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Nat Genet. 2010 May;42(5):385-91. doi: 10.1038/ng.564. Epub 2010 Apr 4.

Mutation spectrum revealed by breakpoint sequencing of human germline CNVs.

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  • 1Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

Abstract

Precisely characterizing the breakpoints of copy number variants (CNVs) is crucial for assessing their functional impact. However, fewer than 10% of known germline CNVs have been mapped to the single-nucleotide level. We characterized the sequence breakpoints from a dataset of all CNVs detected in three unrelated individuals in previous array-based CNV discovery experiments. We used targeted hybridization-based DNA capture and 454 sequencing to sequence 324 CNV breakpoints, including 315 deletions. We observed two major breakpoint signatures: 70% of the deletion breakpoints have 1-30 bp of microhomology, whereas 33% of deletion breakpoints contain 1-367 bp of inserted sequence. The co-occurrence of microhomology and inserted sequence is low (10%), suggesting that there are at least two different mutational mechanisms. Approximately 5% of the breakpoints represent more complex rearrangements, including local microinversions, suggesting a replication-based strand switching mechanism. Despite a rich literature on DNA repair processes, reconstruction of the molecular events generating each of these mutations is not yet possible.

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PMID:
20364136
[PubMed - indexed for MEDLINE]
PMCID:
PMC3428939
Free PMC Article

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