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How do biochemical and environmental factors shape the fitness landscape of synonymous mutations on Hsp90?
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Resumo(s)
Synonymous mutations, i.e., nucleotide mutations that do not change the amino acid in a protein
sequence, have been traditionally considered to have a negligible effect on fitness. However,
accumulating evidence suggests that this is not always the case. Codon bias is a potential
mechanism through which synonymous mutations can affect fitness. The impact of codon bias
is known to vary with the location of the mutation and expression level of the gene (by
differentially affecting the elongation rate, co-translational folding process, and mRNA
structure). Another factor important in determining the fitness effect of synonymous mutations
is the presence of an environmental stress, by imposing additional need for specific protein
quantity, conformation, translational speed or accuracy. Systematic quantifications of the
prevalence of fitness effects of synonymous mutations and which factors shape this effect are
rare.
To fill this gap, we reanalysed published deep mutational scanning data from the chaperone
Hsp90 of Saccharomyces cerevisiae at two expression levels. We estimated the fitness effects
of every possible synonymous mutation when exposed to different environmental stresses.
Overall, there was a strong effect of the environment on mutations under low expression levels.
We also found that the expression level of Hsp90 strongly affected the effect of synonymous
mutations, with a prevalence of neutral mutations under normal expression and stronger
mutations under low expression. This result, together with the lack of correlation between
codon frequency and fitness, suggests that codon usage bias is not the main mechanism
underlying the observed effects. Overall, we find that synonymous mutations can show a wide
range of fitness effects, which are altered by the presence of abiotic stresses and changes in
gene expression. This suggests that synonymous mutations might have a greater impact on
adaptation to novel conditions than traditionally thought.
Descrição
Tese de mestrado, Biologia Evolutiva e do Desenvolvimento, 2025, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Mutações sinónimas Viés do uso de codões Distribuição dos efeitos de fitness Deep mutational scanning Saccharomyces cerevisiae Teses de mestrado - 2025