Abstract
Glyoxalase 1 (Glo1) has been implicated in anxiety-like behavior in mice and in multiple psychiatric diseases in humans. We used mouse Affymetrix exon arrays to detect copy number variants (CNV) among inbred mouse strains and thereby identified a ∼475 kb tandem duplication on chromosome 17 that includes Glo1 (30,174,390–30,651,226 Mb; mouse genome build 36). We developed a PCR-based strategy and used it to detect this duplication in 23 of 71 inbred strains tested, and in various outbred and wild-caught mice. Presence of the duplication is associated with a cis-acting expression QTL for Glo1 (LOD>30) in BXD recombinant inbred strains. However, evidence for an eQTL for Glo1 was not obtained when we analyzed single SNPs or 3-SNP haplotypes in a panel of 27 inbred strains. We conclude that association analysis in the inbred strain panel failed to detect an eQTL because the duplication was present on multiple highly divergent haplotypes. Furthermore, we suggest that non-allelic homologous recombination has led to multiple reversions to the non-duplicated state among inbred strains. We show associations between multiple duplication-containing haplotypes, Glo1 expression and anxiety-like behavior in both inbred strain panels and outbred CD-1 mice. Our findings provide a molecular basis for differential expression of Glo1 and further implicate Glo1 in anxiety-like behavior. More broadly, these results identify problems with commonly employed tests for association in inbred strains when CNVs are present. Finally, these data provide an example of biologically significant phenotypic variability in model organisms that can be attributed to CNVs.
Highlights
Multiple lines of evidence suggest a potential role for GLO1 in human psychiatric disorders
copy number variants (CNV) Analysis We identified CNVs in inbred laboratory mouse strains by hybridizing genomic DNA to GeneChipH Mouse Exon 1.0 ST Arrays, which contain probes that target exons and are ideally suited to identify CNVs that underlie gene expression
CNVs were identified from probe hybridization intensity data using a Hidden Markov Model (HMM) approach
Summary
Multiple lines of evidence suggest a potential role for GLO1 in human psychiatric disorders. An A111E amino acid polymorphism (rs2736654) in GLO1 has been described. The 111E allele was reported to be significantly more common in autism patients versus controls and there was a decrease in GLO1 enzymatic activity in autistic brains [1]. A subsequent study partially replicated this finding by showing evidence that the 111A allele of GLO1 confers protection from autism in unaffected siblings [2]. Two more recent examinations of this and other SNPs in GLO1 failed to replicate any association with autism spectrum disorders [3,4]. There are multiple lines of evidence suggesting a role for GLO1 in various psychiatric traits
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