title: GUIDANCE2: accurate detection of unreliable alignment regions accounting for the uncertainty of multiple parameters.
abstract: Inference of multiple sequence alignments (MSAs) is a critical part of phylogenetic and comparative genomics studies. However, from the same set of sequences different MSAs are often inferred, depending on the methodologies used and the assumed parameters. Much effort has recently been devoted to improving the ability to identify unreliable alignment regions. Detecting such unreliable regions was previously shown to be important for downstream analyses relying on MSAs, such as the detection of positive selection. Here we developed GUIDANCE2, a new integrative methodology that accounts for: (i) uncertainty in the process of indel formation, (ii) uncertainty in the assumed guide tree and (iii) co-optimal solutions in the pairwise alignments, used as building blocks in progressive alignment algorithms. We compared GUIDANCE2 with seven methodologies to detect unreliable MSA regions using extensive simulations and empirical benchmarks. We show that GUIDANCE2 outperforms all previously developed methodologies. Furthermore, GUIDANCE2 also provides a set of alternative MSAs which can be useful for downstream analyses. The novel algorithm is implemented as a web-server, available at: http://guidance.tau.ac.il.
authors.affiliation: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel.
authors.forename: Itamar
authors.initials: I
authors.lastname: Sela
authors.affiliation: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel.
authors.forename: Haim
authors.initials: H
authors.lastname: Ashkenazy
authors.affiliation: Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan Computational Biology Research Center, The National Institute of Advanced Industrial Science and Technology (AIST), Tokyo 135-0064, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Katoh
authors.affiliation: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel talp@post.tau.ac.il.
authors.forename: Tal
authors.initials: T
authors.lastname: Pupko
mesh_terms: D000465:Algorithms; D020407:Internet; D016415:Sequence Alignment / Q000379:methods*; D012984:Software; D035501:Uncertainty