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Replication and narrowing of gene expression quantitative trait loci using inbred mice

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Abstract

Gene expression quantitative trait locus (eQTL) mapping has become a powerful tool in systems biology. While many authors have made important discoveries using this approach, one persistent challenge in eQTL studies is the selection of loci and genes that should receive further biological investigation. In this study we compared eQTL generated from gene expression profiling in the livers of two panels of mouse strains: 41 BXD recombinant inbred and 36 Mouse Diversity Panel (MDP) strains. Cis-eQTL, loci in which the transcript and its maximum QTL are colocated, have been shown to be more reproducible than trans-eQTL, which are not colocated with the transcript. We observed that between 9.9 and 12.1% of cis-eQTL and between 2.0 and 12.6% of trans-eQTL replicated between the two panels depending on the degree of statistical stringency. Notably, a significant eQTL hotspot on distal chromosome 12 observed in the BXD panel was reproduced in the MDP. Furthermore, the shorter linkage disequilibrium in the MDP strains allowed us to considerably narrow the locus and limit the number of candidate genes to a cluster of Serpin genes, which code for extracellular proteases. We conclude that this strategy has some utility in increasing confidence and resolution in eQTL mapping studies; however, due to the high false-positive rate in the MDP, eQTL mapping in inbred strains is best carried out in combination with an eQTL linkage study.

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Acknowledgments

We thank several anonymous reviewers for excellent suggestions and criticism which strengthened the final manuscript. Financial support for these studies was provided in part by the United States Environmental Protection Agency grants RD833825 and F08D20579. However, the research described in this article was not subjected to the Agency’s peer review and policy review and therefore does not necessarily reflect the views of the Agency and no official endorsement should be inferred. DMG was also supported by the UNC Environmental Sciences & Engineering Interdisciplinary Fellowship.

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Authors and Affiliations

  1. Department of Environmental Sciences & Engineering, University of North Carolina, CB 7431, Chapel Hill, NC, 27599, USA

    Daniel M. Gatti, Alison H. Harrill & Ivan Rusyn

  2. Department of Biostatistics, University of North Carolina, Chapel Hill, NC, 27599, USA

    Fred A. Wright

  3. Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA

    David W. Threadgill

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  1. Daniel M. Gatti
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  2. Alison H. Harrill
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  3. Fred A. Wright
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  4. David W. Threadgill
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  5. Ivan Rusyn
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Correspondence to Ivan Rusyn.

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Supplemental Figure 1

eQTL trans-band size under permutation. Each bar represents the proportion of 100 permutations in which an eQTL trans-band of size n occurred at least once. The largest trans-band that occurred by chance contained 17 transcripts. The Chr 12 trans-band contains 19 transcripts and thus is unlikely to have occurred by chance. Supplementary material 1 (TIFF 11786 kb)

Supplementary material 2 (XLS 52 kb)

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Gatti, D.M., Harrill, A.H., Wright, F.A. et al. Replication and narrowing of gene expression quantitative trait loci using inbred mice. Mamm Genome 20, 437–446 (2009). https://doi.org/10.1007/s00335-009-9199-0

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