Abstract

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 CYP1-3 gene families, and we classified the 15 CYP1-3 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 (CYP2C, CYP2D, CYP2E, and CYP3A) showed evidence of diversifying selection while no EM subfamilies demonstrated any consistent signal of diversifying selection. Of these four, CYP2C, CYP2D, and CYP3A 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 CYP2C, CYP2D, CYP2E, and CYP3A subfamilies.

摘要

1. 灵长类动物表现出高度的物种间饮食多样性，这可能使它们接触不同水平的外源化合物。在这里，我们检查了灵长类CYP1-3基因家族的进化，并根据 P450 文献中的来源将15 个CYP1-3基因亚家族分类为外源代谢 (XM) 或内源代谢 (EM)。

2. 我们预测 XM P450 将表现出 (1) 基因拷贝数的更大变异性和 (2) 更多多样化选择的证据，特别是在编码最终酶的底物识别位点 (SRS) 的密码子上。

3. 与我们的第一个预测相反，EM 和 XM P450 在基因拷贝数方面表现出相似的变异水平。然而，我们确实发现四个 XM P450 亚家族（CYP2C、CYP2D、CYP2E和CYP3A）显示出多样化选择的证据，而没有 EM 亚家族表现出任何一致的多样化选择信号。在这四个中，CYP2C、CYP2D和CYP3A显示了 SRS 和多样化选择之间的显着联系。

4. 这些结果揭示了当沿着简单的二元 EM/XM 谱观察 P450 亚家族时无法预期的大量进化活力。我们建议细胞色素 P450 进化的比较研究应重点关注CYP2C、CYP2D、CYP2E和CYP3A亚家族。