Mechanisms of mutation at mouse expanded simple tandem repeat (ESTR) loci

• Main Author: Hardwick, Robert John
• Published: University of Leicester 2007
• Subjects: 591.35
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486724

Mouse expanded simple tandem repeat (ESTR) loci are non-coding, unstable arrays of short repeat units with high spontaneous mutation rates (up to 15% per gamete). Exposure to ionising radiating and some chemicals can elevate the mutation rate further, which makes them useful tools for the assessment of genomic mutation rates.;ESTRs mutate by either gaining or losing repeat units to result in the generation of differentially-sized mutant alleles. However, the mechanism by which this occurs remains unclear, and this hinders the reliable extrapolation of ESTR data to other loci. To address this issue, this thesis aimed to investigate the mechanism of mutation at the ESTR locus Ms6-hm.;Recent evidence has suggested that events at DNA replication are responsible for generating ESTR mutants. It this is the case, then it would be expected that ESTR mutation rate would increase in line with the number of cell division events in a tissue system. In this thesis, the speculated link between cell division rate and ESTR mutation rate was tested in three different tissues of varying mitotic proficiencies: brain (low mitotic index), bone marrow (intermediate mitotic index), and sperm (high mitotic index). In the first instance, spontaneous mutation rates in each of these tissues were assessed in mice of four different age groups: 12, 26, 48 and 96 weeks old; and in the second part of this thesis, in utero-irradiated mice were analysed to evaluate the mitosis-proficient process of embryogenesis.;I report increases in ESTR spontaneous mutation rate in sperm with age, but not in brain, and I also demonstrate that ESTR mutation rates are elevated in each tissue --- including brain --- following in utero -irradiation. I conclude that DNA replication is an important process in the generation of ESTR mutants.