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Évolution des préférences d'usage de codons et manipulation de la fidelité de la traduction

Abstract : Eukaryotic cells contain a complex cellular machinery, that regulates and carries out geneexpression. The standard genetic code that is the basis of this protein production line is redundant,meaning that 64 codons encode for 20 amino acids. This redundancy gives rise to synonymouscodons, that encode for the same amino acid. Synonymous codons are not used at random, genes,tissues and organisms tend to have divergent Codon Usage Preferences (CUPrefs). The role ofCUPrefs and the forces that shape them are not yet clear, although it is certain that they hold animportant regulatory position in gene expression. If a gene’s CUPrefs match the cellular tRNA pool,translation will be fast and efficient, while under- or overmatching CUPrefs may cause either slowand inaccurate translation or competition among genes for resources. Viruses are dependent of thehost cell’s resources to express their genes, therefore the study of their CUPrefs is primordial tounderstand their functioning and interactions with the host. In this work, we attempt to enlarge ourunderstanding of the importance of CUPrefs by analyzing the causes and consequences of CUPrefsin eukaryotes and viruses, and in a long-term evolution experiment.First, we analyzed eleven recombinant Papillomaviruses (PV) that infect exclusively Cetaceans,along with other PVs that infect the same host order: the Cetartiodactyles. We found thatrecombinant PVs, are not different from non-recombinants in terms of CUPrefs. Instead CUPrefsare associated to gene type, with a link to gene function, and expression pattern. They do not matchhost CUPrefs, hinting to an immune evasion strategy by keeping low viral gene expression due tothe undermatch. Next, we looked at the evolution of CUPrefs in the three paralogs in vertebratesencoding for the Polypyrimidin tract binding protein (PTBP). The PTBP paralogs show distinctCUPrefs, with a GC enrichment linked to local mutational forces in PTBP1 in mammals. Wepropose that the divergent nucleotide composition in PTBPs is a result of evolution by sub-functionalisation upon gene duplication, and that it’s linked to gene expression patterns in differenttissues. In an experimental evolution setup we introduced synonymous genes (that only differ inCUPrefs) under strong selection for expression into HEK293 cells, and let them evolve under threeconditions for a hundred generations. When the heterologous genes under are directly underselection, cells overcome CUPrefs mismatch, and in spite of the differences, converge to a similarexpression pattern. In contrast, when the modified genes are subject of genetic hitchhiking,regulatory mechanisms lead to different expression profiles to limit metabolic cost.Overall we show that the CUPrefs play a role in regulating gene expression in terms of its differedtime or place. Further, we suggest that Eukaryote cells can adjust rapidly by complex regulatorymechanisms to overcome the disadvantages of heterologous CUPrefs if they are needed forsurvival, or down-regulate them if their expression is costly.
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Submitted on : Monday, March 21, 2022 - 11:59:08 AM
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Fanni Borveto. Évolution des préférences d'usage de codons et manipulation de la fidelité de la traduction. Sciences agricoles. Université Montpellier, 2021. Français. ⟨NNT : 2021MONTT082⟩. ⟨tel-03615085⟩

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