Pappalardo, Morena (2016) A Computational study of Ebolavirus Pathogenicity and a Modeling approach for human non-synonymous variants. Doctor of Philosophy (PhD) thesis, University of Kent,. (KAR id:57320)
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Abstract
Recent advances in genome sequencing are improving our better understanding of
genetic variation. However, the investigation of the genotype-phenotype relationship
is still challenging, especially for the interpretation of the myriad of discovered
genetic variants that weakly relate to disease.
Recently, researchers have confirmed that disease causing genetic variants typically
occur at functional sites, such as protein-protein or protein-ligand interaction sites.
Giving this observation, several bioinformatics tools have been developed. This
thesis first details VarMod (Variant Modeller), an algorithm that predicts whether
nonsynonymous single nucleotide variants (nsSNVs) affect protein function.
The recent Ebola virus outbreak in West Africa demonstrated the potential for the
virus to cause edipdemics and highlighted our limited understanding of Ebola virus
biology. The second part of this thesis focuses on the investigation of the molecular
determinants of Ebolavirus pathogenicity. In two related analyses knowledge of
differing pathogenicity of Ebolavirus species is used. Firstly, comparison of the
sequences of Reston viruses (the only Ebolavirus species that is not pathogenic in
humans) with the four pathogenic Ebolavirus species, enabled the identification of
Specificity Determining Positions (SDPs) that are differentially conserved between
these two groups. These SDPs were further investigated using analysis of protein
structure and identified variation in the Ebola virus VP24 as likely to have a role in
determining species-specific pathogenicity. The second approach investigated
rodent-adapted Ebola virus. Ebola virus is not pathogenic in rodents but it can be
passaged to induce pathogenicity. Analysis of the mutations identified in four
adaption studies identified that very few mutations are required for adaptation to a
new species and once again the VP24 is likely to have a central role. Subsequent
molecular dynamics simulations compared the interaction of Ebola and Reston virus
VP24 with human karyopherin alpha5. The analysis suggests that Reston virus VP24
has weaker binding with karyopherins and we propose that this change in binding
may reduce the ability of Reston VP24 to inhibit human interferon signaling.
Item Type: | Thesis (Doctor of Philosophy (PhD)) |
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Uncontrolled keywords: | nsSNV, varMod, Ebolavirus pathogenicity, Reston |
Subjects: |
Q Science > QP Physiology (Living systems) Q Science > QR Microbiology R Medicine > RB Pathology |
Divisions: | Divisions > Division of Natural Sciences > Biosciences |
Depositing User: | Users 1 not found. |
Date Deposited: | 16 Sep 2016 11:00 UTC |
Last Modified: | 12 Dec 2022 05:34 UTC |
Resource URI: | https://kar.kent.ac.uk/id/eprint/57320 (The current URI for this page, for reference purposes) |
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