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Strains for eQTL CNV Analysis

ABSTRACT: Background Haplotype association mapping is a recently developed method that can be used to identify expression Quantitative Trait Loci (eQTLs). The underlying genomic structure of the haplotype can be defined by single nucleotide polymorphisms (SNPs), variable number tandem repeats (VNTRs) and copy number variations (CNVs). Microarray genotyping platforms are able to interrogate all three genomic polymorphisms simultaneously. Combined with gene expression data, these data allow for the elucidation of sites responsible for the regulation of transcription. Results Thirty three inbred strains were genotyped on a microarray platform to assess possible contributions of polymorphic regions to gene expression. Over one hundred million statistical correlations were made between probe performance on genotyping and gene expression microarrays. This analysis provided 10,655 trans associations and 31 cis associations. Further investigation of one of the cis associations revealed that a 84kb region of MMU3 acts as a haplotype-specific locus control region for the glutathione-S-transferase mu family in multiple tissues. In the strains that share the minor haplotype, reductions in mRNA levels in members of the Gst mu family are observed. Conclusions We have identified a haplotype containing a putative locus control region for the Gst mu family gene cassette. In the strains with affected haplotype, Gst mu expression is drastically reduced. The reduction in Gst mu levels has important relevance for pharmacology and toxicology studies. The reduction of Gst mu levels in general, and Gstm5 in particular, has implication in models of dopamine metabolism, Parkinson’s disease, and chemical neurotoxicity. Keywords: Liver gene expression, no treatment

ORGANISM(S): Mus musculus

PROVIDER: GSE10377 | GEO | 2008/10/31

SECONDARY ACCESSION(S): PRJNA108115

REPOSITORIES: GEO

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Project description:Background; Haplotype association mapping is a recently developed method that can be used to identify expression Quantitative Trait Loci (eQTLs). The underlying genomic structure of the haplotype can be defined by single nucleotide polymorphisms (SNPs), variable number tandem repeats (VNTRs) and copy number variations (CNVs). Microarray genotyping platforms are able to interrogate all three genomic polymorphisms simultaneously. Combined with gene expression data, these data allow for the elucidation of sites responsible for the regulation of transcription. Results; Thirty three inbred strains were genotyped on a microarray platform to assess possible contributions of polymorphic regions to gene expression. Over one hundred million statistical correlations were made between probe performance on genotyping and gene expression microarrays. This analysis provided 10,655 trans associations and 31 cis associations. Further investigation of one of the cis associations revealed that a 84kb region of MMU3 acts as a haplotype-specific locus control region for the glutathione-S-transferase mu family in multiple tissues. In the strains that share the minor haplotype, reductions in mRNA levels in members of the Gst mu family are observed. Conclusions; We have identified a haplotype containing a putative locus control region for the Gst mu family gene cassette. In the strains with affected haplotype, Gst mu expression is drastically reduced. The reduction in Gst mu levels has important relevance for pharmacology and toxicology studies. The reduction of Gst mu levels in general, and Gstm5 in particular, has implication in models of dopamine metabolism, Parkinsonâs disease, and chemical neurotoxicity. Experiment Overall Design: Samples GSM262266-GSM262267, GSM262270-GSM262272 representing liver gene expression Samples from 10 week old male mouse livers were analyzed in a confirmation study of an identified eQTL. Samples came from pools of three animals, and were compared across strains. Experiment Overall Design: The genotyping summary output file and associated .CEL files are linked below as supplementary files. Briefly: Experiment Overall Design: After hybridization and staining the arrays are scanned on an Affymetrix Scanner 3000 7G 4C using four distinct filters, one for each DNA base (A, C, G, T). These scanned images are saved at .dat files. A grid is superimposed on the .dat array image such that each element of the grid brackets a feature. Once the grid has been applied, GCOS computes one intensity value for each cell, and saves these values in a .CEL file. A .CEL file is generated for each possible base (A, C, G, T). Only the .CEL files are read by GTGS. Experiment Overall Design: The .CEL files computed by GCOS are then imported into GTGS and analyzed. The experiments are then clustered together and used to generate a normalized profile of each probe. From the clustered profiles a genotype call is made for every specific probe on an individual chip. These genotyped calls are then exported from GTGS into a .txt file containing assay id, sample id and relative intensity values for each DNA base over the entire set of SNPs analyzed.

Project description:The glutathione S-transferase (GST) gene family codes for enzymes that detoxify xenobiotics by catalyzing the conjugation of xenobiotics to glutathione. Based on reports that inherited copy number variations (CNV) in the genome modulate some GST expression levels and with the knowledge that cigarette smoke contains >3000 xenobiotics, and that the small airway epithelium and alveolar macrophages are involved early in the pathogensis of smoking-induced lung disease, we asked: do germline CNVs modulate GST expression level in the small airway epithelium and alveolar macrophages? Affymetrix HG U133 Plus 2.0 microarrays were used to survey GST gene expression in the small airway epithelium and alveolar macrophages obtained by bronchoscopic brushings from current smokers (n=35) and nonsmokers (n=35). The CNV genotypes of these 70 subjects were determined by Affymetrix Human SNP array 5.0 chips. Sixteen % of subjects had deletions of both GSTM1 alleles. These deletions were associated with reduced GSTM1 mRNA levels in both the small airway epithelium (p<10-7) and alveolar macrophages (p<0.05). Thirty % of subjects had homozygous deletions of GSTT1 with concomitant reduced mRNA levels in both small airway epithelium and alveolar macrophages (p<10-7). In contrast, genes flanking the CNV regions of both GST genes showed no difference in expression level among subjects with and without the GST deletions (p>0.3). Interestingly, GSTT2B, a duplicate gene of GSTT2, exhibited homozygous deletion in blood in 27% of subjects and was not expressed in small airway epithelium in the remainder of subjects but was expressed in alveolar macrophages of heterozygotes and wild type subjects, proportionate to genotype (p<10-3). These data demonstrate that highly prevalent CNV deletions of genes critical to ameliorating smoking-associated xenobiotic-induced damage in the lung can result in significant modulation of the gene expression levels, with the linear relationship of genotype to expression level suggesting minimal compensation of gene expression levels in heterozygotes consistent with GST polymorphisms playing a role in the risk for development of smoking-induced lung disease.

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Strains for eQTL CNV Analysis

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