Diversifying selection detected in only a minority of xenobiotic-metabolizing <i>CYP1-3</i> genes among primate species

1. Primates exhibit a high degree of among-species dietary diversity, which likely exposes them to varying levels of xenobiotic compounds. Here, we examined the evolution of primate <i>CYP1-3</i> gene families, and we classified the 15 <i>CYP1-3</i> gene subfamilies as either xenobiotic-metabolizing (XM) or endogenous-metabolizing (EM) based on sources in the P450 literature. 2. We predicted that XM P450s would show (1) greater variability in gene-copy number and (2) more evidence of diversifying selection and, especially on codons that encode the substrate-recognition sites (SRSs) for the final enzymes. 3. Counter to our first prediction, EM and XM P450s showed similar levels of variation in gene-copy number. We did find, however, that four XM P450 subfamilies (<i>CYP2C, CYP2D, CYP2E,</i> and <i>CYP3A</i>) showed evidence of diversifying selection while no EM subfamilies demonstrated any consistent signal of diversifying selection. Of these four, <i>CYP2C, CYP2D,</i> and <i>CYP3A</i> showed significant links between SRSs and diversifying selection. 4. These results reveal an amount of evolutionary dynamism that would not be expected when viewing P450 subfamilies along a simple binary EM/XM spectrum. We recommend that comparative studies of cytochrome P450 evolution should focus on the <i>CYP2C, CYP2D, CYP2E,</i> and <i>CYP3A</i> subfamilies.

1. 灵长类动物展现出极高的物种间饮食多样性，这大概率使其暴露于不同水平的外源性化合物（xenobiotic compounds）环境中。本研究针对灵长类<i>CYP1-3</i>基因家族的演化展开考察，并依据细胞色素P450（cytochrome P450，P450）相关文献，将15个<i>CYP1-3</i>基因亚家族划分为外源性物质代谢型（xenobiotic-metabolizing，XM）与内源性物质代谢型（endogenous-metabolizing，EM）两类。2. 本研究提出两项预测：其一，XM型P450的基因拷贝数变异程度更高；其二，该类酶会展现出更多的歧化选择（diversifying selection）证据，尤其体现在编码最终酶底物识别位点（substrate-recognition sites，SRSs）的密码子区域。3. 与第一项预测相悖的是，EM型与XM型P450的基因拷贝数变异水平相近。不过本研究确实发现，4个XM型P450亚家族——<i>CYP2C</i>、<i>CYP2D</i>、<i>CYP2E</i>以及<i>CYP3A</i>——存在歧化选择的信号，而所有EM型亚家族均未展现出一致的歧化选择特征。在这4个亚家族中，<i>CYP2C</i>、<i>CYP2D</i>与<i>CYP3A</i>的底物识别位点与歧化选择之间存在显著关联。4. 上述研究结果揭示了此前仅依据简单的EM/XM二元分类视角看待P450亚家族演化时，无法预料到的演化动态性。本研究建议，细胞色素P450演化的比较研究应聚焦于<i>CYP2C</i>、<i>CYP2D</i>、<i>CYP2E</i>以及<i>CYP3A</i>这4个亚家族。