This study will directly address fundamental questions about the roles of DNA repair systems in shaping the rates, patterns and fitness consequences of spontaneous mutation processes in an animal genome. Six Caenorhabditis elegans genes, all orthologues of excision DNA repair genes extensive characterized in yeast and humans, will e deleted by UV-trimethylpsoralen (UV-TMP) mutagenesis and mutation- accumulation experiments will be initiated for each of the six knockout strains. Mutation rates and patterns in both the nuclear and mitochondrial genomes will be evaluated by detection mutations in each set of repair- deficient nutation-accumulation (MA) lines using direct DNA sequencing approaches. The spectra of mutation prevented by and extent of overlap between different repair pathways in C. elegans will be directly evaluated. The fitness consequences of spontaneous mutation in a long-term set of wild-type C. elegans MA lines will provide an unprecedented standard against which mutations in repair-deficient backgrounds will be examined with life history character assays. Background information on the rates, patterns and fitness consequences of spontaneous mutation in a long-term set of wild-type C. elegans MA lines will provide an unprecedented standard against which mutations in repair-deficient MA lines will be directly compared. Execution of this study will culminate in a greater understanding of the roles of excision DNA repair factors in shaping mutation processes that are the ultimate source of genetic variation, human genetic disorders and fuel for genome evolution.
| Denver, Dee R; Feinberg, Seth; Steding, Catherine et al. (2006) The relative roles of three DNA repair pathways in preventing Caenorhabditis elegans mutation accumulation. Genetics 174:57-65 |
| Denver, Dee R; Feinberg, Seth; Estes, Suzanne et al. (2005) Mutation rates, spectra and hotspots in mismatch repair-deficient Caenorhabditis elegans. Genetics 170:107-13 |
| Denver, Dee R; Swenson, Stephanie L; Lynch, Michael (2003) An evolutionary analysis of the helix-hairpin-helix superfamily of DNA repair glycosylases. Mol Biol Evol 20:1603-11 |
