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The impact of copy number variation on local gene expression in mouse hematopoietic stem and progenitor cells

Nature Genetics volume 41, pages 430–437 (2009)Cite this article

Abstract

The extent to which differences in germline DNA copy number contribute to natural phenotypic variation is unknown. We analyzed the copy number content of the mouse genome to sub–10-kb resolution. We identified over 1,300 copy number variant regions (CNVRs), most of which are <10 kb in length, are found in more than one strain, and, in total, span 3.2% (85 Mb) of the genome. To assess the potential functional impact of copy number variation, we mapped expression profiles of purified hematopoietic stem and progenitor cells, adipose tissue and hypothalamus to CNVRs in cis. Of the more than 600 significant associations between CNVRs and expression profiles, most map to CNVRs outside of the transcribed regions of genes. In hematopoietic stem and progenitor cells, up to 28% of strain-dependent expression variation is associated with copy number variation, supporting the role of germline CNVs as key contributors to natural phenotypic variation in the laboratory mouse.

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Figure 1: CNVR genotyping.
Figure 2: Location of CNVRs in the inbred mouse genome.
Figure 3: Distribution of CNVR sizes.
Figure 4: Colocalization of CNVRs with other genomic elements.
Figure 5: Tissue-specific CNVR eQTLs.
Figure 6: CNVR eQTLs.

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Acknowledgements

This work was supported in part by a grant from the US National Institutes of Health/National Cancer Institute (CA101937). P.C. was supported in part by the National Human Genome Research Institute (T32 HG000045) and a Kauffman Fellowship. Mice were provided through a collaboration with the Mouse Phenome Project (The Jackson Laboratory, Bar Harbor, Maine). Additional mice were provided by M. You (Washington University). We thank T. Ley, D. Link and M. Walter for helpful discussions. Cell sorting was done by the High Speed Cell Sorter Core in the Alvin J. Siteman Cancer Center at Washington University School of Medicine. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant (P30 CA91842).

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Oncology, Stem Cell Biology Section, Washington University, St. Louis, Missouri, USA

    Patrick Cahan, Yedda Li, Masayo Izumi & Timothy A Graubert

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  1. Patrick Cahan
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  2. Yedda Li
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  3. Masayo Izumi
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  4. Timothy A Graubert
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Contributions

P.C. and T.A.G. designed the study; P.C., Y.L. and M.I. performed experiments; P.C. and T.A.G. analyzed the data; P.C., Y.L. and T.A.G. wrote the manuscript.

Corresponding author

Correspondence to Timothy A Graubert.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 and Supplementary Tables 1,3,4,5,7,8 (PDF 2442 kb)

Supplementary Table 2

Annotation of high-confidence CNVRs (XLS 1033 kb)

Supplementary Table 6

Inferred CNVR genotypes in BXD mice (XLS 592 kb)

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Cahan, P., Li, Y., Izumi, M. et al. The impact of copy number variation on local gene expression in mouse hematopoietic stem and progenitor cells. Nat Genet 41, 430–437 (2009). https://doi.org/10.1038/ng.350

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