Replicative mechanisms for CNV formation are error prone.
We investigated 67 breakpoint junctions of gene copy number gains in 31 unrelated subjects. We observed a strikingly high frequency of small deletions and insertions (29%) apparently originating from polymerase slippage events, in addition to frameshifts and point mutations in homonucleotide runs (13%), at or flanking the breakpoint junctions of complex copy number variants. These single-nucleotide variants were generated concomitantly with the de novo complex genomic rearrangement (CGR) event. Our findings implicate low-fidelity, error-prone DNA polymerase activity in synthesis associated with DNA repair mechanisms as the cause of local increase in point mutation burden associated with human CGR.
1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. [2] Centro de Pesquisas René Rachou-FIOCRUZ, Belo Horizonte, Brazil.
Claudia M B
CM
Carvalho
Davut
D
Pehlivan
Melissa B
MB
Ramocki
Ping
P
Fang
Benjamin
B
Alleva
Luis M
LM
Franco
John W
JW
Belmont
P J
PJ
Hastings
James R
JR
Lupski
D001483:Base Sequence; D053960:DNA Breaks; D056915:DNA Copy Number Variations / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D016368:Frameshift Mutation; D015321:Gene Rearrangement / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion