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Modeling HIV-1 Drug Resistance as Episodic Directional Selection

By Ben Murrell, Tulio de Oliveira, Chris Seebregts, Sergei L. Kosakovsky Pond and Konrad Scheffler


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

Topics: Research Article
Publisher: Public Library of Science
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    1. (1994). A codon-based model of nucleotide substitution for protein-coding dna sequences.
    2. (2005). A genetic algorithm approach to detecting lineage-specific variation in selection pressure.
    3. (1994). A likelihood approach for comparing synonymous and nonsynonymous nucleotide substitution rates, with application to the chloroplast genome.
    4. (2008). A maximum likelihood method for detecting directional evolution in protein sequences and its application to inuenza a virus.
    5. (2007). A model of directional selection applied to the evolution of drug resistance in hiv-1.
    6. (2009). A standardized framework for accurate, high-throughput genotyping of recombinant and non-recombinant viral sequences.
    7. (2007). Adaptation of HIV-1 to its human host.
    8. (2006). Adaptation to different human populations by hiv-1 revealed by codon-based analyses.
    9. (1991). Adaptive protein evolution at the adh locus in drosophila.
    10. (2009). An evolutionary model-based algorithm for accurate phylogenetic breakpoint mapping and subtype prediction in hiv-1. PLoS
    11. (1989). Analyzing tables of statistical tests.
    12. Borderı ´a AV (2011) Interplay between RNA structure and protein evolution in HIV-1.
    13. (2002). Codon-substitution models for detecting molecular adaptation at individual sites along specific lineages.
    14. (2010). Codontest: modeling amino acid substitution preferences in coding sequences.
    15. (1994). Convergent evolution: the need to be explicit.
    16. (2010). Correcting the Bias of Empirical Frequency Parameter Estimators in Codon Models.
    17. (1985). Dating of the human-ape splitting by a molecular clock of mitochondrial DNA.
    18. (2005). Detecting amino acid sites under positive selection and purifying selection.
    19. (2010). Detecting positive and purifying selection at synonymous sites in yeast and worm.
    20. (2008). Elucidation of phenotypic adaptations: Molecular analyses of dim-light vision proteins in vertebrates.
    21. (1997). Episodic adaptive evolution of primate lysozymes.
    22. (2010). Epitope discovery with phylogenetic hidden markov models.
    23. (1998). Estimating the rate of evolution of the rate of molecular evolution.
    24. (2005). Evaluation of an improved branch-site likelihood method for detecting positive selection at the molecular level.
    25. (2009). Evidence for an episodic model of protein sequence evolution.
    26. (2009). Evidence of hiv-1 adaptation to host hla alleles following chimp-to-human transmission.
    27. (2006). Hearing silence: non-neutral evolution at synonymous sites in mammals.
    28. (2007). Hivspecific probabilistic models of protein evolution.
    29. (2003). Human immunode_ciency virus reverse transcriptase and protease sequence database.
    30. (2005). Hyphy: hypothesis testing using phylogenies.
    31. (2009). Identifying changes in selective constraints: Host shifts in inuenza.
    32. (2009). Investigating Protein-Coding Sequence Evolution with Probabilistic Codon Substitution Models.
    33. (1998). Likelihood ratio tests for detecting positive selection and application to primate lysozyme evolution.
    34. (2007). Looking for Darwin in all the wrong places: the misguided quest for positive selection at the nucleotide sequence level.
    35. (2000). Maximum likelihood estimation on large phylogenies and analysis of adaptive evolution in human inuenza virus a.
    36. (2001). Maximum-likelihood phylogenetic analysis under a covarionlike model.
    37. (2004). Modeling the sitespecific variation of selection patterns along lineages.
    38. (2009). Models of coding sequence evolution.
    39. (2005). Molecular footprint of drug-selective pressure in a human immunodeficiency virus transmission chain.
    40. (2005). Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection.
    41. (2010). New Algorithms and Methods to Estimate Maximum-Likelihood Phylogenies: Assessing the Performance of PhyML 3.0.
    42. (2005). Not so different after all: A comparison of methods for detecting amino acid sites under selection.
    43. (1999). Parallel evolution of drug resistance in hiv: failure of nonsynonymous/synonymous substitution rate ratio to detect selection.
    44. (1985). Phylogenies and the comparative method.
    45. (2004). Positive selection detection in 40,000 human immunode_ciency virus (hiv) type 1 sequences automatically identifies drug resistance and positive fitness mutations in hiv protease and reverse transcriptase.
    46. (2010). Public database for HIV drug resistance in southern Africa.
    47. (2006). Robust inference of positive selection from recombining coding sequences.
    48. (1986). Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions.
    49. (2005). Site-to-site variation of synonymous substitution rates.
    50. (2008). World health organization surveys to monitor hiv drug resistance prevention and associated factors in sentinel antiretroviral treatment sites.

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