title: SVA retrotransposon insertion-associated deletion represents a novel mutational mechanism underlying large genomic copy number changes with non-recurrent breakpoints.
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.
authors: Julia
authors: J
authors: Vogt
authors: Kathrin
authors: K
authors: Bengesser
authors: Kathleen B M
authors: KB
authors: Claes
authors: Katharina
authors: K
authors: Wimmer
authors: Victor-Felix
authors: VF
authors: Mautner
authors: Rick
authors: R
authors: van Minkelen
authors: Eric
authors: E
authors: Legius
authors: Hilde
authors: H
authors: Brems
authors: Meena
authors: M
authors: Upadhyaya
authors: Josef
authors: J
authors: Högel
authors: Conxi
authors: C
authors: Lazaro
authors: Thorsten
authors: T
authors: Rosenbaum
authors: Simone
authors: S
authors: Bammert
authors: Ludwine
authors: L
authors: Messiaen
authors: David N
authors: DN
authors: Cooper
authors: Hildegard
authors: H
authors: Kehrer-Sawatzki
mesh_terms: D001483:Base Sequence; D056905:Chromosome Breakpoints; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D015894:Genome, Human; D006801:Humans; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins; D009456:Neurofibromatosis 1 / Q000235:genetics; D025542:Neurofibromin 1 / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D018626:Retroelements; D017384:Sequence Deletion; D016615:Telomere / Q000235:genetics; D014157:Transcription Factors
chemical_list: D009363:Neoplasm Proteins; D025542:Neurofibromin 1; D018626:Retroelements; C430461:SUZ12 protein, human; D014157:Transcription Factors; D063151:Polycomb Repressive Complex 2