title: Mutation spectrum revealed by breakpoint sequencing of human germline CNVs.
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.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Donald F
authors.initials: DF
authors.lastname: Conrad
authors.forename: Christine
authors.initials: C
authors.lastname: Bird
authors.forename: Ben
authors.initials: B
authors.lastname: Blackburne
authors.forename: Sarah
authors.initials: S
authors.lastname: Lindsay
authors.forename: Lira
authors.initials: L
authors.lastname: Mamanova
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Turner
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
mesh_terms: D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D004260:DNA Repair; D017353:Gene Deletion; D014644:Genetic Variation; D015894:Genome, Human; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009693:Nucleic Acid Hybridization; D009841:Oligonucleotides / Q000235:genetics; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D009841:Oligonucleotides; D004247:DNA