Author: William Fitzsimmons; Robert J. Woods; John T. McCrone; Andrew Woodman; Jamie J. Arnold; Madhumita Yennawar; Richard Evans; Craig E. Cameron; Adam S. Lauring
Title: A speed-fidelity trade-off determines the mutation rate and virulence of an RNA virus Document date: 2018_4_27
ID: 8p24gszj_7
Snippet: To identify compensatory mutations, we focused our subsequent analysis on nonsynonymous 152 mutations in the RdRp that were found predominantly in r-selected populations, shared among 153 multiple lineages, and more frequent in 3D G64S than in WT. Two mutations -U6261C/3D I92T and 7 the I92T mutation may have arisen first. The 3D I92T mutation, which was found in both r-selected 156 WT (3/5) and 3D G64S (5/5) lineages, did not change either fitne.....
Document: To identify compensatory mutations, we focused our subsequent analysis on nonsynonymous 152 mutations in the RdRp that were found predominantly in r-selected populations, shared among 153 multiple lineages, and more frequent in 3D G64S than in WT. Two mutations -U6261C/3D I92T and 7 the I92T mutation may have arisen first. The 3D I92T mutation, which was found in both r-selected 156 WT (3/5) and 3D G64S (5/5) lineages, did not change either fitness or mutation rate appreciably in 157 the 3D G64S background ( Fig. 2C and 2D ). The r-selected K276R substitution, which was found in 158 3D G64S lineages (4/5) and not in WT populations, decreased overall fitness in both WT (0.92 ± 159 0.03, p=0.0031 vs. WT, t-test) and 3D G64S (0.55 ± 0.03, p=0.005 vs. 3D G64S , t-test) . It had no 160 detectable effect on mutation rate in either background. The G64S/I92T/K276R triple mutant 161 had a significant increase in fitness (0.7637, p=0.0012 vs. 3D G64S , t-test) and mutation rate (8.71 162 x 10 -6 s/n/r, p=0.0120 vs. 3D G64S , t-test) compared to 3D G64S and each double mutant. Therefore, 163 direct selection for replicative speed caused an increase in the poliovirus mutation rate with sign 164 epistasis among the G64S, I92T, and K276R in the RdRp.
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