Viral mRNAs: evolution and structure-function relashionships
Final Report Abstract
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 remained largely uninvestigated. Recent improvements of experimental and computational methods for RNA structure determination as well as the massive increase of completely sequenced viral genomes allowed 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 project was to investigate how viral genomes convey functional information at different levels of their structural organization, with a special focus on RNA secondary structure. Sequences were clustered based on both sequence and structural features. A viral "structurome" was 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 was conducted by large-scale sequence comparison, structure prediction, and clustering. A comprehensive catalog of viral protein families and RNA motifs was created. We were able to recover structural elements from previous studies and discovered a variety of novel structured regions. We provide a compendium of viral protein families and mRNA structural elements in form of regularly updated public resources. One of them, called VOGDB is a database of viral orthologous groups. The second resource, RNASIV is the first compilation of potentially functional conserved RNA structures in viral coding regions, covering the complete RefSeq viral database.
Publications
- Conservation of mRNA secondary structures may filter out mutations in Escherichia coli evolution. Nucleic Acids Res 2013, 41(16):7854-7860
Chursov A, Frishman D, Shneider A
(See online at https://doi.org/10.1093/nar/gkt507) - RNAtips: Analysis of temperatureinduced changes of RNA secondary structure. Nucleic Acids Res 2013, 41 (Web Server issue): W486-491
Chursov A, Kopetzky SJ, Bocharov G, Frishman D, Shneider A
(See online at https://doi.org/10.1093/nar/gkt486) - Challenges in RNA virus bioinformatics. Bioinformatics 2014, 30(13):1793-1799
Marz M, Beerenwinkel N, Drosten C, Fricke M, Frishman D, Hofacker IL, Hoffmann D, Middendorf M, Rattei T, Stadler PF et al.
(See online at https://doi.org/10.1093/bioinformatics/btu105) - Conserved RNA structures in the intergenic regions of ambisense viruses. Sci Rep 2017, 7(1):16625
Kiening M, Weber F, Frishman D
(See online at https://doi.org/10.1038/s41598-017-16875-4) - Conserved Secondary Structures in Viral mRNAs. Viruses 2019, 11(5)
Kiening M, Ochsenreiter R, Hellinger HJ, Rattei T, Hofacker I, Frishman D
(See online at https://doi.org/10.3390/v11050401)
