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The centromere is indicated as a striped pattern. This observation was further supported by twofold reduced nucleotide incorporation in early S-phase pattern Fig. Sampling positions are identical to the positions in the experimental data. In our simulations the average size of replication clusters is comparable Fig. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. Therefore, the combination of a limiting factor and an initial fork speed increase during the first third of S-phase followed by an approximately constant rate for the rest of S-phase 10 , leads to a cell cycle profile consistent with our experimental data. The presence of these peaks in the experiment indicates that indeed there are early firing events in all euchromatic zones, corresponding to a high spontaneous firing probability. Our experimental data suggest that the number of simultaneously active replicons is between 4, and 6, ref. When the genome of eukaryotic cells is duplicated during the S-phase of the cell cycle, it is essential that the entire karyotype is reliably and precisely reproduced. To mimic those experiments, we extracted the replication times of DNA corresponding to experimental sampling positions. Figure 2e shows the resemblance of our results to the experimental data. Due to the induced firing process, the probability for very short distances between firing origins would be much higher than experimentally observed Fig. Induced firing probabilities below 0. The interplay of deterministic and stochastic influences in these processes, which is yet unclear 24 , 25 , needs to be motivated by more detailed experimental data. Here, we propose a comprehensive model of DNA replication in human cells that is based on stochastic, proximity-induced replication initiation. Thus, we introduced a distance around active forks, where firing of potential origins is inhibited the inhibition distance— d i. Besides, an adequate model of genome duplication in eukaryotes must reproduce not only the temporal dynamics, but also the spatial characteristics of DNA replication in vivo. However, the principles behind initiation of potential replication origins and emergence of typical patterns of nuclear replication sites remain unclear. Before the actual replication start, pre-replicative complexes are assembled on the DNA, licensing the origins of replication initiation 2. The probability for spontaneous firing events is assumed to be higher in euchromatic regions than the probability of firing potential origins in facultative and constitutive heterochromatic regions. We advance the one-dimensional DNA replication model to a spatial model by taking into account chromatin folding in the nucleus, and we are able to reproduce the spatial and temporal characteristics of the replication foci distribution throughout S-phase. Metazoan genomes feature a higher order organizational structure, which is not present in the well-characterized yeast model organisms 5 , 6 , 7. Spontaneous firing is dominant in euchromatin and the number of clusters increases rapidly during the initial phase Fig. Thus, only a model which uses a combination of both spontaneous and induced firing reproduces correctly the distribution of distances between fired origins and a distinct middle S-phase during which mainly facultative heterochromatin is replicated. Dashed lines display the other extreme case, where solely spontaneous firing was used. Models of genome duplication in metazoans, therefore, need to include stochastic mechanisms to account for origins initiated at non-predetermined sites 20 and a flexible spatio-temporal structure of S-phase 13 , Recently, a quantitative model of human genome replication was presented by Shaw et al. As the replication of smaller zones is completed the size of the remaining clusters increases because the total fork number stays constant. Thus our model predicts, that not more than one origin is activated per chromatin loop with a passive replication of other potential origins in the loop 28 , 30 , which reproduces the known correlation between the replicon and chromatin loop sizes. Thus, in our model the location of potential origins along the DNA is determined randomly. As long as the fork speed increases until 2. To test whether the difference between the distributions is sufficient to reject the purely spontaneous model, we performed a bootstrap significance test, where the average over a subset of 50 simulated distances between fired origins was calculated. Guilbaud et al. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. However, a full spontaneous model leads to longer average inter-origin distances than experimentally observed 26 Fig. The model reproduces the empirical temporal and chromatin-related properties of DNA replication in human cells. The total genome replication time of It is estimated that the total number of active origins involved in the replication of an entire mammalian genome lies in between 30, and 50, refs 19 , 26 , 38 , which includes the simulated value ranging from 43, to 44, simulation parameters listed in Table 1. The existence of a long-range control of otherwise stochastic or induced firing of origins in the presence of replication forks was subsequently suggested. You are using a browser version with limited support for CSS. Since the combined model includes a very low spontaneous firing probability for origins in heterochromatic zones, most heterochromatin has to be replicated by fronts of clusters entering from adjacent zones. We performed an evaluation of replication timing at the chromosome scale in our simulations and compared it with the microarray data from Woodfine et al. Figure 1 shows a schematic of the induced firing process in the model. The centres of euchromatic regions are on average replicated first and the centres of heterochromatic regions are replicated last with distinctive transition zones in between.{/INSERTKEYS}{/PARAGRAPH} To test whether both spontaneous and induced firing are required, we varied the parameters relating to the two types of firing. The value was directly measured by Chagin et al. The corresponding distribution, averaged over simulations, displays similar features. Potential replication origins are distributed randomly on the DNA at distances down to a few kbp refs 2 , 7 , 18 , 27 and are capable of firing spontaneously. The shape of the DNA flow cytometry histogram and equal replicon numbers throughout S-phase 26 suggest a rate of global DNA duplication approximately constant through most of S-phase. Wide-field images of cells going through different S-phase stages show that, while the overall level of PCNA is rather constant, the total amount of incorporated nucleotides is clearly lower in cells going through early S-phase, indicating a lower synthesis rate. Genome-scale mapping of DNA replication origins demonstrated general plasticity of active origin positions, which was interpreted as replicon size flexibility within a predetermined replicon cluster Accordingly, the replication programme in metazoans demonstrates a high level of plasticity, thus ensuring complete genome duplication in the face of developmental and environmental changes 1. The Background indicates the Giemsa staining, where white regions are interpreted as euchromatin and shaded regions as facultative or constitutive heterochromatin. Analogous figures for other human chromosomes can be found in the Supplementary Figs 4—6. Colours are used to distinguish between the chromatin type specific and total replication. Figure 3f show the number and size of clusters during S-phase using the combined model. The reduced DNA synthesis rate could be a consequence of nucleotide scarcity at the beginning of S-phase, or of the interplay between replication and transcription leading to a slower replication fork speed 39 , 40 , both of which will have the same macroscopic manifestations. The distribution remains at an approximately constant value throughout S-phase, that is, between the G1 and G2 peaks, meaning that the overall rate of replication is constant. If firing of origins is solely simulated by spontaneous events, the average replication time of the chromatin types depends highly on the spontaneous firing probabilities p eu , p fac and p con for euchromatin, facultative and constitutive heterochromatin, respectively. However, the formation of clusters is likely to emerge from more elementary processes. The amount of time needed to duplicate a DNA molecule depends solely on the speed of replication fork movement and the sum and distribution of activated origins. For individual simulations, the euchromatic peaks start at time zero, but because of the specific sampling positions and averaging over simulations, the displayed peaks are less extreme. As seen in Fig. To find the most probable value for d i we compared the experimental distribution of inter-origin distances Fig. Dotted lines show the simulation results, when only induced firing events are allowed. The relative probabilities of individual origins are indicated by dark grey bars. The P value of 0. The concept of a limiting number of available forks was also used in models of metazoan DNA replication to obtain realistic origin activation profiles and synthesis rates 33 , 34 , We assume that the limiting factor moves nearly instantaneously through the nucleus 36 , 37 , starts to become available once the cell enters S-phase, and that its number increases during the first hour until it reaches a maximum level that is maintained until the end of S-phase Methods section and Fig. We directly measured the amount of genomic DNA synthesized in each S-phase sub-period corresponding to the three major S-phase patterns for details see Fig. Increasing the differences beween the spontaneous firing probabilities does not lead to a noticeable lower average since intra chromatin zone firing still allows for very large distances shifting the distribution to larger values. Clustered replication is maintained in our model through individual firing and annihilation events. Induced firing events in the vicinity of active forks lead to clusters of active forks on the one-dimensional 1D DNA string, which expand outwards. The results of the two extreme cases with only spontaneous or only induced firing events are shown as dashed and dotted lines, respectively, in Fig. Both theoretical and experimental replication timing profiles exhibit distinctive peaks due to early replication in the euchromatic zones, including the smallest euchromatin zones. Clusters can therefore split into two parts that move in opposing directions when large stretches of DNA within them have been replicated. As the 1D cluster increases in size, the probability that the next firing event will occur in it or close to it increases also. The remaining 8. LUT as indicated. By introducing clusters of origins which are fired together spontaneously or by activation from a neighbouring cluster, and by implementing the observed temporal variation of fork speed 23 , the authors reproduce S-phase dynamics and replication progression on a cluster scale. The firing probability of origins that are close to forks follows a Gaussian probability density, indicated as shaded areas next to the forks. Importantly, this process must be able to cope with variations in S-phase duration 1 , potential chromosomal abnormalities and ploidy variations. DNA replication dynamics in cells from higher eukaryotes follows very complex but highly efficient mechanisms. {PARAGRAPH}{INSERTKEYS}Thank you for visiting nature. During mid S-phase clusters start splitting into two and thus the number increases again. The sites of DNA synthesis are called replication forks, which normally emerge in bidirectional pairs from each activated origin and travel in opposite directions. We modelled slower replication in early S-phase using a linear increase in fork speed during the first 2. While our curves are averaged over simulations and are therefore smooth compared with the averages of four experimental measurements, the simulated patterns still correspond to the empirical data. Positions and activation times of individual origins can be related to various chromatin features 3 , 10 , 11 , 12 , 13 , 14 , and molecular analyses have shown that positions of active origins, inter-origin distances and the speed of replication fork movement can vary even within individual cells 15 , Biological analyses of replication progression throughout S-phase in mammalian cells led to a domino-like next-in-line model 17 where replication is triggered by replication of adjacent regions. Contrary to yeast, the positions of replication origins in metazoan DNA do not appear to be determined by DNA sequence 8 , 9. The combined model includes both firing events and the results are shown with solid lines. Critical model features are: spontaneous stochastic firing of individual origins in euchromatin and facultative heterochromatin, inhibition of firing at distances below the size of chromatin loops and a domino-like effect by which replication forks induce firing of nearby origins. Here, we use domino-like DNA replication progression and random loop folding of chromatin to present a minimal model of DNA replication in higher eukaryotes that is able to reproduce spatial dynamics of the replication foci RFi throughout S-phase without need for replicon clustering at common synthetic centres as shown in Chagin et al. This leads to good agreement with experimental data Fig. The chromosome boundary near the right edge of the image isolates chromatin belonging to different chromosomes and thus cuts off the induced firing range of the rightmost fork. These origins are activated by specific proteins, which initiate DNA duplication by interacting with the DNA polymerase complex 3. A Nature Research Journal. Subphase durations were obtained using live cell microscopy as described in the accompanying manuscript Chagin et al.