Viral mRNAs: evolution and structure-function relashionships

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The high rate of viral evolution is a major factor in immune escape and the main obstacle for the development of vaccines. A quickly growing body of evidence on amino acid mutations leading to drug resistance is available. At the same time sequence diversity is restricted by the need to preserve stable protein structure and function. Contrary to the general belief that the amino acid sequence of a protein solely determines its expression, folding, and function, reports have started to emerge that silent mutations and mRNA structure can also exert influence on protein function. So far structure-function relationships in viral RNAs remain largely uninvestigated. Recent improvements of experimental and computational methods for RNA structure determination as well as the massive increase of completely sequenced viral genomes allow now for a first systematic attempt to organize the fold space of coding RNA structures in viruses in order to understand how base paring patterns constrain genetic diversity and ultimately influence pathogenesis. The main goal of the proposal is to investigate how viral genomes convey functional information at different levels of their structural organization, with a special focus on RNA secondary structure. Sequences will be clustered based on both sequence and structural features. A viral structurome database will be generated using a whole battery of computational methods based on phylogenetics, thermodynamics, and sequence analysis. A simultaneous analysis of viral evolution both at the level of primary and secondary structure will be conducted by large-scale sequence comparison, structure prediction, and clustering, providing insights into RNA-level selection pressure affecting amino-acid sequences. A comprehensive catalog of viral RNA motifs will be created, and their role in determining mutational robustness of viruses and linking differential sequence diversity to clinical outcome examined. We will study evolutionary and biological factors underlying the formation of RNA structure elements important for genome packaging, replication, protein expression, interaction with the host intracellular machinery, and evading the host defense systems. We will investigate why some viruses have clearly defined secondary structures while others do not, and what role such structures play in virulence, tissue tropism, host adaptation, and inter-species transmission. We hope to understand how the amount of RNA structure enhances or represses gene expression and ultimately to derive recipes for modifying gene sequences in order to optimize secondary structure content and hence expression level. In the long run we envisage creation of a compendium of viral mRNA structural elements in form of a regularly updated public resource.