Network hubs buffer environmental variation in Saccharomyces cerevisiae.
Network hubs buffer environmental variation in Saccharomyces cerevisiae.
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DOI：
10.1371/journal.pbio.0060264
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发表时间：
2008-11-04
期刊：
影响因子：
9.8
通讯作者：
Siegal, Mark L.
中科院分区：
文献类型：
--
作者：
Levy, Sasha F.;Siegal, Mark L.
调控和发育系统产生的表型对环境和遗传变异具有鲁棒性。通常有助于这种鲁棒性的基因产物被称为表型电容器。当表型电容器失效时，例如当受到恶劣环境或突变的挑战时，系统变得不那么稳健，从而产生更大的表型变异。功能表型电容器提供了一种机制，通过这种机制，隐藏的多态性可以积累，而它的失败提供了一种机制，通过这种机制，进化的变化可能会被促进。迄今为止，表型电容器的主要例子是Hsp 90，一种靶向大量信号转导蛋白的分子伴侣。在果蝇和拟南芥中，受损的Hsp 90功能导致依赖于潜在基因型的多效性表型效应。对于某些性状，热休克蛋白90似乎也缓冲随机变异，但环境和遗传缓冲之间的关系仍然是一个重要的未解决的问题。我们以前使用模拟敲除突变的转录网络预测，许多基因产物将作为表型电容器。为了测试这一预测，我们使用高通量的单基因缺失菌株的单个酵母细胞的形态表型，以确定缓冲酿酒酵母中的环境变化的基因产物。我们发现超过300个基因产物，当缺席时，增加形态变异。在这些电容器中占主导地位的是控制染色体组织和DNA完整性、RNA延伸、蛋白质修饰、细胞周期和对刺激（如应激）的反应的基因产物。电容器具有大量的合成-致死相互作用，但这些基因的敲除并不倾向于导致生长速率的严重降低。每个电容器可以根据它是否由基因组中具有paramino的基因编码来分类。具有重复的电容器在蛋白质-蛋白质相互作用网络中高度连接，并且在表达上与其旁系同源物表现出相当大的差异。相比之下，由单基因编码的电容器是高度互连的蛋白质簇的一部分，其其他成员也倾向于影响表型变异性或适应性。这些结果表明，变异的缓冲和释放是一种普遍现象，是由遗传结构中多个水平的不完全功能冗余引起的。大多数物种保持着丰富的遗传变异，并经历了广泛的环境条件，但个体之间的表型差异通常很小。这种现象被称为表型鲁棒性，它提出了一个明显的矛盾：如果生物系统对变异有如此大的抵抗力，那么它们是如何在进化过程中分化和适应的呢？在这里，我们解决这个问题，通过调查的分子机制，表型的鲁棒性和如何打破这些机制可以产生表型异质性。我们通过分析单基因敲除菌株的综合集合中的形态表型的方差来确定有助于酵母中表型稳健性的基因。我们发现，0.5%的酵母基因在敲除时会破坏表型稳健性。这些基因的产物往往参与关键的细胞过程，包括维持DNA稳定性，加工RNA，修饰蛋白质和应对压力环境。这些基因倾向于与大量其他基因在遗传上相互作用，它们的产物倾向于与大量其他基因产物在物理上相互作用。我们的研究结果表明，表型鲁棒性的丧失可能是进化过程中细胞网络被破坏时发生的一种常见现象。酿酒酵母的全基因组筛选鉴定出300多种基因产物，这些基因产物缓冲环境变化-被称为表型电容器-并在蛋白质-蛋白质和合成-致死相互作用网络中起枢纽作用。
Regulatory and developmental systems produce phenotypes that are robust to environmental and genetic variation. A gene product that normally contributes to this robustness is termed a phenotypic capacitor. When a phenotypic capacitor fails, for example when challenged by a harsh environment or mutation, the system becomes less robust and thus produces greater phenotypic variation. A functional phenotypic capacitor provides a mechanism by which hidden polymorphism can accumulate, whereas its failure provides a mechanism by which evolutionary change might be promoted. The primary example to date of a phenotypic capacitor is Hsp90, a molecular chaperone that targets a large set of signal transduction proteins. In both Drosophila and Arabidopsis, compromised Hsp90 function results in pleiotropic phenotypic effects dependent on the underlying genotype. For some traits, Hsp90 also appears to buffer stochastic variation, yet the relationship between environmental and genetic buffering remains an important unresolved question. We previously used simulations of knockout mutations in transcriptional networks to predict that many gene products would act as phenotypic capacitors. To test this prediction, we use high-throughput morphological phenotyping of individual yeast cells from single-gene deletion strains to identify gene products that buffer environmental variation in Saccharomyces cerevisiae. We find more than 300 gene products that, when absent, increase morphological variation. Overrepresented among these capacitors are gene products that control chromosome organization and DNA integrity, RNA elongation, protein modification, cell cycle, and response to stimuli such as stress. Capacitors have a high number of synthetic-lethal interactions but knockouts of these genes do not tend to cause severe decreases in growth rate. Each capacitor can be classified based on whether or not it is encoded by a gene with a paralog in the genome. Capacitors with a duplicate are highly connected in the protein–protein interaction network and show considerable divergence in expression from their paralogs. In contrast, capacitors encoded by singleton genes are part of highly interconnected protein clusters whose other members also tend to affect phenotypic variability or fitness. These results suggest that buffering and release of variation is a widespread phenomenon that is caused by incomplete functional redundancy at multiple levels in the genetic architecture. Most species maintain abundant genetic variation and experience a wide range of environmental conditions, yet phenotypic differences between individuals are usually small. This phenomenon, known as phenotypic robustness, presents an apparent contradiction: if biological systems are so resistant to variation, how do they diverge and adapt through evolutionary time? Here, we address this question by investigating the molecular mechanisms that underlie phenotypic robustness and how these mechanisms can be broken to produce phenotypic heterogeneity. We identify genes that contribute to phenotypic robustness in yeast by analyzing the variance of morphological phenotypes in a comprehensive collection of single-gene knockout strains. We find that ∼5% of yeast genes break phenotypic robustness when knocked out. The products of these genes tend to be involved in critical cellular processes, including maintaining DNA stability, processing RNA, modifying proteins, and responding to stressful environments. These genes tend to interact genetically with a large number of other genes, and their products tend to interact physically with a large number of other gene products. Our results suggest that loss of phenotypic robustness might be a common phenomenon during evolution that occurs when cellular networks are disrupted. A genome-wide screen inSaccharomyces cerevisiae identifies over 300 gene products that buffer environmental variation--dubbed phenotypic capacitors--and function as hubs in protein-protein and synthetic-lethal interaction networks.
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