Non-recurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair

  1. Marijke Bauters1,
  2. Hilde Van Esch2,
  3. Michael J. Friez3,
  4. Odile Boespflug-Tanguy4,
  5. Martin Zenker5,
  6. Angela M. Vianna-Morgante6,
  7. Carla Rosenberg6,
  8. Jaakko Ignatius7,
  9. Martine Raynaud8,
  10. Karen Hollanders1,
  11. Karen Govaerts1,
  12. Kris Vandenreijt1,
  13. Florence Niel4,
  14. Pierre Blanc4,
  15. Roger E. Stevenson3,
  16. Jean-Pierre Fryns2,
  17. Peter Marynen1,
  18. Charles E. Schwartz3, and
  19. Guy Froyen1,9
  1. 1 VIB, K.U.Leuven;
  2. 2 University Hospital Gasthuisberg;
  3. 3 JC Self Research Institute of Human Genetics;
  4. 4 Centre Hospitalier Universitaire, Clermont-FD;
  5. 5 Institute of Human Genetics Erlangen;
  6. 6 University of Sao Paulo;
  7. 7 Oulu University Hospital;
  8. 8 Centre Hospitalier Universitaire de Tours

Abstract

Recurrent submicroscopic genomic copy number changes are the result of non-allelic homologous recombination (NAHR). Non-recurrent aberrations however, can result from different non-exclusive recombination-repair mechanisms. We previously described small microduplications at Xq28 containing MECP2, in four male patients with a severe neurological phenotype. Here, we report on the fine-mapping and breakpoint analysis of 16 unique microduplications. The size of the overlapping copy number changes varies between 0.3 and 2.3 Mb and FISH analysis on three patients demonstrated a tandem orientation. Although 8 of the 32 breakpoint regions coincide with low-copy repeats (LCRs), none of the duplications are the result of NAHR. Bioinformatics analysis of the breakpoint regions demonstrated a 2.5-fold higher frequency of Alu interspersed repeats as compared to control regions, as well as a very high GC content (53%). Unexpectedly, we obtained the junction in only one patient by long-range PCR, which revealed non-homologous end joining (NHEJ) as the mechanism. Breakpoint analysis in two other patients by inverse PCR and subsequent array-CGH analysis, demonstrated the presence of a second duplicated region more telomeric at Xq28, of which one copy was inserted in between the duplicated MECP2 regions. These data suggest a two-step mechanism in which part of Xq28 is first inserted near the MECP2 locus, followed by breakage-induced replication (BIR) with strand invasion of the normal sister chromatid. Our results demonstrate that the mechanism by which copy number changes occur in regions with a complex genomic architecture, can yield complex rearrangements.

Footnotes

    • Received December 21, 2007.
    • Accepted March 17, 2008.

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  1. Published in Advance April 2, 2008, doi: 10.1101/gr.075903.107 Genome Res. gr.075903.107 Copyright © 2008, Cold Spring Harbor Laboratory Press

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