Pharmacokinetics and Bioanalysis Center, Shin Nippon BiomedicalLaboratories, Ltd., Kainan, Wakayama 642-0017, Japan.
BMC Evol Biol. 2011 Oct 1;11:283. doi: 10.1186/1471-2148-11-283.
Elucidating the pattern of evolutionary changes in drug-metabolizing genes is an important subject not only for evolutionary but for biomedical research. We investigated the pattern of divergence and polymorphisms of macaque CYP1A1 and CYP1A2 genes, which are major drug-metabolizing genes in humans. In humans, CYP1A2 is specifically expressed in livers while CYP1A1 has a wider gene expression pattern in extrahepatic tissues. In contrast, macaque CYP1A2 is expressed at a much lower level than CYP1A1 in livers. Interestingly, a previous study has shown that Macaca fascicularis CYP1A2 harbored unusually high genetic diversity within species. Genomic regions showing high genetic diversity within species is occasionally interpreted as a result of balancing selection, where natural selection maintains highly diverged alleles with different functions. Nevertheless many other forces could create such signatures.
We found that the CYP1A1/2 gene copy number and orientation has been highly conserved among mammalian genomes. The signature of gene conversion between CYP1A1 and CYP1A2 was detected, but the last gene conversion event in the simian primate lineage occurred before the Catarrhini-Platyrrhini divergence. The high genetic diversity of macaque CYP1A2 therefore cannot be explained by gene conversion between CYP1A1 and CYP1A2. By surveying CYP1A2 polymorphisms in total 91 M. fascicularis and M. mulatta, we found several null alleles segregating in these species, indicating functional constraint on CYP1A2 in macaques may have weakened after the divergence between humans and macaques. We propose that the high genetic diversity in macaque CYP1A2 is partly due to the degeneration of CpG sites, which had been maintained at a high level by purifying selection, and the rapid degeneration process was initiated by the loss of functional constraint on macaque CYP1A2.
Our findings show that the highly polymorphic CYP1A2 gene in macaques has not been created by balancing selection but by the burst of CpG site degeneration after loss of functional constraint. Because the functional importance of CYP1A1/2 genes is different between humans and macaques, we have to be cautious in extrapolating a drug-testing data using substrates metabolized by CYP1A genes from macaques to humans, despite of their somewhat overlapping substrate specificity.
阐明药物代谢基因的进化变化模式不仅是进化生物学，而且也是生物医学研究的重要课题。我们研究了猕猴 CYP1A1 和 CYP1A2 基因的分化和多态性模式，这两个基因是人类中主要的药物代谢基因。在人类中，CYP1A2 特异性表达于肝脏，而 CYP1A1 在肝外组织中有更广泛的基因表达模式。相比之下，猕猴 CYP1A2 在肝脏中的表达水平远低于 CYP1A1。有趣的是，先前的研究表明，猕猴 CYP1A2 种内具有异常高的遗传多样性。种内显示高遗传多样性的基因组区域偶尔被解释为平衡选择的结果，其中自然选择维持具有不同功能的高度分化的等位基因。然而，许多其他因素也可能产生这种特征。
我们发现 CYP1A1/2 基因的拷贝数和方向在哺乳动物基因组中高度保守。在 CYP1A1 和 CYP1A2 之间检测到基因转换的特征，但灵长类动物谱系中的最后一次基因转换事件发生在类人猿和阔鼻猴分化之前。因此，猕猴 CYP1A2 的高遗传多样性不能用 CYP1A1 和 CYP1A2 之间的基因转换来解释。通过对 91 只恒河猴和猕猴 CYP1A2 多态性的调查，我们发现这些物种中存在几种分离的无效等位基因，表明 CYP1A2 在猕猴中的功能限制可能在人类和猕猴分化后减弱。我们提出，猕猴 CYP1A2 的高遗传多样性部分是由于 CpG 位点的退化，这些位点以前一直受到纯化选择的高水平维持，而功能限制的丧失启动了 CpG 位点的快速退化过程。
我们的研究结果表明，猕猴中高度多态的 CYP1A2 基因不是由平衡选择产生的，而是由于功能限制丧失后 CpG 位点的爆发性退化所致。由于 CYP1A1/2 基因在人类和猕猴中的功能重要性不同，因此，尽管它们的底物特异性有些重叠，我们在将使用 CYP1A 基因代谢的药物测试数据从猕猴外推到人类时必须谨慎。
