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Segmental copy number variation shapes tissue transcriptomes

Nature Genetics volume 41, pages 424–429 (2009)Cite this article

Abstract

Copy number variation (CNV) is a key source of genetic diversity, but a comprehensive understanding of its phenotypic effect is only beginning to emerge. We have generated a CNV map in wild mice and classical inbred strains. Genome-wide expression data from six major organs show not only that expression of genes within CNVs tend to correlate with copy number changes, but also that CNVs influence the expression of genes in their vicinity, an effect that extends up to half a megabase. Genes within CNVs show lower expression and more specific spatial expression patterns than genes mapping elsewhere. Our analyses reveal differential constraint on copy number changes of genes expressed in different tissues. Dosage alterations of brain-expressed genes are less frequent than those of other genes and are buffered by tighter transcriptional regulation. Our study provides initial evidence that CNVs shape tissue transcriptomes on a global scale.

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Figure 1: Expression of genes within CNVs, in neighboring regions and elsewhere in the genome.
Figure 2: Expression variability of CNV and non-CNV transcripts between and within strains.
Figure 3: Spatial expression patterns of CNV genes.

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Acknowledgements

We thank A. Paillusson, O. Hagenbüchle and K. Harshman from the Lausanne DNA Array Facility for technical help; F. Bonhomme, P. Boursot, J. Gilliéron, S. Maret, A. Orth and M. Tafti for reagents; and S. Deutsch and J. Goudet for suggestions. We are grateful to R.W. Williams for sharing expression data and to the Montpellier wild mice genetic repository and the Museum of Natural History of Geneva for mice and tissue samples. This work was supported by grants from the Jérôme Lejeune Foundation, the Désirée and Niels Yde Foundation, the Novartis Foundation, the Swiss National Science Foundation and the European Commission anEUploidy Integrated Project (grant 037627) to A.R.; by grant NIH R01 GM073822 (PI J. Borevitz) to S.Z.; as well as grants from the European Commission (STREP, PKB140404), EMBO Young Investigator Program and Swiss National Science Foundation to H.K.

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Author notes

  1. Charlotte N Henrichsen, Nicolas Vinckenbosch and Sebastian Zöllner: These authors contributed equally to this work.

Authors and Affiliations

  1. The Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

    Charlotte N Henrichsen, Nicolas Vinckenbosch, Evelyne Chaignat, Sylvain Pradervand, Frédéric Schütz, Henrik Kaessmann & Alexandre Reymond

  2. Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA

    Sebastian Zöllner

  3. Department of Psychiatry, University of Michigan, Ann Arbor, Michigan, USA

    Sebastian Zöllner

  4. Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland

    Frédéric Schütz

  5. Department of Mammalogy and Ornithology, Natural History Museum, Geneva, Switzerland

    Manuel Ruedi

Authors
  1. Charlotte N Henrichsen
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Contributions

A.R. and H.K. designed and organized the study. Financial support for the generation of the data was obtained by A.R.; C.N.H., E.C. and M.R. prepared the necessary materials and produced the data; and C.N.H., N.V., S.P. and F.S. conducted the statistical analyses guided by H.K. and A.R. The time-dependent hidden Markov method was designed by S.Z. with contributions from N.V. The manuscript was co-written by H.K. and A.R. with contributions from C.N.H., N.V. and S.Z.

Corresponding authors

Correspondence to Henrik Kaessmann or Alexandre Reymond.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Methods, Supplementary Figures 1–7 and Supplementary Tables 1–5 (PDF 6785 kb)

Supplementary Table 2

Coordinates and aCGH log2 signals of predicted CNVs (XLS 12027 kb)

Supplementary Table 4

Coordinates and validation of predicted CNVs assessed on the high-resolution custom-array (XLS 1534 kb)

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Henrichsen, C., Vinckenbosch, N., Zöllner, S. et al. Segmental copy number variation shapes tissue transcriptomes. Nat Genet 41, 424–429 (2009). https://doi.org/10.1038/ng.345

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