Buchan, Daniel; (2003) Protein domain evolution by comparative genomics. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Modern gene sequencing methods and the genome projects have been depositing data in the public databanks at ever increasing rates for the last twenty years. Biochemistry faces a challenge to generate meaningful analyses of these data since genomic data is generated faster than traditional 'wet lab' techniques can analyse. Bioinformatics can be used to automatically annotate and classify these data and subsequently provide insights into the biochemistry of many organisms. While Bioinformatics provides no direct substitute for the work in the 'wet lab', it is now an indispensible adjunct to modern biochemistry. This thesis is chiefly concerned with the automated assignment of protein domains and protein functions to those sequences that were previously uncharacterised. The first part of the thesis addresses the problem of assigning structural and sequence domains to proteins of unknown domain structure. The construction of a database of these data (GeneSD) is also presented. This is followed by a protocol for assigning protein functions to uncharacterised proteins. For both these studies (domain assignment and functional assignment) statistics are gathered to describe the general trends and patterns that are observed. The subsequent chapters are concerned with the comparative analysis of the data for 32 complete genomes. An analysis of protein domain combinations and its functional ramifications is carried out. It is observed that the data gathered are in good agreement with other studies of this nature. From this, it is also shown that the combinatorics of protein domains impacts significantly on the functional repertoire of these domains. Finally, a temporal order in which the observed protein folds arose is proposed. Using a combination of phylogenetic profiles and functional data a rational protocol for assigning protein folds to points in evolution is suggested. This study also attempts to take into account the action of horizontal transfer. This work was supported by the Biotechnology and Biological Sciences Research Council.

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