High-resolution replication profiles define the stochastic nature of genome replication initiation and termination.
High-resolution replication profiles define the stochastic nature of genome replication initiation and termination.
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DOI：
10.1016/j.celrep.2013.10.014
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发表时间：
2013-11-27
期刊：
影响因子：
8.8
通讯作者：
Nieduszynski CA
中科院分区：
文献类型：
--
作者：
Hawkins M;Retkute R;Müller CA;Saner N;Tanaka TU;de Moura AP;Nieduszynski CA
真核生物的基因组复制是随机的，每个细胞使用不同的复制起点队列。我们证明，用数学模型解释高分辨率的酿酒酵母基因组复制数据可以量化基因组复制的随机性质，包括每个起始点的效率和终止事件的分布。单细胞测量支持随机起始激活时间的推断值。一株有三个起始点被灭活的菌株证实，终止事件的分布主要由起始点的随机激活时间决定。起源活动的细胞到细胞的可变性确保了终止事件在几乎整个基因组中广泛分布。我们认为，起源用途的异质性通过限制潜在有害事件在特定位点的积累来促进基因组的稳定性。深度测序揭示了基因组复制动态的高分辨率视图全基因组建模和单细胞成像揭示了随机起源活动起源活动决定了复制终止事件的位置终止事件广泛地分布在整个基因组中对于是什么决定了DNA复制终止位点的基因组位置知之甚少。在这项研究中，Nieduszynski和他的同事表明，基因组复制在种群内的细胞之间是高度可变的。这种可变性是由随机起源活动引起的，并导致复制终止位点广泛分布在几乎整个基因组中。基因组复制中细胞间的可变性可能通过限制潜在有害事件在特定位点的积累来促进基因组的稳定。
Eukaryotic genome replication is stochastic, and each cell uses a different cohort of replication origins. We demonstrate that interpreting high-resolution Saccharomyces cerevisiae genome replication data with a mathematical model allows quantification of the stochastic nature of genome replication, including the efficiency of each origin and the distribution of termination events. Single-cell measurements support the inferred values for stochastic origin activation time. A strain, in which three origins were inactivated, confirmed that the distribution of termination events is primarily dictated by the stochastic activation time of origins. Cell-to-cell variability in origin activity ensures that termination events are widely distributed across virtually the whole genome. We propose that the heterogeneity in origin usage contributes to genome stability by limiting potentially deleterious events from accumulating at particular loci. Deep sequencing reveals a high-resolution view of genome replication dynamics Genome-wide modeling and single-cell imaging reveal stochastic origin activity Origin activity determines the location of replication termination events Termination events are widely distributed across the whole genome Little is known about what determines the genomic location of DNA replication termination sites. In this study, Nieduszynski and colleagues show that genome replication is highly variable between cells within a population. This variability arises from stochastic origin activity and results in replication termination sites being widely distributed across virtually the whole genome. The variability between cells in genome replication may contribute to genome stability by limiting potentially deleterious events from accumulating at specific loci.
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