Replicative mechanisms for CNV formation are error prone.

TitleReplicative mechanisms for CNV formation are error prone.
Publication TypeJournal Article
Year of Publication2013
AuthorsCarvalho, CMB, Pehlivan, D, Ramocki, MB, Fang, P, Alleva, B, Franco, LM, Belmont, JW, Hastings, PJ, Lupski, JR
JournalNat Genet
Volume45
Issue11
Pagination1319-26
Date Published2013 Nov
ISSN1546-1718
KeywordsBase Sequence, DNA Breaks, DNA Copy Number Variations, DNA Repair, DNA Replication, Frameshift Mutation, Gene Rearrangement, Genetic Variation, Genotype, Humans, Sequence Analysis, DNA, Sequence Deletion
Abstract

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.

DOI10.1038/ng.2768
Alternate JournalNat. Genet.
PubMed ID24056715
PubMed Central IDPMC3821386
Grant List5K08NS062711 / NS / NINDS NIH HHS / United States
5U54HG006542 / HG / NHGRI NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States