The Canon of RNA Proportions

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Minimalistic organisms, such as RNA viruses, are ideally suited to study how physical properties of genomes – and not merely their bare chemical sequence – evolve under selective pressures. Among these physical properties, the three-dimensional organization of the RNA genome is of particular importance for the encapsidation process, a crucial stage of the viral life cycle during which the RNA gets packed inside the self-assembling protein shell (capsid). Previous in silico studies have shown that, for icosahedral viruses, the size of the three-dimensional structure (fold) that viral RNAs spontaneously adopt when free in solution is only slightly larger than the viral shell itself. On the other hand, this was found not to be true for randomized RNA sequences, whose native folds’ size significantly exceeds the size of the capsid, thus making them not as easily encapsidated as the actual viral RNA. These results hinted at the possibility that viral RNA has been evolutionarily selected to have an atypically compact size for facilitating its packaging in the protein shell.

Building on these results, our in silico study was aimed at understanding the interplay of this recently-proposed selective mechanism with other well-known selective pressures, such as the conservation of the viral protein phenotype (synonymity). This problem touches aspects that are crucial for the sequence-structure relationship of viral RNA, and the key question that we wished to address was: if the viral RNA is evolved only through synonymous mutations, what happens to the RNA fold size? Does it preserve its native compactness? Or, despite the severe limitations on the accessible sequence space, does it increase in size significantly beyond the size of the capsid, as happens for random RNAs?
To answer these questions we simulated the evolution of more than 100 RNA genomes under various combinations of selective constraints, and monitored the resulting RNA size. Strikingly, we found that even a small percentage of conservative, synonymous mutations is sufficient to completely erase the distinctive compactness of wild-type RNAs, thus making the size of the mutated genomes indistinguishable from the size of random RNAs. Our study, therefore, strongly supports the independent evolution of viral RNA compactness and proves that the mutational space available for neutral mutation in icosahedral viruses is much smaller than previously thought.

Our cover image was inspired by Leonardo’s drawing of the Vitruvian man, the celebrated male figure harmoniously inscribed in a circle and a square, symbolizing the canon of proportions for the human body. Similarly, our sketch represents the effect of synonymous mutations on “viral RNA proportions.” Although the wild-type RNA on top of the image has the correct size for encapsidation, a synonymous mutant of the same RNA, shown at the bottom of the image, is too large to be packed. In the picture, RNA folds have been produced using ViennaRNA and plotted using VARNA; the capsid in the center has been plotted using CHIMERA. Both the wild-type RNA and the capsid pertain to the MS2 virus. The final image was composed using Inkscape and Gimp.

Our study connects a physical property of viral genomes with evolutionary selection. Clarifying the connection between viral RNA sequences and its properties is not only fundamentally important for our knowledge of evolutionary mechanisms, but may, in the future, allow control of the physical properties of viral RNAs, and specifically their aptitude for efficient packing. This, we believe, may lead to improving and broadening the scope of existing strategies that harness viral mutation rates to achieve virus attenuation and may open up new possibilities for the development of vaccines.

– Luca Tubiana, Anže Lošdorfer Božič, Cristian Micheletti, and Rudolf Podgornik

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