Human Molecular Genetics Advance Access published online on July 15, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn190
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Somatic microindels in human cancer: The insertions are highly error-prone and derive from nearby but not adjacent sense and antisense templates
1 Department of Molecular Genetics, City of Hope National Medical Center, 1500 E. Duarte Rd., Duarte, CA 91010 2 SNP Institute, Nanhua University, Hengyang, Hunan, China 3 Department of Biology, The University of Western Ontario, London, ON Canada N6A 5B7
* Corresponding Author: Steve S. Sommer, M.D., Ph.D. Chair, Department of Molecular Genetics Chair, Department of Molecular Diagnosis Beckman Research Institute City of Hope National Medical Center 1500 East Duarte Road, Duarte, CA 91010 Telephone: (626) 930-5497 Fax: (626) 301-8142 Email: sommeradmin{at}coh.org
Received April 2, 2008; Revised June 11, 2008; Accepted July 1, 2008
Somatic microindels (microdeletions with microinsertions) have been studied in normal mouse tissues using the Big Blue lacI transgenic mutation detection system. Here we analyze microindels in human cancers using an endogenous and transcribed gene, the TP53 gene. Microindel frequency, the enhancement of 1-2 microindels and other features are generally similar to that observed in the non-transcribed lacI gene in normal mouse tissues. The current larger sample of somatic microindels reveals recurroids: mutations in which deletions are identical and the co-localized insertion is similar. The data reveal that the inserted sequences derive from nearby but not adjacent sequences in contrast to the slippage that characterizes the great majority of pure microinsertions. The microindel inserted sequences derive from a template on the sense or antisense strand with similar frequency. The estimated error rate of the insertion process of 13% per bp is by far the largest reported in vivo, with the possible exception of somatic hypermutation in the immunoglobulin gene. The data constrain possible mechanisms of microindels and raise the question of whether microindels are "scars" from the bypass of large DNA adducts by a translesional polymerase, e.g. the "Tarzan model" presented herein.