Improved inference of site-specific positive selection under a generalized parametric codon model when there are multinucleotide mutations and multiple nonsynonymous rates
Abstract
BACKGROUND: An excess of nonsynonymous substitutions, over neutrality, is considered evidence of positive Darwinian selection. Inference for proteins often relies on estimation of the nonsynonymous to synonymous ratio (ω = dN/dS) within a codon model. However, to ease computational difficulties, ω is typically estimated assuming an idealized substitution process where (i) all nonsynonymous substitutions have the same rate (regardless of impact on organism fitness) and (ii) instantaneous double and triple (DT) nucleotide mutations have zero probability (despite evidence that they can occur). It follows that estimates of ω represent an imperfect summary of the intensity of selection, and that tests based on the ω > 1 threshold could be negatively impacted.
RESULTS: We developed a general-purpose parametric (GPP) modelling framework for codons. This novel approach allows specification of all possible instantaneous codon substitutions, including multiple nonsynonymous rates (MNRs) and instantaneous DT nucleotide changes. Existing codon models are specified as special cases of the GPP model. We use GPP models to implement likelihood ratio tests for ω > 1 that accommodate MNRs and DT mutations. Through both simulation and real data analysis, we find that failure to model MNRs and DT mutations reduces power in some cases and inflates false positives in others. False positives under traditional M2a and M8 models were very sensitive to DT changes. This was exacerbated by the choice…
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