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Intrachromosomal mitotic nonallelic homologous recombination is the major molecular mechanism underlying type‐2 NF1 deletions
Author(s) -
Roehl Angelika C.,
Vogt Julia,
Mussotter Tanja,
Zickler Antje N.,
Spöti Helene,
Högel Josef,
Chuzhanova Nadia A.,
Wimmer Katharina,
Kluwe Lan,
Mautner VictorFelix,
Cooper David N.,
KehrerSawatzki Hildegard
Publication year - 2010
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21340
Subject(s) - non allelic homologous recombination , biology , mitotic crossover , breakpoint , genetics , homologous recombination , homologous chromosome , meiosis , gene conversion , pseudogene , genetic recombination , recombination , dna , gene , chromosome , genome
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. Hum Mutat 31:1163–1173, 2010. © 2010 Wiley‐Liss, Inc.