Show simple item record

dc.contributor.advisorSimpson, Ianen
dc.contributor.advisorBramham, Cliveen
dc.contributor.authorPajak, Maciejen
dc.date.accessioned2018-06-07T13:11:29Z
dc.date.available2018-06-07T13:11:29Z
dc.date.issued2018-07-02
dc.identifier.urihttp://hdl.handle.net/1842/31108
dc.description.abstractThe evolution of synapses from early proto-synaptic protein complexes in unicellular eukaryotes to sophisticated machines comprising thousands of proteins parallels the emergence of finely tuned synaptic plasticity, a molecular correlate for memory and learning. Phenotypic change in organisms is ultimately the result of evolution of their genotype at the molecular level. Selection pressure is a measure of how changes in genome sequence that arise though naturally occurring processes in populations are fixed or eliminated in subsequent generations. Inferring phylogenetic information about proteins such as the variation of selection pressure across coding sequences can provide valuable information not only about the origin of proteins, but also the contribution of specific sites within proteins to their current roles within an organism. Recent evolutionary studies of synaptic proteins have generated attractive hypotheses about the emergence of finely-tuned regulatory mechanisms in the post-synaptic proteome related to learning, however, these analyses are relatively superficial. In this thesis, I establish a scalable molecular phylogenetic modelling framework based on three new inference methodologies to investigate temporal and spatial aspects of selection pressure changes for the whole human proteome using protein orthologs from up to 68 taxa. Temporal modelling of evolutionary selection pressure reveals informative features and patterns for the entire human proteome and identifies groups of proteins that share distinct diversification timelines. Multi-ontology enrichment analysis of these gene cohorts was used to aid biological interpretation, but these approaches are statistically under powered and do not capture a clear picture of the emergence of synaptic plasticity. Subsequent pathway-centric analysis of key synaptic pathways extends the interpretation of temporal data and allows for revision of previous hypotheses about the evolution of complex synaptic function. I proceed to integrate inferred selection pressure timeline information in the context of static protein-protein interaction data. A network analysis of the full human proteome reveals systematic patterns linking the temporal profile of proteins’ evolution and their topological role in the interaction graph. These graphs were used to test a mechanistic hypothesis that proposed a propagating diversification signal between interactors using the temporal modelling data and network analysis tools. Finally, I analyse the data of amino-acid level spatial modelling of selection pressure events in Arc, one of the master regulators of synaptic plasticity, and its interactors for which detailed experimental data is available. I use the Arc interactome as an example to discuss episodic and localised diversifying selection pressure events in tightly coupled complexes of protein and showcase potential for a similar systematic analysis of larger complexes of proteins using a pathway-centric approach. Through my work I revised our understanding of temporal evolutionary patterns that shaped contemporary synaptic function through profiling of emergence and refinement of proteins in multiple pathways of the nervous system. I also uncovered systematic effects linking dependencies between proteins with their active diversification, and hypothesised about their extension to domain level selection pressure events.en
dc.contributor.sponsorEngineering and Physical Sciences Research Council (EPSRC)en
dc.language.isoen
dc.publisherThe University of Edinburghen
dc.relation.hasversionPai, B., Siripornmongcolchai, T., Berentsen, B., Pakzad, A., Vieuille, C., Pallesen, S., Pajak, M., Simpson, T. I., Armstrong, J. D., Wibrand, K., and Bramham, C. R. (2014). NMDA receptordependent regulation of miRNA expression and association with Argonaute during LTP in vivo. Frontiers in Cellular Neuroscience, 7(January):1–15.en
dc.subjectbioinformaticsen
dc.subjectdata scienceen
dc.subjectphenotypic changeen
dc.subjectsynaptic proteinsen
dc.subjectphylogenetic modelling frameworken
dc.subjectArc interactomeen
dc.subjecttemporal evolutionary patternsen
dc.titleEvolutionary conservation and diversification of complex synaptic function in human proteomeen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


Files in this item

This item appears in the following Collection(s)

Show simple item record