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Title: How codon choice determines evolvability and evolutionary robustness in short linear motifs
Author: Gunnarsson, Peter
ISNI:       0000 0004 9354 2019
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
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Short linear motifs, made up of 2-10 amino acids in linear sequence space, are a central component of cellular decision making through proteins. They form a modular system in cells where combinations of domains and motifs are used as basic functional building blocks through interactions. Functions mediated through these motifs include cellular localisation, post-translational modifications, degradation and general protein-protein interactions. Since motifs are made up of a small number of amino acids they have unusual evolutionary properties, for instance they can evolve de novo, or be lost, through a small number of substitutions. This is of particular importance in pathogens such as viruses. Many viruses evolve new host-like motifs to interact with the host and change the regulation and signalling landscape within host cells to mediate infection. In this body of work, I have used influenza as a model to elucidate aspects of the evolutionary properties of motifs. I have been able to leverage recent progress made in determining nucleotide mutation rates and have developed a model for motif evolution that is defined from the nucleotide and codon levels. Simulations using this methodology suggested that different codons have varying propensities to evolve into amino acids within a linear motif. In other words, some sequences have higher motif evolvability. The simulations also indicated a fitness benefit to use some codons over others to encode linear motifs, due to the varying propensity to evolve. These findings suggest that motifs that are encoded by specific codons have higher motif evolutionary robustness, i.e. they can tolerate more mutations without affecting function. I went on to investigate if these predicted properties have played a role in motif evolution in influenza. I found that conserved motifs in influenza use the codons inferred to have higher evolutionary robustness. This would lead to increased fitness, as motifs are less often lost through mutations. I also found that this mutational robustness acts on stop codon usage in influenza, suggesting an explanation for an old observation of predominant use of TAA in many organisms. Interestingly, it also appears that evolutionary robustness of a motif can be varied to tune the rate of motif change, which influenza utilises in glycosylation motifs that interface with the host immune system. Finally, I investigated whether the codon choice and evolvability at early stages of viral host shifts could be used to predict the emergence of functional motifs. I have found that motif evolvability can aid the prediction of motif emergence. For influenza strains H1N1 and H3N2, which were introduced in the human population from birds during the 1900s, the sequence of the early strains could be used to predict the majority of the glycosylation sites that would emerge the following decades. The predictability of motif emergence could have important implications for vaccination efforts. The methodologies developed here, and the observations made about how motif evolution is shaped by codon choices in a predictable way will be important for a better understanding of the evolution of complexity and regulation involving motifs. This may have implications for complex diseases such as cancers, and for our understanding of the evolution of pathogen innovations and functionality.
Supervisor: Babu, M. Madan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Evolution ; Robustness ; Evolvability ; Short Linear Motifs ; Influenza ; Codon choice ; Codon bias ; Glycosylation ; Phosphorylation