HapMap-based study of human soluble glutathione S-transferase enzymes: the role of natural selection in shaping the single nucleotide polymorphism diversity of xenobiotic-metabolizing genes.

摘要

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.