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      GUIDANCE: a web server for assessing alignment confidence scores

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          Abstract

          Evaluating the accuracy of multiple sequence alignment (MSA) is critical for virtually every comparative sequence analysis that uses an MSA as input. Here we present the GUIDANCE web-server, a user-friendly, open access tool for the identification of unreliable alignment regions. The web-server accepts as input a set of unaligned sequences. The server aligns the sequences and provides a simple graphic visualization of the confidence score of each column, residue and sequence of an alignment, using a color-coding scheme. The method is generic and the user is allowed to choose the alignment algorithm (ClustalW, MAFFT and PRANK are supported) as well as any type of molecular sequences (nucleotide, protein or codon sequences). The server implements two different algorithms for evaluating confidence scores: (i) the heads-or-tails (HoT) method, which measures alignment uncertainty due to co-optimal solutions; (ii) the GUIDANCE method, which measures the robustness of the alignment to guide-tree uncertainty. The server projects the confidence scores onto the MSA and points to columns and sequences that are unreliably aligned. These can be automatically removed in preparation for downstream analyses. GUIDANCE is freely available for use at http://guidance.tau.ac.il.

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          Most cited references18

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          Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu.

          Human cells possess an antiviral activity that inhibits the release of retrovirus particles, and other enveloped virus particles, and is antagonized by the HIV-1 accessory protein, Vpu. This antiviral activity can be constitutively expressed or induced by interferon-alpha, and it consists of protein-based tethers, which we term 'tetherins', that cause retention of fully formed virions on infected cell surfaces. Using deductive constraints and gene expression analyses, we identify CD317 (also called BST2 or HM1.24), a membrane protein of previously unknown function, as a tetherin. Specifically, CD317 expression correlated with, and induced, a requirement for Vpu during HIV-1 and murine leukaemia virus particle release. Furthermore, in cells where HIV-1 virion release requires Vpu expression, depletion of CD317 abolished this requirement. CD317 caused retention of virions on cell surfaces and, after endocytosis, in CD317-positive compartments. Vpu co-localized with CD317 and inhibited these effects. Inhibition of Vpu function and consequent mobilization of tetherin's antiviral activity is a potential therapeutic strategy in HIV/AIDS.
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            An algorithm for progressive multiple alignment of sequences with insertions.

            Dynamic programming algorithms guarantee to find the optimal alignment between two sequences. For more than a few sequences, exact algorithms become computationally impractical, and progressive algorithms iterating pairwise alignments are widely used. These heuristic methods have a serious drawback because pairwise algorithms do not differentiate insertions from deletions and end up penalizing single insertion events multiple times. Such an unrealistically high penalty for insertions typically results in overmatching of sequences and an underestimation of the number of insertion events. We describe a modification of the traditional alignment algorithm that can distinguish insertion from deletion and avoid repeated penalization of insertions and illustrate this method with a pair hidden Markov model that uses an evolutionary scoring function. In comparison with a traditional progressive alignment method, our algorithm infers a greater number of insertion events and creates gaps that are phylogenetically consistent but spatially less concentrated. Our results suggest that some insertion/deletion "hot spots" may actually be artifacts of traditional alignment algorithms.
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              A comprehensive comparison of multiple sequence alignment programs.

              In recent years improvements to existing programs and the introduction of new iterative algorithms have changed the state-of-the-art in protein sequence alignment. This paper presents the first systematic study of the most commonly used alignment programs using BAliBASE benchmark alignments as test cases. Even below the 'twilight zone' at 10-20% residue identity, the best programs were capable of correctly aligning on average 47% of the residues. We show that iterative algorithms often offer improved alignment accuracy though at the expense of computation time. A notable exception was the effect of introducing a single divergent sequence into a set of closely related sequences, causing the iteration to diverge away from the best alignment. Global alignment programs generally performed better than local methods, except in the presence of large N/C-terminal extensions and internal insertions. In these cases, a local algorithm was more successful in identifying the most conserved motifs. This study enables us to propose appropriate alignment strategies, depending on the nature of a particular set of sequences. The employment of more than one program based on different alignment techniques should significantly improve the quality of automatic protein sequence alignment methods. The results also indicate guidelines for improvement of alignment algorithms.
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                Author and article information

                Journal
                Nucleic Acids Res
                Nucleic Acids Res
                nar
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                1 July 2010
                23 May 2010
                22 May 2010
                : 38
                : Web Server issue
                : W23-W28
                Affiliations
                1Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel and 2Department of Biology and Biochemistry, University of Houston, Houston, TX 77204-5001, USA
                Author notes
                *To whom correspondence should be addressed. Tel: +972 3 6407693; Fax: +972 3 6422046; Email: talp@ 123456post.tau.ac.il

                The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

                Article
                gkq443
                10.1093/nar/gkq443
                2896199
                20497997
                b1a7ea1b-3737-44fa-9d82-5f46fe3bcef3
                © The Author(s) 2010. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 February 2010
                : 25 April 2010
                : 9 May 2010
                Categories
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                Genetics
                Genetics

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