title: Molecular evolution of the CYP2D subfamily in primates: purifying selection on substrate recognition sites without the frequent or long-tract gene conversion.
abstract: The human cytochrome P450 (CYP) 2D6 gene is a member of the CYP2D gene subfamily, along with the CYP2D7P and CYP2D8P pseudogenes. Although the CYP2D6 enzyme has been studied extensively because of its clinical importance, the evolution of the CYP2D subfamily has not yet been fully understood. Therefore, the goal of this study was to reveal the evolutionary process of the human drug metabolic system. Here, we investigate molecular evolution of the CYP2D subfamily in primates by comparing 14 CYP2D sequences from humans to New World monkey genomes. Window analysis and statistical tests revealed that entire genomic sequences of paralogous genes were extensively homogenized by gene conversion during molecular evolution of CYP2D genes in primates. A neighbor-joining tree based on genomic sequences at the nonsubstrate recognition sites showed that CYP2D6 and CYP2D8 genes were clustered together due to gene conversion. In contrast, a phylogenetic tree using amino acid sequences at substrate recognition sites did not cluster the CYP2D6 and CYP2D8 genes, suggesting that the functional constraint on substrate specificity is one of the causes for purifying selection at the substrate recognition sites. Our results suggest that the CYP2D gene subfamily in primates has evolved to maintain the regioselectivity for a substrate hydroxylation activity between individual enzymes, even though extensive gene conversion has occurred across CYP2D coding sequences.
authors: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan hyasukou@proof.ocn.ne.jp.
authors: Yoshiki
authors: Y
authors: Yasukochi
authors: Department of Evolutionary Studies of Biosystems, The Graduate University for Advanced Studies, Shonan Village, Hayama, Kanagawa, 240-0193 Japan.
authors: Yoko
authors: Y
authors: Satta
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019389:Cytochrome P-450 CYP2D6 / Q000145:classification / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D019143:Evolution, Molecular; D005785:Gene Conversion; D014644:Genetic Variation; D015186:Hominidae; D006801:Humans; D005810:Multigene Family; D002679:Pan troglodytes; D010802:Phylogeny; D011323:Primates / Q000235:genetics*; D011544:Pseudogenes; D013379:Substrate Specificity
chemical_list: D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6
keywords: CYP2D6; CpG site methylation; drug metabolism; gene conversion; molecular evolution; purifying selection