Mutation Rate: DNA Repair and Indels Boost Errors

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Nature Reviews Genetics | AoP, published online 27 July 2010; corrected online 19 August 2010; doi:10.1038/nrg2848

MUTATION RATE DNA repair and indels boost errors

Mutation rates vary with genomic into the normal donor sequence that somatic cell genomes. They found locus and cellular context, but enabled them to chemically select that, irrespective of the time separat- there are many unanswered ques- cells in which mutations had arisen ing the genomes, there are increased tions regarding when, where and during gene conversion. Strikingly, single-nucleotide changes in the how elevated mutation rates occur. they found that the mutation rate neighbourhood of structural changes. Two papers now implicate DNA associated with gene conversion was Various DNA-repair mechanisms repair in increased local mutation 1,400 times higher than the rate of could be involved in forming indels, rates, and the results may influence spontaneous mutation in the same and the authors suggest that errors future studies of genetic variation genomic region. introduced during repair, perhaps and tumorigenesis. Hicks et al. showed that the by low-fidelity polymerases, are a Mitotic gene conversion is a majority of mutations were single- cause of the nearby single-nucleotide mechanism for repairing DNA dou- base-pair substitutions, but a high changes. De and Babu note that this ble-strand breaks (DSBs) in which proportion were one-base-pair relationship between indels and SNPs a homologous sequence (donor) is deletions and complex mutations suggests that mutations of different used as a template for repair. Hicks that are probably caused by template- sizes in the vicinity of a marker SNP and colleagues took advantage of the switching during gene conversion. should be considered when inter- gene conversion that is a normal part Surprisingly, the normally high- preting results from genome-wide of mating-type (MAT) switching in fidelity DNA polymerase-δ seems to association studies. Saccharomyces cerevisiae to screen cause these template switches. This Both of these studies provide for errors generated by this repair finding suggests that gene conversion evidence that mechanisms involved process. They inserted a gene (URA3) is less processive than the DNA in maintenance of global genomic synthesis that takes place during integrity can cause damage at a local S phase. Furthermore, the authors level. Therefore, useful insights might suggest that some mutations required be gained from considering observa- for carcinogenesis could result from tions made in the context of disease gene conversion being used to repair genomics or population studies in the increased numbers of DSBs the light of elevated mutation rates triggered by activated oncogenes. resulting from repair pathways. In another study, De and Babu Mary Muers analysed the occurrence of single- nucleotide substitutions (for example, ORIGINAL RESEARCH PAPERS Hicks, W. M., SNPs) near to structural alterations Kim, M. & Haber, J. E. Increased mutagenesis and unique mutation signature associated with (for example, indels) in sequences mitotic gene conversion. Science 329, 82–85 separated by different lengths of (2010) | De, S. & Babu, M. M. A time-invariant principle of genome evolution. Proc. Natl Acad. Sci. time: the reference human and USA 6 Jul 2010 (doi:10.1073/pnas.0914454107)

GETTY chimpanzee genomes, the reference FURTHER READING Hastings, P. J. et al. human genome and human personal Mechanisms of change in gene copy numbers. Nature Rev. Genet. 10, 551–564 (2009) genomes, and human cancer and