Skip to main content

Thank you for visiting 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.

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


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.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. Lee, J.A., Carvalho, C.M. & Lupski, J.R. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131, 1235–1247 (2007).

    CAS  Article  Google Scholar 

  2. 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).

    CAS  Article  Google Scholar 

  3. Ohno, S. Evolution by Gene Duplication (Springer-Verlag, Berlin, 1970).

    Book  Google Scholar 

  4. Gilbert, W. Why genes in pieces? Nature 271, 501 (1978).

    CAS  Article  Google Scholar 

  5. Iafrate, A.J. et al. Detection of large-scale variation in the human genome. Nat. Genet. 36, 949–951 (2004).

    CAS  Article  Google Scholar 

  6. Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).

    CAS  Article  Google Scholar 

  7. Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 444–454 (2006).

    CAS  Article  Google Scholar 

  8. Feuk, L., Carson, A.R. & Scherer, S.W. Structural variation in the human genome. Nat. Rev. Genet. 7, 85–97 (2006).

    CAS  Article  Google Scholar 

  9. Flores, M. et al. Recurrent DNA inversion rearrangements in the human genome. Proc. Natl. Acad. Sci. USA 104, 6099–6106 (2007).

    CAS  Article  Google Scholar 

  10. Korbel, J.O. et al. Paired-end mapping reveals extensive structural variation in the human genome. Science 318, 420–426 (2007).

    CAS  Article  Google Scholar 

  11. Kidd, J.M. et al. Mapping and sequencing of structural variation from eight human genomes. Nature 453, 56–64 (2008).

    CAS  Article  Google Scholar 

  12. Perry, G.H. et al. The fine-scale and complex architecture of human copy-number variation. Am. J. Hum. Genet. 82, 685–695 (2008).

    CAS  Article  Google Scholar 

  13. Gu, W., Zhang, F. & Lupski, J.R. Mechanisms for human genomic rearrangements. PathoGenetics 1, 4 (2008).

    Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  15. Lieber, M.R. The mechanism of human nonhomologous DNA end joining. J. Biol. Chem. 283, 1–5 (2008).

    CAS  Article  Google Scholar 

  16. Kitamura, E., Blow, J.J. & Tanaka, T.U. Live-cell imaging reveals replication of individual replicons in eukaryotic replication factories. Cell 125, 1297–1308 (2006).

    CAS  Article  Google Scholar 

  17. Slack, A., Thornton, P.C., Magner, D.B., Rosenberg, S.M. & Hastings, P.J. On the mechanism of gene amplification induced under stress in Escherichia coli. PLoS Genet. 2, e48 (2006).

    Article  Google Scholar 

  18. Arlt, M.F. et al. Replication stress induces genome-wide copy number changes in human cells that resemble polymorphic and pathogenic variants. Am. J. Hum. Genet. 84, 339–350 (2009).

    CAS  Article  Google Scholar 

  19. Zhang, F., Carvalho, C.M.B. & Lupski, J.R. Complex human chromosomal and genomic rearrangements. Trends Genet. (in the press).

  20. Chen, J.M., Chuzhanova, N., Stenson, P.D., Ferec, C. & Cooper, D.N. Complex gene rearrangements caused by serial replication slippage. Hum. Mutat. 26, 125–134 (2005).

    CAS  Article  Google Scholar 

  21. Vissers, L.E. et al. Complex chromosome 17p rearrangements associated with low-copy repeats in two patients with congenital anomalies. Hum. Genet. 121, 697–709 (2007).

    CAS  Article  Google Scholar 

  22. Tuzun, E. et al. Fine-scale structural variation of the human genome. Nat. Genet. 37, 727–732 (2005).

    CAS  Article  Google Scholar 

  23. Bailey, J.A., Liu, G. & Eichler, E.E. An Alu transposition model for the origin and expansion of human segmental duplications. Am. J. Hum. Genet. 73, 823–834 (2003).

    CAS  Article  Google Scholar 

  24. Sen, S.K. et al. Human genomic deletions mediated by recombination between Alu elements. Am. J. Hum. Genet. 79, 41–53 (2006).

    CAS  Article  Google Scholar 

  25. Lupski, J.R. & Chance, P.F. Hereditary motor and sensory neuropathies involving altered dosage or mutation of PMP22: the CMT1A duplication and HNPP deletion. in Peripheral Neuropathy (eds. Dyck, P.J. and Thomas, P.K.). 1659–1680 (Elsevier Science, Philadelphia, 2005).

    Chapter  Google Scholar 

  26. Payen, C., Koszul, R., Dujon, B. & Fischer, G. Segmental duplications arise from Pol32-dependent repair of broken forks through two alternative replication-based mechanisms. PLoS Genet. 4, e1000175 (2008).

    Article  Google Scholar 

  27. Smith, C.E., Llorente, B. & Symington, L.S. Template switching during break-induced replication. Nature 447, 102–105 (2007).

    CAS  Article  Google Scholar 

  28. Lydeard, J.R., Jain, S., Yamaguchi, M. & Haber, J.E. Break-induced replication and telomerase-independent telomere maintenance require Pol32. Nature 448, 820–823 (2007).

    CAS  Article  Google Scholar 

  29. Long, M. Evolution of novel genes. Curr. Opin. Genet. Dev. 11, 673–680 (2001).

    CAS  Article  Google Scholar 

  30. van Rijk, A.A., de Jong, W.W. & Bloemendal, H. Exon shuffling mimicked in cell culture. Proc. Natl. Acad. Sci. USA 96, 8074–8079 (1999).

    CAS  Article  Google Scholar 

  31. Jones, J.M. et al. The mouse neurological mutant flailer expresses a novel hybrid gene derived by exon shuffling between Gnb5 and Myo5a. Hum. Mol. Genet. 9, 821–828 (2000).

    CAS  Article  Google Scholar 

  32. Bi, W. et al. Increased LIS1 expression affects human and mouse brain development. Nat. Genet. 41, 168–177 (2009).

    CAS  Article  Google Scholar 

  33. Carvalho, C.M. et al. Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching. Hum. Mol. Genet. 18, 2188–2203 (2009).

    CAS  Article  Google Scholar 

  34. Potocki, L. et al. Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am. J. Hum. Genet. 80, 633–649 (2007).

    CAS  Article  Google Scholar 

  35. Doco-Fenzy, M. et al. The clinical spectrum associated with a chromosome 17 short arm proximal duplication (dup 17p11.2) in three patients. Am. J. Med. Genet. A 146, 917–924 (2008).

    Article  Google Scholar 

Download references


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).

Author information

Authors and Affiliations



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.

Ethics declarations

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,

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–4 and Supplementary Figures 1–10 (PDF 868 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


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