Modeling inhomogeneous DNA replication kinetics.

In eukaryotic organisms, DNA replication is initiated at a series of chromosomal locations called origins, where replication forks are assembled proceeding bidirectionally to replicate the genome. The distribution and firing rate of these origins, in conjunction with the velocity at which forks prog...

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Main Authors: Michel G Gauthier, Paolo Norio, John Bechhoefer
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2012-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC3296702?pdf=render
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spelling doaj-067c273ac99a4aa18d7bfc49946e40822020-11-25T00:48:00ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0173e3205310.1371/journal.pone.0032053Modeling inhomogeneous DNA replication kinetics.Michel G GauthierPaolo NorioJohn BechhoeferIn eukaryotic organisms, DNA replication is initiated at a series of chromosomal locations called origins, where replication forks are assembled proceeding bidirectionally to replicate the genome. The distribution and firing rate of these origins, in conjunction with the velocity at which forks progress, dictate the program of the replication process. Previous attempts at modeling DNA replication in eukaryotes have focused on cases where the firing rate and the velocity of replication forks are homogeneous, or uniform, across the genome. However, it is now known that there are large variations in origin activity along the genome and variations in fork velocities can also take place. Here, we generalize previous approaches to modeling replication, to allow for arbitrary spatial variation of initiation rates and fork velocities. We derive rate equations for left- and right-moving forks and for replication probability over time that can be solved numerically to obtain the mean-field replication program. This method accurately reproduces the results of DNA replication simulation. We also successfully adapted our approach to the inverse problem of fitting measurements of DNA replication performed on single DNA molecules. Since such measurements are performed on specified portion of the genome, the examined DNA molecules may be replicated by forks that originate either within the studied molecule or outside of it. This problem was solved by using an effective flux of incoming replication forks at the model boundaries to represent the origin activity outside the studied region. Using this approach, we show that reliable inferences can be made about the replication of specific portions of the genome even if the amount of data that can be obtained from single-molecule experiments is generally limited.http://europepmc.org/articles/PMC3296702?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Michel G Gauthier
Paolo Norio
John Bechhoefer
spellingShingle Michel G Gauthier
Paolo Norio
John Bechhoefer
Modeling inhomogeneous DNA replication kinetics.
PLoS ONE
author_facet Michel G Gauthier
Paolo Norio
John Bechhoefer
author_sort Michel G Gauthier
title Modeling inhomogeneous DNA replication kinetics.
title_short Modeling inhomogeneous DNA replication kinetics.
title_full Modeling inhomogeneous DNA replication kinetics.
title_fullStr Modeling inhomogeneous DNA replication kinetics.
title_full_unstemmed Modeling inhomogeneous DNA replication kinetics.
title_sort modeling inhomogeneous dna replication kinetics.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2012-01-01
description In eukaryotic organisms, DNA replication is initiated at a series of chromosomal locations called origins, where replication forks are assembled proceeding bidirectionally to replicate the genome. The distribution and firing rate of these origins, in conjunction with the velocity at which forks progress, dictate the program of the replication process. Previous attempts at modeling DNA replication in eukaryotes have focused on cases where the firing rate and the velocity of replication forks are homogeneous, or uniform, across the genome. However, it is now known that there are large variations in origin activity along the genome and variations in fork velocities can also take place. Here, we generalize previous approaches to modeling replication, to allow for arbitrary spatial variation of initiation rates and fork velocities. We derive rate equations for left- and right-moving forks and for replication probability over time that can be solved numerically to obtain the mean-field replication program. This method accurately reproduces the results of DNA replication simulation. We also successfully adapted our approach to the inverse problem of fitting measurements of DNA replication performed on single DNA molecules. Since such measurements are performed on specified portion of the genome, the examined DNA molecules may be replicated by forks that originate either within the studied molecule or outside of it. This problem was solved by using an effective flux of incoming replication forks at the model boundaries to represent the origin activity outside the studied region. Using this approach, we show that reliable inferences can be made about the replication of specific portions of the genome even if the amount of data that can be obtained from single-molecule experiments is generally limited.
url http://europepmc.org/articles/PMC3296702?pdf=render
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