title: PHYRN: a robust method for phylogenetic analysis of highly divergent sequences.
abstract: Both multiple sequence alignment and phylogenetic analysis are problematic in the "twilight zone" of sequence similarity (≤ 25% amino acid identity). Herein we explore the accuracy of phylogenetic inference at extreme sequence divergence using a variety of simulated data sets. We evaluate four leading multiple sequence alignment (MSA) methods (MAFFT, T-COFFEE, CLUSTAL, and MUSCLE) and six commonly used programs of tree estimation (Distance-based: Neighbor-Joining; Character-based: PhyML, RAxML, GARLI, Maximum Parsimony, and Bayesian) against a novel MSA-independent method (PHYRN) described here. Strikingly, at "midnight zone" genetic distances (~7% pairwise identity and 4.0 gaps per position), PHYRN returns high-resolution phylogenies that outperform traditional approaches. We reason this is due to PHRYN's capability to amplify informative positions, even at the most extreme levels of sequence divergence. We also assess the applicability of the PHYRN algorithm for inferring deep evolutionary relationships in the divergent DANGER protein superfamily, for which PHYRN infers a more robust tree compared to MSA-based approaches. Taken together, these results demonstrate that PHYRN represents a powerful mechanism for mapping uncharted frontiers in highly divergent protein sequence data sets.
authors.affiliation: Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Bhardwaj
authors.forename: Kyung Dae
authors.initials: KD
authors.lastname: Ko
authors.forename: Yoojin
authors.initials: Y
authors.lastname: Hong
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Zhang
authors.forename: Ngai Lam
authors.initials: NL
authors.lastname: Ho
authors.forename: Sree V
authors.initials: SV
authors.lastname: Chintapalli
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Kline
authors.forename: Matthew
authors.initials: M
authors.lastname: Gotlin
authors.forename: David Nicholas
authors.initials: DN
authors.lastname: Hartranft
authors.forename: Morgen E
authors.initials: ME
authors.lastname: Patterson
authors.forename: Foram
authors.initials: F
authors.lastname: Dave
authors.forename: Evan J
authors.initials: EJ
authors.lastname: Smith
authors.forename: Edward C
authors.initials: EC
authors.lastname: Holmes
authors.forename: Randen L
authors.initials: RL
authors.lastname: Patterson
authors.forename: Damian B
authors.initials: DB
authors.lastname: van Rossum
mesh_terms: D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D019143:Evolution, Molecular; D010802:Phylogeny