Journal Article

Mechanisms for Complex Chromosomal Insertions

Yuan, Bo, Bi, Weimin, Magriñá, Maria A., Song, Rodger H., Bacino, Carlos A., Cooper, Mitchell L., Cheung, Sau Wai, Gu, Shen, Szafranski, Przemyslaw, Patel, Ankita, Lalani, Seema R., Lupski, James R., Breman, Amy M., Smith, Janice L., Akdemir, Zeynep Coban, Stankiewicz, Paweł, Carvalho, Claudia M. B.

2016

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Biology and Life Sciences / Chromosome Aberrations / Chromosome Inversion - genetics / Chromosomes / Comparative Genomic Hybridization / Deoxyribonucleic acid / DNA / DNA Copy Number Variations - genetics / DNA Replication - genetics / Female / Gene Duplication - genetics / Gene expression / Genome, Human / Humans / In Situ Hybridization, Fluorescence / Male / Medicine / Observations / Pediatrics / Physicians / Physiological aspects / Research and Analysis Methods / Sequence Analysis, DNA / Translocation, Genetic