Title |
Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair
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Published in |
Genome Research, April 2008
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DOI | 10.1101/gr.075903.107 |
Pubmed ID | |
Authors |
Marijke Bauters, Hilde Van Esch, Michael J. Friez, Odile Boespflug-Tanguy, Martin Zenker, Angela M. Vianna-Morgante, Carla Rosenberg, Jaakko Ignatius, Martine Raynaud, Karen Hollanders, Karen Govaerts, Kris Vandenreijt, Florence Niel, Pierre Blanc, Roger E. Stevenson, Jean-Pierre Fryns, Peter Marynen, Charles E. Schwartz, Guy Froyen |
Abstract |
Recurrent submicroscopic genomic copy number changes are the result of nonallelic homologous recombination (NAHR). Nonrecurrent aberrations, however, can result from different nonexclusive 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 eight of the 32 breakpoint regions coincide with low-copy repeats, 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 with 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 nonhomologous end joining as the mechanism. Breakpoint analysis in two other patients by inverse PCR and subsequent array comparative genomic hybridization 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 with strand invasion of the normal sister chromatid. Our results indicate that the mechanism by which copy number changes occur in regions with a complex genomic architecture can yield complex rearrangements. |
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