Mutation Rates, Spectra and Hotspots in Mismatch Repair-Deficient Caenorhabditis elegansSequence data from this article have been deposited with the EMBL/GenBank Data Libraries under accession nos. AY863110, AY863111, AY863112, AY863113, AY863114, AY863115, AY863116, AY863117, AY863118, AY863119, AY863120, AY863121, AY863122, AY863123, AY863124, AY863125, AY863126, AY863127, AY863128, AY863129, AY863130, AY863131, AY863132, AY863133, AY863134, AY863135, AY863136, AY863137, AY863138, AY863139, AY863140, AY863141, AY863142, AY863143.

Abstract

Abstract Although it is clear that postreplicative DNA mismatch repair (MMR) plays a critical role in maintaining genomic stability in nearly all forms of life surveyed, much remains to be understood about the genome-wide impact of MMR on spontaneous mutation processes and the extent to which MMR-deficient mutation patterns vary among species. We analyzed spontaneous mutation processes across multiple genomic regions using two sets of mismatch repair-deficient (msh-2 and msh-6) Caenorhabditis elegans mutation-accumulation (MA) lines and compared our observations to mutation spectra in a set of wild-type (WT), repair-proficient C. elegans MA lines. Across most sequences surveyed in the MMR-deficient MA lines, mutation rates were ∼100-fold higher than rates in the WT MA lines, although homopolymeric nucleotide-run (HP) loci composed of A:T base pairs mutated at an ∼500-fold greater rate. In contrast to yeast and humans where mutation spectra vary substantially with respect to different specific MMR-deficient genotypes, mutation rates and patterns were overall highly similar between the msh-2 and msh-6 C. elegans MA lines. This, along with the apparent absence of a Saccharomyces cerevisiae MSH3 ortholog in the C. elegans genome, suggests that C. elegans MMR surveillance is carried out by a single Msh-2/Msh-6 heterodimer.