CpG site degeneration triggered by the loss of functional constraint created a highly polymorphic macaque drug-metabolizing gene, CYP1A2

BACKGROUND: Elucidating the pattern of evolutionary changes in drug-metabolizing genes is an important subject not only for evolutionary but for biomedical research. We investigated the pattern of divergence and polymorphisms of macaque CYP1A1 and CYP1A2 genes, which are major drug-metabolizing genes in humans. In humans, CYP1A2 is specifically expressed in livers while CYP1A1 has a wider gene expression pattern in extrahepatic tissues. In contrast, macaque CYP1A2 is expressed at a much lower level than CYP1A1 in livers. Interestingly, a previous study has shown that Macaca fascicularis CYP1A2 harbored unusually high genetic diversity within species. Genomic regions showing high genetic diversity within species is occasionally interpreted as a result of balancing selection, where natural selection maintains highly diverged alleles with different functions. Nevertheless many other forces could create such signatures. RESULTS: We found that the CYP1A1/2 gene copy number and orientation has been highly conserved among mammalian genomes. The signature of gene conversion between CYP1A1 and CYP1A2 was detected, but the last gene conversion event in the simian primate lineage occurred before the Catarrhini-Platyrrhini divergence. The high genetic diversity of macaque CYP1A2 therefore cannot be explained by gene conversion between CYP1A1 and CYP1A2. By surveying CYP1A2 polymorphisms in total 91 M. fascicularis and M. mulatta, we found several null alleles segregating in these species, indicating functional constraint on CYP1A2 in macaques may have weakened after the divergence between humans and macaques. We propose that the high genetic diversity in macaque CYP1A2 is partly due to the degeneration of CpG sites, which had been maintained at a high level by purifying selection, and the rapid degeneration process was initiated by the loss of functional constraint on macaque CYP1A2. CONCLUSIONS: Our findings show that the highly polymorphic CYP1A2 gene in macaques has not been created by balancing selection but by the burst of CpG site degeneration after loss of functional constraint. Because the functional importance of CYP1A1/2 genes is different between humans and macaques, we have to be cautious in extrapolating a drug-testing data using substrates metabolized by CYP1A genes from macaques to humans, despite of their somewhat overlapping substrate specificity.