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MBE Advance Access originally published online on August 13, 2009
Molecular Biology and Evolution 2009 26(11):2647-2654; doi:10.1093/molbev/msp182
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© The Author 2009. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Research Articles

Age-Related Accumulation of Mutations Supports a Replication-Dependent Mechanism of Spontaneous Mutation at Tandem Repeat DNA Loci in Mice

Robert J. Hardwick*, Michael V. Tretyakov{dagger} and Yuri E. Dubrova*

* Department of Genetics University of Leicester, Leicester, United Kingdom
{dagger} Department of Mathematics, University of Leicester, Leicester, United Kingdom

E-mail: yed2{at}le.ac.uk.

Accepted for publication August 8, 2009.

Expanded simple tandem repeat (ESTR) loci belong to the class of highly unstable loci in the mouse genome. The mechanisms underlying the very high spontaneous instability at these loci still remain poorly understood. Using single-molecule polymerase chain reaction, here we have compared the pattern of mutation accumulation in tissues with different proliferation capacities in male mice of age 12, 26, 48, and 96 weeks. In the nonproliferating brain, we did not observe any measurable age-related accumulation of ESTR mutations. In contrast, a highly elevated frequency of ESTR mutation was detected in the sperm samples taken from old mice; similar changes were also observed in the bone marrow tissue. The spectra of ESTR mutations accumulated in all tissues of young and old mice did not significantly differ. Taken together, these data clearly imply that spontaneous ESTR mutations occur almost exclusively in replication-proficient cells. To gain further insights into the mechanisms of ESTR mutation, we developed a stochastic model of age-related mutation accumulation. The observed spectra of ESTR mutants accumulated in the brain and sperm were fairly accurately approximated assuming the values of ESTR mutation rate, ranging from 0.01 to 0.04 per cell division. As these estimates dramatically exceed those for protein-coding genes and microsatellite loci, our data therefore suggest that ESTRs represent one of the most unstable loci in the mammalian genome. The results of our study also imply that ESTR loci can be regarded as a class of expanded microsatellites, with the mechanism of spontaneous mutation most probably attributed to replication slippage.

Key Words: expanded simple tandem repeat loci • mutation • age • mouse

Diethard Tautz, Associate Editor


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