Rapid Birth–Death Evolution Specific to Xenobiotic Cytochrome P450 Genes in Vertebrates

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Abstract
Genes vary greatly in their long-term phylogenetic stability and there exists no general explanation for these differences. The cytochrome P450 (CYP450) gene superfamily is well suited to investigating this problem because it is large and well studied, and it includes both stable and unstable genes. CYP450 genes encode oxidase enzymes that function in metabolism of endogenous small molecules and in detoxification of xenobiotic compounds. Both types of enzymes have been intensively studied. My analysis of ten nearly complete vertebrate genomes indicates that each genome contains 50–80 CYP450 genes, which are about evenly divided between phylogenetically stable and unstable genes. The stable genes are characterized by few or no gene duplications or losses in species ranging from bony fish to mammals, whereas unstable genes are characterized by frequent gene duplications and losses (birth–death evolution) even among closely related species. All of the CYP450 genes that encode enzymes with known endogenous substrates are phylogenetically stable. In contrast, most of the unstable genes encode enzymes that function as xenobiotic detoxifiers. Nearly all unstable CYP450 genes in the mouse and human genomes reside in a few dense gene clusters, forming unstable gene islands that arose by recurrent local gene duplication. Evidence for positive selection in amino acid sequence is restricted to these unstable CYP450 genes, and sites of selection are associated with substrate-binding regions in the protein structure. These results can be explained by a general model in which phylogenetically stable genes have core functions in development and physiology, whereas unstable genes have accessory functions associated with unstable environmental interactions such as toxin and pathogen exposure. Unstable gene islands in vertebrates share some functional properties with bacterial genomic islands, though they arise by local gene duplication rather than horizontal gene transfer. Genes vary greatly in their long-term phylogenetic stability, and there exists no general explanation for these differences. Stable genes persist as a single copy over a wide range of distantly related species, whereas unstable genes undergo frequent duplication and loss in a process called birth-death evolution. The vertebrate cytochrome P450 (CYP450) gene superfamily includes many genes that are present in a single copy in species ranging from teleost fish to mammals and other groups of genes that undergo active birth-death evolution across the same species. The author found that nearly all stable CYP450 genes encode enzymes known to function in the synthesis and degradation of steroid and retinoid hormones (and related molecules). These hormones function in core developmental pathways in vertebrates. In contrast, most unstable CYP450 genes encode enzymes that detoxify foreign small molecules (called xenobiotics—foreign biochemicals). In addition, many of the unstable CYP450 genes are subject to natural selection to change their amino acid sequence over time (positive selection), probably in response to changes in xenobiotic exposure. These findings suggest that stable and unstable genes differ in their rates of birth-death evolution, because stable genes have core endogenous functions whereas unstable genes respond to changing environmental conditions.