Reconstructing the eukaryotic cell cycle gene network

描述(申请人提供)：真核细胞在一系列复杂的过程中生长和分裂，统称为细胞周期，包括DNA合成、有丝分裂和细胞分裂的有序过程，伴随着细胞骨架和细胞器的完全重组，以及子细胞的受控生长。总而言之，大约。800个基因在细胞周期的过程中改变了表达，表明了这一过程的整体复杂性。细胞周期调控错误在许多人类疾病中起着重要作用，包括多种癌症、遗传性疾病如共济失调毛细血管扩张症，甚至染色体分离错误疾病如唐氏综合症。细胞周期的大多数特征是一次只发现一个蛋白质、突变体和基因，但这个系统的复杂性表明，对细胞周期进程和调控的许多新见解将来自对数百个相关基因的综合检查。我们开发了新的方法(计算遗传学方法)，通过利用基因组中固有的信息和关于基因之间关系的表达数据来重建复杂的基因网络。在我们的初步工作中，我们已经证明了我们可以重建广泛的基因网络，其精度可与实验技术相媲美。我们打算应用这些工具来重建和表征控制酵母细胞周期的基因网络。在这里提出的工作中，我们将(A)整合计算遗传学方法和蛋白质相互作用来重建酵母基因的全基因组网络。我们的初步结果表明，我们可以重建任何生物体已知的最完整和最准确的基因网络之一。(B)我们将描述细胞周期相关基因的子网络，绘制已知细胞周期系统之间的联系，并识别与这些系统相关的新基因。(C)最后，我们将从实验上验证计算结果，通过删除这些网络中与已知细胞周期成分相关联的基因来表征酵母菌株中与细胞周期相关的缺陷。我们预计，我们重建如此广泛的酵母基因网络的新能力将为酵母细胞周期的研究提供一个解释性框架，使我们能够组织涉及的数百个基因，以便更全面地分析它们的相互作用，同时还揭示新基因的参与和周期组件之间的相互作用。

DESCRIPTION (provided by applicant): Eukaryotic cells grow and divide in an intricate series of events known collectively as the cell cycle, consisting of the ordered procession through DNA synthesis, mitosis and cell division, accompanied by complete reorganization of the cytoskeleton and organelles, and controlled growth of the daughter cell. In all, approx. 800 genes change expression over the course of the cell cycle, indicating the overall complexity of the process. Errors in cell cycle regulation play a fundamental role in a wide range of human diseases, including numerous cancers, hereditary disorders such as ataxia telangiectasia, and even chromosome missegregation diseases such as Down's syndrome. Most features of the cell cycle have been discovered one protein, mutant and gene at a time, but the complexity of this system argues that many new insights into cell cycle progression and regulation will come from an integrated examination of the hundreds of genes involved. We have developed novel methods ('computational genetics' methods) to reconstruct complex gene networks by using the information intrinsic in genomes and expression data about the relationships between the genes. In our preliminary work, we have demonstrated that we can reconstruct extensive gene networks with accuracies comparable to experimental techniques. We intend to apply these tools to reconstruct and characterize the network of genes controlling the yeast cell cycle. In the work proposed here, we will (A) integrate computational genetics methods and protein interactions to reconstruct a genome-wide network of yeast genes. Our initial results suggest we can reconstruct one of the most complete and most accurate gene networks known for any organism. (B) We will characterize the sub network derived for cell cycle-related genes, mapping connections between known ceil cycle systems and identifying new genes associated with these systems. (C) Finally, we will experimentally validate the computational results, characterizing the cell cycle related defects in yeast strains with deletions of genes linked in these networks to known cell cycle components. We anticipate that our nascent ability to reconstruct such extensive yeast gene networks will give us an interpretive framework for studies of the yeast cell cycle, allowing us to organize the hundreds of genes involved for more comprehensive analyses of their interplay, while also revealing the involvement of new genes and interactions between the cycle components.