title: Mathematical modelling of whole chromosome replication.
abstract: All chromosomes must be completely replicated prior to cell division, a requirement that demands the activation of a sufficient number of appropriately distributed DNA replication origins. Here we investigate how the activity of multiple origins on each chromosome is coordinated to ensure successful replication. We present a stochastic model for whole chromosome replication where the dynamics are based upon the parameters of individual origins. Using this model we demonstrate that mean replication time at any given chromosome position is determined collectively by the parameters of all origins. Combining parameter estimation with extensive simulations we show that there is a range of model parameters consistent with mean replication data, emphasising the need for caution in interpreting such data. In contrast, the replicated-fraction at time points through S phase contains more information than mean replication time data and allowed us to use our model to uniquely estimate many origin parameters. These estimated parameters enable us to make a number of predictions that showed agreement with independent experimental data, confirming that our model has predictive power. In summary, we demonstrate that a stochastic model can recapitulate experimental observations, including those that might be interpreted as deterministic such as ordered origin activation times.
authors.affiliation: Department of Physics, University of Aberdeen, Aberdeen AB24 3UE and School of Biology, University of Nottingham, Nottingham NG7 2UH, UK.
authors.forename: Alessandro P S
authors.initials: AP
authors.lastname: de Moura
authors.forename: Renata
authors.initials: R
authors.lastname: Retkute
authors.forename: Michelle
authors.initials: M
authors.lastname: Hawkins
authors.forename: Conrad A
authors.initials: CA
authors.lastname: Nieduszynski
mesh_terms: D000465:Algorithms; D002875:Chromosomes / Q000378:metabolism*; D015825:Chromosomes, Fungal / Q000378:metabolism; D003198:Computer Simulation; D004261:DNA Replication; D042522:DNA Replication Timing; D007700:Kinetics; D008957:Models, Genetic; D018741:Replication Origin; D012441:Saccharomyces cerevisiae / Q000235:genetics; D013269:Stochastic Processes
references.citation: Chromosome Res. 2010 Jan;18(1):91-102
references.pmid: 20039120
references.citation: Nucleic Acids Res. 2007 Jan;35(Database issue):D40-6
references.pmid: 17065467
references.citation: Nat Rev Genet. 2009 Feb;10(2):122-33
references.pmid: 19139763
references.citation: Mol Cell. 1998 Aug;2(2):173-82
references.pmid: 9734354
references.citation: Phys Rev E Stat Nonlin Soft Matter Phys. 2008 Oct;78(4 Pt 1):041917
references.pmid: 18999465
references.citation: J Mol Biol. 2008 Jan 4;375(1):12-9
references.pmid: 17999930
references.citation: J Mol Biol. 1968 Mar 14;32(2):327-41
references.pmid: 5689363
references.citation: Mol Cell Biol. 2008 Aug;28(16):5071-81
references.pmid: 18573888
references.citation: Genes Dev. 1999 Sep 15;13(18):2360-4
references.pmid: 10500092
references.citation: Proc Natl Acad Sci U S A. 1979 Mar;76(3):1035-9
references.pmid: 375221
references.citation: Genes Dev. 2009 May 1;23(9):1077-90
references.pmid: 19417103
references.citation: J Biochem Mol Biol. 2004 Jan 31;37(1):93-106
references.pmid: 14761307
references.citation: Mol Cell Biol. 1997 Dec;17(12):7159-68
references.pmid: 9372948
references.citation: J Cell Biol. 2006 Jun 5;173(5):673-83
references.pmid: 16754955
references.citation: Nucleic Acids Res. 2005 Apr 28;33(8):2410-20
references.pmid: 15860777
references.citation: Mol Genet Genomics. 2009 Jul;282(1):25-35
references.pmid: 19306105
references.citation: Mol Cell Biol. 2007 Sep;27(18):6396-406
references.pmid: 17636020
references.citation: PLoS One. 2008 Aug 06;3(8):e2919
references.pmid: 18682801
references.citation: Mol Cell Biol. 1993 Aug;13(8):5043-56
references.pmid: 8336734
references.citation: Science. 2001 Oct 5;294(5540):115-21
references.pmid: 11588253
references.citation: Nat Cell Biol. 2006 Feb;8(2):148-55
references.pmid: 16429127
references.citation: J Theor Biol. 2000 Feb 21;202(4):305-14
references.pmid: 10666362
references.citation: Phys Rev Lett. 2009 Apr 17;102(15):158104
references.pmid: 19518676
references.citation: Cell. 2006 Jun 30;125(7):1297-308
references.pmid: 16814716
references.citation: Genes Dev. 2002 Oct 1;16(19):2485-90
references.pmid: 12368259
references.citation: EMBO Rep. 2009 Apr;10(4):406-12
references.pmid: 19218919
references.citation: Curr Biol. 2004 Sep 21;14(18):R778-86
references.pmid: 15380092
references.citation: Genes Cells. 1997 Nov;2(11):667-78
references.pmid: 9491801
references.citation: Genetics. 2008 Dec;180(4):1833-47
references.pmid: 18832352
references.citation: PLoS Genet. 2009 Dec;5(12):e1000755
references.pmid: 19997491
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10326-31
references.pmid: 18647841
references.citation: Genes Dev. 2003 Aug 1;17(15):1817-22
references.pmid: 12897051
references.citation: Cell. 2009 Mar 6;136(5):852-64
references.pmid: 19269364
references.citation: Nat Cell Biol. 2006 Dec;8(12):1313-6
references.pmid: 17139278
references.citation: Genes Dev. 2006 Jul 15;20(14):1874-9
references.pmid: 16847347
references.citation: Genes Cells. 2002 Aug;7(8):781-9
references.pmid: 12167157
references.citation: PLoS Genet. 2006 Sep 8;2(9):e141
references.pmid: 16965179
references.citation: FEBS Lett. 2005 Feb 7;579(4):877-84
references.pmid: 15680967
references.citation: Annu Rev Biochem. 2002;71:333-74
references.pmid: 12045100
references.citation: PLoS One. 2009 Jun 12;4(6):e5899
references.pmid: 19521533
references.citation: BMC Genomics. 2006 Oct 26;7:276
references.pmid: 17067396
references.citation: Genes Cells. 1997 Nov;2(11):655-65
references.pmid: 9491800
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12295-300
references.pmid: 18713859