延迟遗传调控网络稳定性及分支

本文主要研究了延迟遗传调控网络的局部稳定性和该网络的Hopf分支存在条件．延迟遗传调控网络是无穷维系统,此类系统在平衡点线性化后的特征方程为超越方程。通过对此超越方程进行研究,得到了系统系数不同时的系统稳定的条件及相关结论,又进一步说明了此系统的Hopf分支存在条件．最后,举一个例子进行了数值仿真验证了所得到的结论．     

基于Petri网的基因调控网络建模与分析

如何有效描述与分析复杂的基因调控网络(GRN)是生物学家研究基因表达调控机制的关键步骤.现有大部分方法在建模过程中忽略了生物中广泛存在的协同作用,模型预测结果与实际生物行为之间存在误差.基于混合函数Petri网(HFPN)理论提出了一种对基因调控网络进行定量分析的新方法.首先简要介绍GRN与HFPN的基础理论,然后为HFPN引入两类新元素:逻辑库所与逻辑变迁,描述基因调控网络的逻辑规则以及转录因子间的协同作用,最后构建海胆endo16基因调控网络的Petri网模型,并预测模型在不同位点发生突变时的基因表达水平变化.分析结果与文献实验数据相一致,验证了方法的正确性.     

Recovering Genetic Regulatory Networks from Chromatin Immunoprecipitation and Steady-State Microarray Data

Recent advances in high-throughput DNA microarrays and chromatin immunoprecipitation (ChIP) assays have enabled the learning of the structure and functionality of genetic regulatory networks. In light of these heterogeneous data sets, this paper proposes a novel approach for reconstruction of genetic regulatory networks based on the posterior probabilities of gene regulations. Built within the framework of Bayesian statistics and computational Monte Carlo techniques, the proposed approach prevents the dichotomy of classifying gene interactions as either being connected or disconnected, thereby it reduces significantly the inference errors. Simulation results corroborate the superior performance of the proposed approach relative to the existing state-of-the-art algorithms. A genetic regulatory network for Saccharomyces cerevisiae is inferred based on the published real data sets, and biological meaningful results are discussed.     

Piecewise-linear Models of Genetic Regulatory Networks: Equilibria and their Stability

A formalism based on piecewise-linear (PL) differential equations, originally due to Glass and Kauffman, has been shown to be well-suited to modelling genetic regulatory networks. However, the discontinuous vector field inherent in the PL models raises some mathematical problems in defining solutions on the surfaces of discontinuity. To overcome these difficulties we use the approach of Filippov, which extends the vector field to a differential inclusion. We study the stability of equilibria (called singular equilibrium sets) that lie on the surfaces of discontinuity. We prove several theorems that characterize the stability of these singular equilibria directly from the state transition graph, which is a qualitative representation of the dynamics of the system. We also formulate a stronger conjecture on the stability of these singular equilibrium sets.     

基于GES机制遗传算法构建基因调控网络

目的：基因调控网络在药物研发与疾病防治方面有重要的生物学意义。目前基于芯片数据构建网络的方法普遍效率不高,准确度较低,为此提出了一种新的高效调控网络结构预测算法。方法：提出了一种基于贪婪等价搜索机制的遗传算法构建基因调控网络模型。通过引入遗传算法的多点并行性,使得算法易于摆脱局部最优。通过编码网络结构作为遗传算法的染色体和设计基于GES机制的变异算子,使网络的进化过程基于马尔科夫等价空间而不是有向无环图空间。结果：通过对标准网络ASIA和酵母调控网络的预测,与近期Xue-wen Chen等提出的Order K2算法进行了比较,在网络构建准确率上获得了更佳的结果。与标准遗传算法比较下在执行效率上大大提高。结论：提出的算法在网络结构预测准确率上相对于最近提出的Order K2算法在准确率上效果更佳,并且相较标准遗传算法网络在进化过程上效率更高。     

Mathematical Methods for Inferring Regulatory Networks Interactions: Application to Genetic Regulation

This paper deals with the problem of reconstruction of the intergenic interaction graph from the raw data of genetic co-expression coming with new technologies of bio-arrays (DMA-arrays, protein-arrays, etc.). These new imaging devices in general only give information about the asymptotical part (fixed configurations of co-expression or limit cycles of such configurations) of the dynamical evolution of the regulatory networks (genetic and/or proteic) underlying the functioning of living systems. Extracting the casual structure and interaction coefficients of a gene interaction network from the observed configurations is a complex problem. But if all the fixed configurations are supposedly observed and if they are factorizable into two or more subsets of values, then the interaction graph possesses as many connected components as the number of factors and the solution is obtained in polynomial time. This new result allows us for example to partly solve the topology of the genetic regulatory network ruling the flowering in Arabidopsis thaliana .     

A Parallel Attractor Finding Algorithm Based on Boolean Satisfiability for Genetic Regulatory Networks

In biological systems, the dynamic analysis method has gained increasing attention in the past decade. The Boolean network is the most common model of a genetic regulatory network. The interactions of activation and inhibition in the genetic regulatory network are modeled as a set of functions of the Boolean network, while the state transitions in the Boolean network reflect the dynamic property of a genetic regulatory network. A difficult problem for state transition analysis is the finding of attractors. In this paper, we modeled the genetic regulatory network as a Boolean network and proposed a solving algorithm to tackle the attractor finding problem. In the proposed algorithm, we partitioned the Boolean network into several blocks consisting of the strongly connected components according to their gradients, and defined the connection between blocks as decision node. Based on the solutions calculated on the decision nodes and using a satisfiability solving algorithm, we identified the attractors in the state transition graph of each block. The proposed algorithm is benchmarked on a variety of genetic regulatory networks. Compared with existing algorithms, it achieved similar performance on small test cases, and outperformed it on larger and more complex ones, which happens to be the trend of the modern genetic regulatory network. Furthermore, while the existing satisfiability-based algorithms cannot be parallelized due to their inherent algorithm design, the proposed algorithm exhibits a good scalability on parallel computing architectures.     

An evolutionary system using development and artificial Genetic Regulatory Networks for electronic circuit design

Biology presents incomparable, but desirable, characteristics compared to engineered systems. Inspired by biological development, we have devised a multi-layered design architecture that attempts to capture the favourable characteristics of biological mechanisms for application to design problems. We have identified and implemented essential features of Genetic Regulatory Networks (GRNs) and cell signalling which lead to self-organization and cell differentiation. We have applied this to electronic circuit design.     

基因调控网络的生物信息学研究

调控网络的研究对于深入理解细胞的决定和分化、多细胞生物的生长发育至关重要。在调控网络中调控元件、基序(motif)、组件(module)、网络整体的拓扑学结构等4个结构层次进行的研究已经发展出了几类主要方法,但仍然有些问题需要解决。用理论方法及基于生物工程技术和合成生物学中研究成果的方法,建立调控网络Circuit的可计算模型的标准和数据库也在不断发展中。新近的研究还显示,高拟真度的Circuit模型与Circuit重建的研究方法联用,可以切实地解决许多调控网络研究中的重要问题。     

Discovering Study-Specific Gene Regulatory Networks

Microarrays are commonly used in biology because of their ability to simultaneously measure thousands of genes under different conditions. Due to their structure, typically containing a high amount of variables but far fewer samples, scalable network analysis techniques are often employed. In particular, consensus approaches have been recently used that combine multiple microarray studies in order to find networks that are more robust. The purpose of this paper, however, is to combine multiple microarray studies to automatically identify subnetworks that are distinctive to specific experimental conditions rather than common to them all. To better understand key regulatory mechanisms and how they change under different conditions, we derive unique networks from multiple independent networks built using glasso which goes beyond standard correlations. This involves calculating cluster prediction accuracies to detect the most predictive genes for a specific set of conditions. We differentiate between accuracies calculated using cross-validation within a selected cluster of studies (the intra prediction accuracy) and those calculated on a set of independent studies belonging to different study clusters (inter prediction accuracy). Finally, we compare our method''s results to related state-of-the art techniques. We explore how the proposed pipeline performs on both synthetic data and real data (wheat and Fusarium). Our results show that subnetworks can be identified reliably that are specific to subsets of studies and that these networks reflect key mechanisms that are fundamental to the experimental conditions in each of those subsets.     

Evolving Robust Gene Regulatory Networks

Design and implementation of robust network modules is essential for construction of complex biological systems through hierarchical assembly of ‘parts’ and ‘devices’. The robustness of gene regulatory networks (GRNs) is ascribed chiefly to the underlying topology. The automatic designing capability of GRN topology that can exhibit robust behavior can dramatically change the current practice in synthetic biology. A recent study shows that Darwinian evolution can gradually develop higher topological robustness. Subsequently, this work presents an evolutionary algorithm that simulates natural evolution in silico, for identifying network topologies that are robust to perturbations. We present a Monte Carlo based method for quantifying topological robustness and designed a fitness approximation approach for efficient calculation of topological robustness which is computationally very intensive. The proposed framework was verified using two classic GRN behaviors: oscillation and bistability, although the framework is generalized for evolving other types of responses. The algorithm identified robust GRN architectures which were verified using different analysis and comparison. Analysis of the results also shed light on the relationship among robustness, cooperativity and complexity. This study also shows that nature has already evolved very robust architectures for its crucial systems; hence simulation of this natural process can be very valuable for designing robust biological systems.