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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #312540
Title: Replicative mechanisms for CNV formation are error prone

Author
item CARVALHO, CLAUDIA - Baylor College Of Medicine
item PEHLIVAN, DAVUT - Baylor College Of Medicine
item RAMOCKI, MELISSA - Baylor College Of Medicine
item FANG, PING - Baylor College Of Medicine
item ALLEVA, BENJAMIN - Baylor College Of Medicine
item FRANCO, LUIS - Baylor College Of Medicine
item BELMONT, JOHN - Children'S Nutrition Research Center (CNRC)
item HASTINGS, P - Baylor College Of Medicine
item LUPSKI, JAMES - Baylor College Of Medicine

Submitted to: Nature Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/27/2013
Publication Date: 9/22/2013
Citation: Carvalho, C.M., Pehlivan, D., Ramocki, M.B., Fang, P., Alleva, B., Franco, L.M., Belmont, J.W., Hastings, P.J., Lupski, J.R. 2013. Replicative mechanisms for CNV formation are error prone. Nature Genetics. 45:1319-1326.

Interpretive Summary: Imbalances in the genetic material – DNA – cause birth defects and intellectual disabilities. These imbalances are usually not present in the parents and happen as a new change in the child. These natural accidents occur when the DNA is being copied to form the reproductive cells made by the mom or dad. We showed that there is a large increase in genetic misspellings near the sites of the DNA imbalances. This tells us that problems in copying the DNA are an important part of the process that causes the imbalance. The causes of mistakes in copying DNA are very poorly understood. This work gives the surprising finding that small mutations happen near places in the genetic material where there is a loss of some of the material in the copying process. Nutritional deficiencies are thought to increase the rate of errors in copying the genes. This work will allow a new way to test which nutritional factors are most important for this process.

Technical 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.