Intrachromosomal Mitotic Nonallelic Homologous Recombination Is the Major Molecular Mechanism Underlying Type-2 NF1 Deletions

Institute of Human Genetics, University of Ulm, Ulm, Germany.
Human Mutation (Impact Factor: 5.14). 10/2010; 31(10):1163-73. DOI: 10.1002/humu.21340
Source: PubMed


Nonallelic homologous recombination (NAHR) is responsible for the recurrent rearrangements that give rise to genomic disorders. Although meiotic NAHR has been investigated in multiple contexts, much less is known about mitotic NAHR despite its importance for tumorigenesis. Because type-2 NF1 microdeletions frequently result from mitotic NAHR, they represent a good model in which to investigate the features of mitotic NAHR. We have used microsatellite analysis and SNP arrays to distinguish between the various alternative recombinational possibilities, thereby ascertaining that 17 of 18 type-2 NF1 deletions, with breakpoints in the SUZ12 gene and its highly homologous pseudogene, originated via intrachromosomal recombination. This high proportion of intrachromosomal NAHR causing somatic type-2 NF1 deletions contrasts with the interchromosomal origin of germline type-1 NF1 microdeletions, whose breakpoints are located within the NF1-REPs (low-copy repeats located adjacent to the SUZ12 sequences). Further, meiotic NAHR causing type-1 NF1 deletions occurs within recombination hotspots characterized by high GC-content and DNA duplex stability, whereas the type-2 breakpoints associated with the mitotic NAHR events investigated here do not cluster within hotspots and are located within regions of significantly lower GC-content and DNA stability. Our findings therefore point to fundamental mechanistic differences between the determinants of mitotic and meiotic NAHR.

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    • "In ectopic recombination, double-strand breaks are repaired using a ''wrong'' (i.e., ectopic, or non-allelic) template sequence— typically another locus with a high degree of sequence similarity to the break site. Such ectopic genomic regions can be on (1) sister chromatids, (2) non-sister chromatids/ homologous chromosomes, or (3) the same chromatid as the break site (Devos et al. 2002; Roehl et al. 2010). If double-strand breaks occur within the LTR portions of LTR retrotransposon sequences, ectopic recombination can produce deletions that remove the internal transposon sequence and the equivalent of one of the two LTR sequences. "
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    • "They encompass 1.2-Mb and are characterized by breakpoints located within the SUZ12 gene (MIM #606245) and its pseudogene SUZ12P. Type-2 NF1 deletions are frequently of postzygotic origin as concluded from somatic mosaicism with normal cells in affected patients [Kehrer-Sawatzki et al., 2004; Roehl et al., 2010, 2012; Vogt et al., 2012]. By contrast, type-1 and type-3 NF1 deletions are mostly germline deletions present in all cells of the corresponding patients [Messiaen et al., 2011; Zickler et al., 2012]. "
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    • "To further investigate gene conversion during mitotic NAHR, we analyzed the breakpoint regions of 32 type-2 NF1 deletions, a specific type of NF1 deletion known to be predominantly of post-zygotic origin [Roehl et al., 2010, 2012; Vogt et al., 2012]. None of the 32 type-2 NF1 deletions investigated by us in the present study exhibited discontinuous gene conversion in the breakpointflanking regions. "
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