基因转录调控网络模型

摘要：基因转录调控网络是细胞内基因之间的相互作用关系的整体表示，是生命功能在基因表达层面的展现. 最近多种生物信息学（计算分子生物学）工具和高通量实验技术的发展，使得重建复杂的基因调控网络成为可能. 基因调控网络模型试图从DNA微阵列等海量数据中推断基因之间的调控关系，从而揭示复杂的生命现象， 虽远未完成，但从现有实验数据中重建基因调控网络的工作可以促进在分子和遗传水平上系统地剖析细胞的功能，是功能基因组学中的重要研究内容，也是当前生物信息学和系统生物学研究的最具挑战性的前沿课题之一. 简要评述了几类典型数学模型的最新研究进展.     

AP数据源融合算法构建基因调控网络

针对单一数据集构建基因调控网络算法数据量不足及构建网络结果不精确的问题, 提出一种基于能力与信任(AP)的数据源融合算法. 该算法将基因表达数据、 蛋白质相互作用数据和基序数据集, 分别通过控制与被控制双向数据流传输来分析和构建基因调控网络, 并与ReMoDiscovery,CLR和C3Net三种已开发模型在酵母全基因组网络构建结果的AUC值进行对比. 对比结果表明, 该算法在构建基因调控网络算法方面执行效率更高、 收敛性更强.     

AP 数据源融合算法构建基因调控网络

针对单一数据集构建基因调控网络算法数据量不足及构建网络结果不精确的问题, 提出一种基于能力与信任(AP)的数据源融合算法. 该算法将基因表达数据、 蛋白质相互作用数据和基序数据集, 分别通过控制与被控制双向数据流传输来分析和构建基因调控网络, 并与ReMoDiscovery,CLR和C3Net三种已开发模型在酵母全基因组网络构建结果的AUC值进行对比. 对比结果表明, 该算法在构建基因调控网络算法方面执行效率更高、 收敛性更强.     

果蝇体极性基因网络的稳定性分析

果蝇的全基因组的序列测定早已完成,但是,对于基因之间是如何相互调控以实现复杂的生物功能,还需要深入的研究.认识并解析复杂的基因调控网络的构成和动力学机制,已成为现代生命科学中的前沿课题之一.在本文中,我们重点研究了果蝇的胚胎发育过程中图式形成的体极性基因网络调控.这一调控是通过相邻细胞中的基因网络的相互影响而达成的.本文主要考察这种基因网络调控对于初始条件的稳定性,以此说明生物胚胎发育对于初始条件的相对稳定性.我们发现该调控系统对于特定位置的干扰有极好的稳定性,对于整个系统的小干扰有良好的稳定性.     

共有基因模块构建大规模基因调控网络

目的 提出一种利用共有基因模块构建大规模基因调控网络算法(Common Gene Mod-ules Network,CGMN),有效降低传统基因调控网络构建基因节点规模较大的基因调控网络(包含几百个,甚至几千个基因节点)时时间复杂度过大的缺陷.方法 CGMN算法从基因表达数据出发,采用6种常用聚类算法把基因表达模式相似的基因聚类成功能模块,找出6种聚类方法的共有模块,并将其作为功能模块基因节点,采用局部贝叶斯网络(Local Bayesian Network,LBN)算法构建功能模块基因-基因调控网络.结果 与结论 大规模细胞周期基因表达数据集上仿真实验结果表明,搜索共有模块压缩基因节点数目策略,能够有效降低大规模基因调控网络重构时间复杂度,且验证了CGMN算法构建大规模基因调控网络的有效性.     

基于潜在调控因子筛选的高阶动态贝叶斯建模方法

为了解决目前用于构建基因调控网络的方法中所存在的网络构建准确率低、网络构建时间过长等问题，以及减小网络构建的复杂度，提高网络构建效率，提出了一种基于潜在调控因子筛选的高阶动态贝叶斯网络建模方法(high-order dynamic Bayesian network modeling method based on potential regulatory factor screening, PRS-HO-DBN).该方法将关联模型与高阶动态贝叶斯网络模型相结合，首先利用潜在调控因子筛选的方法在不同的时间延迟下删除与目标基因关联程度较低的基因，保留与目标基因关联程度较高的基因并作为目标基因的潜在调控因子集，以减小搜索空间；然后利用高阶动态贝叶斯模型进行结构学习，以提高网络构建的精确率.与其他的网络构建模型方法相比，该方法可以极大地缩短网络构建的时间，提升效率和精确度.     

基于改进贝叶斯方法的基因调控网络构建

为了研究基因之间的复杂调控关系,使用贝叶斯网络模型来构建基因调控网络,针对以往单一贝叶斯网络模型结构学习算法精度低的问题,提出一种结合信息论构建初始网络并在该网络上进行评分搜索的基因调控网络学习方法,使用最大信息系数筛选有较高关联性的节点构建初始网络以提高解的质量,在评分搜索中使用禁忌搜索和BDe评分训练生成最终网络。之后在一组单细胞的蛋白质因果表达网络数据和大肠杆菌表达网络数据上进行构建基因调控网络实验,并在不同数据量,不同性能指标上与其他网络构建算法进行对比。实验结果表明,构建方法在不同规模的数据集上的有效性和准确率优于用于对比的其他算法。     

构建基因调控布尔网络的一种方法

为了重构基因调控网络,提出可以通过基因之间的布尔逻辑代数和逻辑电路网络得到基因调控的动态转换。进而找到整个基因网络的动态变化。利用熵互信息理论对基因表达进行处理,构建基因调控布尔网络。     

一种改进的多元回归估计基因调控网络的方法

针对用多元回归分析估计基因调控网络时遇到的计算量过大的问题,提出了先用线性模型构建基因类间的调控网络,再用多元回归模型构建基因间调控网络的改进方案,利用类间网络提供的参考信息可以大大减少多元回归分析的计算量.将该方案应用到人类基因调控网络的估计中,并通过现有文献验证了部分调控关系,从而初步证明了该方法的有效性.     

基于动态贝叶斯网络的多时延基因调控网络构建

分子生物学的主要挑战是如何更好地理解基因间的调控机理。重构调控网络有助于探索生命系统的本质问题。目前,已提出的方法大多数都不考虑基因表达之间的时延,或者假定其时延是一个常量。这为深入理解基因调控的时-空机制带来了困难。现提出一个用连续DBNs构建具有多时延基因调控网络的方法,它可以系统地分析基因之间的调控关系。将其应用于酵母菌的转录调控网络中,结果显示,该方法能更好地估计转录时延,进一步提高了调控网络构建的精度。     

Network Visualization in Cell Biology

Many of the processes known to take place in biological cells are analyzed in the form of different types of network.The complexity of these networks increases along with our knowledge of these processes,making their analysis more difficult.Network visualization is a powerful analysis method that will have to be developed further to deal with this complexity.This survey provides a brief overview of network visualization in general,followed by an in-depth discussion of its application to three network types specific to cell biology,namely gene regulatory,protein interaction,and metabolic networks.Finally,we discuss the difficulty of visually integrating these network types and trying to compare networks of cells that belong to different organisms.     

A Novel Method of Gene Regulatory Network Structure Inference from Gene Knock-Out Expression Data

Inferring Gene Regulatory Networks(GRNs) structure from gene expression data has been a challenging problem in systems biology. It is critical to identify complicated regulatory relationships among genes for understanding regulatory mechanisms in cells. Various methods based on information theory have been developed to infer GRNs. However, these methods introduce many redundant regulatory relationships in the network inference process due to external noise in the original data, topology sparseness in the network structure, and non-linear dependency among genes. Especially as the network size increases, the performance of these methods decreases dramatically. In this paper, a novel network structure inference method named Loc-PCA-CMI is proposed that first identifies local overlapped gene clusters, and then infers the local network structure for each cluster by a Path Consistency Algorithm based on Conditional Mutual Information(PCA-CMI). The final structure of the GRN is denoted as dependence among genes by an ensemble of the obtained local network structures. Loc-PCA-CMI was evaluated on DREAM3 knock-out datasets, and its performance was compared to other information theorybased network inference methods including ARACNE, MRNET, PCA-CMI, and PCA-PMI. Experimental results demonstrate our novel method Loc-PCA-CMI outperforms the other four methods in DREAM3 datasets especially in size 50 and 100 networks.     

Engineered gene circuits

A central focus of postgenomic research will be to understand how cellular phenomena arise from the connectivity of genes and proteins. This connectivity generates molecular network diagrams that resemble complex electrical circuits, and a systematic understanding will require the development of a mathematical framework for describing the circuitry. From an engineering perspective, the natural path towards such a framework is the construction and analysis of the underlying submodules that constitute the network. Recent experimental advances in both sequencing and genetic engineering have made this approach feasible through the design and implementation of synthetic gene networks amenable to mathematical modelling and quantitative analysis. These developments have signalled the emergence of a gene circuit discipline, which provides a framework for predicting and evaluating the dynamics of cellular processes. Synthetic gene networks will also lead to new logical forms of cellular control, which could have important applications in functional genomics, nanotechnology, and gene and cell therapy.     

A gene regulatory network controlling the embryonic specification of endoderm

Specification of endoderm is the prerequisite for gut formation in the embryogenesis of bilaterian organisms. Modern lineage labelling studies have shown that in the sea urchin embryo model system, descendants of the veg1 and veg2 cell lineages produce the endoderm, and that the veg2 lineage also gives rise to mesodermal cell types. It is known that Wnt/β-catenin signalling is required for endoderm specification and Delta/Notch signalling is required for mesoderm specification. Some direct cis-regulatory targets of these signals have been found and various phenomenological patterns of gene expression have been observed in the pre-gastrular endomesoderm. However, no comprehensive, causal explanation of endoderm specification has been conceived for sea urchins, nor for any other deuterostome. Here we propose a model, on the basis of the underlying genomic control system, that provides such an explanation, built at several levels of biological organization. The hardwired core of the control system consists of the cis-regulatory apparatus of endodermal regulatory genes, which determine the relationship between the inputs to which these genes are exposed and their outputs. The architecture of the network circuitry controlling the dynamic process of endoderm specification then explains, at the system level, a sequence of developmental logic operations, which generate the biological process. The control system initiates non-interacting endodermal and mesodermal gene regulatory networks in veg2-derived cells and extinguishes the endodermal gene regulatory network in mesodermal precursors. It also generates a cross-regulatory network that specifies future anterior endoderm in veg2 descendants and institutes a distinct network specifying posterior endoderm in veg1-derived cells. The network model provides an explanatory framework that relates endoderm specification to the genomic regulatory code.