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Replicative mechanisms for CNV formation are error prone

Nature Genetics volume 45, pages 1319–1326 (2013)Cite this article

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Abstract

We investigated 67 breakpoint junctions of gene copy number gains in 31 unrelated subjects. We observed a strikingly high frequency of small deletions and insertions (29%) apparently originating from polymerase slippage events, in addition to frameshifts and point mutations in homonucleotide runs (13%), at or flanking the breakpoint junctions of complex copy number variants. These single-nucleotide variants were generated concomitantly with the de novo complex genomic rearrangement (CGR) event. Our findings implicate low-fidelity, error-prone DNA polymerase activity in synthesis associated with DNA repair mechanisms as the cause of local increase in point mutation burden associated with human CGR.

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Figure 1: Breakpoint junction mutation load in subjects BAB2626 and BAB2628.
Figure 2: Short and long template switches can be observed on either or both sides of CGR breakpoint junctions.
Figure 3: Breakpoint junction mutational load in subject BAB3027.
Figure 4: Representation of the types of mutations that can be observed at and flanking the breakpoint junctions of MECP2 duplications.

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Acknowledgements

We thank the families for their participation in the study. We gratefully acknowledge G. Ira for helpful discussions. This work was supported in part by US National Institute of Neurological Disorders and Stroke (NINDS) grants R01 NS058529 to J.R.L. and 5K08NS062711 to M.B.R, the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), a Young Investigator fellowship from the Science without Borders Program to C.M.B.C. and the National Human Genome Research Institute (NHGRI) grant 5U54HG006542. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS or the US National Institutes of Health.

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Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

    Claudia M B Carvalho, Davut Pehlivan, Ping Fang, Benjamin Alleva, Luis M Franco, John W Belmont, P J Hastings & James R Lupski

  2. Centro de Pesquisas René Rachou–FIOCRUZ, Belo Horizonte, Brazil

    Claudia M B Carvalho

  3. Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA

    Melissa B Ramocki, John W Belmont & James R Lupski

  4. Texas Children's Hospital, Houston, Texas, USA

    Melissa B Ramocki & James R Lupski

  5. Department of Biology, Cornell College, Mt. Vernon, Iowa, USA

    Benjamin Alleva

  6. Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

    Luis M Franco

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  1. Claudia M B Carvalho
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Contributions

C.M.B.C. conducted high-density aCGH, breakpoint sequencing and data analysis. D.P. assisted with high-density aCGH and breakpoint sequencing. C.M.B.C. and B.A. designed, performed and implemented microsatellite repeat experiments. M.B.R. coordinated clinical studies and subject recruitment. L.M.F. and J.W.B. conducted SNP genotyping and data analysis. P.F. conducted confirmatory CNV studies. P.J.H. and J.R.L. were involved in research design and data analyses. C.M.B.C., P.J.H. and J.R.L. prepared the manuscript.

Corresponding author

Correspondence to James R Lupski.

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Competing interests

J.R.L. is a paid consultant for Athena Diagnostics, holds stock ownership in 23andMe, Inc., and Ion Torrent Systems, Inc., and is a coinventor on multiple US and European patents related to molecular diagnostics. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular genetic testing offered in the Medical Genetics Laboratories (http://www.bcm.edu/geneticlabs/).

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Carvalho, C., Pehlivan, D., Ramocki, M. et al. Replicative mechanisms for CNV formation are error prone. Nat Genet 45, 1319–1326 (2013). https://doi.org/10.1038/ng.2768

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