title: Crossovers are associated with mutation and biased gene conversion at recombination hotspots.
abstract: Meiosis is a potentially important source of germline mutations, as sites of meiotic recombination experience recurrent double-strand breaks (DSBs). However, evidence for a local mutagenic effect of recombination from population sequence data has been equivocal, likely because mutation is only one of several forces shaping sequence variation. By sequencing large numbers of single crossover molecules obtained from human sperm for two recombination hotspots, we find direct evidence that recombination is mutagenic: Crossovers carry more de novo mutations than nonrecombinant DNA molecules analyzed for the same donors and hotspots. The observed mutations were primarily CG to TA transitions, with a higher frequency of transitions at CpG than non-CpGs sites. This enrichment of mutations at CpG sites at hotspots could predominate in methylated regions involving frequent single-stranded DNA processing as part of DSB repair. In addition, our data set provides evidence that GC alleles are preferentially transmitted during crossing over, opposing mutation, and shows that GC-biased gene conversion (gBGC) predominates over mutation in the sequence evolution of hotspots. These findings are consistent with the idea that gBGC could be an adaptation to counteract the mutational load of recombination.
authors: Institute of Biophysics, Johannes Kepler University, 4020 Linz, Austria;
authors: Barbara
authors: B
authors: Arbeithuber
authors: Institut für Populationsgenetik, Vetmeduni Vienna, 1210 Vienna, Austria;
authors: Andrea J
authors: AJ
authors: Betancourt
authors: Department of Gynecological Endocrinology and Kinderwunsch Zentrum, Landes- Frauen- und Kinderklinik, 4020 Linz, Austria; and Institute of Human Genetics, Medical University of Graz, 8010 Graz, Austria.
authors: Thomas
authors: T
authors: Ebner
authors: Institute of Biophysics, Johannes Kepler University, 4020 Linz, Austria; irene.tiemann@jku.at.
authors: Irene
authors: http://orcid.org/0000-0002-3621-7020
authors: I
authors: Tiemann-Boege
mesh_terms: D000483:Alleles; D003434:Crossing Over, Genetic; D005260:Female; D005785:Gene Conversion; D006801:Humans; D008297:Male; D009154:Mutation; D011995:Recombination, Genetic
keywords: biased gene conversion; crossover; meiotic recombination; mutation; sequence evolution
references: Genetics. 2000 Sep;156(1):297-304
references: 10978293
references: Genome Res. 2013 Dec;23(12):1974-84
references: 23990608
references: Trends Genet. 2001 Sep;17(9):481-5
references: 11525814
references: Mol Biol Evol. 2002 Jul;19(7):1181-97
references: 12082137
references: Nat Genet. 2002 Jul;31(3):267-71
references: 12089523
references: Trends Genet. 2002 Jul;18(7):337-40
references: 12127766
references: Nucleic Acids Res. 2003 May 1;31(9):2261-71
references: 12711670
references: J Chronic Dis. 1981;34(9-10):463-8
references: 7276136
references: Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1642-6
references: 8127859
references: Nucleic Acids Res. 1994 Mar 25;22(6):972-6
references: 8152929
references: Genetics. 1995 Jul;140(3):965-72
references: 7672595
references: J Natl Cancer Inst. 1959 Apr;22(4):719-48
references: 13655060
references: Genome Res. 2005 Sep;15(9):1222-31
references: 16140990
references: PLoS Genet. 2006 May;2(5):e70
references: 16680198
references: Nat Genet. 2009 May;41(5):625-9
references: 19349985
references: Annu Rev Genomics Hum Genet. 2009;10:285-311
references: 19630562
references: Science. 2010 Feb 12;327(5967):876-9
references: 20044541
references: Nat Genet. 2010 Oct;42(10):859-63
references: 20818382
references: Methods Mol Biol. 2011;688:143-53
references: 20938837
references: PLoS Biol. 2011;9(2):e1000594
references: 21347245
references: Nature. 2011 Apr 21;472(7343):375-8
references: 21460839
references: Genome Biol Evol. 2011;3:516-27
references: 21670083
references: PLoS Genet. 2014 Feb;10(2):e1004106
references: 24516398
references: Science. 2014 Nov 14;346(6211):1256442
references: 25395542
references: PLoS Genet. 2006 Sep 22;2(9):e148
references: 17044736
references: Nature. 2007 Oct 18;449(7164):851-61
references: 17943122
references: Epigenetics. 2008 Jan-Feb;3(1):5-13
references: 18259118
references: PLoS Genet. 2008 May;4(5):e1000071
references: 18464896
references: Nature. 2008 Jul 24;454(7203):479-85
references: 18615017
references: Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10471-6
references: 18650392
references: Genetics. 2001 May;158(1):109-22
references: 11333222
references: Nat Rev Genet. 2011 Nov;12(11):756-66
references: 21969038
references: Trends Genet. 2012 Mar;28(3):101-9
references: 22154475
references: Nucleic Acids Res. 2012 Mar;40(6):2611-22
references: 22135286
references: Science. 2012 Apr 13;336(6078):193-8
references: 22422862
references: PLoS Genet. 2012;8(4):e1002659
references: 22532806
references: Genetics. 2012 May;191(1):215-32
references: 22377632
references: PLoS One. 2012;7(4):e36064
references: 22558329
references: Nature. 2012 May 31;485(7400):642-5
references: 22660327
references: Nature. 2012 Aug 23;488(7412):471-5
references: 22914163
references: Nat Genet. 2012 Nov;44(11):1277-81
references: 23001126
references: Nat Rev Genet. 2013 Apr;14(4):262-74
references: 23478346
references: Genome Res. 2013 May;23(5):749-61
references: 23478400
references: Mol Biol Evol. 2013 Jun;30(6):1409-19
references: 23505044
references: Mol Biol Evol. 2013 Dec;30(12):2612-8
references: 24030552
references: PLoS Biol. 2009 Jan 27;7(1):e26
references: 19175294