A large variation in the rates of synonymous substitution for RNA viruses and its relationship to a diversity of viral infection and transmission modes

Abstract

RNA viruses successfully adapt to various environments by repeatedly producing new mutants, often through generating a number of nucleotide substitutions. To estimate the degree of variation in mutation rates of RNA viruses and to understand the source of such variation, we studied the synonymous substitution rate because synonymous substitution is exempt from functional constraints at the protein level, and its rate reflects the mutation rate to a great extent. We estimated the synonymous substitution rates for a total of 49 different species of RNA viruses, and we found that the rates had tremendous variation by 5 orders of magnitude (from 1.3 x 10(-7) to 6.2 x 10(-2) /synonymous site/year). Comparing the synonymous substitution rates with the replication frequencies and replication error rates for the RNA viruses, we found that the main source of the rate variation was differences in the replication frequency because the rates of replication error were roughly constant over different RNA viruses. Moreover, we examined a relationship between viral life strategies and synonymous substitution rates to understand which viral life strategies affect replication frequencies. The results show that the variation of synonymous substitution rates has been influenced most by either the difference in the infection modes or the differences in the transmission modes. In conclusion, the variation of mutation rates for RNA viruses is caused by different replication frequencies, which are affected strongly by the infection and transmission modes.

Fig. 1.

Transitions-type and transversions-type nucleotide differences plotted against the evolutionary distance of Kimura's two parameter method. No crossing of the different symbols (solid diamonds and open circles), representing transitions and transversions, respectively, suggests rejection of substitution saturation, which is exemplified by the data set of human enterovirus A

Fig. 2.

Comparison of synonymous substitution rates among RNA viruses. Virus species belonging to the same family were represented by the same color. The end “viridae” of all family names was omitted. For example, Astro indicates Astroviridae. As exceptions, both hepatitis D virus and hepatitis E virus are represented by the same color (gray), since they are not classified into any virus family. The ordinate represents log synonymous substitution rate. Each virus species is ranked by each virus family along the axis of abscissas

Fig. 3.

Comparison between synonymous substitution rate and the infection and transmission modes. The synonymous substitution rates are ranked in descending order on the abscissa. The viral life strategies are classified into two major categories. The first category is the infection modes such as acute, persistent, and latent infection. The combination of acute and persistent infection is also included in this category. The second category is the transmission modes such as aerosol transmission, contagious transmission, fecal-oral route transmission, transmission via blood (inducing sexual relationship and artificial injection), transmission via a bite and transmission via a vector. The first category, i.e., infection modes, is represented by a circle in the different color above the vertical bars, whereas the second category, i.e., transmission modes, is represented by a vertical bar in a different color. The ordinate represents the log synonymous substitution rate