Projektbeschreibung
Evolutionäre Genomik für eine bessere Medizin
Einblicke in die Mechanismen der Genomevolution im Laufe der Zeit sind von grundlegender Bedeutung, um die genetischen Grundlagen von Krankheiten und das komplexe Zusammenspiel zwischen Genen zu verstehen und verbesserte Gentherapien zu entwickeln. Wie entschärft das Genom Fehler, die bei der DNA-Replikation entstehen? Gibt es stille Orte im Genom, an denen Fehler keine Auswirkungen haben? Im Rahmen des vom Europäischen Forschungsrat finanzierten Projekts EvoGenMed soll erforscht werden, wie Fehler zu evolutionären Veränderungen und neuen Merkmalen führen können und wie stark diese Selektion ist. Durch die Analyse von Mutationen und Gennetzwerken wollen die Forschenden bessere Diagnostikinstrumente entwickeln, krankheitsverursachende Mutationen identifizieren und sichere Stellen für die Einbringung therapeutischer Gene finden.
Ziel
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.
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-ADG - Advanced GrantGastgebende Einrichtung
BA2 7AY Bath
Vereinigtes Königreich