Many human RNA viruses show extraordinarily stringent selective constraints on protein evolution.

Lin, Jinn-Jy; Bhattacharjee, Maloyjo Joyraj; Yu, Chun-Ping; Tseng, Yan Yuan; Li, Wen-Hsiung

How negative selection, positive selection, and population size contribute to the large variation in nucleotide substitution rates among RNA viruses remains unclear. Here, we studied the ratios of nonsynonymous-to-synonymous substitution rates (d N/d S) in protein-coding genes of human RNA and DNA viruses and mammals. Among the 21 RNA viruses studied, 18 showed a genome-average d N/d S from 0.01 to 0.10, indicating that over 90% of nonsynonymous mutations are eliminated by negative selection. Only HIV-1 showed a d N/d S (0.31) higher than that (0.22) in mammalian genes. By comparing the d N/d S values among genes in the same genome and among species or strains, we found that both positive selection and population size play significant roles in the d N/d S variation among genes and species. Indeed, even in flaviviruses and picornaviruses, which showed the lowest ratios among the 21 species studied, positive selection appears to have contributed significantly to d N/d S We found the view that positive selection occurs much more frequently in influenza A subtype H3N2 than subtype H1N1 holds only for the hemagglutinin and neuraminidase genes, but not for other genes. Moreover, we found no support for the view that vector-borne RNA viruses have lower d N/d S ratios than non-vector-borne viruses. In addition, we found a correlation between d N and d S, implying a correlation between d N and the mutation rate. Interestingly, only 2 of the 8 DNA viruses studied showed a d N/d S < 0.10, while 4 showed a d N/d S > 0.22. These observations increase our understanding of the mechanisms of RNA virus evolution.