Mechanisms for Complex Chromosomal Insertions.
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 for...
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doaj-f2390e2325234092888cd316fbc87b0d2020-11-25T02:25:44ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042016-11-011211e100644610.1371/journal.pgen.1006446Mechanisms for Complex Chromosomal Insertions.Shen GuPrzemyslaw SzafranskiZeynep Coban AkdemirBo YuanMitchell L CooperMaria A MagriñáCarlos A BacinoSeema R LalaniAmy M BremanJanice L SmithAnkita PatelRodger H SongWeimin BiSau Wai CheungClaudia M B CarvalhoPaweł StankiewiczJames R LupskiChromosomal 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.http://europepmc.org/articles/PMC5120786?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shen Gu Przemyslaw Szafranski Zeynep Coban Akdemir Bo Yuan Mitchell L Cooper Maria A Magriñá Carlos A Bacino Seema R Lalani Amy M Breman Janice L Smith Ankita Patel Rodger H Song Weimin Bi Sau Wai Cheung Claudia M B Carvalho Paweł Stankiewicz James R Lupski |
spellingShingle |
Shen Gu Przemyslaw Szafranski Zeynep Coban Akdemir Bo Yuan Mitchell L Cooper Maria A Magriñá Carlos A Bacino Seema R Lalani Amy M Breman Janice L Smith Ankita Patel Rodger H Song Weimin Bi Sau Wai Cheung Claudia M B Carvalho Paweł Stankiewicz James R Lupski Mechanisms for Complex Chromosomal Insertions. PLoS Genetics |
author_facet |
Shen Gu Przemyslaw Szafranski Zeynep Coban Akdemir Bo Yuan Mitchell L Cooper Maria A Magriñá Carlos A Bacino Seema R Lalani Amy M Breman Janice L Smith Ankita Patel Rodger H Song Weimin Bi Sau Wai Cheung Claudia M B Carvalho Paweł Stankiewicz James R Lupski |
author_sort |
Shen Gu |
title |
Mechanisms for Complex Chromosomal Insertions. |
title_short |
Mechanisms for Complex Chromosomal Insertions. |
title_full |
Mechanisms for Complex Chromosomal Insertions. |
title_fullStr |
Mechanisms for Complex Chromosomal Insertions. |
title_full_unstemmed |
Mechanisms for Complex Chromosomal Insertions. |
title_sort |
mechanisms for complex chromosomal insertions. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2016-11-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC5120786?pdf=render |
work_keys_str_mv |
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