically important variation in the inactivation of drugs and environmental chemicals. Several mutant haplotypes of CYP2D6 have been identified by restriction analysis and by PCR-based allele-specific amplification. To understand the evolutionary sequence of mutational events as well as recently discovered interracial differences, we analyzed the arrangement of the CYP2D haplotype containing a common mutant allele of CYP2D6 associated with a XbaI 44-kb fragment. This haplotype contains four CYP2D genes instead of three. Comparison of the sequences of these genes with those of previously characterized haplotypes suggests that an early point mutation was followed by a crossover and a gene conversion event, the latter found preferentially in Caucasians. These data are consistent with the rapid evolution of this locus during "plant-animal warfare" with practical consequences for present-day defense of the organism against environmental adversity.