Advances in Bayesian Modeling of Protein Structure Evolution

Schmidler, Scott C

Larson, Gary

2018-09-21T16:09:35Z

2018-09-21T16:09:35Z

2018

Statistical Science

This thesis contributes to a statistical modeling framework for protein sequence and structure evolution. An existing Bayesian model for protein structure evolution is extended in two unique ways. Each of these model extensions addresses an important limitation which has not yet been satisfactorily addressed in the wider literature. These extensions are followed by work regarding inherent statistical bias in models for sequence evolution.

Most available models for protein structure evolution do not model interdependence between the backbone sites of the protein, yet the assumption that the sites evolve independently is known to be false. I argue that ignoring such dependence leads to biased estimation of evolutionary distance between proteins. To mitigate this bias, I express an existing Bayesian model in a generalized form and introduce site-dependence via the generalized model. In the process, I show that the effect of protein structure information on the measure of evolutionary distance can be suppressed by the model formulation, and I further modify the model to help mitigate this problem. In addition to the statistical model itself, I provide computational details and computer code. I modify a well-known bioinformatics algorithm in order to preserve efficient computation under this model. The modified algorithm can be easily understood and used by practitioners familiar with the original algorithm. My approach to modeling dependence is computationally tractable and interpretable with little additional computational burden over the model on which it is based.

The second model expansion allows for evolutionary inference on protein pairs having structural discrepancies attributable to backbone flexion. Thus, the model expansion exposes flexible protein structures to the capabilities of Bayesian protein structure alignment and phylogenetics. Unlike most of the few existing methods that deal with flexible protein structures, our Bayesian flexible alignment model requires no prior knowledge of the presence or absence of flexion points in the protein structure, and uncertainty measures are available for the alignment and other parameters of interest. The model can detect subtle flexion while not overfitting non-flexible protein pairs, and is demonstrated to improve phylogenetic inference in a simulated data setting and in a difficult-to-align set of proteins. The flexible model is a unique addition to the small but growing set of tools available for analysis of flexible protein structure. The ability to perform inference on flexible proteins in a Bayesian framework is likely to be of immediate interest to the structural phylogenetics community.

Finally, I present work related to the study of bias in site-independent models for sequence evolution. In the case of binary sequences, I discuss strategies for theoretical proof of bias and provide various details to that end, including detailing efforts undertaken to produce a site-dependent sequence model with similar properties to the site-dependent structural model introduced in an earlier chapter. I highlight the challenges of theoretical proof for this bias and include miscellaneous related work of general interest to researchers studying dependent sequence models.

https://hdl.handle.net/10161/17523

Statistics

Biology

Bayesian statistics

Evolution

Markov chain Monte Carlo

Phylogenetics

protein alignment

protein evolution

Advances in Bayesian Modeling of Protein Structure Evolution

Dissertation