Abstract
Genomic DNA replicates according to a defined temporal program in which early-replicating loci are associated with open chromatin, higher gene density, and increased gene expression levels, while late-replicating loci tend to be heterochromatic and show higher rates of genomic instability. The ability to measure DNA replication dynamics at genome scale has proven crucial for understanding the mechanisms and cellular consequences of DNA replication timing. Several methods, such as quantification of nucleotide analog incorporation and DNA copy number analyses, can accurately reconstruct the genomic replication timing profiles of various species and cell types. More recent developments have expanded the DNA replication genomic toolkit to assays that directly measure the activity of replication origins, while single-cell replication timing assays are beginning to reveal a new level of replication timing regulation. The combination of these methods, applied on a genomic scale and in multiple biological systems, promises to resolve many open questions and lead to a holistic understanding of how eukaryotic cells replicate their genomes accurately and efficiently.
Similar content being viewed by others
Abbreviations
- MFA:
-
Marker frequency analysis
- ORC:
-
Origin recognition complex
- MCM:
-
Mini-chromosome maintenance
- ChIP:
-
Chromatin immunoprecipitation
- ARS:
-
Autonomous replicating sequence
- SNS-seq:
-
Short nascent strand sequencing
- NSCR:
-
Nascent strand capture and release
- HU:
-
Hydroxyurea
- ini-seq:
-
Initiation site sequencing
- TSS:
-
Transcription start sites
- G4:
-
G-quadruplex
- LCL:
-
Lymphoblastoid cell line
- ESC:
-
Embryonic stem cell
- FISH:
-
Fluorescence in situ hybridization
- SMARD:
-
Single-molecule analysis of replicating DNA
- WGA:
-
Whole-genome amplification
- DOP-PCR:
-
Degenerate-oligonucleotide-primed PCR
- MALBAC:
-
Multiple annealing and looping-based amplification cycles
- LIANTI:
-
Linear amplification via transposon insertion
References
Agier N, Delmas S, Zhang Q, Fleiss A, Jaszczyszyn Y, van Dijk E, Thermes C, Weigt M, Cosentino-Lagomarsino M, Fischer G (2018) The evolution of the temporal program of genome replication. Nat Commun 9:2199
Aladjem MI, Redon CE (2017) Order from clutter: selective interactions at mammalian replication origins. Nat Rev Genet 18:101–116
Almeida R, Fernandez-Justel JM, Santa-Maria C, Cadoret JC, Cano-Aroca L, Lombrana R, Herranz G, Agresti A, Gomez M (2018) Chromatin conformation regulates the coordination between DNA replication and transcription. Nat Commun 9:1590
Arneson, N., Hughes, S., Houlston, R., and Done, S. (2008). Whole-genome amplification by degenerate oligonucleotide primed PCR (DOP-PCR). CSH Protoc 2008, pdb prot4919.
Artemov AV, Andrianova, Bazykin, Seplyarskiy (2019) POLD replicates both strands of small kilobase-long replication bubbles initiated at a majority of human replication origins. BioRxiv. https://doi.org/10.1101/174730
Bartholdy B, Mukhopadhyay R, Lajugie J, Aladjem MI, Bouhassira EE (2015) Allele-specific analysis of DNA replication origins in mammalian cells. Nat Commun 6:7051
Bell SP, Stillman B (1992) ATP-dependent recognition of eukaryotic origins of DNA replication by a multiprotein complex. Nature 357:128–134
Bensimon A, Simon A, Chiffaudel A, Croquette V, Heslot F, Bensimon D (1994) Alignment and sensitive detection of DNA by a moving interface. Science 265:2096–2098
Besnard E, Babled A, Lapasset L, Milhavet O, Parrinello H, Dantec C, Marin JM, Lemaitre JM (2012) Unraveling cell type-specific and reprogrammable human replication origin signatures associated with G-quadruplex consensus motifs. Nat Struct Mol Biol 19:837–844
Bester AC, Roniger M, Oren YS, Im MM, Sarni D, Chaoat M, Bensimon A, Zamir G, Shewach DS, Kerem B (2011) Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell 145:435–446
Bielinsky AK, Gerbi SA (1998) Discrete start sites for DNA synthesis in the yeast ARS1 origin. Science 279:95–98
Biernacka A, Zhu Y, Skrzypczak M, Forey R, Pardo B, Grzelak M, Nde J, Mitra A, Kudlicki A, Crosetto N et al (2018) i-BLESS is an ultra-sensitive method for detection of DNA double-strand breaks. Commun Biol 1:181
Blainey PC (2013) The future is now: single-cell genomics of bacteria and archaea. FEMS Microbiol Rev 37:407–427
Blow JJ, Gillespie PJ, Francis D, Jackson DA (2001) Replication origins in Xenopus egg extract are 5-15 kilobases apart and are activated in clusters that fire at different times. J Cell Biol 152:15–25
Brody Y, Kimmerling RJ, Maruvka YE, Benjamin D, Elacqua JJ, Haradhvala NJ, Kim J, Mouw KW, Frangaj K, Koren A et al (2018) Quantification of somatic mutation flow across individual cell division events by lineage sequencing. Genome Res 28:1901–1918
Bryan DS, Ransom M, Adane B, York K, Hesselberth JR (2014) High resolution mapping of modified DNA nucleobases using excision repair enzymes. Genome Res 24:1534–1542
Cadoret JC, Meisch F, Hassan-Zadeh V, Luyten I, Guillet C, Duret L, Quesneville H, Prioleau MN (2008) Genome-wide studies highlight indirect links between human replication origins and gene regulation. Proc Natl Acad Sci U S A 105:15837–15842
Canela A, Sridharan S, Sciascia N, Tubbs A, Meltzer P, Sleckman BP, Nussenzweig A (2016) DNA breaks and end resection measured genome-wide by end sequencing. Mol Cell 63:898–911
Cayrou C, Ballester B, Peiffer I, Fenouil R, Coulombe P, Andrau JC, van Helden J, Mechali M (2015) The chromatin environment shapes DNA replication origin organization and defines origin classes. Genome Res 25:1873–1885
Cayrou C, Coulombe P, Vigneron A, Stanojcic S, Ganier O, Peiffer I, Rivals E, Puy A, Laurent-Chabalier S, Desprat R et al (2011) Genome-scale analysis of metazoan replication origins reveals their organization in specific but flexible sites defined by conserved features. Genome Res 21:1438–1449
Chen C, Xing D, Tan L, Li H, Zhou G, Huang L, Xie XS (2017) Single-cell whole-genome analyses by linear amplification via transposon insertion (LIANTI). Science 356:189–194
Chen CL, Rappailles A, Duquenne L, Huvet M, Guilbaud G, Farinelli L, Audit B, d'Aubenton-Carafa, Y., Arneodo, A., Hyrien, O., et al. (2010) Impact of replication timing on non-CpG and CpG substitution rates in mammalian genomes. Genome Res 20:447–457
Chen YH, Keegan S, Kahli M, Tonzi P, Fenyo D, Huang TT, Smith DJ (2019) Transcription shapes DNA replication initiation and termination in human cells. Nat Struct Mol Biol 26:67–77
Clarke J, Wu HC, Jayasinghe L, Patel A, Reid S, Bayley H (2009) Continuous base identification for single-molecule nanopore DNA sequencing. Nat Nanotechnol 4:265–270
Clausen AR, Lujan SA, Burkholder AB, Orebaugh CD, Williams JS, Clausen MF, Malc EP, Mieczkowski PA, Fargo DC, Smith DJ et al (2015) Tracking replication enzymology in vivo by genome-wide mapping of ribonucleotide incorporation. Nat Struct Mol Biol 22:185–191
Comoglio F, Schlumpf T, Schmid V, Rohs R, Beisel C, Paro R (2015) High-resolution profiling of Drosophila replication start sites reveals a DNA shape and chromatin signature of metazoan origins. Cell Rep 11:821–834
Concia L, Brooks AM, Wheeler E, Zynda GJ, Wear EE, LeBlanc C, Song J, Lee TJ, Pascuzzi PE, Martienssen RA et al (2018) Genome-wide analysis of the Arabidopsis replication timing program. Plant Physiol 176:2166–2185
Czajkowsky DM, Liu J, Hamlin JL, Shao Z (2008) DNA combing reveals intrinsic temporal disorder in the replication of yeast chromosome VI. J Mol Biol 375:12–19
Daigaku Y, Keszthelyi A, Muller CA, Miyabe I, Brooks T, Retkute R, Hubank M, Nieduszynski CA, Carr AM (2015) A global profile of replicative polymerase usage. Nat Struct Mol Biol 22:192–198
Davis Bell, A., Mello, Nemesh, Brumbaugh, Wysoker, and McCarroll (2019). Insights about variation in meiosis from 31,228 human sperm genomes. BioRxiv https://doi.org/10.1101/625202.
De Carli F, Gaggioli V, Millot GA, Hyrien O (2016) Single-molecule, antibody-free fluorescent visualisation of replication tracts along barcoded DNA molecules. Int J Dev Biol 60:297–304
De Carli F, Menezes B, Barbe G, Hyrien O (2018) High-throughput optical mapping of replicating DNA. Small Methods. https://doi.org/10.1002/smtd.201800146
de Moura AP, Retkute R, Hawkins M, Nieduszynski CA (2010) Mathematical modelling of whole chromosome replication. Nucleic Acids Res 38:5623–5633
Dellino GI, Cittaro D, Piccioni R, Luzi L, Banfi S, Segalla S, Cesaroni M, Mendoza-Maldonado R, Giacca M, Pelicci PG (2013) Genome-wide mapping of human DNA-replication origins: levels of transcription at ORC1 sites regulate origin selection and replication timing. Genome Res 23:1–11
Desprat R, Thierry-Mieg D, Lailler N, Lajugie J, Schildkraut C, Thierry-Mieg J, Bouhassira EE (2009) Predictable dynamic program of timing of DNA replication in human cells. Genome Res 19:2288–2299
Diffley JF, Cocker JH (1992) Protein-DNA interactions at a yeast replication origin. Nature 357:169–172
Dileep V, Gilbert DM (2018) Single-cell replication profiling to measure stochastic variation in mammalian replication timing. Nat Commun 9:427
Du Q, Bert SA, Armstrong NJ, Caldon CE, Song JZ, Nair SS, Gould CM, Luu PL, Peters T, Khoury A et al (2019) Replication timing and epigenome remodelling are associated with the nature of chromosomal rearrangements in cancer. Nat Commun 10:416
Fangman WL, Brewer BJ (1991) Activation of replication origins within yeast chromosomes. Annu Rev Cell Biol 7:375–402
Farkash-Amar S, Lipson D, Polten A, Goren A, Helmstetter C, Yakhini Z, Simon I (2008) Global organization of replication time zones of the mouse genome. Genome Res 18:1562–1570
Farkash-Amar S, Simon I (2010) Genome-wide analysis of the replication program in mammals. Chromosom Res 18:115–125
Feng W, Collingwood D, Boeck ME, Fox LA, Alvino GM, Fangman WL, Raghuraman MK, Brewer BJ (2006) Genomic mapping of single-stranded DNA in hydroxyurea-challenged yeasts identifies origins of replication. Nat Cell Biol 8:148–155
Foss EJ, Sripathy G-S, Kwak T, Lao, Bedalov (2019) Chromosomal Mcm2-7 distribution is a primary driver of genome replication timing in budding yeast, fission yeast and mouse. BioRxiv. https://doi.org/10.1101/737742
Foulk MS, Urban JM, Casella C, Gerbi SA (2015) Characterizing and controlling intrinsic biases of lambda exonuclease in nascent strand sequencing reveals phasing between nucleosomes and G-quadruplex motifs around a subset of human replication origins. Genome Res 25:725–735
Frum RA, Khondker ZS, Kaufman DG (2009) Temporal differences in DNA replication during the S phase using single fiber analysis of normal human fibroblasts and glioblastoma T98G cells. Cell Cycle 8:3133–3148
Gaboriaud J, Wu PJ (2019) Insights into the link between the organization of DNA replication and the mutational landscape. Genes (Basel) 10
Gartler SM, Goldstein L, Tyler-Freer SE, Hansen RS (1999) The timing of XIST replication: dominance of the domain. Hum Mol Genet 8:1085–1089
Gawad C, Koh W, Quake SR (2016) Single-cell genome sequencing: current state of the science. Nat Rev Genet 17:175–188
Gdula MR, Nesterova TB, Pintacuda G, Godwin J, Zhan Y, Ozadam H, McClellan M, Moralli D, Krueger F, Green CM et al (2019) The non-canonical SMC protein SmcHD1 antagonises TAD formation and compartmentalisation on the inactive X chromosome. Nat Commun 10:30
Georgieva D, Liu Q, Wang K, Egli D (2019) Detection of base analogs incorporated during DNA replication by nanopore sequencing. BioRxiv. https://doi.org/10.1101/549220
Gilbert DM (2004) In search of the holy replicator. Nat Rev Mol Cell Biol 5:848–855
Gispan A, Carmi M, Barkai N (2014) Checkpoint-independent scaling of the Saccharomyces cerevisiae DNA replication program. BMC Biol 12:79
Gispan A, Carmi M, Barkai N (2017) Model-based analysis of DNA replication profiles: predicting replication fork velocity and initiation rate by profiling free-cycling cells. Genome Res 27:310–319
Gitlin AD, Mayer CT, Oliveira TY, Shulman Z, Jones MJ, Koren A, Nussenzweig MC (2015) HUMORAL IMMUNITY. T cell help controls the speed of the cell cycle in germinal center B cells. Science 349:643–646
Guilbaud G, Rappailles A, Baker A, Chen CL, Arneodo A, Goldar A, d'Aubenton-Carafa Y, Thermes C, Audit B, Hyrien O (2011) Evidence for sequential and increasing activation of replication origins along replication timing gradients in the human genome. PLoS Comput Biol 7:e1002322
Hansen RS, Canfield TK, Gartler SM (1995) Reverse replication timing for the XIST gene in human fibroblasts. Hum Mol Genet 4:813–820
Hansen RS, Canfield TK, Lamb MM, Gartler SM, Laird CD (1993) Association of fragile X syndrome with delayed replication of the FMR1 gene. Cell 73:1403–1409
Hansen RS, Thomas S, Sandstrom R, Canfield TK, Thurman RE, Weaver M, Dorschner MO, Gartler SM, Stamatoyannopoulos JA (2010) Sequencing newly replicated DNA reveals widespread plasticity in human replication timing. Proc Natl Acad Sci U S A 107:139–144
Haradhvala NJ, Polak P, Stojanov P, Covington KR, Shinbrot E, Hess JM, Rheinbay E, Kim J, Maruvka YE, Braunstein LZ et al (2016) Mutational strand asymmetries in cancer genomes reveal mechanisms of DNA damage and repair. Cell 164:538–549
Hennion M, Arbona, Cruaud, Proux, Tallec L, Novikova, Engelen, Lemainque, Audit, Hyrien (2018) Mapping DNA replication with nanopore sequencing. BioRxiv. https://doi.org/10.1101/426858
Herrick J, Stanislawski P, Hyrien O, Bensimon A (2000) Replication fork density increases during DNA synthesis in X. laevis egg extracts. J Mol Biol 300:1133–1142
Hiratani I, Ryba T, Itoh M, Yokochi T, Schwaiger M, Chang CW, Lyou Y, Townes TM, Schubeler D, Gilbert DM (2008) Global reorganization of replication domains during embryonic stem cell differentiation. PLoS Biol 6:e245
Hoshina S, Yura K, Teranishi H, Kiyasu N, Tominaga A, Kadoma H, Nakatsuka A, Kunichika T, Obuse C, Waga S (2013) Human origin recognition complex binds preferentially to G-quadruplex-preferable RNA and single-stranded DNA. J Biol Chem 288:30161–30171
Hu J, Adar S, Selby CP, Lieb JD, Sancar A (2015) Genome-wide analysis of human global and transcription-coupled excision repair of UV damage at single-nucleotide resolution. Genes Dev 29:948–960
Huberman JA, Riggs AD (1968) On the mechanism of DNA replication in mammalian chromosomes. J Mol Biol 32:327–341
Huvet M, Nicolay S, Touchon M, Audit B, d'Aubenton-Carafa, Y., Arneodo, A., and Thermes, C. (2007) Human gene organization driven by the coordination of replication and transcription. Genome Res 17:1278–1285
Hyrien O (2015) Peaks cloaked in the mist: the landscape of mammalian replication origins. J Cell Biol 208:147–160
Jeon Y, Bekiranov S, Karnani N, Kapranov P, Ghosh S, MacAlpine D, Lee C, Hwang DS, Gingeras TR, Dutta A (2005) Temporal profile of replication of human chromosomes. Proc Natl Acad Sci U S A 102:6419–6424
Jinks-Robertson S, Klein HL (2015) Ribonucleotides in DNA: hidden in plain sight. Nat Struct Mol Biol 22:176–178
Jodkowska K, Pancaldi A, Rigau G-C, Fernández-Justel R-A, Rubio-Camarillo P, C.-d.S., Pisano et al (2019) Three-dimensional connectivity and chromatin environment mediate the activation efficiency of mammalian DNA replication origins. BioRxiv. https://doi.org/10.1101/644971
Karnani N, Taylor CM, Malhotra A, Dutta A (2010) Genomic study of replication initiation in human chromosomes reveals the influence of transcription regulation and chromatin structure on origin selection. Mol Biol Cell 21:393–404
Keller H, Kiosze K, Sachsenweger J, Haumann S, Ohlenschlager O, Nuutinen T, Syvaoja JE, Gorlach M, Grosse F, Pospiech H (2014) The intrinsically disordered amino-terminal region of human RecQL4: multiple DNA-binding domains confer annealing, strand exchange and G4 DNA binding. Nucleic Acids Res 42:12614–12627
Klein HL (2017) Genome instabilities arising from ribonucleotides in DNA. DNA Repair (Amst) 56:26–32
Klein K, Wang B, Chan Z, Weng H, Chen G, Rhind (2017) Genome-wide identification of early-firing human replication origins by optical replication mapping. BioRxiv. https://doi.org/10.1101/214841
Knott SR, Peace JM, Ostrow AZ, Gan Y, Rex AE, Viggiani CJ, Tavare S, Aparicio OM (2012) Forkhead transcription factors establish origin timing and long-range clustering in S. cerevisiae. Cell 148:99–111
Koren A, Handsaker RE, Kamitaki N, Karlic R, Ghosh S, Polak P, Eggan K, McCarroll SA (2014) Genetic variation in human DNA replication timing. Cell 159:1015–1026
Koren A, McCarroll SA (2014) Random replication of the inactive X chromosome. Genome Res 24:64–69
Koren A, Polak P, Nemesh J, Michaelson JJ, Sebat J, Sunyaev SR, McCarroll SA (2012) Differential relationship of DNA replication timing to different forms of human mutation and variation. Am J Hum Genet 91:1033–1040
Koren A, Soifer I, Barkai N (2010a) MRC1-dependent scaling of the budding yeast DNA replication timing program. Genome Res 20:781–790
Koren A, Tsai HJ, Tirosh I, Burrack LS, Barkai N, Berman J (2010b) Epigenetically-inherited centromere and neocentromere DNA replicates earliest in S-phase. PLoS Genet 6:e1001068
Kumagai A, Dunphy WG (2017) MTBP, the partner of Treslin, contains a novel DNA-binding domain that is essential for proper initiation of DNA replication. Mol Biol Cell 28:2998–3012
Kunnev D, Freeland A, Qin M, Leach RW, Wang J, Shenoy RM, Pruitt SC (2015) Effect of minichromosome maintenance protein 2 deficiency on the locations of DNA replication origins. Genome Res 25:558–569
Labit H, Perewoska I, Germe T, Hyrien O, Marheineke K (2008) DNA replication timing is deterministic at the level of chromosomal domains but stochastic at the level of replicons in Xenopus egg extracts. Nucleic Acids Res 36:5623–5634
Lacroix J, Pelofy S, Blatche C, Pillaire MJ, Huet S, Chapuis C, Hoffmann JS, Bancaud A (2016) Analysis of DNA replication by optical mapping in nanochannels. Small 12:5963–5970
Laks E, McPherson A, Zahn H, Lai D, Steif A, Brimhall J, Biele J, Wang B, Masud T, Ting J et al (2019) Clonal decomposition and DNA replication states defined by scaled single-cell genome sequencing. Cell 179:1207–1221 e1222
Lamm N, Maoz K, Bester AC, Im MM, Shewach DS, Karni R, Kerem B (2015) Folate levels modulate oncogene-induced replication stress and tumorigenicity. EMBO Mol Med 7:1138–1152
Langley AR, Graf S, Smith JC, Krude T (2016) Genome-wide identification and characterisation of human DNA replication origins by initiation site sequencing (ini-seq). Nucleic Acids Res 44:10230–10247
Lebofsky R, Heilig R, Sonnleitner M, Weissenbach J, Bensimon A (2006) DNA replication origin interference increases the spacing between initiation events in human cells. Mol Biol Cell 17:5337–5345
Li B, Su T, Ferrari R, Li JY, Kurdistani SK (2014) A unique epigenetic signature is associated with active DNA replication loci in human embryonic stem cells. Epigenetics 9:257–267
Liachko I, Youngblood RA, Keich U, Dunham MJ (2013) High-resolution mapping, characterization, and optimization of autonomously replicating sequences in yeast. Genome Res 23:698–704
Liachko I, Youngblood RA, Tsui K, Bubb KL, Queitsch C, Raghuraman MK, Nislow C, Brewer BJ, Dunham MJ (2014) GC-rich DNA elements enable replication origin activity in the methylotrophic yeast Pichia pastoris. PLoS Genet 10:e1004169
Lombrana R, Alvarez A, Fernandez-Justel JM, Almeida R, Poza-Carrion C, Gomes F, Calzada A, Requena JM, Gomez M (2016) Transcriptionally driven DNA replication program of the human parasite Leishmania major. Cell Rep 16:1774–1786
Lynch KL, Alvino GM, Kwan EX, Brewer BJ, Raghuraman MK (2019) The effects of manipulating levels of replication initiation factors on origin firing efficiency in yeast. PLoS Genet 15:e1008430
MacAlpine HK, Gordan R, Powell SK, Hartemink AJ, MacAlpine DM (2010) Drosophila ORC localizes to open chromatin and marks sites of cohesin complex loading. Genome Res 20:201–211
Macheret M, Halazonetis TD (2018) Intragenic origins due to short G1 phases underlie oncogene-induced DNA replication stress. Nature 555:112–116
Maine GT, Sinha P, Tye BK (1984) Mutants of S. cerevisiae defective in the maintenance of minichromosomes. Genetics 106:365–385
Mantiero D, Mackenzie A, Donaldson A, Zegerman P (2011) Limiting replication initiation factors execute the temporal programme of origin firing in budding yeast. EMBO J 30:4805–4814
Mao P, Brown AJ, Malc EP, Mieczkowski PA, Smerdon MJ, Roberts SA, Wyrick JJ (2017) Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity. Genome Res 27:1674–1684
Martin MM, Ryan M, Kim R, Zakas AL, Fu H, Lin CM, Reinhold WC, Davis SR, Bilke S, Liu H et al (2011) Genome-wide depletion of replication initiation events in highly transcribed regions. Genome Res 21:1822–1832
Masai H, Kakusho N, Fukatsu R, Ma Y, Iida K, Kanoh Y, Nagasawa K (2018) Molecular architecture of G-quadruplex structures generated on duplex Rif1-binding sequences. J Biol Chem 293:17033–17049
Massey DJ, Kim D, Brooks KE, Smolka MB, Koren A (2019) Next-generation sequencing enables spatiotemporal resolution of human centromere replication timing. Genes (Basel) 10
Massip F, Laurent M, Brossas C, Fernandez-Justel JM, Gomez M, Prioleau MN, Duret L, Picard F (2019) Evolution of replication origins in vertebrate genomes: rapid turnover despite selective constraints. Nucleic Acids Res 47:5114–5125
McGuffee SR, Smith DJ, Whitehouse I (2013) Quantitative, genome-wide analysis of eukaryotic replication initiation and termination. Mol Cell 50:123–135
Mesner LD, Valsakumar V, Cieslik M, Pickin R, Hamlin JL, Bekiranov S (2013) Bubble-seq analysis of the human genome reveals distinct chromatin-mediated mechanisms for regulating early- and late-firing origins. Genome Res 23:1774–1788
Michalet X, Ekong R, Fougerousse F, Rousseaux S, Schurra C, Hornigold N, van Slegtenhorst M, Wolfe J, Povey S, Beckmann JS et al (1997) Dynamic molecular combing: stretching the whole human genome for high-resolution studies. Science 277:1518–1523
Miotto B, Ji Z, Struhl K (2016) Selectivity of ORC binding sites and the relation to replication timing, fragile sites, and deletions in cancers. Proc Natl Acad Sci U S A 113:E4810–E4819
Miura H, Takahashi S, Poonperm R, Tanigawa A, Takebayashi SI, Hiratani I (2019) Single-cell DNA replication profiling identifies spatiotemporal developmental dynamics of chromosome organization. Nat Genet 51:1356–1368
Moller HD, Mohiyuddin M, Prada-Luengo I, Sailani MR, Halling JF, Plomgaard P, Maretty L, Hansen AJ, Snyder MP, Pilegaard H et al (2018) Circular DNA elements of chromosomal origin are common in healthy human somatic tissue. Nat Commun 9:1069
Mukhopadhyay R, Lajugie J, Fourel N, Selzer A, Schizas M, Bartholdy B, Mar J, Lin CM, Martin MM, Ryan M et al (2014) Allele-specific genome-wide profiling in human primary erythroblasts reveal replication program organization. PLoS Genet 10:e1004319
Muller CA, Boemo MA, Spingardi P, Kessler BM, Kriaucionis S, Simpson JT, Nieduszynski CA (2019) Capturing the dynamics of genome replication on individual ultra-long nanopore sequence reads. Nat Methods 16:429–436
Muller CA, Hawkins M, Retkute R, Malla S, Wilson R, Blythe MJ, Nakato R, Komata M, Shirahige K, de Moura AP et al (2014) The dynamics of genome replication using deep sequencing. Nucleic Acids Res 42:e3
Muller CA, Nieduszynski CA (2012) Conservation of replication timing reveals global and local regulation of replication origin activity. Genome Res 22:1953–1962
Nieduszynski CA, Knox Y, Donaldson AD (2006) Genome-wide identification of replication origins in yeast by comparative genomics. Genes Dev 20:1874–1879
Norio P, Kosiyatrakul S, Yang Q, Guan Z, Brown NM, Thomas S, Riblet R, Schildkraut CL (2005) Progressive activation of DNA replication initiation in large domains of the immunoglobulin heavy chain locus during B cell development. Mol Cell 20:575–587
Norio P, Schildkraut CL (2001) Visualization of DNA replication on individual Epstein-Barr virus episomes. Science 294:2361–2364
Owiti N, Wei S, Bhagwat AS, Kim N (2018) Unscheduled DNA synthesis leads to elevated uracil residues at highly transcribed genomic loci in Saccharomyces cerevisiae. PLoS Genet 14:e1007516
Pasero P, Bensimon A, Schwob E (2002) Single-molecule analysis reveals clustering and epigenetic regulation of replication origins at the yeast rDNA locus. Genes Dev 16:2479–2484
Patel PK, Arcangioli B, Baker SP, Bensimon A, Rhind N (2006) DNA replication origins fire stochastically in fission yeast. Mol Biol Cell 17:308–316
Peace JM, Villwock SK, Zeytounian JL, Gan Y, Aparicio OM (2016) Quantitative BrdU immunoprecipitation method demonstrates that Fkh1 and Fkh2 are rate-limiting activators of replication origins that reprogram replication timing in G1 phase. Genome Res 26:365–375
Perkins TT, Dalal RV, Mitsis PG, Block SM (2003) Sequence-dependent pausing of single lambda exonuclease molecules. Science 301:1914–1918
Petryk N, Dalby M, Wenger A, Stromme CB, Strandsby A, Andersson R, Groth A (2018) MCM2 promotes symmetric inheritance of modified histones during DNA replication. Science 361:1389–1392
Petryk N, Kahli M, d'Aubenton-Carafa Y, Jaszczyszyn Y, Shen Y, Silvain M, Thermes C, Chen CL, Hyrien O (2016) Replication landscape of the human genome. Nat Commun 7:10208
Picard F, Cadoret JC, Audit B, Arneodo A, Alberti A, Battail C, Duret L, Prioleau MN (2014) The spatiotemporal program of DNA replication is associated with specific combinations of chromatin marks in human cells. PLoS Genet 10:e1004282
Piunti A, Rossi A, Cerutti A, Albert M, Jammula S, Scelfo A, Cedrone L, Fragola G, Olsson L, Koseki H et al (2014) Polycomb proteins control proliferation and transformation independently of cell cycle checkpoints by regulating DNA replication. Nat Commun 5:3649
Polak P, Arndt PF (2009) Long-range bidirectional strand asymmetries originate at CpG islands in the human genome. Genome Biol Evol 1:189–197
Pomerantz RT, O'Donnell M (2008) The replisome uses mRNA as a primer after colliding with RNA polymerase. Nature 456:762–766
Pope BD, Gilbert DM (2013) The replication domain model: regulating replicon firing in the context of large-scale chromosome architecture. J Mol Biol 425:4690–4695
Pope BD, Ryba T, Dileep V, Yue F, Wu W, Denas O, Vera DL, Wang Y, Hansen RS, Canfield TK et al (2014) Topologically associating domains are stable units of replication-timing regulation. Nature 515:402–405
Prioleau MN (2017) G-quadruplexes and DNA replication origins. Adv Exp Med Biol 1042:273–286
Prioleau MN, MacAlpine DM (2016) DNA replication origins-where do we begin? Genes Dev 30:1683–1697
Prorok P, Artufel M, Aze A, Coulombe P, Peiffer I, Lacroix L, Guedin A, Mergny JL, Damaschke J, Schepers A et al (2019) Involvement of G-quadruplex regions in mammalian replication origin activity. Nat Commun 10:3274
Raghuraman MK, Brewer BJ (2010) Molecular analysis of the replication program in unicellular model organisms. Chromosom Res 18:19–34
Raghuraman MK, Winzeler EA, Collingwood D, Hunt S, Wodicka L, Conway A, Lockhart DJ, Davis RW, Brewer BJ, Fangman WL (2001) Replication dynamics of the yeast genome. Science 294:115–121
Ravoityte B, Wellinger RE (2017) Non-canonical replication initiation: you’re fired! Genes (Basel) 8
Reijns MAM, Kemp H, Ding J, de Proce SM, Jackson AP, Taylor MS (2015) Lagging-strand replication shapes the mutational landscape of the genome. Nature 518:502–506
Rhind N, Gilbert DM (2013) DNA replication timing. Cold Spring Harb Perspect Biol 5:a010132
Rhind N, Yang SC, Bechhoefer J (2010) Reconciling stochastic origin firing with defined replication timing. Chromosom Res 18:35–43
Rivera-Mulia JC, Buckley Q, Sasaki T, Zimmerman J, Didier RA, Nazor K, Loring JF, Lian Z, Weissman S, Robins AJ et al (2015) Dynamic changes in replication timing and gene expression during lineage specification of human pluripotent stem cells. Genome Res 25:1091–1103
Rivera-Mulia JC, Dimond A, Vera D, Trevilla-Garcia C, Sasaki T, Zimmerman J, Dupont C, Gribnau J, Fraser P, Gilbert DM (2018) Allele-specific control of replication timing and genome organization during development. Genome Res 28:800–811
Rivera-Mulia JC, Sasaki T, Trevilla-Garcia C, Nakamichi N, Knapp D, Hammond CA, Chang BH, Tyner JW, Devidas M, Zimmerman J et al (2019) Replication timing alterations in leukemia affect clinically relevant chromosome domains. Blood Adv 3:3201–3213
Rudolph CJ, Upton AL, Stockum A, Nieduszynski CA, Lloyd RG (2013) Avoiding chromosome pathology when replication forks collide. Nature 500:608–611
Ryba T, Hiratani I, Lu J, Itoh M, Kulik M, Zhang J, Schulz TC, Robins AJ, Dalton S, Gilbert DM (2010) Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell types. Genome Res 20:761–770
Schubeler D, Scalzo D, Kooperberg C, van Steensel B, Delrow J, Groudine M (2002) Genome-wide DNA replication profile for Drosophila melanogaster: a link between transcription and replication timing. Nat Genet 32:438–442
Sequeira-Mendes J, Diaz-Uriarte R, Apedaile A, Huntley D, Brockdorff N, Gomez M (2009) Transcription initiation activity sets replication origin efficiency in mammalian cells. PLoS Genet 5:e1000446
Sequeira-Mendes J, Vergara Z, Peiro R, Morata J, Araguez I, Costas C, Mendez-Giraldez R, Casacuberta JM, Bastolla U, Gutierrez C (2019) Differences in firing efficiency, chromatin, and transcription underlie the developmental plasticity of the Arabidopsis DNA replication origins. Genome Res 29:784–797
Shibata Y, Kumar P, Layer R, Willcox S, Gagan JR, Griffith JD, Dutta A (2012) Extrachromosomal microDNAs and chromosomal microdeletions in normal tissues. Science 336:82–86
Shinbrot E, Henninger EE, Weinhold N, Covington KR, Goksenin AY, Schultz N, Chao H, Doddapaneni H, Muzny DM, Gibbs RA et al (2014) Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication. Genome Res 24:1740–1750
Siefert JC, Georgescu C, Wren JD, Koren A, Sansam CL (2017) DNA replication timing during development anticipates transcriptional programs and parallels enhancer activation. Genome Res 27:1406–1416
Smith DJ, Whitehouse I (2012) Intrinsic coupling of lagging-strand synthesis to chromatin assembly. Nature 483:434–438
Smith OK, Kim R, Fu H, Martin MM, Lin CM, Utani K, Zhang Y, Marks AB, Lalande M, Chamberlain S et al (2016) Distinct epigenetic features of differentiation-regulated replication origins. Epigenetics Chromatin 9:18
Stuckey R, Garcia-Rodriguez N, Aguilera A, Wellinger RE (2015) Role for RNA:DNA hybrids in origin-independent replication priming in a eukaryotic system. Proc Natl Acad Sci U S A 112:5779–5784
Sueoka N, Yoshikawa H (1965) The chromosome of Bacillus subtilis. I. Theory of marker frequency analysis. Genetics 52:747–757
Sugimoto N, Maehara K, Yoshida K, Ohkawa Y, Fujita M (2018) Genome-wide analysis of the spatiotemporal regulation of firing and dormant replication origins in human cells. Nucleic Acids Res 46:6683–6696
Takahashi S, Miura H, Shibata T, Nagao K, Okumura K, Ogata M, Obuse C, Takebayashi SI, Hiratani I (2019) Genome-wide stability of the DNA replication program in single mammalian cells. Nat Genet 51:529–540
Tanaka S, Nakato R, Katou Y, Shirahige K, Araki H (2011) Origin association of Sld3, Sld7, and Cdc45 proteins is a key step for determination of origin-firing timing. Curr Biol 21:2055–2063
Telenius H, Carter NP, Bebb CE, Nordenskjold M, Ponder BA, Tunnacliffe A (1992) Degenerate oligonucleotide-primed PCR: general amplification of target DNA by a single degenerate primer. Genomics 13:718–725
Tomkova M, Tomek J, Kriaucionis S, Schuster-Bockler B (2018) Mutational signature distribution varies with DNA replication timing and strand asymmetry. Genome Biol 19:129
Touchon M, Nicolay S, Audit B, Brodie of Brodie, E.B, d'Aubenton-Carafa Y, Arneodo A, Thermes C (2005) Replication-associated strand asymmetries in mammalian genomes: toward detection of replication origins. Proc Natl Acad Sci U S A 102:9836–9841
Tubbs A, Sridharan S, van Wietmarschen N, Maman Y, Callen E, Stanlie A, Wu W, Wu X, Day A, Wong N et al (2018) Dual roles of poly(dA:dT) tracts in replication initiation and fork collapse. Cell 174:1127–1142 e1119
Tye BK (1999) MCM proteins in DNA replication. Annu Rev Biochem 68:649–686
Urban JM, Foulk MS, Casella C, Gerbi SA (2015) The hunt for origins of DNA replication in multicellular eukaryotes. F1000Prime Rep 7, 30
Valton AL, Hassan-Zadeh V, Lema I, Boggetto N, Alberti P, Saintome C, Riou JF, Prioleau MN (2014) G4 motifs affect origin positioning and efficiency in two vertebrate replicators. EMBO J 33:732–746
Van der Aa N, Cheng J, Mateiu L, Zamani Esteki M, Kumar P, Dimitriadou E, Vanneste E, Moreau Y, Vermeesch JR, Voet T (2013) Genome-wide copy number profiling of single cells in S-phase reveals DNA-replication domains. Nucleic Acids Res 41:e66
Vashee S, Cvetic C, Lu W, Simancek P, Kelly TJ, Walter JC (2003) Sequence-independent DNA binding and replication initiation by the human origin recognition complex. Genes Dev 17:1894–1908
Vitak SA, Torkenczy KA, Rosenkrantz JL, Fields AJ, Christiansen L, Wong MH, Carbone L, Steemers FJ, Adey A (2017) Sequencing thousands of single-cell genomes with combinatorial indexing. Nat Methods 14:302–308
Williams JS, Lujan SA, Kunkel TA (2016) Processing ribonucleotides incorporated during eukaryotic DNA replication. Nat Rev Mol Cell Biol 17:350–363
Wong PG, Winter SL, Zaika E, Cao TV, Oguz U, Koomen JM, Hamlin JL, Alexandrow MG (2011) Cdc45 limits replicon usage from a low density of preRCs in mammalian cells. PLoS One 6:e17533
Woodfine K, Fiegler H, Beare DM, Collins JE, McCann OT, Young BD, Debernardi S, Mott R, Dunham I, Carter NP (2004) Replication timing of the human genome. Hum Mol Genet 13:191–202
Wu X, Kabalane H, Kahli M, Petryk N, Laperrousaz B, Jaszczyszyn Y, Drillon G, Nicolini FE, Perot G, Robert A et al (2018) Developmental and cancer-associated plasticity of DNA replication preferentially targets GC-poor, lowly expressed and late-replicating regions. Nucleic Acids Res 46:10157–10172
Wyrick JJ, Aparicio JG, Chen T, Barnett JD, Jennings EG, Young RA, Bell SP, Aparicio OM (2001) Genome-wide distribution of ORC and MCM proteins in S. cerevisiae: high-resolution mapping of replication origins. Science 294:2357–2360
Xiao M, Phong A, Ha C, Chan TF, Cai D, Leung L, Wan E, Kistler AL, DeRisi JL, Selvin PR et al (2007) Rapid DNA mapping by fluorescent single molecule detection. Nucleic Acids Res 35:e16
Xu B, Clayton DA (1996) RNA-DNA hybrid formation at the human mitochondrial heavy-strand origin ceases at replication start sites: an implication for RNA-DNA hybrids serving as primers. EMBO J 15:3135–3143
Yabuki N, Terashima H, Kitada K (2002) Mapping of early firing origins on a replication profile of budding yeast. Genes Cells 7:781–789
Yaffe E, Farkash-Amar S, Polten A, Yakhini Z, Tanay A, Simon I (2010) Comparative analysis of DNA replication timing reveals conserved large-scale chromosomal architecture. PLoS Genet 6:e1001011
Yang SC, Rhind N, Bechhoefer J (2010) Modeling genome-wide replication kinetics reveals a mechanism for regulation of replication timing. Mol Syst Biol 6:404
Yang Y, Gu Q, Zhang Y, Sasaki T, Crivello J, O'Neill RJ, Gilbert DM, Ma J (2018) Continuous-trait probabilistic model for comparing multi-species functional genomic data. Cell Syst 7(208-218):e211
Yanga W, Lib X (2013) Next-generation sequencing of Okazaki fragments extracted from Saccharomyces cerevisiae. FEBS Lett 587:2441–2447
Yehuda Y, Blumenfeld B, Mayorek N, Makedonski K, Vardi O, Cohen-Daniel L, Mansour Y, Baror-Sebban S, Masika H, Farago M et al (2018) Germline DNA replication timing shapes mammalian genome composition. Nucleic Acids Res 46:8299–8310
Yin Y, Jiang Y, Lam KG, Berletch JB, Disteche CM, Noble WS, Steemers FJ, Camerini-Otero RD, Adey AC, Shendure J (2019) High-throughput single-cell sequencing with linear amplification. Mol Cell
Yoshida K, Bacal J, Desmarais D, Padioleau I, Tsaponina O, Chabes A, Pantesco V, Dubois E, Parrinello H, Skrzypczak M et al (2014) The histone deacetylases sir2 and rpd3 act on ribosomal DNA to control the replication program in budding yeast. Mol Cell 54:691–697
Yoshikawa H, Sueoka N (1963) Sequential replication of Bacillus subtilis chromosome. I. Comparison of marker frequencies in exponential and stationary growth phases. Proc Natl Acad Sci U S A 49:559–566
Yudkin D, Hayward BE, Aladjem MI, Kumari D, Usdin K (2014) Chromosome fragility and the abnormal replication of the FMR1 locus in fragile X syndrome. Hum Mol Genet 23:2940–2952
Zahn H, Steif A, Laks E, Eirew P, VanInsberghe M, Shah SP, Aparicio S, Hansen CL (2017) Scalable whole-genome single-cell library preparation without preamplification. Nat Methods 14:167–173
Zentner GE, Kasinathan S, Xin B, Rohs R, Henikoff S (2015) ChEC-seq kinetics discriminates transcription factor binding sites by DNA sequence and shape in vivo. Nat Commun 6:8733
Zong C, Lu S, Chapman AR, Xie XS (2012) Genome-wide detection of single-nucleotide and copy-number variations of a single human cell. Science 338:1622–1626
Funding
Work in the Koren lab is supported by grants DP2GM123495 from the National Institutes of Health and MCB-1921341 from the National Science Foundation. MLH is supported by the National Science Foundation Graduate Research Fellowship DGE-1650441.
Author information
Authors and Affiliations
Contributions
MLH, DJM, and AK wrote the paper.
Corresponding author
Additional information
Michelle L. Hulke and Dashiell J. Massey contributed equally to this work.
Responsible Editor: Beth A Sullivan
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Hulke, M.L., Massey, D.J. & Koren, A. Genomic methods for measuring DNA replication dynamics. Chromosome Res 28, 49–67 (2020). https://doi.org/10.1007/s10577-019-09624-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10577-019-09624-y