Bioinformatics
Biomolecular databases
Jacques van Helden
B!GRe
Bioinformatique des
Génomes et Réseaux
Jacques.van-Helden@univ-amu.fr
Université 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
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
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Nucleic sequences: Genbank, EMBL, and DDBJ
Protein sequences: UniProt
The Gene Ontology (GO) project
Issues and perspectives for biological databases
Biomolecular Databases
Examples of biomolecular databases
Examples of biomolecular databases

Sequence and structure databases
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Genome sequences and annotations

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Genome-specific databases (SGD, FlyBase, AceDB, PlasmoDB, …)
Multiple genomes (Integr8, NCBI, KEGG, TIGR, …)
Molecular functions


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Protein sequences (UniProt)
DNA sequences (EMBL, Genbank, DDBJ)
3D structures (PDB)
Structural motifs (CATH)
Sequence motifs (PROSITE, PRODOM)
Transcriptional regulation (TRANSFAC, RegulonDB, InteractDB)
Enzymatic catalysis (Expasy, LIGAND/KEGG, BRENDA)
Transport (YTPdb)
Biological processes
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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



The same journal maintains a database of databases: the Molecular Biology
Database Collection


http://nar.oupjournals.org/
2011 Issue: http://nar.oxfordjournals.org/content/39/suppl_1
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/
Biomolecular Databases
Nucleic sequence databases:
GenBank, EMBL, and DDBJ
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.
Okubo et al. (2006) NAR 34: D6-D9
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

Adapted from Didier Gonze
Size of the nucleotide database
EMBL Nucleotide Sequence Database: Release Notes - Release 113 September 2012
http://www.ebi.ac.uk/embl/Documentation/Release_notes/current/relnotes.html
Class
entries
nucleotides
-----------------------------------------------------------------CON:Constructed
7,236,371 359,112,791,043
EST:Expressed Sequence Tag
73,715,376 40,997,082,803
GSS:Genome Sequence Scan
34,528,104 21,985,922,905
HTC:High Throughput CDNA sequencing
491,770
594,229,662
HTG:High Throughput Genome sequencing
152,599 25,159,746,658
PAT:Patents
24,364,832 12,117,896,594
STD:Standard
13,920,617 37,665,112,606
STS:Sequence Tagged Site
1,322,570
636,037,867
TSA:Transcriptome Shotgun Assembly
8,085,693
5,663,938,279
WGS: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 14,420,391,278
FUN:Fungi
6,522,586 11,614,472,226
HUM:Human
32,094,500 38,072,362,804
INV:Invertebrates
31,907,138 52,527,673,643
MAM:Other Mammals
40,012,731 145,678,620,711
MUS:Mus musculus
11,745,671 19,701,637,499
PHG:Bacteriophage
8,511
85,549,111
PLN:Plants
52,428,994 55,570,452,118
PRO:Prokaryotes
2,808,489 28,807,572,238
ROD:Rodents
6,554,012 33,326,106,733
SYN:Synthetic
4,045,013
782,174,055
TGN:Transgenic
285,307
849,743,891
UNC:Unclassified
8,617,225
4,957,442,673
VRL:Viruses
1,358,528
1,518,575,082
VRT: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 Japan
http://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.
DDBJ
EMBL
GenBank
URL
http://www.ddbj.nig.ac.jp/
http://www.ebi.ac.uk/embl/
http://www.ncbi.nlm.nih.gov/
Sequences
2.0E+06
4.6E+07
Bases
(without
shotgun)
1.7E+09
5.1E+10
bases
(including
shotgun) Organisms
1.0E+11
1.0E+11
2.0E+05
2.1E+05
Biomolecular Databases
UniProt : protein sequences
and functional annotations
UniProt - the Universal Protein Resource
http://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 protein
Header : name and synonyms
UniProt example - Human Pax-6 protein
Human-based annotation by specialists
UniProt example - Human Pax-6 protein
Structured annotation : keywords and Gene Ontology terms
UniProt example - Human Pax-6 protein
Protein interactions; Alternative products
UniProt example - Human Pax-6 protein
Detailed description of regions, variations, and secondary structure
UniProt example - Human Pax-6 protein
Peptidic sequence
UniProt example - Human Pax-6 protein
References to original publications
UniProt example - Human Pax-6 protein
Cross-references to many databases (fragment shown)
3D Structure of macromolecules
PDB - The Protein Data Bank
http://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 Browser
http://ecrbrowser.dcode.org/
EnsEMBL - Example: Drosophila gene Pax6
http://www.ensembl.org/
Comparative genomics
Integr8 - access to complete genomes and proteomes
http://www.ebi.ac.uk/integr8/
Integr8 - genome summaries
http://www.ebi.ac.uk/integr8/
Integr8 - clusters of orthologous genes (COGs)
http://www.ebi.ac.uk/integr8/
Integr8 - clusters of paralogous genes
http://www.ebi.ac.uk/integr8/
Databases of protein domains
Prosite - protein domains, families and functional sites
http://www.expasy.ch/prosite/
Prosite - aligned sequences and logo
http://www.expasy.ch/prosite/


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Some of the sequences that were
used to built the Prosite profile for
the Zn(2)-C6 fungal-type DNAbinding 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 matrix
http://www.expasy.ch/prosite/
Prosite - Example of sequence logo
http://www.expasy.ch/prosite/
Prosite - Example of domain signature
http://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 Classification
http://www.cathdb.info/

CATH is a hierarchical classification of
protein domain structures, which clusters
proteins at four major levels:


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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 Classification
http://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)
Biomolecular Databases
The Gene Ontology (GO) database
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 determinations
Le Petit Robert - dictionnaire alphabétique et analogique de la langue française. 1993
The "bio-ontologies"
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Answer to the problem of inconsistencies in the annotations

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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 Database
http://www.geneontology.org/
Gene Ontology Database (http://www.geneontology.org/)
Example: methionine biosynthetic process
Status of GO annotations (NAR DB issue 2006)
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Term definitions
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Genomes with annotation

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Biological process terms
Molecular function terms
Cellular component terms
Sequence Ontology terms
9,805
7,076
1,574
963
30
Excludes annotations from UniProt, which represent 261 annotated proteomes.
Annotated gene products



Total
Electronic only
Manually curated
1,618,739
1,460,632
158,107
QuickGO (http://www.ebi.ac.uk/QuickGO/)

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Web site
http://www.ebi.ac.uk/Quic
kGO/
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



Nothing to do with the philosophical concept of ontology



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



A "bio-ontologies" is usually nothing more than a taxonomical classification of
the terms of a controlled vocabulary
Multiple possibilities of classification criteria


controlled vocabulary (choice among synonyms)
hierarchical relationships between the concepts
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).
Biomolecular Databases
Small compounds, reactions
and metabolic pathways
LIGAND - Small compounds and metabolic reactions
KEGG - Kyoto Encycplopaedia of Genes and Genomes
Ecocyc, BioCyc and Metacyc - Metabolic pathways
Biomolecular Databases
Protein interaction networks
and transduction pathways
Biomolecular Databases
Microarray 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.