Research Department of Genetics, Evolution and Environment, University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK.
BMC Genet. 2013 May 3;14:34. doi: 10.1186/1471-2156-14-34.
Cytochrome P450 3A5 (CYP3A5) is an enzyme involved in the metabolism of many therapeutic drugs. CYP3A5 expression levels vary between individuals and populations, and this contributes to adverse clinical outcomes. Variable expression is largely attributed to four alleles, CYP3A51 (expresser allele); CYP3A53 (rs776746), CYP3A56 (rs10264272) and CYP3A57 (rs41303343) (low/non-expresser alleles). Little is known about CYP3A5 variability in Africa, a region with considerable genetic diversity. Here we used a multi-disciplinary approach to characterize CYP3A5 variation in geographically and ethnically diverse populations from in and around Africa, and infer the evolutionary processes that have shaped patterns of diversity in this gene. We genotyped 2538 individuals from 36 diverse populations in and around Africa for common low/non-expresser CYP3A5 alleles, and re-sequenced the CYP3A5 gene in five Ethiopian ethnic groups. We estimated the ages of low/non-expresser CYP3A5 alleles using a linked microsatellite and assuming a step-wise mutation model of evolution. Finally, we examined a hypothesis that CYP3A5 is important in salt retention adaptation by performing correlations with ecological data relating to aridity for the present day, 10,000 and 50,000 years ago.
We estimate that ~43% of individuals within our African dataset express CYP3A5, which is lower than previous independent estimates for the region. We found significant intra-African variability in CYP3A5 expression phenotypes. Within Africa the highest frequencies of high-activity alleles were observed in equatorial and Niger-Congo speaking populations. Ethiopian allele frequencies were intermediate between those of other sub-Saharan African and non-African groups. Re-sequencing of CYP3A5 identified few additional variants likely to affect CYP3A5 expression. We estimate the ages of CYP3A53 as ~76,400 years and CYP3A56 as ~218,400 years. Finally we report that global CYP3A5 expression levels correlated significantly with aridity measures for 10,000 [Spearmann's Rho= -0.465, p=0.004] and 50,000 years ago [Spearmann's Rho= -0.379, p=0.02].
Significant intra-African diversity at the CYP3A5 gene is likely to contribute to multiple pharmacogenetic profiles across the continent. Significant correlations between CYP3A5 expression phenotypes and aridity data are consistent with a hypothesis that the enzyme is important in salt-retention adaptation.
细胞色素 P450 3A5（CYP3A5）是参与许多治疗药物代谢的酶。CYP3A5 的表达水平在个体和人群之间存在差异，这导致了不良的临床结果。这种差异主要归因于四个等位基因，CYP3A51（表达等位基因）；CYP3A53（rs776746）、CYP3A56（rs10264272）和 CYP3A57（rs41303343）（低/非表达等位基因）。关于非洲的 CYP3A5 变异性知之甚少，非洲是一个遗传多样性相当大的地区。在这里，我们使用多学科的方法来描述来自非洲内部和周围地理和种族多样化的人群中的 CYP3A5 变异，并推断塑造该基因多样性模式的进化过程。我们对来自非洲内部和周围的 36 个不同人群的 2538 个人进行了常见的低/非表达 CYP3A5 等位基因的基因分型，并在五个埃塞俄比亚族群中重新测序了 CYP3A5 基因。我们使用连锁微卫星和假设逐步突变进化模型来估计低/非表达 CYP3A5 等位基因的年龄。最后，我们通过与与现今、10000 年前和 50000 年前干旱有关的生态数据进行相关性分析，检验了 CYP3A5 对盐保留适应很重要的假设。
我们估计，在我们的非洲数据集内，约有 43%的个体表达 CYP3A5，这低于该地区以前的独立估计值。我们发现 CYP3A5 表达表型在非洲内部存在显著的变异性。在非洲内部，高活性等位基因的频率在赤道和尼日尔-刚果语系人群中最高。埃塞俄比亚的等位基因频率在其他撒哈拉以南非洲和非非洲群体之间处于中间位置。对 CYP3A5 的重新测序只发现了少数可能影响 CYP3A5 表达的其他变体。我们估计 CYP3A53 的年龄约为 76400 年，CYP3A56 的年龄约为 218400 年。最后，我们报告全球 CYP3A5 表达水平与 10000 年前[Spearman's Rho=-0.465，p=0.004]和 50000 年前[Spearman's Rho=-0.379，p=0.02]的干旱测量值显著相关。
CYP3A5 基因在非洲内部存在显著的多样性，这可能导致整个非洲大陆存在多种药物遗传学特征。CYP3A5 表达表型与干旱数据之间的显著相关性与酶在盐保留适应中很重要的假设一致。
