1. Introduction to bioinformatics
Barbera van Schaik
Bioinformatics Laboratory
Academic Medical Centre (AMC)

2. Schedule 2013
See (Education) for course material

3. Databases and ontologies
Genome analysis
Bioimage informatics
Sequence analysis
Databases and ontologies
Phylogenetics
Subjects in
bioinformatics
Data and text mining
Systems biology
Structural bioinformatics
Gene expression
Genetics and population analysis

4. What is not in the schedule?
Proteomics (MS, MS/MS, LC-MS)
Systems Biology (mathematical modeling)
Information Management
(Multivariate) statistics
Phylogenetics
Genotype – Phenotype analysis
Text mining
Visualization
(high-throughput) biomolecular imaging
Comparative genomics
Protein modeling / protein docking
Experimental design
etc

5. Other courses http://www.amc.nl/graduateschool/
Computing in R – October 2013
DNA technology –March 2013
Practical biostatistics – September 2013
Introduction to next generation sequencing
Analysis of microarray gene expression data
NGS data analysis
EBI roadshow at AMC – 9+10 April 2013

6. Bioinformatics

7. Lost in translation (biology and informatics)
Inheritance
Protocol
NGS
Infrastructure
String
Sequence
Sonic hedgehog
Virus

8. Information Management / e-Science
Clinical genomics
Health care
Molecular
Biology/
Genomics
Information Management / e-Science

9. Definitions of bioinformatics
Adapted definition according to Wikipedia The application of information technology and statistics to the field of molecular biology. The creation and advancement of databases, algorithms, computational and statistical techniques, and theory to solve formal and practical problems arising from the management, analysis and interpretation of biological data.

10. Bioinformatics Extraction of biological knowledge from complex data

11. Bioinformatics And information management.........
*convert data to knowledge
*generate new hypotheses
Experimental
Data
Knowledge
From public
databases
*Design new experiments
And information management

12. How does molecule A interact with protein B?
A schematic visual model of oxygen-binding process, showing all four monomersand hemes, and protein chains only as diagramatic coils, to facilitate visualization into the molecule. (

13. Study migration

14. Study evolution

15. Which gene(s) causes disease X?
Study of families with particular disease.
Some people are affected (in grey)
Search for mutations or genes which are involved (bioinformatics)
About chances that a particular gene is important (biostatistics)

16. Bioinformatics Laboratory (AMC) Medical Bioinformatics & e-Bioscience
Part of the KEBB
You are welcome if you need bioinformatics expertise

17. Focus

18. Netherlands Bioinformatics Centre (NBIC)
Research, Support and Education

19. Other bioinformatics organisations
European Bioinformatics Institute (EBI)
National Center for Biotechnology
Information (NCBI)
EMBnet
International Society for
Computational Biology (ISCB)

20. Profile of a bioinformatician
(General) knowledge of biology and genome sciences
Translation biology <-> informatics
Knowledge of Unix-based operating systems
Programming skills (Java, Python, Shell/Perl scripting, R)
(Parallel) computing environments
Data storage and database technology
Statistics
Mathematics
Tux from:
Freely adapted from Richter et al (2009) PLoS computational biology

21. People who contribute to bioinformatics
Jim Kent
Michael Eisen
Lincoln Stein
Michael Eisen: cluster analysis microarrays (background: biology)
Lincoln Stein: reactome, wormbase, bioperl, encode, gmod, cloud computing (background: medicine and cell biology)
Jim Kent: human genome project (background: graphics)
Robert Gentleman: R, Bioconductor (background: statistics)
Carol Goble: e-science (background: computer science)
Ewan Birney: interpro, bioperl, encode project (background: biochemistry)
Women in bioinformatics: ~25% (
Robert Gentleman
Carol Goble
Ewan Birney

22. History of bioinformatics
1965 Margaret Dayhoff's Atlas of Protein Sequences
1970 Needleman-Wunsch algorithm (global alignment)
1977 DNA sequencing and software to analyze it (Staden)
1981 Smith-Waterman algorithm developed (local sequence alignment)
1981 The concept of a sequence motif (Doolittle)
1982 GenBank made public
1983 Sequence database searching algorithm (Wilbur-Lipman)
1987 Perl (Practical Extraction Report Language) is released by Larry Wall.
1988 National Center for Biotechnology Information (NCBI) created at NIH/NLM
1988 EMBnet network for database distribution
1990 BLAST: fast sequence similarity searching
1990 The HTTP 1.0 specification is published. First HTML document.
1990 Grid computing as a metaphor for making computer power as easy to access
as an electric power grid.
1994 EMBL European Bioinformatics Institute (EBI), Hinxton, UK
1995 Microsoft version 1.0 of IE. Sun version 1.0 of Java. Version 1.0 of Apache.
1997 PSI-BLAST
1997 International Society for Computational Biology was founded
1998 Worm (multicellular) genome completely sequenced
1999 e-Science was introduced by John Taylor, the Director General of the
United Kingdom's Office of Science and Technology
2000 Gene Ontology (GO)
2001 The human genome (3 Giga base pairs) is published.
2001 Minimum information about a microarray experiment (MIAME; Brazma).
2001 Genetical Genomics (Ritsert Jansen)
2002 BioMoby. Web-service repository
2003 myGrid: personalised bioinformatics on the information grid (e.g, Taverna).
2004 Bioconductor: open software development for computational biology and bioinformatics
2005 Reactome: knowledge base of biological pathways
History of bioinformatics

23. Publication history

24. 1965 Margaret Dayhoff's Atlas of Protein Sequences
1970 Needleman-Wunsch algorithm (global alignment)
1977 DNA sequencing and software to analyze it (Staden)
1981 Smith-Waterman algorithm developed (local sequence alignment)
1981 The concept of a sequence motif (Doolittle)
1982 GenBank made public
1983 Sequence database searching algorithm (Wilbur-Lipman)
1987 Perl (Practical Extraction Report Language) is released by Larry Wall.
1988 National Center for Biotechnology Information (NCBI) created at NIH/NLM
1988 EMBnet network for database distribution
1990 BLAST: fast sequence similarity searching
1990 The HTTP 1.0 specification is published. First HTML document.
1990 Grid computing as a metaphor for making computer power as easy to access
as an electric power grid.
1994 EMBL European Bioinformatics Institute (EBI), Hinxton, UK
1995 Microsoft version 1.0 of IE. Sun version 1.0 of Java. Version 1.0 of Apache.
1997 PSI-BLAST
1997 International Society for Computational Biology was founded
1998 Worm (multicellular) genome completely sequenced
1999 e-Science was introduced by John Taylor, the Director General of the
United Kingdom's Office of Science and Technology
2000 Gene Ontology (GO)
2001 The human genome (3 Giga base pairs) is published.
2001 Minimum information about a microarray experiment (MIAME; Brazma).
2001 Genetical Genomics (Ritsert Jansen)
2002 BioMoby. Web-service repository
2003 myGrid: personalised bioinformatics on the information grid (e.g, Taverna).
2004 Bioconductor: open software development for computational biology and bioinformatics
2005 Reactome: knowledge base of biological pathways

25. 1970 Needleman-Wunsch algorithm (global alignment)
1965 Margaret Dayhoff's Atlas of Protein Sequences
1970 Needleman-Wunsch algorithm (global alignment)
1977 DNA sequencing and software to analyze it (Staden)
1981 Smith-Waterman algorithm developed (local sequence alignment)
1981 The concept of a sequence motif (Doolittle)
1982 GenBank made public
1983 Sequence database searching algorithm (Wilbur-Lipman)
1987 Perl (Practical Extraction Report Language) is released by Larry Wall.
1988 National Center for Biotechnology Information (NCBI) created at NIH/NLM
1988 EMBnet network for database distribution
1990 BLAST: fast sequence similarity searching
1990 The HTTP 1.0 specification is published. First HTML document.
1990 Grid computing as a metaphor for making computer power as easy to access
as an electric power grid.
1994 EMBL European Bioinformatics Institute (EBI), Hinxton, UK
1995 Microsoft version 1.0 of IE. Sun version 1.0 of Java. Version 1.0 of Apache.
1997 PSI-BLAST
1997 International Society for Computational Biology was founded
1998 Worm (multicellular) genome completely sequenced
1999 e-Science was introduced by John Taylor, the Director General of the
United Kingdom's Office of Science and Technology
2000 Gene Ontology (GO)
2001 The human genome (3 Giga base pairs) is published.
2001 Minimum information about a microarray experiment (MIAME; Brazma).
2001 Genetical Genomics (Ritsert Jansen)
2002 BioMoby. Web-service repository
2003 myGrid: personalised bioinformatics on the information grid (e.g, Taverna).
2004 Bioconductor: open software development for computational biology and bioinformatics
2005 Reactome: knowledge base of biological pathways

26. Global alignment (toy example)
CATGATGA
CTGAGAT
Can you “align” these two sequences
 introduce “gaps” in these two sequences such that you maximize the number of matching nucleotides

27. Global alignment (toy example)
CATGATGA
CTGAGAT
CATGATGA-
C-TGA-GAT
Helps us to understand the function of
‘new’DNA
Dynamic programming gives optimal solution…
… but is slow. Often heuristic methods are used (BLAST, BLAT)

28. 1978
Paulien Hogeweg (1943)
Dutch theoretical biologist and complex systems researcher studying biological systems as dynamic information processing systems at many interconnected levels.
Together with Ben Hesper she coined the term Bioinformatics in 1978 as the study of informatic processes in biotic systems
Hogeweg, P. (1978). Simulating the growth of cellular forms. Simulation 31, 90-96;
Hogeweg, P. and Hesper, B. (1978) Interactive instruction on population interactions. Comput Biol Med 8:

29. 1981 Smith-Waterman algorithm developed (local sequence alignment)
1965 Margaret Dayhoff's Atlas of Protein Sequences
1967 Scientific director of NBIC was born
1970 Needleman-Wunsch algorithm (global alignment)
1977 DNA sequencing and software to analyze it (Staden)
1981 Smith-Waterman algorithm developed (local
sequence alignment)
1981 The concept of a sequence motif (Doolittle)
1982 GenBank made public
1983 Sequence database searching algorithm (Wilbur-Lipman)
1987 Perl (Practical Extraction Report Language) is released by Larry Wall.
1988 National Center for Biotechnology Information (NCBI) created at NIH/NLM
1988 EMBnet network for database distribution
1990 BLAST: fast sequence similarity searching
1990 The HTTP 1.0 specification is published. First HTML document.
1990 Grid computing as a metaphor for making computer power as easy to access
as an electric power grid.
1994 EMBL European Bioinformatics Institute (EBI), Hinxton, UK
1995 Microsoft version 1.0 of IE. Sun version 1.0 of Java. Version 1.0 of Apache.
1997 PSI-BLAST
1997 International Society for Computational Biology was founded
1998 Worm (multicellular) genome completely sequenced
1999 e-Science was introduced by John Taylor, the Director General of the
United Kingdom's Office of Science and Technology
2000 Gene Ontology (GO)
2001 The human genome (3 Giga base pairs) is published.
2001 Minimum information about a microarray experiment (MIAME; Brazma).
2001 Genetical Genomics (Ritsert Jansen)
2002 BioMoby. Web-service repository
2003 myGrid: personalised bioinformatics on the information grid (e.g, Taverna).
2004 Bioconductor: open software development for computational biology and bioinformatics
2005 Reactome: knowledge base of biological pathways

30. 1965 Margaret Dayhoff's Atlas of Protein Sequences
1967 Scientific director of NBIC was born
1970 Needleman-Wunsch algorithm (global alignment)
1977 DNA sequencing and software to analyze it (Staden)
1981 Smith-Waterman algorithm developed (local sequence alignment)
1981 The concept of a sequence motif (Doolittle)
1982 GenBank made public
1983 Sequence database searching algorithm (Wilbur-Lipman)
1987 Perl (Practical Extraction Report Language) is released by Larry Wall.
1988 National Center for Biotechnology Information (NCBI) created at NIH/NLM
1988 EMBnet network for database distribution
1990 BLAST: fast sequence similarity searching
1990 The HTTP 1.0 specification is published. First HTML document.
1990 Grid computing as a metaphor for making computer power as easy to access
as an electric power grid.
1994 EMBL European Bioinformatics Institute (EBI), Hinxton, UK
1995 Microsoft version 1.0 of IE. Sun version 1.0 of Java. Version 1.0 of Apache.
1997 PSI-BLAST
1997 International Society for Computational Biology was founded
1998 Worm (multicellular) genome completely sequenced
1999 e-Science was introduced by John Taylor, the Director General of the
United Kingdom's Office of Science and Technology
2000 Gene Ontology (GO)
2001 The human genome (3 Giga base pairs) is published.
2001 Minimum information about a microarray experiment (MIAME; Brazma).
2001 Genetical Genomics (Ritsert Jansen)
2002 BioMoby. Web-service repository
2003 myGrid: personalised bioinformatics on the information grid (e.g, Taverna).
2004 Bioconductor: open software development for computational biology and bioinformatics
2005 Reactome: knowledge base of biological pathways

31. 1988 EMBnet network for database distribution
1965 Margaret Dayhoff's Atlas of Protein Sequences
1967 Scientific director of NBIC was born
1970 Needleman-Wunsch algorithm (global alignment)
1977 DNA sequencing and software to analyze it (Staden)
1981 Smith-Waterman algorithm developed (local sequence alignment)
1981 The concept of a sequence motif (Doolittle)
1982 GenBank made public
1983 Sequence database searching algorithm (Wilbur-Lipman)
1987 Perl (Practical Extraction Report Language) is released by Larry Wall.
1988 National Center for Biotechnology Information (NCBI) created at NIH/NLM
1988 EMBnet network for database distribution
1990 BLAST: fast sequence similarity searching
1990 The HTTP 1.0 specification is published. First HTML document.
1990 Grid computing as a metaphor for making computer power as
easy to access as an electric power grid.
1994 EMBL European Bioinformatics Institute (EBI), Hinxton, UK
1995 Microsoft version 1.0 of IE. Sun version 1.0 of Java. Version 1.0
of Apache.
1997 PSI-BLAST
1997 International Society for Computational Biology was founded
1998 Worm (multicellular) genome completely sequenced
1999 e-Science was introduced by John Taylor, the Director General of the
United Kingdom's Office of Science and Technology
2000 Gene Ontology (GO)
2001 The human genome (3 Giga base pairs) is published.
2001 Minimum information about a microarray experiment (MIAME; Brazma).
2001 Genetical Genomics (Ritsert Jansen)
2002 BioMoby. Web-service repository
2003 myGrid: personalised bioinformatics on the information grid (e.g, Taverna).
2004 Bioconductor: open software development for computational biology and bioinformatics
2005 Reactome: knowledge base of biological pathways

32. 1998 Worm (multicellular) genome completely sequenced
1965 Margaret Dayhoff's Atlas of Protein Sequences
1967 Scientific director of NBIC was born
1970 Needleman-Wunsch algorithm (global alignment)
1977 DNA sequencing and software to analyze it (Staden)
1981 Smith-Waterman algorithm developed (local sequence alignment)
1981 The concept of a sequence motif (Doolittle)
1982 GenBank made public
1983 Sequence database searching algorithm (Wilbur-Lipman)
1987 Perl (Practical Extraction Report Language) is released by Larry Wall.
1988 National Center for Biotechnology Information (NCBI) created at NIH/NLM
1988 EMBnet network for database distribution
1990 BLAST: fast sequence similarity searching
1990 The HTTP 1.0 specification is published. First HTML document.
1990 Grid computing as a metaphor for making computer power as easy to access
as an electric power grid.
1994 EMBL European Bioinformatics Institute (EBI), Hinxton, UK
1995 Microsoft version 1.0 of IE. Sun version 1.0 of Java. Version 1.0 of Apache.
1997 PSI-BLAST
1997 International Society for Computational Biology was founded
1998 Worm (multicellular) genome completely sequenced
1999 e-Science was introduced by John Taylor, the
Director General of the United Kingdom's Office of
Science and Technology
2000 Gene Ontology (GO)
2001 The human genome (3 Giga base pairs) is published.
2001 Minimum information about a microarray experiment (MIAME; Brazma).
2001 Genetical Genomics (Ritsert Jansen)
2002 BioMoby. Web-service repository
2003 myGrid: personalised bioinformatics on the information grid (e.g, Taverna).
2004 Bioconductor: open software development for computational biology and bioinformatics
2005 Reactome: knowledge base of biological pathways

33. 2001 Genetical Genomics (Ritsert Jansen, Jan Peter Nap)
1965 Margaret Dayhoff's Atlas of Protein Sequences
1967 Scientific director of NBIC was born
1970 Needleman-Wunsch algorithm (global alignment)
1977 DNA sequencing and software to analyze it (Staden)
1981 Smith-Waterman algorithm developed (local sequence alignment)
1981 The concept of a sequence motif (Doolittle)
1982 GenBank made public
1983 Sequence database searching algorithm (Wilbur-Lipman)
1987 Perl (Practical Extraction Report Language) is released by Larry Wall.
1988 National Center for Biotechnology Information (NCBI) created at NIH/NLM
1988 EMBnet network for database distribution
1990 BLAST: fast sequence similarity searching
1990 The HTTP 1.0 specification is published. First HTML document.
1990 Grid computing as a metaphor for making computer power as easy to access
as an electric power grid.
1994 EMBL European Bioinformatics Institute (EBI), Hinxton, UK
1995 Microsoft version 1.0 of IE. Sun version 1.0 of Java. Version 1.0 of Apache.
1997 PSI-BLAST
1997 International Society for Computational Biology was founded
1998 Worm (multicellular) genome completely sequenced
1999 The term e-Science was created by John Taylor, the Director General of the
United Kingdom's Office of Science and Technology
2000 Gene Ontology (GO)
2001 The human genome (3 Giga base pairs) is published.
2001 Minimum information about a microarray experiment (MIAME; Brazma).
2001 Genetical Genomics (Ritsert Jansen, Jan Peter Nap)
2002 BioMoby. Web-service repository
2003 myGrid: personalised bioinformatics on the information grid (e.g, Taverna).
2004 Bioconductor: open software development for computational biology and bioinformatics
2005 Reactome: knowledge base of biological pathways
Expression profiling and marker-based fingerprinting of each individual of a segregating population
Quantitative trait loci analysis

34. 1976 Pauline Hogeweg (theoretical biology) 1979 Gert Vriend (proteins)
Bioinformatics in the Netherlands
1976 Pauline Hogeweg (theoretical biology)
1979 Gert Vriend (proteins)
1985 Computer Assisted Organic Synthesis/Computer Assisted Molecular
Modelling Centre (CAOS/CAMM) was founded (Nijmegen, Jan
Noordik)
1989 Jack Leunissen (first Dutch researcher with PhD in Bioinformatics)
90 ‘s Driving forces: Herman Berendsen, Charles Buys, Jacob de Vlieg
1999 CAOS/CAMM was reorganized; Gert Vriend becomes director of CMBI.
1999 KNAW committee(chaired by Berendsen) wrote the report ‘Bioexact’
in which strong stimulation of bioinformatics was recommended.
2000 KNCV working group bioinformatics
2000 NWO-BMI (Biomolecular informatics); program committee chaired by
De Vlieg
2001 NWO/KNAW workshop ‘The future of bioinformatics in the
Netherlands’
2002 Position paper ‘De toekomst van de bioinformatica in Nederland’
representing the vision of the NWO/KNAW
2003 NBIC was founded
2003 First BioRange proposal (Vriend, Berendsen, Hertzberger, Tellegen)
2005 Start of BioRange (NBIC-I)
2008 ……………

35. Open Source &
Open Access, Open
Standards, WIKI

36. Bioinformatics tools and databases
Many different bioinformatic tools are freely available
BLAST, EMBOSS, EnsEMBL, GenScan, BioConductor,
Many different biological databases are freely available
GenBank, UniProtKB, KEGG,
Many publications in open access journals
BMC bioinformatics
PLoS computational biology
Also many commercial software packages available
Spotfire, Rosetta Resolver, Genelogic,
Bioinformaticians write their own tools for specialized tasks

37. Nucleic acid research – annual web server issue

38. Cytoscape
Lesser General Public License (LGPL)

39. Open Access Unrestricted access to data
Allows researchers to use data and make discoveries
Discoveries are not necessarily open access
Open access is applicable to any kind of data you want to apply it to:
Sequence data (DNA, RNA or protein)
Gene expression data
Protein-protein interaction data
Literature

40. Why Open Standards? Freedom to operate No vendor lock-in Share
Collaborations
Flexibility
Examples
Protocols
TCP/IP, SOAP
File formats
ODF, PNG, HTML

41. The Original Wiki-Wiki
Shuttlebus on Honolulu (quick)

42. What is a wiki? Open source Management of Collaboration
Issues
Projects
Documents
Knowledge
Collaboration
Add, edit, delete web page content

43. Wikipedia

44. www.bioinformaticslaboratory.nl == TWIKI

45. WikiPathways

46. @AMC: genomics, metabolomics
Bioinformatics Extraction of biological knowledge from complex data
@AMC: genomics, metabolomics
and proteomics data

47. What is genomics?
The application of high-throughput automated technologies to molecular biology. OR
The experimental study of complete genomes.
On a large scale: genomics (since the last ~15 years)

48. DNA microarrays
Short summary, each spot is one gene (actually a few spots per gene)
Intensity according to amount of sample RNA
Each spot consists of single stranded nucleotide sequences
Each spot represents a gene (if questions by courseparticipants: actually a few spots per gene, drawing on whiteboard of gene with probes)
One sample (e.g. Healthy tissue) labelled green, one tissue (e.g. Disease tissue) in red
Mixture over plate
Competition of two samples
Intensity is measured
Red = more RNA of disease tissue
Green = more RNA of healthy tissue
Yellow = equal amount, no change
Black = no RNA from either sample
Other techniques: one sample at the time, e.g. Affymetrix, not a "ratio" measure, but quantitive measure per sample

49. Automated DNA sequencing
Sanger sequencing. Capillary system. Development in sequencing process was very important for HGP.

50. High throughput sequencing
Roche, 454
Applied biosystems, SOLiD
Illumina, Solexa
Now-a-days even faster sequencing machines
At the moment 3 types
In AMC we have the solid machines
One run takes... produces... costs...
Analysis not doable by hand -> bioinformatics

51. Sample storage
Sample have to be stored and kept track of. (LIMS)

52. Confused by genomics? Genomics Transcriptomics Proteomics Metabolomics
Nutrigenomics
Pharmacogenomics
Epigenomics
Infectomics
Patientomics
other 'omics'
Genomics: study of genomes on large scale
Transcriptomics: study of gene expression on large scale
Proteomics: study of proteins on large scale
Etc

53. Sign @ Wellcome-Sanger, Cambridge, UK
Anyway... You have loads of data
Therefore: Bioinformatics to the rescue
image credit: Digital Vision, PhotoDisc, Matt Ray/EHP
Wellcome-Sanger, Cambridge, UK