Rewiring the yeast brain: Redundancy and interference in genetic networks

描述(由申请人提供) 摘要：与动物的神经网络相似，细胞中的分子网络可以产生双稳态或振荡动力学，分别维持对先前事件(如表观遗传开关)或有序周期性事件(如细胞周期)的记忆。在细胞中，通过调节反馈相互作用的基因网络实现了这种动态。与大脑中的学习类似，细胞可以通过突变将环境信号中的相关性编码到基因网络动态中，这是一种在几代人的时间尺度上发生的“重新连接”过程，从而可以“学习”环境信号中的相关性。学习环境信号的统计规律和相关性的问题，最好的例证是“生物钟”的进化，这是一种振荡的基因电路，已经学会了将24小时明暗昼夜周期内在化。值得注意的是，昼夜节律时钟多次独立进化，这表明存在某种选择压力和/或进化机制，反复有利于自主振荡的收敛进化。我的研究建议的假设是，重复基因中的某些类型的功能丧失突变(称为显性-负突变)可以很容易地在现有的监管网络中产生双稳和振荡。基因复制后发生功能丧失突变可产生显性负值。显性负突变是一种部分功能丧失突变，使基因复制在功能上不活跃，但仍能与原始复制、上游效应器和/或下游靶点相互作用。因此，显性否定很容易干扰原始复制品的适当调节和活动。由于基因复制和功能丧失突变在进化过程中频繁发生，这为基因调控网络中快速产生双稳态和自主振荡提供了一种进化机制。我计划在未来五年进行的研究将把实验和理论结合起来，以了解基因复制和显性负突变在多大程度上促进了调控网络中表观遗传开关和生物钟的进化。我们将在一个易于处理的真核生物(酿酒酵母)中使用计算机模拟和实验定向进化方法来测试细胞学习其耦合环境信号的统计规律的能力。了解单细胞微生物和寄生虫如何以及为什么学会预测它们的环境，对于了解它们未来对不断变化的宿主条件的进化至关重要。 公共卫生相关性：寄生虫学习和适应不断变化的宿主条件和环境的能力对人类健康构成了挑战。我的研究计划的目的是了解单细胞中的基因网络学习和预测其环境的统计规律的能力。发现寄生虫进化和预测宿主环境变化的局限性和能力，对于治疗许多人类疾病将是无价的。

DESCRIPTION (Provided by the applicant) Abstract: Similar to neural networks in animals, molecular networks in cells can generate bistable or oscillatory dynamics that maintain memories of previous events (e.g. epigenetic switch) or order periodic events (e.g. cell cycle), respectively. In cells, networks of genes interacting with one another through regulatory feedback implement such dynamics. Analogous to learning in brains, cells can ""learn"" correlations in their environmental signals by encoding such correlations into their gene network dynamics through mutation, a ""re-wiring"" process that occurs on the timescale of generations. The issue of learning the statistical regularities and correlations of environmental signals is best exemplified by the evolution of ""circadian clocks"", which are oscillatory gene circuits that have learned to internalize the 24-hour light-dark circadian cycle. Strikingly, circadian clocks have evolved independently multiple times, which suggests there exists some selection pressure and/or evolutionary mechanism that repeatedly favor the convergent evolution of autonomous oscillation. The hypothesis of my research proposal is that certain types of loss-of-function mutations in duplicated genes (known as dominant-negative mutations) can easily generate bistability and oscillation in existing regulatory networks. Gene duplication followed by a loss-of-function mutation can generate a dominant-negative. A dominant negative mutation is a partial loss-of-function mutation that renders a gene duplicate functionally inactive, yet still capable of interacting with the original duplicate, the upstream effectors, and/or downstream targets. Thus, dominant-negatives can easily interfere with the proper regulation and activity of the original duplicate. Because both gene duplication and loss-of-function mutations occur frequently in evolution, this presents an evolutionary mechanism for rapidly generating bistability and autonomous oscillation in gene regulatory networks. My proposed research over the next five years will integrate experiment and theory to understand the extent to which gene duplication and dominant-negative mutations facilitate the evolution of epigenetic switches and circadian clocks in regulatory networks. We will use computer simulation and an experimental directed evolution approach in a tractable, model eukaryote (Saccharomyces cerevisiae) to test the ability of cells to learn the statistical regularities of their coupled environmental signals. Understanding how and why single-cell microbes and parasites have learned to predict their environment is essential for understanding their future evolution to changing host conditions. Public Health Relevance: The ability of parasites to learn and adapt to changing host conditions and environments presents a challenge to human health. The objective of my research proposal is to understand the capacity of gene networks in single cells to learn and predict the statistical regularities of their environment. Discovering the limitations and abilities of parasites to evolve and anticipate changes in their host environment will be invaluable for the treatment of many human diseases.