Retained duplications and deletions of CYP2C genes among primates

Abstract

The human genome encodes about 60 functional enzymes of the cytochrome P450 superfamily, including four functional enzymes of the cytochrome P450 2C (CYP2C) subfamily. These enzymes have been shown to metabolize drugs and xenobiotic toxins, such as those in the diet, and are therefore of great importance for biomedical research and applications. While the pharmacology of P450 enzymes has been studied extensively, our understanding of molecular evolution of this gene family is incomplete, in part because a great variation exists in the number of CYP2C homologs across genomes. In humans, the enzymes encoded by these genes are responsible for the metabolism of more than 20% of clinical drugs, but this is not the naturalistic function of these enzymes, which is the metabolism of xenobiotics such as plant secondary metabolites. In this paper, we sought to correlate evolutionary relationships among primate CYP2C genes with known dietary profiles from these species, testing the hypothesis that these genes have evolved under the pressure of dietary toxins. Aside from a small number of deeply divergent genes, primate CYP2C paralogs form three separate clades: CYP2C18, CYP2C9/CYP2C19, and CYP2C8/CYP2C20. Our results showed that the CYP2C18 gene has been separately lost in Nomascus leucogenys and the Panini genomes, and there is no evidence that this gene has been under any positive selection among primates. While CYP2C20 has been retained in cercopithecoids, orthologous loci were separately lost in platyrrhines and hominoids. Notably, nine codons exhibited signature of positive selection. Finally, the CYP2C19 locus was duplicated in basal catarrhines, resulting in the birth of CYP2C9; but the ancestral locus was only retained in hominoid taxa. Overall, our findings support the hypothesis that primate CYP2C genes have evolved in response to selective pressures provided by dietary toxins, although not all gene clusters have evolved in the same manner. Our results may indicate an evolutionarily deep difference in ecology or physiology among higher-order primate taxa.