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SVA retrotransposon insertion-associated deletion represents a novel mutational mechanism underlying large genomic copy number changes with non-recurrent breakpoints

Julia Vogt, Kathrin Bengesser, Kathleen Claes UGent, Katharina Wimmer, Victor-Felix Mautner, Rick van Minkelen, Eric Legius, Hilde Brems, Meena Upadhyaya, Josef Högel, et al. (2014) GENOME BIOLOGY. 15(6).
abstract
Background: Genomic disorders are caused by copy number changes that may exhibit recurrent breakpoints processed by nonallelic homologous recombination. However, region-specific disease-associated copy number changes have also been observed which exhibit non-recurrent breakpoints. The mechanisms underlying these non-recurrent copy number changes have not yet been fully elucidated. Results: We analyze large NF1 deletions with non-recurrent breakpoints as a model to investigate the full spectrum of causative mechanisms, and observe that they are mediated by various DNA double strand break repair mechanisms, as well as aberrant replication. Further, two of the 17 NF1 deletions with non-recurrent breakpoints, identified in unrelated patients, occur in association with the concomitant insertion of SINE/variable number of tandem repeats/Alu (SVA) retrotransposons at the deletion breakpoints. The respective breakpoints are refractory to analysis by standard breakpoint-spanning PCRs and are only identified by means of optimized PCR protocols designed to amplify across GC-rich sequences. The SVA elements are integrated within SUZ12P intron 8 in both patients, and were mediated by target-primed reverse transcription of SVA mRNA intermediates derived from retrotranspositionally active source elements. Both SVA insertions occurred during early postzygotic development and are uniquely associated with large deletions of 1 Mb and 867 kb, respectively, at the insertion sites. Conclusions: Since active SVA elements are abundant in the human genome and the retrotranspositional activity of many SVA source elements is high, SVA insertion-associated large genomic deletions encompassing many hundreds of kilobases could constitute a novel and as yet under-appreciated mechanism underlying large-scale copy number changes in the human genome.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
DOUBLE-STRAND BREAKS, NONALLELIC HOMOLOGOUS RECOMBINATION, B DNA CONFORMATIONS, LARGE NF1 DELETIONS, L1 RETROTRANSPOSITION, NEUROFIBROMATOSIS TYPE-1, INVERTED REPEATS, SOMATIC RETROTRANSPOSITION, LINE-1 RETROTRANSPOSITION, COMPLEX REARRANGEMENTS
journal title
GENOME BIOLOGY
Genome Biol.
volume
15
issue
6
article number
R80
pages
17 pages
Web of Science type
Article
Web of Science id
000341269300006
JCR category
BIOTECHNOLOGY & APPLIED MICROBIOLOGY
JCR impact factor
10.81 (2014)
JCR rank
5/163 (2014)
JCR quartile
1 (2014)
ISSN
1465-6906
DOI
10.1186/gb-2014-15-6-r80
language
English
UGent publication?
yes
classification
A1
copyright statement
I have retained and own the full copyright for this publication
id
5825377
handle
http://hdl.handle.net/1854/LU-5825377
date created
2015-01-27 15:42:30
date last changed
2016-12-21 15:41:32
@article{5825377,
  abstract     = {Background: Genomic disorders are caused by copy number changes that may exhibit recurrent breakpoints processed by nonallelic homologous recombination. However, region-specific disease-associated copy number changes have also been observed which exhibit non-recurrent breakpoints. The mechanisms underlying these non-recurrent copy number changes have not yet been fully elucidated. 
Results: We analyze large NF1 deletions with non-recurrent breakpoints as a model to investigate the full spectrum of causative mechanisms, and observe that they are mediated by various DNA double strand break repair mechanisms, as well as aberrant replication. Further, two of the 17 NF1 deletions with non-recurrent breakpoints, identified in unrelated patients, occur in association with the concomitant insertion of SINE/variable number of tandem repeats/Alu (SVA) retrotransposons at the deletion breakpoints. The respective breakpoints are refractory to analysis by standard breakpoint-spanning PCRs and are only identified by means of optimized PCR protocols designed to amplify across GC-rich sequences. The SVA elements are integrated within SUZ12P intron 8 in both patients, and were mediated by target-primed reverse transcription of SVA mRNA intermediates derived from retrotranspositionally active source elements. Both SVA insertions occurred during early postzygotic development and are uniquely associated with large deletions of 1 Mb and 867 kb, respectively, at the insertion sites. 
Conclusions: Since active SVA elements are abundant in the human genome and the retrotranspositional activity of many SVA source elements is high, SVA insertion-associated large genomic deletions encompassing many hundreds of kilobases could constitute a novel and as yet under-appreciated mechanism underlying large-scale copy number changes in the human genome.},
  articleno    = {R80},
  author       = {Vogt, Julia and Bengesser, Kathrin and Claes, Kathleen and Wimmer, Katharina and Mautner, Victor-Felix and van Minkelen, Rick and Legius, Eric and Brems, Hilde and Upadhyaya, Meena and H{\"o}gel, Josef and Lazaro, Conxi and Rosenbaum, Thorsten and Bammert, Simone and Messiaen, Ludwine and Cooper, David N and Kehrer-Sawatzki, Hildegard},
  issn         = {1465-6906},
  journal      = {GENOME BIOLOGY},
  keyword      = {DOUBLE-STRAND BREAKS,NONALLELIC HOMOLOGOUS RECOMBINATION,B DNA CONFORMATIONS,LARGE NF1 DELETIONS,L1 RETROTRANSPOSITION,NEUROFIBROMATOSIS TYPE-1,INVERTED REPEATS,SOMATIC RETROTRANSPOSITION,LINE-1 RETROTRANSPOSITION,COMPLEX REARRANGEMENTS},
  language     = {eng},
  number       = {6},
  pages        = {17},
  title        = {SVA retrotransposon insertion-associated deletion represents a novel mutational mechanism underlying large genomic copy number changes with non-recurrent breakpoints},
  url          = {http://dx.doi.org/10.1186/gb-2014-15-6-r80},
  volume       = {15},
  year         = {2014},
}

Chicago
Vogt, Julia, Kathrin Bengesser, Kathleen Claes, Katharina Wimmer, Victor-Felix Mautner, Rick van Minkelen, Eric Legius, et al. 2014. “SVA Retrotransposon Insertion-associated Deletion Represents a Novel Mutational Mechanism Underlying Large Genomic Copy Number Changes with Non-recurrent Breakpoints.” Genome Biology 15 (6).
APA
Vogt, J., Bengesser, K., Claes, K., Wimmer, K., Mautner, V.-F., van Minkelen, R., Legius, E., et al. (2014). SVA retrotransposon insertion-associated deletion represents a novel mutational mechanism underlying large genomic copy number changes with non-recurrent breakpoints. GENOME BIOLOGY, 15(6).
Vancouver
1.
Vogt J, Bengesser K, Claes K, Wimmer K, Mautner V-F, van Minkelen R, et al. SVA retrotransposon insertion-associated deletion represents a novel mutational mechanism underlying large genomic copy number changes with non-recurrent breakpoints. GENOME BIOLOGY. 2014;15(6).
MLA
Vogt, Julia, Kathrin Bengesser, Kathleen Claes, et al. “SVA Retrotransposon Insertion-associated Deletion Represents a Novel Mutational Mechanism Underlying Large Genomic Copy Number Changes with Non-recurrent Breakpoints.” GENOME BIOLOGY 15.6 (2014): n. pag. Print.