Vera Pendino

MicroRNAs (miRNAs) are endogenous short sequences that interfere with messenger RNAs leading to translational inhibition. The peculiarity of miRNA-mediated regulation resides in their ability to finely tune the levels of protein expression. From an evolutionary perspective, this miRNA property may play a role in buffering the perturbation introduced by gene duplication. In this thesis, I developed a strategy to date the evolutionary appearance and the origin of duplication of miRNA targets and studied the relationships between the evolution of miRNA regulatory system and the evolution of their human target genes. I found that singleton targets were mostly acquired with metazoans or later, while duplicated targets are old genes, whose orthologs can be traced back in early eukaryotes and in prokaryotes. Interestingly, also the expansion of these duplicated genes occurred in metazoans. Moreover, duplicated targets tend to be regulated by a higher number of miRNAs than singletons, and often these miRNAs are also duplicated. The results of my study strengthen the idea that miRNAs triggered the fate of genes after duplication, contributing to the acquisition of new genes and to the increase of morphological complexity during the evolution of metazoans. Further they indicate that miRNA regulation is conserved among paralogs, which are co-regulated by the same miRNAs. In the context of cancer, this study contributes a better understanding of the properties of cancer genes, since they undergo miRNA regulation more than the rest of human genes. Indeed, cancer genes are fragile toward perturbations and dosage modifications may affect their function.