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The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans

Nature Genetics volume 41, pages 849–853 (2009)Cite this article

Abstract

We recently proposed a DNA replication–based mechanism of fork stalling and template switching (FoSTeS) to explain the complex genomic rearrangements associated with a dysmyelinating central nervous system disorder in humans1. The FoSTeS mechanism has been further generalized and molecular mechanistic details have been provided in the microhomology-mediated break-induced replication (MMBIR) model that may underlie many structural variations in genomes from all domains of life2. Here we provide evidence that human genomic rearrangements ranging in size from several megabases to a few hundred base pairs can be generated by FoSTeS/MMBIR. Furthermore, we show that FoSTeS/MMBIR-mediated rearrangements can occur mitotically and can result in duplication or triplication of individual genes or even rearrangements of single exons. The FoSTeS/MMBIR mechanism can explain both the gene duplication-divergence hypothesis3 and exon shuffling4, suggesting an important role in both genome and single-gene evolution.

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Figure 1: Nonrecurrent genomic duplicati1ons in 17p.
Figure 2: Complex 17p11.2 rearrangements revealed by oligonucleotide aCGH and sequence analysis and the underlying FoSTeS/MMBIR mechanism.
Figure 3: Nonrecurrent rearrangements involving the PMP22 gene were confirmed by oligonucleotide aCGH.
Figure 4: FoSTeS/MMBIR-mediated sequence complexity at the deletion breakpoint of two affected subjects (A15 and her sibling) and the mosaicism in the unaffected mother.

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Acknowledgements

We thank all participating subjects and families for their kind cooperation in the study. We also thank W. Bi, W. Gu, J.A. Lee and P. Stankiewicz for their critical reviews and C.M.B. Carvalho and M.A. Withers for their assistance. This work was supported in part by the Charcot Marie Tooth Association and the National Institute of Neurological Disorders and Stroke (NINDS, NIH).

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Authors and Affiliations

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

    Feng Zhang, Mehrdad Khajavi & James R Lupski

  2. Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri, USA

    Anne M Connolly

  3. Athena Diagnostics, Inc., Worcester, Massachusetts, USA

    Charles F Towne & Sat Dev Batish

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

    James R Lupski

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

    James R Lupski

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Contributions

F.Z., M.K. and J.R.L. designed and interpreted the experiments; F.Z. and M.K. performed the experiments. A.M.C. provided clinical data; A.M.C., C.F.T. and S.D.B. provided subject samples; C.F.T. and S.D.B. provided MLPA data; F.Z. and J.R.L. wrote the manuscript.

Corresponding author

Correspondence to James R Lupski.

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Competing interests

J.R.L. is a consultant for Athena Diagnostics, 23andMe and Ion Torrent Systems Inc., and holds multiple US and European patents for DNA diagnostics. Furthermore, the Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular diagnostic testing (MGL, http://www.bcm.edu/geneticlabs/).

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Zhang, F., Khajavi, M., Connolly, A. et al. The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. Nat Genet 41, 849–853 (2009). https://doi.org/10.1038/ng.399

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