Characterization of the nonallelic homologous recombination hotspot PRS3 associated with type-3 NF1 deletions

Zickler, Antje M., Hampp, Stephanie, Messiaen, Ludwine, Bengesser, Kathrin, Mussotter, Tanja, Roehl, Angelika C., Wimmer, Katharina, Mautner, Victor-Felix, Kluwe, Lan, Upadhyaya, Meena, Pasmant, Eric, Chuzhanova, Nadia, Kestler, Hans A., Högel, Josef, Legius, Eric, Claes, Kathleen, Cooper, David Neil ORCID: https://orcid.org/0000-0002-8943-8484 and Kehrer-Sawatzki, Hildegard 2012. Characterization of the nonallelic homologous recombination hotspot PRS3 associated with type-3 NF1 deletions. Human Mutation 33 (2) , pp. 372-383. 10.1002/humu.21644

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Abstract

Nonallelic homologous recombination (NAHR) is the major mechanism underlying recurrent genomic rearrangements, including the large deletions at 17q11.2 that cause neurofibromatosis type 1 (NF1). Here, we identify a novel NAHR hotspot, responsible for type-3 NF1 deletions that span 1.0 Mb. Breakpoint clustering within this 1-kb hotspot, termed PRS3, was noted in 10 of 11 known type-3 NF1 deletions. PRS3 is located within the LRRC37B pseudogene of the NF1-REPb and NF1-REPc low-copy repeats. In contrast to other previously characterized NAHR hotspots, PRS3 has not developed on a preexisting allelic homologous recombination hotspot. Furthermore, the variation pattern of PRS3 and its flanking regions is unusual since only NF1-REPc (and not NF1-REPb) is characterized by a high single nucleotide polymorphism (SNP) frequency, suggestive of unidirectional sequence transfer via nonallelic homologous gene conversion (NAHGC). By contrast, the previously described intense NAHR hotspots within the CMT1A-REPs, and the PRS1 and PRS2 hotspots underlying type-1 NF1 deletions, experience frequent bidirectional sequence transfer. PRS3 within NF1-REPc was also found to be involved in NAHGC with the LRRC37B gene, the progenitor locus of the LRRC37B-P duplicons, as indicated by the presence of shared SNPs between these loci. PRS3 therefore represents a weak (and probably evolutionarily rather young) NAHR hotspot with unique properties.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	Q Science > QH Natural history > QH426 Genetics
Uncontrolled Keywords:	Nonallelic homologous recombination hotspot ; Neurofibromatosis type 1 ; NF1 ; Gene conversion
Publisher:	Wiley Blackwell
ISSN:	1059-7794
Last Modified:	19 Oct 2022 09:59
URI:	https://orca.cardiff.ac.uk/id/eprint/22852

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