Multi-objective formulation of MSA for phylogeny estimation (Do phylogeny-aware measures guide towards better phylogenetic tree?)

Abstract

Multiple sequence alignment (MSA) is a basic step in many analyses in computational biology, including predicting the structure and function of proteins, orthology prediction and estimating phylogenies. The objective of MSA is to infer the homology among the sequences of chosen species. Commonly, the MSAs are inferred by optimizing a single function or objective. The alignments estimated under one criterion may be different to the alignments generated by other criteria, inferring discordant homologies and thus leading to different evolutionary histories relating the sequences. In recent past, researchers have advocated for the multi-objective formulation of MSA, to address this issue, where multiple conflicting objective functions are being optimized simultaneously to generate a set of alignments. However, no theoretical or empirical justification with respect to a real-life application has been shown for a particular multi-objective formulation. In this study, we investigate the impact of multi-objective formulation in the context of phylogenetic tree estimation. Employing multi-objective metaheuristics, we demonstrate that trees estimated on the alignments generated by multi-objective formulation are substantially better than the trees estimated by the state-of-the-art MSA tools, including PASTA, MUSCLE, CLUSTAL, MAFFT etc. We also demonstrate that highly accurate alignments with respect to popular measures like sum-of-pair (SP) score and total-column (TC) score do not necessarily lead to highly accurate phylogenetic trees. Thus in essence we ask the question whether a phylogeny-aware metric can guide us in choosing appropriate multi-objective formulations that can result in better phylogeny estimation. And we answer the question affirmatively through carefully designed extensive empirical study. As a by-product we also suggest a methodology for primary selection of a set of objective functions for a multi-objective formulation based on the association with the resulting phylogenetic tree.