Abstract
The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS) which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance.
Highlights
Among positively selected evolutionary changes, a distinction can be made between diversifying selection, where any nucleotide substitutions that change the amino acid are favored, and directional selection, where only substitutions towards a small number of target amino acids are selected for
HIV-1 and other rapidly evolving viruses have the capacity to acquire drug resistance mutations (DRAMs), which limit the efficacy of antivirals
While the evolution of drug resistance is a classic example of natural selection, existing analyses fail to detect the majority of drug resistance associated mutations (DRAMs)
Summary
Among positively selected evolutionary changes, a distinction can be made between diversifying selection, where any nucleotide substitutions that change the amino acid are favored, and directional selection, where only substitutions towards a small number of target amino acids are selected for. Detection of genes or sites evolving under positive selection [1,2,3,4,5,6] has been dominated by methods which explicitly or implicitly assume diversifying positive selection. This assumption allows evolution to be modeled as a continuoustime Markov process without assuming that any particular residue is the preferred target of substitutions at any sites. By making a distinction among all possible targets of a substitution, such models allow the detection of positive selection favoring mutations towards one amino acid, even at sites where the overall rate of amino acid change is decreased by purifying selection. For a review of codon models of selection, see [10]
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