Browsing by Author "Delport, Wayne"

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    Benchmarking multi-rate codon models
    (Public Library of Science, 2010-07-21) Delport, Wayne; Scheffler, Konrad; Gravenor, Mike B.; Muse, Spencer V.; Pond, Sergei Kosakovsky
    The single rate codon model of non-synonymous substitution is ubiquitous in phylogenetic modeling. Indeed, the use of a non-synonymous to synonymous substitution rate ratio parameter has facilitated the interpretation of selection pressure on genomes. Although the single rate model has achieved wide acceptance, we argue that the assumption of a single rate of non-synonymous substitution is biologically unreasonable, given observed differences in substitution rates evident from empirical amino acid models. Some have attempted to incorporate amino acid substitution biases into models of codon evolution and have shown improved model performance versus the single rate model. Here, we show that the single rate model of non-synonymous substitution is easily outperformed by a model with multiple non-synonymous rate classes, yet in which amino acid substitution pairs are assigned randomly to these classes. We argue that, since the single rate model is so easy to improve upon, new codon models should not be validated entirely on the basis of improved model fit over this model. Rather, we should strive to both improve on the single rate model and to approximate the general time-reversible model of codon substitution, with as few parameters as possible, so as to reduce model over-fitting. We hint at how this can be achieved with a Genetic Algorithm approach in which rate classes are assigned on the basis of sequence information content. © 2010 Delport et al.
  • Thumbnail Image
    Item
    Codon test : modeling amino acid substitution preferences in coding sequences
    (PLOS Computational Biology, 2010-08) Delport, Wayne; Scheffler, Konrad; Botha, Gordon; Gravenor, Mike B.; Muse, Spencer V.; Pond, Sergei L. Kosakovsky
    Codon models of evolution have facilitated the interpretation of selective forces operating on genomes. These models, however, assume a single rate of non-synonymous substitution irrespective of the nature of amino acids being exchanged. Recent developments have shown that models which allow for amino acid pairs to have independent rates of substitution offer improved fit over single rate models. However, these approaches have been limited by the necessity for large alignments in their estimation. An alternative approach is to assume that substitution rates between amino acid pairs can be subdivided into K rate classes, dependent on the information content of the alignment. However, given the combinatorially large number of such models, an efficient model search strategy is needed. Here we develop a Genetic Algorithm (GA) method for the estimation of such models. A GA is used to assign amino acid substitution pairs to a series of K rate classes, where K is estimated from the alignment. Other parameters of the phylogenetic Markov model, including substitution rates, character frequencies and branch lengths are estimated using standard maximum likelihood optimization procedures. We apply the GA to empirical alignments and show improved model fit over existing models of codon evolution. Our results suggest that current models are poor approximations of protein evolution and thus gene and organism specific multi-rate models that incorporate amino acid substitution biases are preferred. We further anticipate that the clustering of amino acid substitution rates into classes will be biologically informative, such that genes with similar functions exhibit similar clustering, and hence this clustering will be useful for the evolutionary fingerprinting of genes.
  • Thumbnail Image
    Item
    Correcting the bias of empirical frequency parameter estimators in codon models
    (Public Library of Science -- PLOS, 2010-07) Kosakovsky Pond, Sergei; Delport, Wayne; Muse, Spencer V.; Scheffler, Konrad
    Markov models of codon substitution are powerful inferential tools for studying biological processes such as natural selection and preferences in amino acid substitution. The equilibrium character distributions of these models are almost always estimated using nucleotide frequencies observed in a sequence alignment, primarily as a matter of historical convention. In this note, we demonstrate that a popular class of such estimators are biased, and that this bias has an adverse effect on goodness of fit and estimates of substitution rates. We propose a ‘‘corrected’’ empirical estimator that begins with observed nucleotide counts, but accounts for the nucleotide composition of stop codons. We show via simulation that the corrected estimates outperform the de facto standard F3|4 estimates not just by providing better estimates of the frequencies themselves, but also by leading to improved estimation of other parameters in the evolutionary models. On a curated collection of 856 sequence alignments, our estimators show a significant improvement in goodness of fit compared to the F3|4 approach. Maximum likelihood estimation of the frequency parameters appears to be warranted in many cases, albeit at a greater computational cost. Our results demonstrate that there is little justification, either statistical or computational, for continued use of the F3|4-style estimators.
  • Thumbnail Image
    Item
    Frequent toggling between alternative amino acids Is driven by selection in HIV-1
    (Public Library of Science, 2008) Delport, Wayne; Scheffler, Konrad; Seoighe, Cathal
    Host immune responses against infectious pathogens exert strong selective pressures favouring the emergence of escape mutations that prevent immune recognition. Escape mutations within or flanking functionally conserved epitopes can occur at a significant cost to the pathogen in terms of its ability to replicate effectively. Such mutations come under selective pressure to revert to the wild type in hosts that do not mount an immune response against the epitope. Amino acid positions exhibiting this pattern of escape and reversion are of interest because they tend to coincide with immune responses that control pathogen replication effectively. We have used a probabilistic model of protein coding sequence evolution to detect sites in HIV-1 exhibiting a pattern of rapid escape and reversion. Our model is designed to detect sites that toggle between a wild type amino acid, which is susceptible to a specific immune response, and amino acids with lower replicative fitness that evade immune recognition. Through simulation, we show that this model has significantly greater power to detect selection involving immune escape and reversion than standard models of diversifying selection, which are sensitive to an overall increased rate of non-synonymous substitution. Applied to alignments of HIV-1 protein coding sequences, the model of immune escape and reversion detects a significantly greater number of adaptively evolving sites in env and nef. In all genes tested, the model provides a significantly better description of adaptively evolving sites than standard models of diversifying selection. Several of the sites detected are corroborated by association between Human Leukocyte Antigen (HLA) and viral sequence polymorphisms. Overall, there is evidence for a large number of sites in HIV-1 evolving under strong selective pressure, but exhibiting low sequence diversity. A phylogenetic model designed to detect rapid toggling between wild type and escape amino acids identifies a larger number of adaptively evolving sites in HIV-1, and can in some cases correctly identify the amino acid that is susceptible to the immune response.