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- Title
Mutation spectrum revealed by breakpoint sequencing of human germline CNVs.
- Authors
Conrad, Donald F; Bird, Christine; Blackburne, Ben; Lindsay, Sarah; Mamanova, Lira; Lee, Charles; Turner, Daniel J; Hurles, Matthew E
- 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.
- Publication
Nature genetics, 2010, Vol 42, Issue 5, p385
- ISSN
1546-1718
- Publication type
Journal Article
- DOI
10.1038/ng.564