Biomolecular databases

Bioinformatics

Jacques van Helden

Jacques.van-Helden@univ-amu.frUniversité d’Aix-Marseille, France

Lab. Technological Advances for Genomics and Clinics (TAGC, INSERM Unit U1090)

http://jacques.van-helden.perso.luminy.univ-amu.fr/

Contents

Examples of biological databases Nucleic sequences: Genbank, EMBL, and DDBJ Protein sequences: UniProt The Gene Ontology (GO) project

Issues and perspectives for biological databases

Examples of biomolecular databases

Biomolecular Databases

Examples of biomolecular databases

Sequence and structure databases Protein sequences (UniProt) DNA sequences (EMBL, Genbank, DDBJ) 3D structures (PDB) Structural motifs (CATH) Sequence motifs (PROSITE, PRODOM)

Genome sequences and annotations Genome-specific databases (SGD, FlyBase, AceDB, PlasmoDB, …) Multiple genomes (Integr8, NCBI, KEGG, TIGR, …)

Molecular functions Transcriptional regulation (TRANSFAC, RegulonDB, InteractDB) Enzymatic catalysis (Expasy, LIGAND/KEGG, BRENDA) Transport (YTPdb)

Biological processes Metabolic pathways (EcoCyc, LIGAND/KEGG, Biocatalysis/biodegradation) Signal transduction pathways (CSNdb, Transpath) Protein-protein interactions (DIP, BIND, MINT) Gene networks (GeneNet, FlyNets)

Databases of databases

There are hundreds of databases related to molecular biology and biochemistry. New databases are created every year.

Every year, the first issue of Nucleic Acids Research is dedicated to biological databases

http://nar.oupjournals.org/ 2011 Issue: http://nar.oxfordjournals.org/content/39/suppl_1

The same journal maintains a database of databases: the Molecular Biology Database Collection

http://www.oxfordjournals.org/nar/database/c/ Some bioinformatics centres maintain multiple database, with cross-links

between them. The SRS server at EBI holds an impressive collection of databases.

http://srs.ebi.ac.uk/

Nucleic sequence databases: GenBank, EMBL, and DDBJ

Biomolecular Databases

Okubo et al. (2006) NAR 34: D6-D9

Nucleic sequence databases

To publish an article dealing with a sequence, scientific journals impose to have previously deposited this sequence in a reference database.

There are 3 main repositories for nucleic acid sequences. Sequences deposited in any of these 3 databases are automatically

synchronized in the 2 other ones.

Adapted from Didier Gonze

The sequencing pace Nucleic sequences

Genbank (April 2011) http://www.ncbi.nlm.nih.gov/genbank/

• 126,551,501,141 bases in 135,440,924 sequence records in the traditional GenBank divisions

• 191,401,393,188 bases in 62,715,288 sequence records in the Whole Genome Ssequencing

Entire genomes GOLD Release V.2 (Oct 2011) contains ~2000 completely

sequenced genomes. http://www.genomesonline.org/gold_statistics.htm

Protein sequences Essentially obtained by translation of putative genes in nucleic

sequences (almost no direct protein sequencing). UniProtKB/TrEMBL (2011) contains 17 millions of protein sequences. http://www.ebi.ac.uk/swissprot/sptr_stats/index.html

Size of the nucleotide databaseEMBL Nucleotide Sequence Database: Release Notes - Release 113 September 2012http://www.ebi.ac.uk/embl/Documentation/Release_notes/current/relnotes.html

Class entries nucleotides------------------------------------------------------------------CON:Constructed 7,236,371 359,112,791,043EST:Expressed Sequence Tag 73,715,376 40,997,082,803GSS:Genome Sequence Scan 34,528,104 21,985,922,905HTC:High Throughput CDNA sequencing 491,770 594,229,662HTG:High Throughput Genome sequencing 152,599 25,159,746,658PAT:Patents 24,364,832 12,117,896,594STD:Standard 13,920,617 37,665,112,606STS:Sequence Tagged Site 1,322,570 636,037,867TSA:Transcriptome Shotgun Assembly 8,085,693 5,663,938,279WGS:Whole Genome Shotgun 88,288,431 305,661,696,545 ----------- ---------------Total 252,106,363 450,481,663,919

Division entries nucleotides------------------------------------------------------------------ENV:Environmental Samples 30,908,230 14,420,391,278FUN:Fungi 6,522,586 11,614,472,226HUM:Human 32,094,500 38,072,362,804INV:Invertebrates 31,907,138 52,527,673,643MAM:Other Mammals 40,012,731 145,678,620,711MUS:Mus musculus 11,745,671 19,701,637,499PHG:Bacteriophage 8,511 85,549,111PLN:Plants 52,428,994 55,570,452,118PRO:Prokaryotes 2,808,489 28,807,572,238ROD:Rodents 6,554,012 33,326,106,733SYN:Synthetic 4,045,013 782,174,055TGN:Transgenic 285,307 849,743,891UNC:Unclassified 8,617,225 4,957,442,673VRL:Viruses 1,358,528 1,518,575,082VRT:Other Vertebrates 22,809,428 42,568,889,857 ----------- ---------------Total 252,106,363 450,481,663,919

Genbank (NCBI - USA) http://www.ncbi.nlm.nih.gov/Genbank/

The EMBL Nucleotide Sequence Database (EBI - UK)http://www.ebi.ac.uk/embl/

DDBJ - DNA Data Bank of Japanhttp://www.ddbj.nig.ac.jp/

Size of the nucleic sequence databases

Summary of database contents for the 3 main databases of nucleic sequences. Source: NAR database issue January 2006.

UniProt : protein sequencesand functional annotations

Biomolecular Databases

UniProt - the Universal Protein Resourcehttp://www.uniprot.org/

Database content (Sept 2012) UniProtKB:

• 24,532,088 entries• Translation of EMBL coding sequences

(non-redundant with Swiss-Prot) UniProtKB/Swiss-Prot section (reviewed):

• 537,505 entries• annotation by experts• high information content• many references to the literature• good reliability of the information

The rest (90% of the entries)• Automatic annotation by sequence

similarity. Features

The most comprehensive protein database in the world.

A huge team: >100 annotators + developers. Annotation by experts: annotators are

specialized for different types of proteins or organisms.

World-wide recognized as an essential resource.

References Bairoch et al. The SWISS-PROT protein

sequence data bank. Nucleic Acids Res (1991) vol. 19 Suppl pp. 2247-9

The UniProt Consortium. The Universal Protein Resource (UniProt) 2009. Nucleic Acids Res (2008). Database Issue.

Number of entries (polypeptides) in Swiss-Prot

http://www.expasy.org/sprot/relnotes/relstat.html

Taxonomic distribution of the sequences

Within Eukaryotes

UniProt example - Human Pax-6 proteinHeader : name and synonyms

UniProt example - Human Pax-6 proteinHuman-based annotation by specialists

UniProt example - Human Pax-6 proteinStructured annotation : keywords and Gene Ontology terms

UniProt example - Human Pax-6 proteinProtein interactions; Alternative products

UniProt example - Human Pax-6 proteinDetailed description of regions, variations, and secondary structure

UniProt example - Human Pax-6 proteinPeptidic sequence

UniProt example - Human Pax-6 proteinReferences to original publications

UniProt example - Human Pax-6 proteinCross-references to many databases (fragment shown)

3D Structure of macromolecules

PDB - The Protein Data Bankhttp://www.rcsb.org/pdb/

Genome browsers

EnsEMBL Genome Browser (Sanger Institute + EBI) http://www.ensembl.org/

UCSC Genome Browser (University California Santa Cruz - USA)http://genome.ucsc.edu/

Human gene Pax6 aligned with Vertebrate genomes

UCSC Genome Browser (University California Santa Cruz - USA)http://genome.ucsc.edu/

Drosophila gene eyeless (homolog to Pax6) aligned with Insect genomes

UCSC Genome Browser (University California Santa Cruz - USA)http://genome.ucsc.edu/

Drosophila 120kb chromosomal region covering the Achaete-Scute Complex

ECR Browserhttp://ecrbrowser.dcode.org/

EnsEMBL - Example: Drosophila gene Pax6http://www.ensembl.org/

Comparative genomics

Integr8 - access to complete genomes and proteomeshttp://www.ebi.ac.uk/integr8/

Integr8 - genome summarieshttp://www.ebi.ac.uk/integr8/

Integr8 - clusters of orthologous genes (COGs)http://www.ebi.ac.uk/integr8/

Integr8 - clusters of paralogous geneshttp://www.ebi.ac.uk/integr8/

Databases of protein domains

Prosite - protein domains, families and functional siteshttp://www.expasy.ch/prosite/

Prosite - aligned sequences and logohttp://www.expasy.ch/prosite/

Some of the sequences that were used to built the Prosite profile for the Zn(2)-C6 fungal-type DNA-binding domain (ZN2_CY6_FUNGAL_2, PS50048).

The Sequence Logo (below) indicates the level of conservation of each residue in each column of the alignment.

Note the 6 cysteines, characteristic of this domain.

Prosite - Example of profile matrixhttp://www.expasy.ch/prosite/

Prosite - Example of sequence logohttp://www.expasy.ch/prosite/

Prosite - Example of domain signaturehttp://www.expasy.ch/prosite/

The domain signature is a string-based pattern representing the residues that are characteristic of a domain.

PFAM (Sanger Institute - UK) http://pfam.sanger.ac.uk/ Protein families represented by multiple sequence alignments and hidden Markov models (HMMs)

CATH - Protein Structure Classificationhttp://www.cathdb.info/

CATH is a hierarchical classification of protein domain structures, which clusters proteins at four major levels:

Class (C), Architecture (A), Topology (T) Homologous superfamily (H).

The boundaries and assignments for each protein domain are determined using a combination of automated and manual procedures which include computational techniques, empirical and statistical evidence, literature review and expert analysis.

References Orengo et al. The CATH Database

provides insights into protein structure/function relationships. Nucleic Acids Res (1999) vol. 27 (1) pp. 275-9

Cuff et al. The CATH classification revisited--architectures reviewed and new ways to characterize structural divergence in superfamilies. Nucleic Acids Res (2008) pp.

CATH - Protein Structure Classificationhttp://www.cathdb.info/

InterPro (EBI - UK)http://www.ebi.ac.uk/interpro/

“A database of protein families, domains, repeats and sites in which identifiable features found in known proteins can be applied to new protein sequences.”

InterPro (EBI - UK)Antennapedia-like Homeobox (entry IPR001827)

The Gene Ontology (GO) database

Biomolecular Databases

Ontology definition

Ontologie: partie de la métaphysique qui s'intéresse à l'être en tant qu'être, indépendamment de ses déterminations particulières

Ontology: part of the metaphysics that focusses on the being as a beging, independently of its particular determinationsLe Petit Robert - dictionnaire alphabétique et analogique de la langue française. 1993

The "bio-ontologies"

Answer to the problem of inconsistencies in the annotations Controlled vocabulary Hierarchical classification between the terms of the controlled vocabulary

E.g.: The Gene Ontology molecular function ontology process ontology cellular component ontology

Gene ontology: processes

Gene ontology: molecular functions

Gene ontology: cellular components

Gene Ontology Databasehttp://www.geneontology.org/

Gene Ontology Database (http://www.geneontology.org/)

Example: methionine biosynthetic process

Status of GO annotations (NAR DB issue 2006)

Term definitions Biological process terms 9,805 Molecular function terms 7,076 Cellular component terms 1,574 Sequence Ontology terms 963

Genomes with annotation 30 Excludes annotations from UniProt, which represent 261 annotated proteomes.

Annotated gene products Total 1,618,739 Electronic only 1,460,632 Manually curated 158,107

QuickGO (http://www.ebi.ac.uk/QuickGO/)

Web sitehttp://www.ebi.ac.uk/QuickGO/

A user-friendly Web interface to the Gene Ontology.

Graphical display of the hierarchical relationships between terms.

Convenient browsing between classes.

Remarks on "bio-ontologies"

Improvement compared to free text controlled vocabulary (choice among synonyms) hierarchical relationships between the concepts

Nothing to do with the philosophical concept of ontology A "bio-ontologies" is usually nothing more than a taxonomical classification of

the terms of a controlled vocabulary Multiple possibilities of classification criteria

e.g. compartment subtypes (plasma membrane is a membrane) e.g. compartment locations (nucleus is inside cytoplasm is inside plasma

membrane) To be useful, should remain purpose-based

each biologist might wish to define his/her own classification based on his/her needs and scope of interest

impossible to define a unifying standard for all biologists No representation of molecular interactions

relationships between objects are only hierarchical, not horizontal or cyclic e.g. does not describe which genes are the target of a given transcription

factor

What is biological function ?

A general definition Fonction: action, rôle caractéristique d’un élément, d’un organe, dans un ensemble

(souvent opposé à structure). Source: Le Petit Robert - dictionnaire alphabetique et analogique de la langue francaise. 1982.

Function: characteristic action (role) of an element (organ) within an set(often opposed to structure)

Function and gene ontology Understanding the function requires to establish the link between molecular activity

and the context in which it takes place (process). Multifunctionality

• Same activity can play different roles in different processes. Example: scute gene in Drosophila melanogaster: a transcription factor

(activity) involved in sex determination, determination of neural precursors and malpighian tubules (3 processes).

• Multiple activities of a same protein in a given process Example: aspatokinase PutA in Escherichia coli, contains 2 enzymatic

domains (enzymatic activities) + a DNA-binding domain (DNA binding transcription factor) -> 3 molecular activities in the same process (proline utilization).

Small compounds, reactions and metabolic pathways

Biomolecular Databases

LIGAND - Small compounds and metabolic reactions

KEGG - Kyoto Encycplopaedia of Genes and Genomes

Ecocyc, BioCyc and Metacyc - Metabolic pathways

Protein interaction networks and transduction pathways

Biomolecular Databases

Microarray databases

Biomolecular Databases

Human genome resources

HapMap http://www.hapmap.org/

The International HapMap Project is a multi-country effort to identify and catalog genetic similarities and differences in human beings.

Associations between genetic variations (SNPs, ...) and diseases + response to pharmaceuticals.