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Distribution and functional impact of DNA copy number variation in the rat

Nature Genetics volume 40, pages 538–545 (2008)Cite this article

Abstract

The abundance and dynamics of copy number variants (CNVs) in mammalian genomes poses new challenges in the identification of their impact on natural and disease phenotypes. We used computational and experimental methods to catalog CNVs in rat and found that they share important functional characteristics with those in human. In addition, 113 one-to-one orthologous genes overlap CNVs in both human and rat, 80 of which are implicated in human disease. CNVs are nonrandomly distributed throughout the genome. Chromosome 18 is a cold spot for CNVs as well as evolutionary rearrangements and segmental duplications, suggesting stringent selective mechanisms underlying CNV genesis or maintenance. By exploiting gene expression data available for rat recombinant inbred lines, we established the functional relationship of CNVs underlying 22 expression quantitative trait loci. These characteristics make the rat an excellent model for studying phenotypic effects of structural variation in relation to human complex traits and disease.

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Figure 1: Detection and verification of CNVs and genome assembly artifacts.
Figure 2: Distribution of CNVs, genome misassemblies and large gaps in the rat.
Figure 3: Gene expression levels correlate with copy number status in the RI strains.

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Acknowledgements

We thank S. Kurz for technical assistance. This work was supported by the award “Exploiting natural and induced genetic variation in the laboratory rat” to E.C. from the European Heads of Research Councils and European Science Foundation EURYI (European Young Investigator) Award scheme, the EURATools integrated project funded by the Sixth Framework Programme of the European Union, grants from the Ministry of Education of the Czech Republic and support from the Howard Hughes Medical Institute to M.P., and US National Institutes of Health grant CA77876 to J.D.S.

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Authors and Affiliations

  1. Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences & University Medical Centre Utrecht, Uppsalalaan 8, Utrecht, 3584, CT, The Netherlands

    Victor Guryev, Mark Verheul, Sebastiaan A A C van Heesch & Edwin Cuppen

  2. Max-Delbrück Center for Molecular Medicine,

    Kathrin Saar & Norbert Hubner

  3. Robert-Rössle-Strasse 10, D-13092, Berlin, 13125, Germany

    Kathrin Saar & Norbert Hubner

  4. Human and Molecular Genetics Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, 53226, Wisconsin, USA

    Tatjana Adamovic & Howard Jacob

  5. Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK

    Stuart Cook & Timothy Aitman

  6. Institute of Physiology, Academy of Sciences of the Czech Republic, 1 Videnska 1083, Prague, 14220, Czech Republic

    Michal Pravenec

  7. Institute of Biology and Medical Genetics, First Medical Faculty, Charles University, Albertov 4, Prague 2, 12800, Czech Republic

    Michal Pravenec

  8. Department of Genetics, Cell Biology and Anatomy, 985805 University of Nebraska Medical Center, Omaha, 68198-5805, Nebraska, USA

    James D Shull

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  1. Victor Guryev
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Contributions

V.G. generated data, performed bioinformatic analyses and wrote the manuscript. K.S., T. Adamovic, M.V., S.A.A.C.v.H. and S.C. performed microarray and quantitative PCR experiments. M.P., T. Aitman., H.J., J.D.S. and N.H. contributed material, data and discussion. E.C. supervised the project and wrote the manuscript.

Corresponding author

Correspondence to Edwin Cuppen.

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Guryev, V., Saar, K., Adamovic, T. et al. Distribution and functional impact of DNA copy number variation in the rat. Nat Genet 40, 538–545 (2008). https://doi.org/10.1038/ng.141

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