Krause, Antje;Meinel, Thomas;Stoye, Jens;Schmidt, Heiko A.;Luz, Hannes;Vingron, Martin

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Title: The SYSTERS Protein Family Web Server	P84
Krause, Antje; Meinel, Thomas; Stoye, Jens; Schmidt, Heiko A.; Luz, Hannes; Vingron, Martin krause_a@molgen.mpg.de Max Planck Institute for Molecular Genetics

With the overwhelming growth of biological sequence databases comes the question of how to effectively handle these amounts of data. Protein sequences constitute one such data type for which the databases have grown to an impressive size.

A protein family contains evolutionarily related sequences. Generally, this is reflected by sequence similarity. Therefore, one aims at organizing the set of all protein sequences into family clusters based on their sequence similarity.

Clustering a large set of sequences as opposed to dealing only with the individual sequences offers several advantages. A frequent problem is the identification of sequences that are similar to a new query sequence. This task can be executed much quicker when only one comparison to an entire cluster has to be performed rather than one comparison per database sequence.

Another important application lies in the possibility of analyzing evolutionary relationships among the sequences in a cluster and the species they come from. Additionally, a clustered protein sequence database can be used for selecting candidates for protein structure analysis.

SYSTERS [1] is a method for grouping protein sequences hierarchically into superfamily and family clusters. The classification is based on an all-against-all database search using gapped BLAST [4]. The graph-based algorithms take into account the topology of the sequence space induced by the data itself.
We have applied our algorithms to a set of 395,089 non-redundant sequences from the Swiss-Prot [6], TrEMBL [6], and PIR [8] databases. The data splits into 64,282 superfamilies, which are further divided into 82,450 family clusters with an overall number of 55,182 single sequence clusters.

So far our hierarchy consists of two layers representing protein superfamilies and families. For the third layer located at the domain level we currently rely on the Pfam [5] domain database.

In the SYSTERS web server (http://systers.molgen.mpg.de), information of the original data set are recorded as well as cross-references to the databases concerning protein structure (PDB, IMB), nucleotide sequence (EMBL), protein function (ENZYME), and protein domains (PROSITE).

The sequences in every family cluster have been multiply aligned using ClustalW [7], and for each cluster an unrooted phylogenetic tree is available. For each family cluster a MView [3] output is generated, and a majority consensus sequence is calculated from the resulting partial multiple alignment.

The SYSTERS consensus sequences and/or the original sequences build a searchable database. The result of a BLAST search is visualised as a sequence alignment.

SYSTERS protein families can be selected by the sequence accession number of the original as well as the cross-linked databases, any keyword, a Pfam domain, or a taxon (based on the NCBI taxonomy [9]). The taxonomic selection cannot only be entered on the species level but also at any other taxonomic rank.

SYSTERS is integrated into a database framework of mRNA/EST consensus sequences (GeneNest [2], http://genenest.molgen.mpg.de) and genomic DNA (SpliceNest, http://splicenest.molgen.mpg.de). Links from SYSTERS to GeneNest and vice versa permit an over-all exploration of the whole sequence space.

[1] A. Krause, S.A. Haas, E. Coward, and M. Vingron. SYSTERS, GeneNest, SpliceNest: Exploring Sequence Space from Genome to Protein. Nucleic Acids Research, 30 (1):299-300, 2002.
[2] S.A. Haas, T. Beißbarth, E. Rivals, A. Krause, and M. Vingron. GeneNest: automated generation and visualization of gene indices. Trends in Genetics, 16 (11):521-523, 2000.
[3] N.P. Brown, C. Leroy, and C. Sander. MView: a web-compatible database search or multiple alignment viewer. Bioinformatics, 14 (4): 380-381, 1998.
[4] S.F. Altschul et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Research, 25 (17):3389-3402, 1997.
[5] A. Bateman et al. The Pfam Protein Families Database. Nucleic Acids Research, 30 (1):276-280, 2002.
[6] A. Bairoch and R. Apweiler. The SWISS-PROT protein sequence database and its supplement TrEMBL in 2000. Nucleic Acids Research, 28 (1):45-48, 2000.
[7] J.D. Thompson, D.G. Higgins, and T.J. Gibson. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Research, 22 (22):4673-4680, 1994.
[8] C.H. Wu et al. The Protein Information Resource: an integrated public resource of functional annotation of proteins. Nucleic Acids Research, 30 (1):35-37, 2002.
[9] David L. Wheeler et al. Database resources of the National Center for Biotechnology Information: 2002 update. Nucleic Acids Research, 30 (1):13-16, 2002.