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. 2014 Jan;10(1):e1003838.
doi: 10.1371/journal.ppat.1003838. Epub 2014 Jan 9.

Cell tropism predicts long-term nucleotide substitution rates of mammalian RNA viruses

Allison L Hicks  1 , Siobain Duffy  1
Affiliations

Cell tropism predicts long-term nucleotide substitution rates of mammalian RNA viruses

Allison L Hicks et al. PLoS Pathog. 2014 Jan.

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Nucleotide substitution rates and ecological properties of mammalian RNA viruses.
Log scale mean substitution rate (log10(nucleotide substitutions/site/year, NS/S/Y)) estimates for different target cells (A and B), transmission routes (C and D), infection modes (E and F), and host ranges (G and H). Plots on the left show rates based on structural genes, while the plots on the right show those of non-structural genes. Each black bar indicates the mean of each level, and the levels of each variable are sorted by increasing mean substitution rate. Sources of the rates are given in Table S1.
Figure 2
Figure 2. Nucleotide substitution rates and genomic properties of mammalian RNA viruses.
Log scale mean substitution rate (log10(nucleotide substitutions/site/year, NS/S/Y)) estimates for different genomic architectures (sense/strandedness, A and B, and whether or not the genome is segmented, C and D) and plotted against genome lengths (E and F). The plots on the left show rates based on structural genes, while the plots on the right show those of non-structural genes. Each black bar in A–D indicates the mean of each level, and the levels of each of these variables are sorted by increasing mean substitution rate. The line of best fit is shown in E and F. The coefficients of determination (R 2) for the linear regression models of genome lengths vs. substitution rates were 0.06 for the structural gene dataset and 0.08 for the non-structural gene dataset. Sources of the rates are given in Table S1.
Figure 3
Figure 3. Standardized coefficients for predictors of viral substitution rates.
Standardized coefficients with 95% confidence intervals for the different predictor variables of structural (left) and non-structural (right) gene substitution rates. A and B show the coefficients from the first ANCOVA analysis, C and D show coefficients from the second ANCOVA analysis, and E and F show coefficients from the third ANCOVA analysis. Coefficients are indicated by the same symbols used in Figures 1 and 2. Dark coefficients correspond to significant substitution rate predictors (P<0.01: neural, leukocyte, hepatocyte, and epithelial target cells in A, leukocyte and epithelial target cells in C, neural and epithelial target cells in E, and neural target cells in F), while the other coefficients are shown in gray.
Figure 4
Figure 4. Nucleotide substitution rates and principle target cells of mammalian RNA viruses.
Log scale mean nucleotide substitution rates (log10(nucleotide substitutions per site per year, NS/S/Y)) of all RNA viruses included in this study with 95% credibility intervals. Credibility intervals that are not visible are eclipsed by the symbol or, in three cases (NoV GII.b, HEV, and TBEV), were not available from the published source. Sources of the rates are given in Table S1.
Figure 5
Figure 5. Nucleotide substitution rate variation among arboviruses and fecal-oral/respiratory transmitted viruses with different cell tropisms.
The means of the log-scale mean nucleotide substitution rates of neurotopic (n = 13) and non-neurotropic (n = 38) arboviruses are shown as squares on the left, and the means of the log-scale mean nucleotide substitution rates of viruses that are transmitted through the fecal-oral/respiratory routes and primarily target epithelial cells (n = 73) and those that are transmitted through the fecal-oral/respiratory routes and primarily target other cells (n = 15) are shown as the triangles on the right. The mean of each group is shown with 95% confidence intervals (CIs), except for non-neurotropic arboviruses, where the CIs are eclipsed by the symbol.
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