An investigation of human protein interactions using the comparative method

Protein-protein interactions;Human genetics;Bioinformatics;Phylogeny--Molecular aspects;Eukaryotic cells--Genetics

Ur-Rehman, Saif ; Barker, Daniel ; Barker, Daniel

University:University of St Andrews

Department:Biology (School of)

关键词: Protein-protein interactions;    Human genetics;    Bioinformatics;    Phylogeny--Molecular aspects;    Eukaryotic cells--Genetics;   

Others  :  https://research-repository.st-andrews.ac.uk/bitstream/handle/10023/3119/SaifUr-RehmanPhDThesis.pdf?sequence=6&isAllowed=y

来源: DR-NTU

【 摘 要 】

There is currently a large increase in the speed of production of DNA sequence data as nextgeneration sequencing technologies become more widespread. As such there is a need forrapid computational techniques to functionally annotate data as it is generated. Onecomputational method for the functional annotation of protein-coding genes is via detectionof interaction partners. If the putative partner has a functional annotation then this annotationcan be extended to the initial protein via the established principle of “guilt by association”.This work presents a method for rapid detection of functional interaction partners forproteins through the use of the comparative method. Functional links are sought betweenproteins through analysis of their patterns of presence and absence amongst a set of 54eukaryotic organisms. These links can be either direct or indirect protein interactions. Thesepatterns are analysed in the context of a phylogenetic tree.The method used is a heuristic combination of an established accurate methodologyinvolving comparison of models of evolution the parameters of which are estimated usingmaximum likelihood, with a novel technique involving the reconstruction of ancestral statesusing Dollo parsimony and analysis of these reconstructions through the use of logisticregression. The methodology achieves comparable specificity to the use of gene coexpressionas a means to predict functional linkage between proteins.The application of this method permitted a genome-wide analysis of the humangenome, which would have otherwise demanded a potentially prohibitive amount ofcomputational resource.Proteins within the human genome were clustered into orthologous groups. 10 ofthese proteins, which were ubiquitous across all 54 eukaryotes, were used to reconstruct aphylogeny. An application of the heuristic predicted a set of functional protein interactions inhuman cells. 1,142 functional interactions were predicted. Of these predictions 1,131 werenot present in current protein-protein interaction databases.