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Title: Characterising gene-gene and gene-environment interactions within the fitness landscape of a snoRNA
Author: Williamson, Luke Jonathan
ISNI:       0000 0004 7969 1827
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
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Empirical fitness landscapes allow a previously hypothetical concept describing the genotype-phenotype relationship to be visualised and dissected. The fitness landscapes of entire molecules have only recently begun to be elucidated, with gene-gene and gene-environment interactions being largely unexplored in this context. U3 small nucleolar RNA (snoRNA) represents a suitable model in which to examine these interactions, with the strategy of deep mutational scanning enabling mutational effects to be studied at a single nucleotide resolution. In yeast, the U3 snoRNA directs three essential cleavage events of the pre-ribosomal RNA (pre-rRNA), facilitated by complementarity between the 5' region of U3 snoRNA and the 35S pre-rRNA transcript. These cleavage events along with folding of the pre-rRNA are facilitated by a series of proteins, some of which bind with U3 snoRNA to form the U3 snoRNP. Since U3 snoRNA interacts with several proteins, it is an ideal candidate to study the molecular mechanisms behind gene-gene interactions. I have used the auxin inducible degron system to downregulate eight proteins that interact with U3 snoRNA. The disruption of these essential genes demonstrated intermolecular epistasis, altering the fitness landscape in a gene specific manner. Conditionally deleterious mutations were enriched in regions of U3 snoRNA whose role is related to that of the hypomorphic protein. To simulate the changing environments that an organism may face, and observe the resulting impact, I measured the fitness landscape of U3 snoRNA in three different temperature environments. This highlighted numerous gene-environment interactions, related to structural and protein binding regions of U3 snoRNA. Various genotypes tolerated at physiological temperature become deleterious at higher and lower temperatures.
Supervisor: Kudla, Grzegorz ; Caceres, Javier Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: gene mutations ; temperature variations ; U3 small nucleolar RNA ; snoRNA ; gene-gene interactions ; changing environment