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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Small-scale Copy Number Variation And Large-scale Changes In Gene Expression
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Small-scale Copy Number Variation And Large-scale Changes In Gene Expression

机译：基因表达的小拷贝数变异和大变化

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摘要

The expression dynamics of interacting genes depends, in part, on the structure of regulatory networks. Genetic regulatory networks include an overrepresentation of subgraphs commonly known as network motifs. In this article, we demonstrate that gene copy number is an omnipresent parameter that can dramatically modify the dynamical function of network motifs. We consider positive feedback, bistable feedback, and toggle switch motifs and show that variation in gene copy number, on the order of a single or few copies, can lead to multiple orders of magnitude change in gene expression and, in some cases, switches in deterministic control. Further, small changes in gene copy number for a 3-gene motif with successive inhibition (the "repressilator") can lead to a qualitative switch in system behavior among oscillatory and equilibrium dynamics. In all cases, the qualitative change in expression is due to the nonlinear nature of transcriptional feedback in which duplicated motifs interact via common pools of transcription factors. We are able to implicitly determine the critical values of copy number which lead to qualitative shifts in system behavior. In some cases, we are able to solve for the sufficient condition for the existence of a bifurcation in terms of kinetic rates of transcription, translation, binding, and degradation. We discuss the relevance of our findings to ongoing efforts to link copy number variation with cell fate determination by viruses, dynamics of synthetic gene circuits, and constraints on evolutionary adaptation.
机译：相互作用基因的表达动力学部分取决于调节网络的结构。遗传调控网络包括通常称为网络基序的子图的过多表示。在本文中，我们证明了基因拷​​贝数是一个无所不在的参数，可以极大地改变网络基序的动态功能。我们考虑了正反馈，双稳态反馈和拨动开关基序，并表明基因拷贝数的变化（以单个拷贝或几个拷贝的顺序）会导致基因表达的多个数量级变化，并且在某些情况下，在确定性控制。此外，具有连续抑制作用的3基因基序（“ repressilator”）的基因拷贝数的细微变化可导致系统行为在振荡和平衡动力学之间发生质变。在所有情况下，表达的质变是由于转录反馈的非线性特性，其中重复的基元通过转录因子的公共库相互作用。我们能够隐含地确定导致系统行为发生质变的拷贝数的临界值。在某些情况下，就转录，翻译，结合和降解的动力学速率而言，我们能够解决存在分叉的充分条件。我们讨论了我们的发现与正在进行的将拷贝数变异与病毒决定细胞命运，合成基因电路的动力学以及对进化适应的限制联系在一起的努力的相关性。

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