Abstract
The high rates of RNA virus evolution are generally attributed to replication with error-prone RNA-dependent RNA polymerases. However, these long-term nucleotide substitution rates span three orders of magnitude and do not correlate well with mutation rates or selection pressures. This substitution rate variation may be explained by differences in virus ecology or intrinsic genomic properties. We generated nucleotide substitution rate estimates for mammalian RNA viruses and compiled comparable published rates, yielding a dataset of 118 substitution rates of structural genes from 51 different species, as well as 40 rates of non-structural genes from 28 species. Through ANCOVA analyses, we evaluated the relationships between these rates and four ecological factors: target cell, transmission route, host range, infection duration; and three genomic properties: genome length, genome sense, genome segmentation. Of these seven factors, we found target cells to be the only significant predictors of viral substitution rates, with tropisms for epithelial cells or neurons (P<0.0001) as the most significant predictors. Further, one-tailed t-tests showed that viruses primarily infecting epithelial cells evolve significantly faster than neurotropic viruses (P<0.0001 and P<0.001 for the structural genes and non-structural genes, respectively). These results provide strong evidence that the fastest evolving mammalian RNA viruses infect cells with the highest turnover rates: the highly proliferative epithelial cells. Estimated viral generation times suggest that epithelial-infecting viruses replicate more quickly than viruses with different cell tropisms. Our results indicate that cell tropism is a key factor in viral evolvability.
Highlights
RNA viruses are responsible for a disproportionate number of emerging human diseases, including influenza, ebola hemorrhagic fever, hantavirus pulmonary syndrome, and Middle East respiratory syndrome, which place tremendous health and economic burdens on both the developing and developed world [1,2]
We found that cell tropism is the most significant predictor of long-term rates of mammalian RNA virus evolution
Because transmission through arthropod vectors was found to be a significant rate predictor in the ANCOVA analyses based on the combined datasets and because of the correlation between epithelial cell tropism and fecal-oral/respiratory transmission, we evaluated any significant variation among substitution rates of viruses with different transmission routes
Summary
RNA viruses are responsible for a disproportionate number of emerging human diseases, including influenza, ebola hemorrhagic fever, hantavirus pulmonary syndrome, and Middle East respiratory syndrome, which place tremendous health and economic burdens on both the developing and developed world [1,2]. The implementation of many intervention strategies has either failed or been delayed as a result of the evolutionary dynamics of these pathogens [1,5,6,7,8,9]. Differences in viral evolutionary dynamics, such as rates of evolution, can explain why certain viruses have the capacity to adapt to new host species, increase in virulence, or develop resistance to antivirals [7,8,9,10,11]. Though extremely high nucleotide substitution rates are a defining feature of RNA virus evolution [1,13,14,15], there have been few attempts to comprehensively examine the driving genomic and ecological factors behind these rates
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