Homologous unequal cross-over within the human CYP2A gene cluster as a mechanism for the deletion of the entire CYP2A6 gene associated with the poor metabolizer phenotype

To clarify the molecular mechanisms involved in the generation of the CYP2A 6 gene deletion (E-type variant), we analyzed the CYP2A7 gene, which is loc ated in the 5'-flanking region of the GYP2A6 gene, from individuals with th e E-type variant and compared it wit;lr the sequences of wild type CYP2A7 a nd CYP2A6 genes. The 3'-downstream sequence (up to 324 bp from the SacI sit e in exon 9) of the CYP2A7 gene of the E-type variant is identical to that of the wild CYP2A7 gene. However, the 3'-downstream sequence (starting from 325 bp from the SacI site in exon 9) of the CYP2A7 gene of the E-type vari ant is identical to that of the wild CYP2A6 gene, indicating that the 3'-do wnstream region of CYP2A7 and the 3'-downstream region of CYP2A6 linked dir ectly eliminating the whole CYP2A6 gene, PCR analysis using primers specifi c to the CYP2A7 gene and the CYP2A6 and CYP2A7 genes confirmed that all DNA samples obtained from 7 individuals carrying the E-type variant possessed the same break points. These results indicate that the breakpoint of the CY P2A6 gene deletion lies in the 3'-downstream region of the CYP2A7 and CYP2A 6 genes.