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Expression Quantitative Trait Loci Mapping Identifies New Genetic Models of Glutathione S-Transferase Variation

Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida

Expression quantitative trait loci (eQTL) mapping can be used to identify the genetic variations that underlie inherited differences in gene transcription. We performed eQTL mapping by combining whole genome transcriptional data from the hypothalami of 33 strains of inbred mice with a detailed haplotype map of those same strains, revealing 10,655 trans associations and 31 cis eQTLs. One of the cis associations was found to be driven by strain-specific variation in the expression of Glutathione S-transferase, mu 5 (Gstm5). Gstm5 is one of seven members of the glutathione S-transferase, Mu family of genes. The glutathione S-transferases are phase II metabolic enzymes and are key regulators of drug and toxin clearance. In mouse, all seven family members are tightly clustered on mouse chromosome 3. Investigation of the Gstm5 cis association in multiple tissues types revealed that an 84-kilobase region on MMU3 acts as a haplotype-specific locus control region for the glutathione S-transferase, Mu cluster. In the strains that share the minor haplotype, drastic reductions in mRNA levels in multiple members of the Gst Mu family were observed. The strain-specific differences in Gst Mu transcription characterized here accurately model the human population, in which extreme variations in expression of GST Mu family members have been observed. Furthermore, the reduction in Gst Mu levels has important relevance for pharmacology and toxicology studies conducted in these strains. For instance, the reduced levels of Gst Mu in general and Gstm5 in particular have implications in models of dopamine metabolism, Parkinson's disease, and chemical neurotoxicity.