Department of Biology, University of Rome Tor Vergata, Rome, Italy.
Pharmacogenet Genomics. 2011 Oct;21(10):665-72. doi: 10.1097/FPC.0b013e328349da4d.
Glutathione S-transferase enzymes (GSTs; EC: 2.5.1.18) constitute the principal phase II superfamily, which plays a key role in cellular detoxification. GST genes are organized in chromosomal clusters; most of these genes are polymorphic, mainly due to single nucleotide substitutions. Different studies proved significant interethnic differences in GST allelic frequencies but, at present, the role of natural selection in human genetic variability of GSTs is poorly understood. The aim of this study is to investigate the role of natural selection in shaping single nucleotide polymorphism (SNP) diversity of soluble GST genes.
Using the HapMap database, we analyzed the population differences in the soluble GST genes using the phasing data from unrelated individuals shared among 11 populations in the International HapMap project. A Fst-based selection test was applied to HapMap data to detect soluble GST loci under selection.
Comparisons between GST gene polymorphisms among HapMap populations highlight that ethnicity is an influencing factor of GST genetic variability. By applying a genome scan based on F-statistics, we identified nine SNPs that present F-coefficients significantly more different than those expected under neutrality (rs2239892, rs3814309, rs7483, rs1571858, rs929166, rs11807, rs4715344, rs4715354, and rs3734431).
Our study confirms that GST gene variation reflects human demographic history, but it also demonstrates that natural selection could shape the genetic profile of some GST SNPs. Moreover, the identification of human genome regions and targets of natural selection may have detected candidate genes for complex diseases. In analyzing the literature, we provide complex disease hypothesis (male infertility, embryotoxicity) for the identified GST SNPs.
谷胱甘肽 S-转移酶（GSTs；EC：2.5.1.18）构成主要的 II 相超家族，在细胞解毒中起着关键作用。GST 基因在染色体簇中组织；这些基因大多是多态性的，主要是由于单核苷酸取代。不同的研究证明 GST 等位基因频率存在显著的种族间差异，但目前，自然选择在人类 GST 遗传多态性中的作用还知之甚少。本研究旨在探讨自然选择在塑造可溶性 GST 基因单核苷酸多态性（SNP）多样性中的作用。
利用 HapMap 数据库，我们使用国际 HapMap 项目中 11 个群体共享的无关个体的相位数据，分析了可溶性 GST 基因的群体差异。应用基于 Fst 的选择检验方法对 HapMap 数据进行分析，以检测可溶性 GST 基因座是否受到选择。
HapMap 人群中 GST 基因多态性的比较突出表明，种族是 GST 遗传多态性的一个影响因素。通过应用基于 F 统计量的全基因组扫描，我们鉴定了 9 个 SNP，其 F 系数与中性条件下预期的 SNP 明显不同（rs2239892、rs3814309、rs7483、rs1571858、rs929166、rs11807、rs4715344、rs4715354 和 rs3734431）。
我们的研究证实 GST 基因变异反映了人类的人口历史，但也表明自然选择可能塑造了一些 GST SNP 的遗传特征。此外，对人类基因组区域和自然选择目标的鉴定可能已经检测到了复杂疾病的候选基因。在分析文献时，我们为鉴定出的 GST SNP 提供了复杂疾病假说（男性不育、胚胎毒性）。
