A Common and Unstable Copy Number Variant Is Associated with Differences in Glo1 Expression and Anxiety-Like Behavior

Richard Williams; Jackie E Lim; Bettina Harr; Claudia Wang; Ryan Walters; Margaret G Distler; Meike Teschke; Chunlei Wu; Tim Wiltshire; Andrew I Su; Greta Sokoloff; Lisa M Tarantino; Justin O Borevitz; Abraham A Palmer

doi:10.1371/journal.pone.0004649

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A Common and Unstable Copy Number Variant Is Associated with Differences in Glo1 Expression and Anxiety-Like Behavior

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A Common and Unstable Copy Number Variant Is Associated with Differences in Glo1 Expression and Anxiety-Like Behavior

Richard Williams, Jackie E Lim, Bettina Harr, Claudia Wang, Ryan Walters, Margaret G Distler, Meike Teschke, Chunlei Wu, Tim Wiltshire, Andrew I Su, …

PloS one, Vol.4(3), pp.e4649-e4649

03/06/2009

DOI: 10.1371/journal.pone.0004649

PMCID: PMC2650792

PMID: 19266052

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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 similar to 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.

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Title: Subtitle: A Common and Unstable Copy Number Variant Is Associated with Differences in Glo1 Expression and Anxiety-Like Behavior
Creators: Richard Williams - University of Chicago
Jackie E Lim - University of Chicago
Bettina Harr - Max Planck Society
Claudia Wang - Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA
Ryan Walters - University of Chicago
Margaret G Distler - University of Chicago
Meike Teschke - Max Planck Society
Chunlei Wu - Genomics Institute of the Novartis Research Foundation
Tim Wiltshire - University of North Carolina at Chapel Hill
Andrew I Su - Genomics Institute of the Novartis Research Foundation
Greta Sokoloff - University of Chicago
Lisa M Tarantino - University of North Carolina at Chapel Hill
Justin O Borevitz - University of Chicago
Abraham A Palmer - University of Chicago
Resource Type: Journal article
Publication Details: PloS one, Vol.4(3), pp.e4649-e4649
DOI: 10.1371/journal.pone.0004649
PMID: 19266052
PMCID: PMC2650792
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: PUBLIC LIBRARY SCIENCE
Number of pages: 13
Language: English
Date published: 03/06/2009
Academic Unit: Psychological and Brain Sciences
Record Identifier: 9984256929102771

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