Efthymiou, Christos; (2024) Computational Analysis of Genetic Variants: Structural Dynamics and Implications in Coagulation and Complement Disorders. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Simplified advanced sequencing technologies have significantly increased the number of known variants across the human genome. Several flat list databases store this information but are limited in their utility as they do not clarify the molecular mechanisms which drive disease. Furthermore, the substantial number of known variants disqualifies wet-lab experimentation as a realistic method to understand structural and mechanistic effects of these variants. In this thesis, interactive web databases were developed and updated for coagulation proteins Factor V (FV), Factor VIII (FVIII) and 17 genes of the complement system. These interactive interfaces enable variants to be analysed alongside the genetic and protein sequences, clinical phenotypes, and known three-dimensional protein structures. Predictive scores for mutations and evolutionary alignments are also provided. Altogether, the sites serve as a comprehensive resource for illuminating variant significance and mechanistic effects. Variants in the homologous FV and FVIII proteins are associated with severe bleeding disorders FV deficiency and haemophilia A. The widespread distribution of variants across both sequences in combination with a high proportion of buried variant residues indicated that both proteins are susceptible to disruption by small perturbations throughout their globular structures. The 17 gene complement system database clarified the molecular mechanisms underlying atypical haemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), and age-related macular degeneration (AMD), with distinct hotspots for each disorder explaining how mutations in the same proteins cause different phenotypes. Molecular dynamics (MD) simulations reflected experimental classification of aHUS variants and clarified their damaging effects on residue interaction networks by studying mutant C3d binding to CFH SCR 19-20. This finding will allow researchers to narrow the scope for wet-lab experiments. Database creation for heart development proteins T-box Transcription Factor 5 (TBX5) and GATA Binding Protein 4 (GATA4) demonstrated the utility in this methodological framework for other systems, as well as underscored the importance of intrinsically disordered regions in protein function.

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