title: Replicative mechanisms of CNV formation preferentially occur as intrachromosomal events: evidence from Potocki-Lupski duplication syndrome.
abstract: Copy number variations (CNVs) in the human genome contribute significantly to disease. De novo CNV mutations arise via genomic rearrangements, which can occur in 'trans', i.e. via interchromosomal events, or in 'cis', i.e. via intrachromosomal events. However, what molecular mechanisms occur between chromosomes versus between or within chromatids has not been systematically investigated. We hypothesized that distinct CNV mutational mechanisms, based on their intrinsic properties, may occur in a biased intrachromosomal versus interchromosomal manner. Here, we studied 62 genomic duplications observed in association with sporadic Potocki-Lupski syndrome (PTLS), in which multiple mutational mechanisms appear to be operative. Intriguingly, more interchromosomal than intrachromosomal events were identified in recurrent PTLS duplications mediated by non-allelic homologous recombination, whereas the reciprocal distribution was found for replicative mechanisms and non-homologous end-joining, likely reflecting the differences in spacial proximity of homologous chromosomes during different mutational processes.
authors.affiliation: State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Sun
authors.forename: Pengfei
authors.initials: P
authors.lastname: Liu
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Jia
authors.forename: Marjorie A
authors.initials: MA
authors.lastname: Withers
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
mesh_terms: D000015:Abnormalities, Multiple; D025063:Chromosome Disorders; D058674:Chromosome Duplication; D002886:Chromosomes, Human, Pair 17; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D059766:DNA End-Joining Repair; D004261:DNA Replication; D020440:Gene Duplication; D006801:Humans; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D058496:Smith-Magenis Syndrome / Q000235:genetics*