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Title: Structural and functional analysis of single amino acid replacements in proteins : insights from protein evolution into the disease aetiology
Author: Gong, S. S.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2011
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I first focus on the use of amino acid substitution model and address how the description of amino acid replacement could be improved by discriminating local structural environments from the following four categories of functional restraints: i) protein-protein interactions, ii) protein-nucleic acid interactions, iii) protein-ligand interactions and iv) catalytic activity of enzymes. From the observation of amino acid replacements which are under restraints of the local structural and functional environments, I apply those principles in the study of human genetic variation from the following three categories: i) Mendelian disease-related variants, ii) neutral polymorphisms and iii) cancer somatic mutations. I characterize structural and functional environments where the variants occur and compare how the environments are different amongst three groups. I show that various types of variants are under different degrees of structural and functional restraints, which affect their occurrence in human proteome. Then, I exemplify how the understanding of structural and functional restraints imposed on proteins could help identify genetic variations associated with a disease by demonstrating analysis of genetic variations responsible for type 1 diabetes. Finally, I describe a development web-based database system which houses structural and functional annotations of amino acid residues which have been used during this study. The system, named SAMUL, interconnects the Blundell group’s in-house databases focused on molecular interactomes and external data sources such as PDB, UniProt and Ensembl. SAMUL accommodates amino acid variation and mutation data and provides an interface in which people can navigate the mutations in the context of three-dimensional structure of proteins, if available, and interpret their severity in conjunction with the structural and functional environments where the variants occur at the wild type amino acid.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available