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Sequence-based characterization of structural variation in the mouse genome

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.

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

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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.

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Authors and Affiliations

Authors

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.

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The authors declare no competing financial interests.

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

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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

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