Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Sequence-based characterization of structural variation in the mouse genome

Nature volume 477, pages 326–329 (2011)Cite this article

Subjects

Abstract

Structural variation is widespread in mammalian genomes1,2 and is an important cause of disease3, but just how abundant and important structural variants (SVs) are in shaping phenotypic variation remains unclear4,5. Without knowing how many SVs there are, and how they arise, it is difficult to discover what they do. Combining experimental with automated analyses, we identified 711,920 SVs at 281,243 sites in the genomes of thirteen classical and four wild-derived inbred mouse strains. The majority of SVs are less than 1 kilobase in size and 98% are deletions or insertions. The breakpoints of 160,000 SVs were mapped to base pair resolution, allowing us to infer that insertion of retrotransposons causes more than half of SVs. Yet, despite their prevalence, SVs are less likely than other sequence variants to cause gene expression or quantitative phenotypic variation. We identified 24 SVs that disrupt coding exons, acting as rare variants of large effect on gene function. One-third of the genes so affected have immunological functions.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Impact of SVs on gene expression.
Figure 2: Experimental analysis of SVs.

Similar content being viewed by others

References

  1. Mills, R. E. et al. Mapping copy number variation by population-scale genome sequencing. Nature 470, 59–65 (2011)

    Article  CAS  Google Scholar 

  2. Quinlan, A. R. et al. Genome-wide mapping and assembly of structural variant breakpoints in the mouse genome. Genome Res. 20, 623–635 (2010)

    Article  CAS  Google Scholar 

  3. Zhang, F., Gu, W., Hurles, M. E. & Lupski, J. R. Copy number variation in human health, disease, and evolution. Annu. Rev. Genomics Hum. Genet. 10, 451–481 (2009)

    Article  CAS  Google Scholar 

  4. Conrad, D. F. et al. Origins and functional impact of copy number variation in the human genome. Nature 464, 704–712 (2010)

    Article  CAS  Google Scholar 

  5. Stranger, B. E. et al. Population genomics of human gene expression. Nature Genet. 39, 1217–1224 (2007)

    Article  CAS  Google Scholar 

  6. Agam, A. et al. Elusive copy number variation in the mouse genome. PLoS ONE 5, e12839 (2010)

    Article  ADS  Google Scholar 

  7. Cahan, P., Li, Y., Izumi, M. & Graubert, T. A. The impact of copy number variation on local gene expression in mouse hematopoietic stem and progenitor cells. Nature Genet. 41, 430–437 (2009)

    Article  CAS  Google Scholar 

  8. Henrichsen, C. N. et al. Segmental copy number variation shapes tissue transcriptomes. Nature Genet. 41, 424–429 (2009)

    Article  CAS  Google Scholar 

  9. Schadt, E. E. et al. An integrative genomics approach to infer causal associations between gene expression and disease. Nature Genet. 37, 710–717 (2005)

    Article  CAS  Google Scholar 

  10. Zhang, F. et al. The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. Nature Genet. 41, 849–853 (2009)

    Article  CAS  Google Scholar 

  11. Ma, J. L., Kim, E. M., Haber, J. E. & Lee, S. E. Yeast Mre11 and Rad1 proteins define a Ku-independent mechanism to repair double-strand breaks lacking overlapping end sequences. Mol. Cell. Biol. 23, 8820–8828 (2003)

    Article  CAS  Google Scholar 

  12. Stankiewicz, P. & Lupski, J. R. Structural variation in the human genome and its role in disease. Annu. Rev. Med. 61, 437–455 (2010)

    Article  CAS  Google Scholar 

  13. Stankiewicz, P. & Lupski, J. R. Genome architecture, rearrangements and genomic disorders. Trends Genet. 18, 74–82 (2002)

    Article  CAS  Google Scholar 

  14. Hastings, P. J., Ira, G. & Lupski, J. R. A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet. 5, e1000327 (2009)

    Article  CAS  Google Scholar 

  15. Huang, G. J. et al. High resolution mapping of expression QTLs in heterogeneous stock mice in multiple tissues. Genome Res. 19, 1133–1140 (2009)

    Article  CAS  Google Scholar 

  16. Yalcin, B., Flint, J. & Mott, R. Using progenitor strain information to identify quantitative trait nucleotides in outbred mice. Genetics 171, 673–681 (2005)

    Article  CAS  Google Scholar 

  17. Valdar, W. et al. Genome-wide genetic association of complex traits in heterogeneous stock mice. Nature Genet. 38, 879–887 (2006)

    Article  CAS  Google Scholar 

  18. Keane, T. M. et al. Mouse genomic variation and its effect on phenotypes and gene regulation. Nature doi:10.1038/nature10413 (this issue).

  19. Yalcin, B. et al. Commercially available outbred mice for genome-wide association studies. PLoS Genet. 6, e1001085 (2010)

    Article  Google Scholar 

  20. Best, S., Le Tissier, P., Towers, G. & Stoye, J. P. Positional cloning of the mouse retrovirus restriction gene Fv1 . Nature 382, 826–829 (1996)

    Article  ADS  CAS  Google Scholar 

  21. Boyden, L. M. et al. Skint1, the prototype of a newly identified immunoglobulin superfamily gene cluster, positively selects epidermal γδ T cells. Nature Genet. 40, 656–662 (2008)

    Article  CAS  Google Scholar 

  22. Nelson, T. M., Munger, S. D. & Boughter, J. D., Jr Haplotypes at the Tas2r locus on distal chromosome 6 vary with quinine taste sensitivity in inbred mice. BMC Genet. 6, 32 (2005)

    Article  Google Scholar 

  23. Persson, K., Heby, O. & Berger, F. G. The functional intronless S-adenosylmethionine decarboxylase gene of the mouse (Amd-2) is linked to the ornithine decarboxylase gene (Odc) on chromosome 12 and is present in distantly related species of the genus Mus . Mamm. Genome 10, 784–788 (1999)

    Article  CAS  Google Scholar 

  24. Wu, B. et al. Mutations in sterol O-acyltransferase 1 (Soat1) result in hair interior defects in AKR/J mice. J. Invest. Dermatol. 130, 2666–2668 (2010)

    Article  CAS  Google Scholar 

  25. Tareen, S. U., Sawyer, S. L., Malik, H. S. & Emerman, M. An expanded clade of rodent Trim5 genes. Virology 385, 473–483 (2009)

    Article  CAS  Google Scholar 

  26. Taylor, K. et al. Defensin-related peptide 1 (Defr1) is allelic to Defb8 and chemoattracts immature DC and CD4+ T cells independently of CCR6. Eur. J. Immunol. 39, 1353–1360 (2009)

    Article  CAS  Google Scholar 

  27. Ye, K., Schulz, M. H., Long, Q., Apweiler, R. & Ning, Z. Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads. Bioinformatics 25, 2865–2871 (2009)

    Article  CAS  Google Scholar 

  28. Chen, K. et al. BreakDancer: an algorithm for high-resolution mapping of genomic structural variation. Nature Methods 6, 677–681 (2009)

    Article  CAS  Google Scholar 

  29. Simpson, J. T., McIntyre, R. E., Adams, D. J. & Durbin, R. Copy number variant detection in inbred strains from short read sequence data. Bioinformatics 26, 565–567 (2010)

    Article  CAS  Google Scholar 

  30. Manske, H. M. & Kwiatkowski, D. P. LookSeq: a browser-based viewer for deep sequencing data. Genome Res. 19, 2125–2132 (2009)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Whitley, G. Durrant, A. M. Hammond, D. J. Fabrigar, L. Chen, M. Johannesson, E. Cong and G. Blázquez for helping B.Y. with various laboratory-based work. We also thank C. P. Ponting for comments on the manuscript. This project was supported by The Medical Research Council, UK, and the Wellcome Trust. D.J.A. is supported by Cancer Research UK.

Author information

Author notes

  1. Binnaz Yalcin, Kim Wong, Avigail Agam and Martin Goodson: These authors contributed equally to this work.

Authors and Affiliations

  1. The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK ,

    Binnaz Yalcin, Avigail Agam, Martin Goodson, Xiangchao Gan, Leo Goodstadt, Jérôme Nicod, Amarjit Bhomra, Polinka Hernandez-Pliego, Helen Whitley, James Cleak, Rebekah Dutton, Deborah Janowitz, Richard Mott & Jonathan Flint

  2. The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK ,

    Kim Wong, Thomas M. Keane & David J. Adams

  3. Department of Physiology, MRC Functional Genomics Unit, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK,

    Avigail Agam & Christoffer Nellåker

  4. Department of Psychiatry and Psychotherapy, Ernst-Moritz-Arndt-Universität Greifswald Klinikum der Hansestadt Stralsund, Rostocker Chaussee 70, 18437 Stralsund, Germany,

    Deborah Janowitz

Authors
  1. Binnaz Yalcin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kim Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Avigail Agam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martin Goodson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas M. Keane
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiangchao Gan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christoffer Nellåker
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Leo Goodstadt
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jérôme Nicod
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Amarjit Bhomra
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Polinka Hernandez-Pliego
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Helen Whitley
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. James Cleak
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Rebekah Dutton
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Deborah Janowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Richard Mott
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. David J. Adams
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Jonathan Flint
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D.J.A. and J.F. conceived the study and directed the research. J.F. wrote the core of the paper. K.W. and T.K. performed the genome-wide SV discovery and local assembly for SV breakpoint resolution. K.W. carried out the sensitivity and specificity analyses. K.W. and B.Y. liaised regularly to integrate experimental work into genome-wide SV discovery pipeline. This resulted in a highly accurate map of SV across the mouse genome, essential to downstream analyses. A.B., P.H.P., H.W., J.C., R.D. and D.J. carried out experimental work, led by B.Y. A.B. and B.Y. analysed Sanger-based sequencing data, resolved SV breakpoints at nucleotide-level resolution and inferred mechanism of SV formation. M.G. performed the genome-wide SV mechanism of formation and outgroup analysis, with contributions from A.A. and B.Y.; J.F. and A.A. analysed functional impact of SVs on expression and phenotypes. C.N., L.G., J.N., A.A. and R.M. carried out additional analyses. B.Y. characterized function of individual SV examples.

Corresponding authors

Correspondence to David J. Adams or Jonathan Flint.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-2 with legends, Supplementary Methods, Supplementary References and Supplementary Tables 1-5. (PDF 722 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yalcin, B., Wong, K., Agam, A. et al. Sequence-based characterization of structural variation in the mouse genome. Nature 477, 326–329 (2011). https://doi.org/10.1038/nature10432

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10432

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing