CORDIS - Forschungsergebnisse der EU

From co-transcriptional splicing kinetics to the evolutionary impact of exon and intron definition


Codierung oder nicht Codierung, das ist hier die evolutionäre Frage

Die Expression von Genen (Produktion entsprechender Proteine) beruht auf ihrer Transkription und Translation. Bei der Transkription wird die DNA-Information auf ein mRNA-Molekül (Messenger-RNA) übertragen, bei der Translation hingegen werden auf Basis der mRNA-Sequenz Aminosäuren zusammengebaut, die dann das Protein bilden. In einigen Genen kodiert nicht die ganze DNA-Sequenz für das Protein. Stattdessen werden so genannte Introns nach der Transkription herausgespleißt, sodass nur die verbleibenden Exons im fertigen RNA-Molekül das Protein herstellen. Obwohl das Spleißen entscheidend für die Sequenzevolution ist, sind die zugrunde liegenden Mechanismen noch wenig erforscht. Das Projekt EvolSpliceKinetics führt die erste genomweite Analyse zur Definition von Exons und Introns durch. Ein zukunftsweisendes Sequenzierungsverfahren an einem Modellorganismus in Kombination mit maschinellem Lernen und Populationsgenetik wird erstmals Einblicke in die evolutionäre Rolle der Spleißkinetik bieten.


The need to preserve correct splicing is a major source of constraint on sequence evolution. This includes selection on the splice sites as well as on regulatory elements in exons and introns. Are all exons and introns constrained similarly by splicing related pressures? This is a crucial problem not only for understanding genome evolution but also for predicting where disease-causing mutations occur.

Any variation in the prevalence of splicing information most likely reflects mechanistic variation in how the splicing process unfolds at different introns. Notably, it is often assumed that the relative importance of intronic and exonic splicing information depends on whether the splicing machinery recognizes introns or exons as the initial unit. However, this common model has never been tested directly because it is currently not possible to investigate splicing mechanism at this level of detail genome-wide. Existing studies on the distribution of splicing information are therefore based on proxies of unclear mechanistic significance, such as intron size.

My host lab has developed a nascent RNA sequencing technique that allows unprecedented insight into splicing dynamics transcriptome-wide. They have recently applied this method to Drosophila melanogaster, a species thought to use a diversity of splicing strategies. I propose to use this data, combined with a machine learning approach, to conduct the first genome-wide study into exon and intron definition based on direct kinetic evidence. I will then use population genetics methods to determine how the prevalence and strength of selection on different types of splicing information covaries with splicing dynamics.


€ 147 815,04
1649 028 Lisboa

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€ 147 815,04