title: Smoothed Bootstrap Aggregation for Assessing Selection Pressure at Amino Acid Sites.
abstract: To detect positive selection at individual amino acid sites, most methods use an empirical Bayes approach. After parameters of a Markov process of codon evolution are estimated via maximum likelihood, they are passed to Bayes formula to compute the posterior probability that a site evolved under positive selection. A difficulty with this approach is that parameter estimates with large errors can negatively impact Bayesian classification. By assigning priors to some parameters, Bayes Empirical Bayes (BEB) mitigates this problem. However, as implemented, it imposes uniform priors, which causes it to be overly conservative in some cases. When standard regularity conditions are not met and parameter estimates are unstable, inference, even under BEB, can be negatively impacted. We present an alternative to BEB called smoothed bootstrap aggregation (SBA), which bootstraps site patterns from an alignment of protein coding DNA sequences to accommodate the uncertainty in the parameter estimates. We show that deriving the correction for parameter uncertainty from the data in hand, in combination with kernel smoothing techniques, improves site specific inference of positive selection. We compare BEB to SBA by simulation and real data analysis. Simulation results show that SBA balances accuracy and power at least as well as BEB, and when parameter estimates are unstable, the performance gap between BEB and SBA can widen in favor of SBA. SBA is applicable to a wide variety of other inference problems in molecular evolution.
authors.affiliation: Department of Mathematics and Statistics, Dalhousie University, Halifax, NS, Canada Centre for Comparative Genomics and Evolutionary Bioinformatics, Dalhousie University, Halifax, NS, Canada jrm@ftfl.ca.
authors.forename: Joseph
authors.initials: J
authors.lastname: Mingrone
authors.affiliation: Department of Mathematics and Statistics, Dalhousie University, Halifax, NS, Canada Centre for Comparative Genomics and Evolutionary Bioinformatics, Dalhousie University, Halifax, NS, Canada.
authors.forename: Edward
authors.initials: E
authors.lastname: Susko
authors.affiliation: Department of Mathematics and Statistics, Dalhousie University, Halifax, NS, Canada Centre for Comparative Genomics and Evolutionary Bioinformatics, Dalhousie University, Halifax, NS, Canada Department of Biology, Dalhousie University, Halifax, NS, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Bielawski
mesh_terms: D000596:Amino Acids / Q000235:genetics*; D001499:Bayes Theorem; D005075:Biological Evolution; D003062:Codon / Q000235:genetics; D003198:Computer Simulation; D019143:Evolution, Molecular; D016013:Likelihood Functions; D008390:Markov Chains; D008957:Models, Genetic; D015233:Models, Statistical; D011336:Probability; D012641:Selection, Genetic; D016415:Sequence Alignment / Q000379:methods*; D017422:Sequence Analysis, DNA / Q000379:methods*; D035501:Uncertainty
chemical_list: D000596:Amino Acids; D003062:Codon
keywords: Bayes empirical Bayes; adaptive evolution; bootstrap; codon models; kernel smoothing; positive selection