Mutation spectrum revealed by breakpoint sequencing of human germline CNVs

Donald F. Conrad, Christine Bird, Ben Blackburne, Sarah Lindsay, Lira Mamanova, Charles Lee, Daniel J. Turner, Matthew E. Hurles

Research output: Contribution to journalArticle

169 Scopus citations

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 130 bp of microhomology, whereas 33% of deletion breakpoints contain 1367 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.

Original languageEnglish (US)
Pages (from-to)385-391
Number of pages7
JournalNature genetics
Volume42
Issue number5
DOIs
StatePublished - May 2010

ASJC Scopus subject areas

  • Genetics

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    Conrad, D. F., Bird, C., Blackburne, B., Lindsay, S., Mamanova, L., Lee, C., Turner, D. J., & Hurles, M. E. (2010). Mutation spectrum revealed by breakpoint sequencing of human germline CNVs. Nature genetics, 42(5), 385-391. https://doi.org/10.1038/ng.564