title: Frequency of nonallelic homologous recombination is correlated with length of homology: evidence that ectopic synapsis precedes ectopic crossing-over.
abstract: Genomic disorders constitute a class of diseases that are associated with DNA rearrangements resulting from region-specific genome instability, that is, genome architecture incites genome instability. Nonallelic homologous recombination (NAHR) or crossing-over in meiosis between sequences that are not in allelic positions (i.e., paralogous sequences) can result in recurrent deletions or duplications causing genomic disorders. Previous studies of NAHR have focused on description of the phenomenon, but it remains unclear how NAHR occurs during meiosis and what factors determine its frequency. Here we assembled two patient cohorts with reciprocal genomic disorders; deletion associated Smith-Magenis syndrome and duplication associated Potocki-Lupski syndrome. By assessing the full spectrum of rearrangement types from the two cohorts, we find that complex rearrangements (those with more than one breakpoint) are more prevalent in copy-number gains (17.7%) than in copy-number losses (2.3%); an observation that supports a role for replicative mechanisms in complex rearrangement formation. Interestingly, for NAHR-mediated recurrent rearrangements, we show that crossover frequency is positively associated with the flanking low-copy repeat (LCR) length and inversely influenced by the inter-LCR distance. To explain this, we propose that the probability of ectopic chromosome synapsis increases with increased LCR length, and that ectopic synapsis is a necessary precursor to ectopic crossing-over.
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Pengfei
authors: P
authors: Liu
authors: Melanie
authors: M
authors: Lacaria
authors: Feng
authors: F
authors: Zhang
authors: Marjorie
authors: M
authors: Withers
authors: P J
authors: PJ
authors: Hastings
authors: James R
authors: JR
authors: Lupski
mesh_terms: D000015:Abnormalities, Multiple; D000483:Alleles; D001483:Base Sequence; D025063:Chromosome Disorders; D058674:Chromosome Duplication; D023902:Chromosome Pairing; D002886:Chromosomes, Human, Pair 17 / Q000648:ultrastructure; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D003434:Crossing Over, Genetic; D017353:Gene Deletion; D018628:Gene Dosage; D059765:Homologous Recombination; D006801:Humans; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000235:genetics; D011995:Recombination, Genetic; D058496:Smith-Magenis Syndrome / Q000235:genetics; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics
chemical_list: D009841:Oligonucleotides; C431552:RAI1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors