Replicative mechanisms for CNV formation are error prone

Abstract

SummaryWe investigated 67 breakpoint junctions of gene copy number gains (CNVs) 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 CNVs. These simple nucleotide variants (SNV) were generated concomitantly with the de novo complex genomic rearrangement (CGR) event. Our findings implicate a low fidelity error-prone DNA polymerase in synthesis associated with DNA repair mechanisms that leads to a local increase in point mutation burden associated with human CGR.