Abstract
The small size of RNA virus genomes (2-to-32 kb) has been attributed to high mutation rates during replication, which is thought to lack proof-reading. This paradigm is being revisited owing to the discovery of a 3′-to-5′ exoribonuclease (ExoN) in nidoviruses, a monophyletic group of positive-stranded RNA viruses with a conserved genome architecture. ExoN, a homolog of canonical DNA proof-reading enzymes, is exclusively encoded by nidoviruses with genomes larger than 20 kb. All other known non-segmented RNA viruses have smaller genomes. Here we use evolutionary analyses to show that the two- to three-fold expansion of the nidovirus genome was accompanied by a large number of replacements in conserved proteins at a scale comparable to that in the Tree of Life. To unravel common evolutionary patterns in such genetically diverse viruses, we established the relation between genomic regions in nidoviruses in a sequence alignment-free manner. We exploited the conservation of the genome architecture to partition each genome into five non-overlapping regions: 5′ untranslated region (UTR), open reading frame (ORF) 1a, ORF1b, 3′ORFs (encompassing the 3′-proximal ORFs), and 3′ UTR. Each region was analyzed for its contribution to genome size change under different models. The non-linear model statistically outperformed the linear one and captured >92% of data variation. Accordingly, nidovirus genomes were concluded to have reached different points on an expansion trajectory dominated by consecutive increases of ORF1b, ORF1a, and 3′ORFs. Our findings indicate a unidirectional hierarchical relation between these genome regions, which are distinguished by their expression mechanism. In contrast, these regions cooperate bi-directionally on a functional level in the virus life cycle, in which they predominantly control genome replication, genome expression, and virus dissemination, respectively. Collectively, our findings suggest that genome architecture and the associated region-specific division of labor leave a footprint on genome expansion and may limit RNA genome size.
Highlights
Genome size is the net result of evolution driven by the environment, mutation, and the genetics of a given organism [1,2]
The genome size of RNA viruses is restricted to a range of,2 to 32 kb that corresponds to a very narrow band on the genome size scale across which genome size increase is correlated with mutation rate decrease [7]
We sought to estimate the amount of accumulated replacements in conserved nidovirus proteins and to place it into a biological perspective by comparing it with that accumulated by proteins of cellular species in the Tree of Life (ToL)
Summary
Genome size is the net result of evolution driven by the environment, mutation, and the genetics of a given organism [1,2]. Replication fidelity, genome size, and genetic complexity were postulated to lock each other, through a triangular relation [10], in a low state in primitive self-replicating molecules [11] This trapping, known as the ‘‘Eigen paradox’’ [12], was extended to include RNA viruses [13], providing a conceptual rationale for the small range of genome sizes in these viruses. Recent studies of the order Nidovirales, a large group of RNA viruses that includes those with the largest genomes known to date, provided strong support for the postulated triangular relation [10,14] They revealed how nidoviruses may have solved the Eigen paradox by acquiring a proof-reading enzyme. These advancements implied that the control of genome size may be more complex than previously thought, in RNA viruses in general, and in nidoviruses
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