Identifying functionally and topologically cohesive modules in protein interaction networks

Systems biology offers a holistic perspectl% e \\ here indi% idual proteins are vie%\ ed as elements in a network of protein-protein interactions. in %%hich the proteins ha"e contextual functions within functional rnodules. In order to facilitate the identification and analysis of such modules. %\e here propose novel approaches that combine knowledge, in terms of Gene Ontology annotation xýith network topolov'ý information. The majority of previous methods for identifying rnodules in protein interaction networks are based solely on analýslng topological features of the networks. In contrast, we propose the use of integrated functionally Informed clustering coefficients to identify biologically plausible network modules. The main part of the thesis is focused on the method named SWEMODF (Semantic WEights for MODule Elucidation), which uses a weighted clustering coefficient to ldentifv netý\ork functional modules. We demonstrate that the proposed methods are able to identif\. " the key functional modules in protein interaction networks. We also investigate the functional and topological features of the proteins that are involved in multiple modules, as well as their role in the interconnectivity between modules. The results indicate that the majority of, so called multi-modular proteins are involved in the assembly and arrangement of cell structures. such as the cell wall and cell envelope. Acknowledgments First and foremost, I would like to deeply thank m,,, ' supervisors. Bj6rn Olsson and David Corne for their enormous support and guidance. Fý16rn, rny supervisor at the University of Sk6vde, has led me through both niý MSc and PhD projects. and without his valuable insights and generous help \\ith all aspects of rn\ thesis \ýork, this thesis would not have been possible. David's experienced pieces of advice \ýere invaluable for the completion of this thesis. Thanks must also go to Ajit Narayanan. my fon-ner supervisor, for his enthusiasm that vas one of the reasons for me to pursue this area of research. Special thanks to the examiners of m-% thesis for taking the time to review mv work. II Thanks to all colleagues, especiall\, Jonas Gamalielsson, for providing technical support, being a critical eý, e, and making his famous jokes. Thanks to Angelica Lindlbf, for all valuable discussions. and for being a great colleague and an even better friend. I am very grateful to rny parents, the main reason that I am here, for their endless love and encouragement. I also thank my sister who used to sabotage my work on the PhD thesis by stealing my weekend hours. Thanks should also go to my parents in low for standing by me during my PhD years. My PhD years will always be the most special part of my life, partly thanks to two little persons that came into my life. The first being my daughter Melina. who came into the world in the middle of my PhD studies, and taught me to be more efficient, focused and structured. The second being rny baby Alma who taught me that it is very difficult to plan the exact time of delivery. when it comes to babies and theses. I am deeply grateful to my fianc6 Amirýý ho was al ý\ a,,, ýs there for me through thick and thin. Finallý,, -. thanks to all friends and relatives for putting up ý\ ith me through some tough periods. ACADEMIC REGISTRY Research Thesis Submission Name: ZýAk? U4, q /a6c School/PGI: Version: (i. e. First, Resubmission, Final) Degree Sought: ? Ap Declaration In accordance with the appropriate regulations I hereby submit my thesis and I declare that: 1) the thesis embodies the results of my own work and has been composed by myself 2) where appropriate, I have made acknowledgement of the work of others and have made reference to work carried out in collaboration with other persons 3) the thesis is the correct version of the thesis for submission and is the same version as any electronic versions submitted*. 4) my thesis for the award referred to, deposited in the Heriot-Watt University Library, should be made available for loan or photocopying and be available via the Institutional Repository, subject to such conditions as the Librarian may require 5) 1 understand that as a student of the University I am required to abide by the Regulations of the University and to conform to its discipline. Please note that it is the responsibility of the candidate to ensure that the correct version of the thesis is submitted. Signature of Candidate: e, -2z la c Date: