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PLoS Genet. 2016 Nov 23;12(11):e1006446. doi: 10.1371/journal.pgen.1006446. eCollection 2016 Nov.

Mechanisms for Complex Chromosomal Insertions.

Author information

1
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
2
Medical Specialties Unit From City Hall São José dos Campos, São Paulo, Brazil.
3
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
4
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
5
Texas Children's Hospital, Houston, Texas, United States of America.

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.

PMID:
27880765
PMCID:
PMC5120786
DOI:
10.1371/journal.pgen.1006446
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

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/).

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