Mutation rates, spectra and hotspots in mismatch repair-deficient Caenorhabditis elegans.
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 approximately 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 approximately 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.
Denver
Dee R
DR
Department of Biology, Indiana University, Bloomington, 47405, USA. ddenver@bio.indiana.edu
Feinberg
Seth
S
Estes
Suzanne
S
Thomas
W Kelley
WK
Lynch
Michael
M
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005838:Genotype; D008969:Molecular Sequence Data; D051719:MutS DNA Mismatch-Binding Protein; D009154:Mutation
D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; C450145:msh-2 protein, C elegans; C510643:msh-6 protein, C elegans; D051719:MutS DNA Mismatch-Binding Protein
J Mol Evol. 2004 May;58(5):584-95
15170261
Genetics. 2004 Mar;166(3):1269-79
15082546
Nature. 1993 Apr 22;362(6422):709-15
8469282
J Biol Chem. 1994 Nov 25;269(47):29984-92
7961998
Genes Dev. 1996 Feb 15;10(4):407-20
8600025
Mutat Res. 1996 May;316(5-6):249-59
8649458
Methods Enzymol. 1996;266:383-402
8743695
Curr Biol. 1996 Sep 1;6(9):1185-7
8805366
Mol Cell Biol. 1996 Oct;16(10):5604-15
8816473
Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13629-34
8942985
Mol Cell Biol. 1997 May;17(5):2859-65
9111358
Carcinogenesis. 1997 Jun;18(6):1127-33
9214593
Nucleic Acids Res. 1998 Sep 15;26(18):4291-300
9722651
Nature. 2004 Aug 5;430(7000):625-6
15295584
Genetics. 1999 Nov;153(3):1271-83
10545458
Mutat Res. 1999 Dec 7;435(3):171-213
10606811
Mutat Res. 2000 Feb 14;447(2):155-64
10751599
Plant Cell. 2000 Jun;12(6):991-1002
10852942
Carcinogenesis. 2000 Jul;21(7):1291-5
10874005
Evolution. 2000 Aug;54(4):1234-46
11005291
Science. 2000 Sep 29;289(5488):2342-4
11009418
Annu Rev Genet. 2000;34:359-399
11092832
Genetics. 2001 May;158(1):65-75
11333218
Genome Res. 2001 Jul;11(7):1269-74
11435410
Science. 2002 Jan 4;295(5552):127-31
11778048
Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2158-63
11830642
Genetics. 2002 Jun;161(2):651-60
12072462
Mol Cell. 2002 Jul;10(1):199-205
12150919
Oncogene. 2002 Oct 10;21(46):7126-30
12370835
Mol Cell Biol. 2002 Dec;22(24):8756-62
12446792
Nature. 2004 Aug 5;430(7000):679-82
15295601