Abstract
Natural selection operating at the amino acid sequence level can be detected by comparing the rates of syn- onymous (rS) and nonsynonymous (rN) substitutions for the protein-coding nucleotide sequence, where relationships rN > rS and rN < rS conventionally indicate positive and negative selection, respectively. The direction and magnitude of natural selection operating on a protein may change during evolution because the environmental conditions may vary along with time. Here a phylogenetic window analysis method is proposed for examining the chronological change in natural selec- tion and for detecting natural selection that has operated temporarily in the phylogenetic tree. The phylogenetic window was defined as an interval between two time points in the phylogenetic tree, which was constructed under the assumption of a molecular clock. The total numbers of synonymous and nonsynonymous changes that have occurred for all the parts of branches overlapping with the window were compared to detect natural selection. When this method was applied to the analysis of the intra-host evolution for hypervariable region 1 of hepatitis C virus (HCV), which was known as the major target of humoral immunity, it was found that the pattern of chronological change in natural selection was heterogeneous among patients. The rN/rS value was sometimes elevated temporarily, where positive selection was detected, suggesting that the antigenic evolution was punctuated during chronic infection of HCV.
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