title: Analysis of crossover breakpoints yields new insights into the nature of the gene conversion events associated with large NF1 deletions mediated by nonallelic homologous recombination.
abstract: Large NF1 deletions are mediated by nonallelic homologous recombination (NAHR). An in-depth analysis of gene conversion operating in the breakpoint-flanking regions of large NF1 deletions was performed to investigate whether the rate of discontinuous gene conversion during NAHR with crossover is increased, as has been previously noted in NAHR-mediated rearrangements. All 20 germline type-1 NF1 deletions analyzed were mediated by NAHR associated with continuous gene conversion within the breakpoint-flanking regions. Continuous gene conversion was also observed in 31/32 type-2 NF1 deletions investigated. In contrast to the meiotic type-1 NF1 deletions, type-2 NF1 deletions are predominantly of post-zygotic origin. Our findings therefore imply that the mitotic as well as the meiotic NAHR intermediates of large NF1 deletions are processed by long-patch mismatch repair (MMR), thereby ensuring gene conversion tract continuity instead of the discontinuous gene conversion that is characteristic of short-patch repair. However, the single type-2 NF1 deletion not exhibiting continuous gene conversion was processed without MMR, yielding two different deletion-bearing chromosomes, which were distinguishable in terms of their breakpoint positions. Our findings indicate that MMR failure during NAHR, followed by post-meiotic/mitotic segregation, has the potential to give rise to somatic mosaicism in human genomic rearrangements by generating breakpoint heterogeneity.
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Bengesser
authors.forename: Julia
authors.initials: J
authors.lastname: Vogt
authors.forename: Tanja
authors.initials: T
authors.lastname: Mussotter
authors.forename: Victor-Felix
authors.initials: VF
authors.lastname: Mautner
authors.forename: Ludwine
authors.initials: L
authors.lastname: Messiaen
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.forename: Hildegard
authors.initials: H
authors.lastname: Kehrer-Sawatzki
mesh_terms: D056905:Chromosome Breakpoints; D002886:Chromosomes, Human, Pair 17; D053843:DNA Mismatch Repair; D005785:Gene Conversion; D016514:Genes, Neurofibromatosis 1; D018095:Germ-Line Mutation; D059765:Homologous Recombination; D006801:Humans; D008540:Meiosis; D008938:Mitosis; D009030:Mosaicism; D009456:Neurofibromatosis 1 / Q000235:genetics*; D025542:Neurofibromin 1 / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: D025542:Neurofibromin 1
keywords: NF1; gene conversion; genomic disorder; microdeletion; neurofibromatosis type 1