Effects of mutations on gene expression noise and cellular memory

描述（由申请人提供）：噪声是遗传网络的一个不可避免的特征，即使在相同的环境条件下，也会导致遗传相同的细胞之间的变异。由于表达是一个涉及许多生化反应的多步骤过程，许多最近的研究表明，自然选择可以调整噪音水平，以避免可能损害细胞功能的波动。选择试验中的一个重要参数是突变产生性状新变异的速率。该提案旨在（1）使用经过充分研究的酿酒酵母半乳糖网络作为模型系统，估计噪声及其对网络活性的影响仅由于突变而演变的速率，（2）测量该网络的关键正反馈回路对调控突变的鲁棒性，（3）用理论和模拟的方法分析了一个基本调控网络在突变和选择作用下的演化。目的（1）和（2）将通过体内监测暴露于不同水平的半乳糖的细胞中的基因和网络活性来实现，所述半乳糖在整个基因组中随机携带突变（1），或靶向特定的网络组分（2）。突变等位基因在先天性疾病中起着重要作用，突变的积累是细胞进展为癌症的特征之一。在这两种情况下，突变等位基因可能会破坏正常的遗传网络功能，因此了解遗传网络如何缓冲突变的影响以及网络功能如何容易受到损害是很重要的。

DESCRIPTION (provided by applicant): Noise is an inescapable feature of genetic networks, causing variation among genetically identical cells even under identical environmental conditions. Because expression is a multistep process involving many biochemical reactions, many recent studies have conjectured that natural selection can tune levels of noise to avoid fluctuations which could impair cellular function. One important parameter in tests for selection is the rate at which new variation in a trait is generated by mutation. This proposal aims to (1) estimate the rate at which noise and its effects on network activity evolve solely due to mutation, using the well-studied galactose network of Saccharomyces cerevisiae as a model system, (2) measure how robust the key positive feedback loop of this network is to regulatory mutations, and (3) use theory and simulation to analyze the evolution of a basic regulatory network under mutation and selection. Aims (1) and (2) will be pursued through in vivo monitoring of gene and network activity in cells exposed to varying levels of galactose carrying mutations randomly throughout the genome (1), or targeted to a particular network component (2). Mutant alleles play an important role in congenital diseases, and the accumulation of mutations is one of the features of cellular progression to cancer. In both of these cases, mutant alleles probably disrupt normal genetic network functioning, and so it is important to understand how genetic networks buffer the effects of mutations and how easily network function can be compromised.