Unbiased Estimate of Synonymous and Nonsynonymous Substitution Rates with Nonstationary Base Composition

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The measurement of synonymous and nonsynonymous substitution rates (dSand dN) is useful for assessing selection operating on protein sequences or for investigating mutational processes affecting genomes. In particular, the ratioSymbolis expected to be a good proxy forω, the ratio of fixation probabilities of nonsynonymous mutations relative to that of neutral mutations. Standard methods for estimating dN, dS, orωrely on the assumption that the base composition of sequences is at the equilibrium of the evolutionary process. In many clades, this assumption of stationarity is in fact incorrect, and we show here through simulations and analyses of empirical data that nonstationarity biases the estimate of dN, dS, andω. We show that the bias in the estimate ofωcan be fixed by explicitly taking into consideration nonstationarity in the modeling of codon evolution, in a maximum likelihood framework. Moreover, we propose an exact method for estimating dNand dSon branches, based on stochastic mapping, that can take into account nonstationarity. This method can be directly applied to any kind of codon evolution model, as long as neutrality is clearly parameterized.

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