title: Fine mapping of meiotic NAHR-associated crossovers causing large NF1 deletions.
abstract: Large deletions encompassing the NF1 gene and its flanking regions belong to the group of genomic disorders caused by copy number changes that are mediated by the local genomic architecture. Although nonallelic homologous recombination (NAHR) is known to be a major mutational mechanism underlying such genomic copy number changes, the sequence determinants of NAHR location and frequency are still poorly understood since few high-resolution mapping studies of NAHR hotspots have been performed to date. Here, we have characterized two NAHR hotspots, PRS1 and PRS2, separated by 20 kb and located within the low-copy repeats NF1-REPa and NF1-REPc, which flank the human NF1 gene region. High-resolution mapping of the crossover sites identified in 78 type 1 NF1 deletions mediated by NAHR indicated that PRS2 is a much stronger NAHR hotspot than PRS1 since 80% of these deletions exhibited crossovers within PRS2, whereas 20% had crossovers within PRS1. The identification of the most common strand exchange regions of these 78 deletions served to demarcate the cores of the PRS1 and PRS2 hotspots encompassing 1026 and 1976 bp, respectively. Several sequence features were identified that may influence hotspot intensity and direct the positional preference of NAHR to the hotspot cores. These features include regions of perfect sequence identity encompassing 700 bp at the hotspot core, the presence of PRDM9 binding sites perfectly matching the consensus motif for the most common PRDM9 variant, specific pre-existing patterns of histone modification and open chromatin conformations that are likely to facilitate PRDM9 binding.
authors.affiliation: Institute of Human Genetics, University of Ulm, 89081 Ulm, Germany.
authors.forename: Morten
authors.initials: M
authors.lastname: Hillmer
authors.affiliation: Institute of Human Genetics, University of Ulm, 89081 Ulm, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Wagner
authors.affiliation: Institute of Human Genetics, University of Ulm, 89081 Ulm, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Summerer
authors.affiliation: Institute of Human Genetics, University of Ulm, 89081 Ulm, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Daiber
authors.affiliation: Department of Neurology, University Hospital Hamburg Eppendorf, 20246 Hamburg, Germany.
authors.forename: Victor-Felix
authors.initials: VF
authors.lastname: Mautner
authors.affiliation: Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35242, USA and.
authors.forename: Ludwine
authors.initials: L
authors.lastname: Messiaen
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.affiliation: Institute of Human Genetics, University of Ulm, 89081 Ulm, Germany, hildegard.kehrer-sawatzki@uni-ulm.de.
authors.forename: Hildegard
authors.initials: H
authors.lastname: Kehrer-Sawatzki
mesh_terms: D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17 / Q000737:chemistry*; D003434:Crossing Over, Genetic; D056915:DNA Copy Number Variations; D017353:Gene Deletion; D015870:Gene Expression; D015894:Genome, Human; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D059765:Homologous Recombination; D006801:Humans; D008540:Meiosis; D025542:Neurofibromin 1 / Q000172:deficiency / Q000235:genetics*; D011485:Protein Binding; D056916:Segmental Duplications, Genomic
chemical_list: D002843:Chromatin; D006657:Histones; D025542:Neurofibromin 1; D011495:Histone-Lysine N-Methyltransferase; C544431:PRDM9 protein, human