Research On Key Technologies For RNA Secondary Structure Topologization And Its Applications

As one of the most important macromolecules,Ribonucleic Acid(RNA) plays various indispensable roles in life.Researches on RNA molecules will result in deep recognitions of the core problems in the life science,as well as important applications. RNomics,which aims to reveal sequences and structure of all types of RNAs,has been proposed by Filipowicz in 2000.The emergence of RNomics present new requests for new methods for computational analysis of RNA high structure,topologization of RNA secondary structure,i.e.quantitative methods of RNA secondary structure are especially required.Some new methods for RNA secondary structure topologization are presented in this dissertation and applied to many researches,including visualization of RNA configuration space,RNA deleterious mutation prediction,quantitative evaluation of RNA structural robustness,multistable RNA molecules design,and RNA evolutionary dynamics.The main contents and contributions of the dissertation are summarized as follows:(1) RNA secondary structure topologizationTopologization of RNA secondary structure aims at constructing topological indices which can describe RNA secondary structure quantitatively.RNA secondary structure topologization is a newly emerging direction in the field of RNA structural analysis.To provide a complete and fine scheme for RNA secondary structure,a combination of three vertex-weighted element-contact graphs(ECGs) is first proposed. Both the stem and loop topologies are completely encoded in ECG groups.Three typical topological index families defined on ECGs are investigated.The numerical features of these indices for possible RNA topologies are explored.Fractal dimensions based on mountain representation of RNA secondary structure are also presented.Using the weakly self-affine(WSA) model of RNA secondary structure,a functional domain recognition method is presented in this dissertation.(2) Basic applications of RNA secondary structure topologizationThe RNA topological indices establish the foundation for the quantitative description of RNA configuration space.However,the use of these indices may result in "Dimension Disaster" in applications.A method of visualization of RNA configuration space based on manifold learning is presented,where RNA secondary structures are quantitatively described by these bopological indices.The method is successfully applied in interactive recognition and clustering of miRNAs,and clustering of ncRNAs.Two methods of RNA deleterious mutation prediction are proposed.One is based on the structural difference,and the other is based on the structural difference and multiple sequence alignment.Also,a web server of RNA deleterious mutation analysis is implemented.These methods are successfully applied in the design of LAIV(Live Attenuated Influenza Vaccine).(3) RNA structural robustness and muitistable RNA molecules designEvolutionary biologists have a long-standing interest in quantitative measure of robustness.Many merits of RNA secondary structure make them an ideal system to study robustness.A method of quantitatively measuring robustness of structural elements based on neutrality is first developed,and the robustness of structural elements in miRNAs is analyzed using this method.This dissertation presents a method of quantitatively measuring robustness of RNA secondary structure,and investigates the structural robustness of miRNAs.Furthermore,this dissertation discusses the evolution of genetic robustness in miRNAs,and proposes the hypothesis of congruent evolution of genetic and environmental robustness.Finally,a web server of RNA structural robustness evaluation is implemented for the study of robustness.Based on the theory and algorithm of the design of bistable RNA molecules,the design of multistable RNA molecules can be described as the combinatorial optimization problem on the set of compatible sequences.Using the graph theory,this problem can be reduced into a vertex coloring problem of dependency graph.An algorithm for multistable RNA molecular design is presented,where the cost function involves the information of thermodynamic stability and genetic robustness of RNA molecules.The designed RNA sequences satisfy the requests well.(4) Simulation of RNA evolutionary dynamics and its theory modelTheoretical biologists have paid close attention to the study of simulation and theoretical model of RNA evolutionary dynamics.Using Monte Carlo method,this dissertation simulates the process of RNA evolution,and establishes the corresponding structural and free energy landscape.The landscapes of miRNAs have been analyzed in detail.Furthermore,a theoretical model of RNA landscape is developed based on Gaussian mixture model.Finally,a simulation platform is implemented for the study of RNA evolutionary dynamics.