MultiSeq: unifying sequence and structure data for evolutionary analysis

Abstract

Background: Since the publication of the first draft of the human genome in 2000, bioinformatic data have been accumulating at an overwhelming pace. Currently, more than 3 million sequences and 35 thousand structures of proteins and nucleic acids are available in public databases. Finding correlations in and between these data to answer critical research questions is extremely challenging. This problem needs to be approached from several directions: information science to organize and search the data; information visualization to assist in recognizing correlations; mathematics to formulate statistical inferences; and biology to analyze chemical and physical properties in terms of sequence and structure changes.

Results: Here we present MultiSeq, a unified bioinformatics analysis environment that allows one to organize, display, align and analyze both sequence and structure data for proteins and nucleic acids. While special emphasis is placed on analyzing the data within the framework of evolutionary biology, the environment is also flexible enough to accommodate other usage patterns. The evolutionary approach is supported by the use of predefined metadata, adherence to standard ontological mappings, and the ability for the user to adjust these classifications using an electronic notebook. MultiSeq contains a new algorithm to generate complete evolutionary profiles that represent the topology of the molecular phylogenetic tree of a homologous group of distantly related proteins. The method, based on the multidimensional QR factorization of multiple sequence and structure alignments, removes redundancy from the alignments and orders the protein sequences by increasing linear dependence, resulting in the identification of a minimal basis set of sequences that spans the evolutionary space of the homologous group of proteins.

Conclusion: MultiSeq is a major extension of the Multiple Alignment tool that is provided as part of VMD, a structural visualization program for analyzing molecular dynamics simulations. Both are freely distributed by the NIH Resource for Macromolecular Modeling and Bioinformatics and MultiSeq is included with VMD starting with version 1.8.5. The MultiSeq website has details on how to download and use the software: http://www.scs.uiuc.edu/~schulten/multiseq/

Figure 1

MultiSeq Overview. Overview of the MultiSeq environment showing aligned sequence and structural data. (1) 1D representation of structural data colored by structural conservation. (2) 1D representation of sequence data colored by sequence identity. (3) 3D representation of structural data colored by structural conservation, as shown by VMD. For structural data, the coloring is synchronized between the 1D representation and the 3D representation.

Figure 2

BLAST Results Viewer. BLAST search results viewer showing the outcome of a BLAST search. (1) The name of the matching sequence is shown along with (2) the expectation value of the match. (3) The BLAST aligned regions are shown as an MSA; non-matched regions on either side of the aligned region are shown grayed out. (4) The search results can be filtered by BLAST e-score, taxonomy, or sequence QR based redundancy.

Figure 3

Grouping. [A] Grouping in MultiSeq. (1) Group headers show the name of the group and allow the user to manage the group. (2) The status bar shows summary information about the group. [B] MultiSeq allows data to be automatically grouped by taxonomic classification. (3) The taxonomy dialog allows the user to select the level of taxonomy by which to group the data. (4) Taxonomic information about the data is then used to create the groupings.

Figure 4

MultiSeq Tools. (1) The electronic notebook displays various metadata associated with the sequence and also provides space for making annotations about a sequence. Changes will be saved in the MultiSeq session. (2) The phylogenetic tree viewer shows evolutionary relationships amongst the data. Data are labeled by species name and colored by domain of life, those highlighted in yellow are part of the selected non-redundant set. (3) The QR ordering of the non-redundant set is also displayed, lower numbers indicate data that are more linearly independent. (4) The plotter allows a metric to be plotted along the length (or a subset) of the sequence. All of the coloring metrics can also be used by the plotter.