Intrachromosomal mitotic non-allelic homologous recombination is the major molecular mechanism underlying type-2 NF1 deletions

Angelika C. Roehl (1) , Julia Vogt (1) , Tanja Mussotter (1) , Antje Zickler (1) , Helene Spoeri (1) , Josef Hoegel (1) , Nadia Chuzhanova (2) , Katharina Wimmer (3) , Lan Kluwe (4) , Victor Mautner (5) , David N. Cooper (6) , Hildegard Kehrer-Sawatzki (1)

1 Human Genetics
2 Nottingham Trent University
3 Medical Genetics Section, Department of Medical Genetics, Molecular and Clinical Pharmacology
4 Maxillofacial Surgery
5 Maxillofacial Surgery
6 Institute of Medical Genetics, College of Medicine

Non-allelic 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. Since 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.

Mots clés: Life Sciences

Angelika C. Roehl, Julia Vogt, Tanja Mussotter, Antje Zickler, Helene Spoeri, et al.. Intrachromosomal mitotic non-allelic homologous recombination is the major molecular mechanism underlying type-2 NF1 deletions. Human Mutation, 2010, 31 (10), pp.1163. ⟨10.1002/humu.21340⟩. ⟨hal-00599473⟩