hASTV-SHuman Astrovirus structural geneHAV-SHepatitis A virus - structural geneHAV-NSHepatitis A virus - non-structural geneBEFV-SBovine ephemeral fever virusRVA-NSRotavirus A - non-structural geneRVC-NSRotavirus C - non-structural geneRVC-SRotavirus C - structural geneCCHFV-NSCrimean-Congo hemorrhagic fever virus - non-structural geneBDV-NBorna disease virus - structural geneRabV-LRabies virus - non-structural geneRVA-G2-SRotavirus A G2 - structural geneRVA-G3-SRotavirus A G3 - structural geneEAV-SEquine arteritis virus - structural geneLasV-SLassa virus - structural geneLasV - S.nexYFV-NSYellow fever virus - non-structural virusJEV-NSJapanese encephalitis virus - non-structural genePRRSV-NSNoV GII.4-NSNorovirus GII.4 - non-structural genebovineCoV-SBovine coronavirus - structural genePowV-SPowassan virus - structural geneMuV-SMumps virus - structural geneMeV-NSMeasles virus - non-structural geneSEOV - SSeoul virus - structural geneRRV-SRoss River virus - structural geneRuV-SRubella virus - structural geneWEEV-SWestern equine encephalitis virus - structural geneVEEV-SVenezuelan equine encephalitis virus - structural geneVEEV-NSVenezuelan equine encephalitis virus - non-structural geneTBEV-NSTick-borne encephalitis virus - non-structural geneCVA16-Scoxsackievirus A16 - structural geneCVB4-Scoxsackievirus B4 - structural geneCVA16-NScoxsackievirus A16 - non-structural geneCHIKV-NSChikungunya virus - non-structural geneE6-SEchovirus 6 - structural geneE9-NSechovirus 9 - non-structural geneE11-NSechovirus 11 - non-structural geneE13-Sechovirus 13 - structural geneE30-Sechovirus 30 - structural geneE30-NSechovirus 30 - non-structural geneE33-Sechovirus 33 - structural geneSVDV-Sswine vesicular disease virus - structural geneCVA24-Scoxsackievirus A24 - structural geneCVA24-NScoxsackievirus A24 - non-structural genePV1-Spoliovirus type 1 - structural genePV1-NSpoliovirus type 1 - non-structural gene

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.