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The R code for implementing the hierarchical models is freely available at http://www.ams.ucsc.edu/∼raquel/software/.

Assessing the selective influence of amino acid properties is important in understanding evolution at the molecular level. A collection of methods and models has been developed in recent years to determine if amino acid sites in a given DNA sequence alignment display substitutions that are altering or conserving a prespecified set of amino acid properties. Residues showing an elevated number of substitutions that favorably alter a physicochemical property are considered targets of positive natural selection. Such approaches usually perform independent analyses for each amino acid property under consideration, without taking into account the fact that some of the properties may be highly correlated. We propose a Bayesian hierarchical regression model with latent factor structure that allows us to determine which sites display substitutions that conserve or radically change a set of amino acid properties, while accounting for the correlation structure that may be present across such properties. We illustrate our approach by analyzing simulated data sets and an alignment of lysin sperm DNA.

BackgroundStatistical models and methods that associate changes in the physicochemical properties of amino acids with natural selection at the molecular level typically do not take into account the correlations between such properties. We propose a Bayesian hierarchical regression model with a generalization of the Dirichlet process prior on the distribution of the regression coefficients that describes the relationship between the changes in amino acid distances and natural selection in protein-coding DNA sequence alignments.ResultsThe Bayesian semiparametric approach is illustrated with simulated data and the abalone lysin sperm data. Our method identifies groups of properties which, for this particular dataset, have a similar effect on evolution. The model also provides nonparametric site-specific estimates for the strength of conservation of these properties.ConclusionsThe model described here is distinguished by its ability to handle a large number of amino acid properties simultaneously, while taking into account that such data can be correlated. The multi-level clustering ability of the model allows for appealing interpretations of the results in terms of properties that are roughly equivalent from the standpoint of molecular evolution.

Protein sequence data arise more and more often in vaccine and infectious disease research. These types of data are discrete, high-dimensional, and complex. We propose to study the impact of protein sequences on binary outcomes using a kernel-based logistic regression model, which models the effect of protein through a random effect whose variance-covariance matrix is mostly determined by a kernel function. We propose a novel, biologically motivated, profile hidden Markov model (HMM)-based mutual information (MI) kernel. Hypothesis testing can be carried out using the maximum of the score statistics and a parametric bootstrap procedure. To improve the power of testing, we propose intuitive modifications to the test statistic. We show through simulation studies that the profile HMM-based MI kernel can be substantially more powerful than competing kernels, and that the modified test statistics bring incremental gains in power. We use these proposed methods to investigate two problems from HIV-1 vaccine research: (1) identifying segments of HIV-1 envelope (Env) protein that confer resistance to neutralizing antibody and (2) identifying segments of Env that are associated with attenuation of protective vaccine effect by antibodies of isotype A in the RV144 vaccine trial.