title: Differences in genome-wide repeat sequence instability conferred by proofreading and mismatch repair defects.
abstract: Mutation rates are used to calibrate molecular clocks and to link genetic variants with human disease. However, mutation rates are not uniform across each eukaryotic genome. Rates for insertion/deletion (indel) mutations have been found to vary widely when examined in vitro and at specific loci in vivo. Here, we report the genome-wide rates of formation and repair of indels made during replication of yeast nuclear DNA. Using over 6000 indels accumulated in four mismatch repair (MMR) defective strains, and statistical corrections for false negatives, we find that indel rates increase by 100 000-fold with increasing homonucleotide run length, representing the greatest effect on replication fidelity of any known genomic parameter. Nonetheless, long genomic homopolymer runs are overrepresented relative to random chance, implying positive selection. Proofreading defects in the replicative polymerases selectively increase indel rates in short repetitive tracts, likely reflecting the distance over which Pols δ and ϵ interact with duplex DNA upstream of the polymerase active site. In contrast, MMR defects hugely increase indel mutagenesis in long repetitive sequences. Because repetitive sequences are not uniformly distributed among genomic functional elements, the quantitatively different consequences on genome-wide repeat sequence instability conferred by defects in proofreading and MMR have important biological implications.
authors.affiliation: Genome Instability and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, NC 27709, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Lujan
authors.affiliation: Genome Instability and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, NC 27709, USA.
authors.forename: Alan B
authors.initials: AB
authors.lastname: Clark
authors.affiliation: Genome Instability and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, NC 27709, USA kunkel@niehs.nih.gov.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kunkel
mesh_terms: D053843:DNA Mismatch Repair; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D016681:Genome, Fungal; D042822:Genomic Instability; D054643:INDEL Mutation; D009154:Mutation; D059645:Mutation Rate; D012091:Repetitive Sequences, Nucleic Acid
chemical_list: D004259:DNA-Directed DNA Polymerase
references.citation: PLoS One. 2014;9(4):e94835
references.pmid: 24733111
references.citation: Biochemistry. 1996 Jan 23;35(3):1046-53
references.pmid: 8547240
references.citation: Genome Res. 2014 Nov;24(11):1751-64
references.pmid: 25217194
references.citation: Mol Cell. 2008 Apr 25;30(2):137-44
references.pmid: 18439893
references.citation: Mol Cell Biol. 2005 Jan;25(1):461-71
references.pmid: 15601866
references.citation: Int J Oncol. 2014 Jul;45(1):77-81
references.pmid: 24788313
references.citation: Cell Rep. 2012 Jan 26;1(1):36-42
references.pmid: 22832106
references.citation: J Biol Chem. 2007 Jan 26;282(4):2324-32
references.pmid: 17121822
references.citation: Nat Genet. 2013 Feb;45(2):136-44
references.pmid: 23263490
references.citation: Cell. 2003 Feb 7;112(3):391-401
references.pmid: 12581528
references.citation: Nat Struct Mol Biol. 2015 Apr;22(4):291-7
references.pmid: 25751426
references.citation: Genetics. 2010 Oct;186(2):493-503
references.pmid: 20660644
references.citation: J Natl Cancer Inst. 2004 Feb 18;96(4):261-8
references.pmid: 14970275
references.citation: Nat Chem Biol. 2010 Oct;6(10):774-81
references.pmid: 20729855
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17674-9
references.pmid: 20876092
references.citation: Nucleic Acids Res. 2011 Mar;39(4):1360-71
references.pmid: 20961955
references.citation: Proc Natl Acad Sci U S A. 2014 Feb 4;111(5):1897-902
references.pmid: 24449905
references.citation: G3 (Bethesda). 2013 Sep;3(9):1453-65
references.pmid: 23821616
references.citation: Genetics. 1997 Jul;146(3):769-79
references.pmid: 9215886
references.citation: Eur J Hum Genet. 2011 Mar;19(3):320-5
references.pmid: 21157497
references.citation: Trends Biochem Sci. 2006 Apr;31(4):206-14
references.pmid: 16545956
references.citation: Hum Mol Genet. 2013 Jul 15;22(14):2820-8
references.pmid: 23528559
references.citation: IUBMB Life. 2014 May;66(5):339-51
references.pmid: 24861832
references.citation: Cold Spring Harb Symp Quant Biol. 2000;65:81-91
references.pmid: 12760023
references.citation: Cold Spring Harb Symp Quant Biol. 2009;74:91-101
references.pmid: 19903750
references.citation: Mol Cell Biol. 1997 May;17(5):2859-65
references.pmid: 9111358
references.citation: Nat Struct Mol Biol. 2014 Jan;21(1):49-55
references.pmid: 24292646
references.citation: Biochemistry. 1990 Sep 4;29(35):8003-11
references.pmid: 1702019
references.citation: Nat Struct Mol Biol. 2009 Sep;16(9):979-86
references.pmid: 19718023
references.citation: Nature. 2013 May 2;497(7447):67-73
references.pmid: 23636398
references.citation: Cold Spring Harb Symp Quant Biol. 1966;31:77-84
references.pmid: 5237214
references.citation: PLoS Genet. 2012;8(10):e1003016
references.pmid: 23071460
references.citation: J Pathol. 2013 Jun;230(2):148-53
references.pmid: 23447401
references.citation: Curr Opin Genet Dev. 2014 Feb;24:107-13
references.pmid: 24583393
references.citation: Genome Res. 2013 Jul;23(7):1054-62
references.pmid: 23817046
references.citation: Biochim Biophys Acta. 2010 May;1804(5):1049-63
references.pmid: 19545649
references.citation: Front Oncol. 2013 Oct 31;3:272
references.pmid: 24199172
references.citation: Biochemistry. 1993 Apr 20;32(15):4083-9
references.pmid: 8385995
references.citation: Science. 2007 Jul 6;317(5834):127-30
references.pmid: 17615360
references.citation: Nature. 2012 Jul 19;487(7407):330-7
references.pmid: 22810696