Replicative mechanisms for CNV formation are error prone

• Published in: Nature genetics Vol. 45; no. 11; pp. 1319 - 1326
• Main Authors: Carvalho, Claudia M B, Pehlivan, Davut, Ramocki, Melissa B, Fang, Ping, Alleva, Benjamin, Franco, Luis M, Belmont, John W, Hastings, P J, Lupski, James R
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2013; Nature Publishing Group
• Subjects: 631/208/1516; 631/208/191; 631/208/212/2166; 631/208/514; Agriculture; Animal Genetics and Genomics; Base Sequence; Biomedicine; Cancer Research; Chromosome replication; Copy number variations; Deoxyribonucleic acid; DNA; DNA Breaks; DNA Copy Number Variations - genetics; DNA Repair - genetics; DNA Replication - genetics; Frameshift Mutation; Gene expression; Gene Function; Gene Rearrangement - genetics; Genetic screening; Genetic testing; Genetic Variation; Genomes; Genomics; Genotype; Human Genetics; Humans; Identification and classification; Methods; Mutation; Observations; Sequence Analysis, DNA; Sequence Deletion
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.2768

James Lupski and colleagues report a high-resolution analysis of 67 breakpoint junctions in 31 unrelated individuals with MECP2 duplication syndrome. They find that ~52% of genomic rearrangements in these individuals represent complex events in which the sequences flanking the breakpoints acquire additional changes, including small insertions, deletions and point mutations, likely resulting from error-prone DNA polymerase activity. 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.