title: Mechanisms for Complex Chromosomal Insertions.
abstract: Chromosomal insertions are genomic rearrangements with a chromosome segment inserted into a non-homologous chromosome or a non-adjacent locus on the same chromosome or the other homologue, constituting ~2% of nonrecurrent copy-number gains. Little is known about the molecular mechanisms of their formation. We identified 16 individuals with complex insertions among 56,000 individuals tested at Baylor Genetics using clinical array comparative genomic hybridization (aCGH) and fluorescence in situ hybridization (FISH). Custom high-density aCGH was performed on 10 individuals with available DNA, and breakpoint junctions were fine-mapped at nucleotide resolution by long-range PCR and DNA sequencing in 6 individuals to glean insights into potential mechanisms of formation. We observed microhomologies and templated insertions at the breakpoint junctions, resembling the breakpoint junction signatures found in complex genomic rearrangements generated by replication-based mechanism(s) with iterative template switches. In addition, we analyzed 5 families with apparently balanced insertion in one parent detected by FISH analysis and found that 3 parents had additional small copy-number variants (CNVs) at one or both sides of the inserting fragments as well as at the inserted sites. We propose that replicative repair can result in interchromosomal complex insertions generated through chromothripsis-like chromoanasynthesis involving two or three chromosomes, and cause a significant fraction of apparently balanced insertions harboring small flanking CNVs.
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Shen
authors.identifier: http://orcid.org/0000-0002-2142-9848
authors.initials: S
authors.lastname: Gu
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Szafranski
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Zeynep Coban
authors.initials: ZC
authors.lastname: Akdemir
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Cooper
authors.affiliation: Medical Specialties Unit From City Hall São José dos Campos, São Paulo, Brazil.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Magriñá
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bacino
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Seema R
authors.initials: SR
authors.lastname: Lalani
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Amy M
authors.identifier: http://orcid.org/0000-0003-0299-0100
authors.initials: AM
authors.lastname: Breman
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Janice L
authors.identifier: http://orcid.org/0000-0002-2088-5710
authors.initials: JL
authors.lastname: Smith
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Rodger H
authors.initials: RH
authors.lastname: Song
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Claudia M B
authors.initials: CM
authors.lastname: Carvalho
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Paweł
authors.identifier: http://orcid.org/0000-0002-6456-7490
authors.initials: P
authors.lastname: Stankiewicz
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.|Texas Children's Hospital, Houston, Texas, United States of America.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D002869:Chromosome Aberrations; D007446:Chromosome Inversion / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics; D004261:DNA Replication / Q000235:genetics*; D005260:Female; D020440:Gene Duplication / Q000235:genetics*; D015894:Genome, Human; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D017422:Sequence Analysis, DNA; D014178:Translocation, Genetic