Recent studies have shown that single-stranded (ss) viral RNAs fold into more compact structures than random RNA sequences with similar chemical composition and identical length. Based on this comparison, it has been suggested that wild-type viral RNA may have evolved to be atypically compact so as to aid its encapsidation and assist the viral assembly process. To further explore the compactness selection hypothesis, we systematically compare the predicted sizes of >100 wild-type viral sequences with those of their mutants, which are evolved in silico and subject to a number of known evolutionary constraints. In particular, we enforce mutation synonynimity, preserve the codon-bias, and leave untranslated regions intact. It is found that progressive accumulation of these restricted mutations still suffices to completely erase the characteristic compactness imprint of the viral RNA genomes, making them in this respect physically indistinguishable from randomly shuffled RNAs. This shows that maintaining the physical compactness of the genome is indeed a primary factor among ssRNA viruses' evolutionary constraints, contributing also to the evidence that synonymous mutations in viral ssRNA genomes are not strictly neutral.
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