title: Rare pathogenic microdeletions and tandem duplications are microhomology-mediated and stimulated by local genomic architecture.
abstract: Genomic copy number variation (CNV) plays a major role in various human diseases as well as in normal phenotypic variability. For some recurrent disease-causing CNVs that convey genomic disorders, the causative mechanism is meiotic, non-allelic, homologous recombination between breakpoint regions exhibiting extensive sequence homology (e.g. low-copy repeats). For the majority of recently identified rare pathogenic CNVs, however, the mechanism is unknown. Recently, a model for CNV formation implicated mitotic replication-based mechanisms, such as (alternative) non-homologous end joining and fork stalling and template switching, in the etiology of human pathogenic CNVs. The extent to which such mitotic mechanisms contribute to rare pathogenic CNVs remains to be determined. In addition, it is unexplored whether genomic architectural features such as repetitive elements or sequence motifs associated with DNA breakage stimulate the formation of rare pathogenic CNVs. To this end, we have sequenced breakpoint junctions of 30 rare pathogenic microdeletions and eight tandem duplications, representing the largest series of such CNVs examined to date in this much detail. Our results demonstrate the presence of (micro)homology ranging from 2 to over 75 bp, in 79% of the breakpoint junctions. This indicates that microhomology-mediated repair mechanisms, including the recently reported fork stalling and template switching and/or microhomology-mediated break-induced replication, prevail in rare pathogenic CNVs. In addition, we found that the vast majority of all breakpoints (81%) were associated with at least one of the genomic architectural features evaluated. Moreover, 75% of tandem duplication breakpoints were associated with the presence of one of two novel sequence motifs. These data suggest that rare pathogenic microdeletions and tandem duplications do not occur at random genome sequences, but are stimulated and potentially catalyzed by various genomic architectural features.
authors: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. l.vissers@antrg.umcn.nl
authors: Lisenka E L M
authors: LE
authors: Vissers
authors: Samarth S
authors: SS
authors: Bhatt
authors: Irene M
authors: IM
authors: Janssen
authors: Zhilian
authors: Z
authors: Xia
authors: Seema R
authors: SR
authors: Lalani
authors: Rolph
authors: R
authors: Pfundt
authors: Katarzyna
authors: K
authors: Derwinska
authors: Bert B A
authors: BB
authors: de Vries
authors: Christian
authors: C
authors: Gilissen
authors: Alexander
authors: A
authors: Hoischen
authors: Monika
authors: M
authors: Nesteruk
authors: Barbara
authors: B
authors: Wisniowiecka-Kowalnik
authors: Marta
authors: M
authors: Smyk
authors: Han G
authors: HG
authors: Brunner
authors: Sau Wai
authors: SW
authors: Cheung
authors: Ad Geurts
authors: AG
authors: van Kessel
authors: Joris A
authors: JA
authors: Veltman
authors: Pawel
authors: P
authors: Stankiewicz
mesh_terms: D020087:Alu Elements; D001483:Base Sequence; D019457:Chromosome Breakage; D004194:Disease / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D020440:Gene Duplication; D015894:Genome, Human; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D017384:Sequence Deletion; D012689:Sequence Homology, Nucleic Acid