PMID- 27880765 OWN - NLM STAT- MEDLINE DCOM- 20170509 LR - 20201215 IS - 1553-7404 (Electronic) IS - 1553-7390 (Print) IS - 1553-7390 (Linking) VI - 12 IP - 11 DP - 2016 Nov TI - Mechanisms for Complex Chromosomal Insertions. PG - e1006446 LID - 10.1371/journal.pgen.1006446 [doi] LID - e1006446 AB - 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. FAU - Gu, Shen AU - Gu S AUID- ORCID: 0000-0002-2142-9848 AD - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America. FAU - Szafranski, Przemyslaw AU - Szafranski P AD - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America. FAU - Akdemir, Zeynep Coban AU - Akdemir ZC AD - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America. FAU - Yuan, Bo AU - Yuan B AD - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America. FAU - Cooper, Mitchell L AU - Cooper ML AD - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America. FAU - Magrina, Maria A AU - Magrina MA AD - Medical Specialties Unit From City Hall Sao Jose dos Campos, Sao Paulo, Brazil. FAU - Bacino, Carlos A AU - Bacino CA AD - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America. AD - Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America. FAU - Lalani, Seema R AU - Lalani SR AD - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America. AD - Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America. FAU - Breman, Amy M AU - Breman AM AUID- ORCID: 0000-0003-0299-0100 AD - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America. FAU - Smith, Janice L AU - Smith JL AUID- ORCID: 0000-0002-2088-5710 AD - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America. FAU - Patel, Ankita AU - Patel A AD - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America. FAU - Song, Rodger H AU - Song RH AD - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America. FAU - Bi, Weimin AU - Bi W AD - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America. FAU - Cheung, Sau Wai AU - Cheung SW AD - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America. FAU - Carvalho, Claudia M B AU - Carvalho CM AD - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America. FAU - Stankiewicz, Pawel AU - Stankiewicz P AUID- ORCID: 0000-0002-6456-7490 AD - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America. FAU - Lupski, James R AU - Lupski JR AD - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America. AD - Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America. AD - Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America. AD - Texas Children's Hospital, Houston, Texas, United States of America. LA - eng GR - P30 HD024064/HD/NICHD NIH HHS/United States GR - R01 GM106373/GM/NIGMS NIH HHS/United States GR - R01 NS058529/NS/NINDS NIH HHS/United States GR - U54 HG006542/HG/NHGRI NIH HHS/United States PT - Journal Article DEP - 20161123 PL - United States TA - PLoS Genet JT - PLoS genetics JID - 101239074 SB - IM MH - *Chromosome Aberrations MH - Chromosome Inversion/*genetics MH - Comparative Genomic Hybridization MH - DNA Copy Number Variations/genetics MH - DNA Replication/*genetics MH - Female MH - Gene Duplication/*genetics MH - Genome, Human MH - Humans MH - In Situ Hybridization, Fluorescence MH - Male MH - Sequence Analysis, DNA MH - Translocation, Genetic PMC - PMC5120786 COIS- JRL has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, has stock options in Lasergen, Inc., is on the Scientific Advisory Board of Baylor Genetics, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical exome sequencing offered in the Baylor Genetics (https://www.bcm.edu/research/medical-genetics-labs/). EDAT- 2016/11/24 06:00 MHDA- 2017/05/10 06:00 PMCR- 2016/11/01 CRDT- 2016/11/24 06:00 PHST- 2016/06/29 00:00 [received] PHST- 2016/10/24 00:00 [accepted] PHST- 2016/11/24 06:00 [entrez] PHST- 2016/11/24 06:00 [pubmed] PHST- 2017/05/10 06:00 [medline] PHST- 2016/11/01 00:00 [pmc-release] AID - PGENETICS-D-16-01432 [pii] AID - 10.1371/journal.pgen.1006446 [doi] PST - epublish SO - PLoS Genet. 2016 Nov 23;12(11):e1006446. doi: 10.1371/journal.pgen.1006446. eCollection 2016 Nov.