Description du projet
La génomique évolutive au service de la médecine
Appréhender le mécanisme d’évolution du génome au fil du temps est d’une importance fondamentale pour comprendre la base génétique des maladies et l’interaction complexe entre les gènes, et pour améliorer les thérapies basées sur les gènes. Comment le génome atténue-t-il les erreurs inhérentes à la réplication de l’ADN? Existe-t-il des sites silencieux où les erreurs n’ont pas d’incidence? Financé par le Conseil européen de la recherche, le projet EvoGenMed vise à étudier comment les erreurs peuvent conduire à des changements évolutifs et à de nouvelles caractéristiques, et la force de cette sélection. En analysant les mutations et les réseaux de gènes, l’équipe entend développer de meilleurs outils de diagnostic, identifier les mutations à l’origine de maladies et trouver des sites sûrs pour l’insertion de gènes thérapeutiques.
Objectif
To make for better diagnostics and safer applications of genomics we need a better understanding of our genome and how it functions. Until recently we thought we knew: intergenic sequence must be largely “junk” and mutations that, for example, affect genes but not the protein (synonymous mutations) must be effectively neutral. This degenerate genome view accords with the nearly-neutral theory’s prediction that selection will be weaker when populations are small. But is this all there is to it? I shall investigate two new interrelated perspectives on genome evolution. First, I suggest that to mitigate errors, owing to our high error rates, our genome can be under stronger, not weaker, selection. Second, that errors might be a source of evolutionary novelty. Error mitigation, my team has shown, often involves selection on seemingly innocuous mutations such as synonymous changes. Remarkably, we discovered that selection to ensure error-proof splicing is possibly more prevalent on synonymous mutations when populations are small, making seemingly innocuous mutations stronger candidates for human diseases. I shall provide the first test of the new error-proofing perspective through comparative genomic analysis on synonymous site evolution. To investigate error as a source of novelty I shall consider whether expression piggy-backing (expression of a gene affecting its neighbors) forces rewiring of gene networks. Importantly, I shall translate our new understanding to enable better diagnostics and improved therapeutics. I shall develop a much-needed computer package to identify candidate disease-causing synonymous changes. In addition, knowing how synonymous sites modulate splicing will allow me to design better intronless transgenes. Transgenes must also be inserted in genomic regions immune to piggy-backing. I will examine transposable element related piggy-backing to characterize “safe” sites for therapeutic gene insertion and mammalian transgenesis more generally.
Champ scientifique
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Programme(s)
Thème(s)
Régime de financement
ERC-ADG - Advanced GrantInstitution d’accueil
BA2 7AY Bath
Royaume-Uni