Enhancing systems biology models through semantic data integration

Studying and modelling biology at a systems level requires a large amount of data of different experimental types. Historically, each of these types is stored in its own distinct format, with its own internal structure for holding the data produced by those experiments. While the use of community data standards can reduce the need for specialised, independent formats by providing a common syntax, standards uptake is not universal and a single standard cannot yet describe all biological data. In the work described in this thesis, a variety of integrative methods have been developed to reuse and restructure already extant systems biology data. SyMBA is a simple Web interface which stores experimental metadata in a published, common format. The creation of accurate quantitative SBML models is a time-intensive manual process. Modellers need to understand both the systems they are modelling and the intricacies of the SBML format. However, the amount of relevant data for even a relatively small and well-scoped model can be overwhelming. Saint is a Web application which accesses a number of external Web services and which provides suggested annotation for SBML and CellML models. MFO was developed to formalise all of the knowledge within the multiple SBML specification documents in a manner which is both human and computationally accessible. Rule-based mediation, a form of semantic data integration, is a useful way of reusing and re-purposing heterogeneous datasets which cannot, or are not, structured according to a common standard. This method of ontology-based integration is generic and can be used in any context, but has been implemented specifically to integrate systems biology data and to enrich systems biology models through the creation of new biological annotations. The work described in this thesis is one step towards the formalisation of biological knowledge useful to systems biology. Experimental metadata has been transformed into common structures, a Web application has been created for the retrieval of data appropriate to the annotation of systems biology models and multiple data models have been formalised and made accessible to semantic integration techniques.EThOS - Electronic Theses Online ServiceBBSRCEPSRCGBUnited Kingdo

Quantitative Fitness Analysis Shows That NMD Proteins and Many Other Protein Complexes Suppress or Enhance Distinct Telomere Cap Defects

To better understand telomere biology in budding yeast, we have performed systematic suppressor/enhancer analyses on yeast strains containing a point mutation in the essential telomere capping gene CDC13 (cdc13-1) or containing a null mutation in the DNA damage response and telomere capping gene YKU70 (yku70Δ). We performed Quantitative Fitness Analysis (QFA) on thousands of yeast strains containing mutations affecting telomere-capping proteins in combination with a library of systematic gene deletion mutations. To perform QFA, we typically inoculate 384 separate cultures onto solid agar plates and monitor growth of each culture by photography over time. The data are fitted to a logistic population growth model; and growth parameters, such as maximum growth rate and maximum doubling potential, are deduced. QFA reveals that as many as 5% of systematic gene deletions, affecting numerous functional classes, strongly interact with telomere capping defects. We show that, while Cdc13 and Yku70 perform complementary roles in telomere capping, their genetic interaction profiles differ significantly. At least 19 different classes of functionally or physically related proteins can be identified as interacting with cdc13-1, yku70Δ, or both. Each specific genetic interaction informs the roles of individual gene products in telomere biology. One striking example is with genes of the nonsense-mediated RNA decay (NMD) pathway which, when disabled, suppress the conditional cdc13-1 mutation but enhance the null yku70Δ mutation. We show that the suppressing/enhancing role of the NMD pathway at uncapped telomeres is mediated through the levels of Stn1, an essential telomere capping protein, which interacts with Cdc13 and recruitment of telomerase to telomeres. We show that increased Stn1 levels affect growth of cells with telomere capping defects due to cdc13-1 and yku70Δ. QFA is a sensitive, high-throughput method that will also be useful to understand other aspects of microbial cell biology