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Introduction to Bioinformatics

and Biocomputing I
Dr Tan Tin Wee
Director
Bioinformatics Centre
http://www.bic.nus.edu.sg/
http://www.apbionet.org/
Twin pillars of Economy
Two Major Late 20th Century
Technologies

A new emerging area


Historical Background
• Life Science - young compared to physics and
chemistry
• 1953 Structure of DNA
• 1960s Understanding of “code of life”
• 1970s Genetic manipulation technology
• 1980s Widespread innovation -biotechnology/genetic
revolution
• 1990s Human Genome Project
• 2000s Structural Genomics ?
GenBank DNA Sequence Databank Growth Chart
Internet Growth
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Two Serious Problems
• Overwhelming rate of unorganised proliferation of
insufficiently structured scientific data in some
disciplines
- example in life sciences: Genome Project etc.
• Low and Uncertain Performance of Network Data
Communications and bandwidth limitation
– example of APBionet-APAN collaboration
Bottleneck
• From Sequence
• To Structure
• To Function
• Predicting Function: From Genes to
Genomes and Back
» J.Mol Biol (1998) 283, 707-725
Goal of the Human Genome
Program
(and the Genomes Projects!)
• Sequence the 3 billion base pairs of
humanDNA and identify the 100,000
genes contained in the human genome
• Do it for other genomes
Genomes Project!
• Human
• Vertebrates - mouse, dog, sheep, cattle, fish etc etc
• Invertebrates - C elegans, drosophila
• Plants - arabidopsis etc
• Microbes
– E coli, H. Influenzae, H. pylori, Mycoplasma genitalium,
B subtilis, Borrelia, Chlamydia, Aquifex, Methanocccus
Methanobacterium….
DOE Program NIH PROGRAM

TECHNOLOGY HUMAN GENOME UNDERSTANDING


APPLICATIONS PROJECT BIOLOGICAL FUNCTION
• TECHNOLOGY DEVELOPMENT
• MAPPING(GENETIC, PHYSICAL)
• SEQUENCING
• GENE IDENTIFICATION
• DATABASES
• MODEL ORGANISMS
• EHTICAL, LEGAL, SOCIAL ISSUES
GENETIC DISEASES STUDIES OF
• DIAGNOSTICS HUMAN DIVERSITY
• THERAPY
AND EVOLUTION

GENETIC SUSPECTIBILITIES
• PREVENTIVE MEDICINE
• RISK ASSESSMENT
Large Throughput
Sequencing Now Happening
will deluge us with more
data/information
New DOE/NIH Five-Year Plan
(continued)
Sequencing - Related Goals
• Model Organisms
- C. Elegans - 1998
- Drosophila - 2002
- Mouse - 2008
• Full length cDNAs - 2003
• Continued technology development
• Sustained sequencing capacity
Ambitious JGI Sequencing
Goals in FY 2000
Microbial Genome Research
• Capitalises on advances in human
genome program
• Map/sequence microbes with
- environmental/energy relevance
- phylogenetic significance
- commercial value
• Predict gene function, regulation,
and interactions
Microbial Genome Program
Sequencing Will Advance Biotechnology for
a Sustainable Future
• biosensors and biomonitoring
• bioremediation and biorestoration
• manufacturing and bioprocessing
• biofuels - biohydrogen, ethanol, biodiesel
• photosynthesis and biomass production
• disease and drought resistance
• 180 paradigm shift in how biology is done
Microbial Genome Program
Sequencing Completed --
• Mycoplasma genitalium -- free living , smallest genome
• Methanococcus jannaschii -- methane producer
• Archaeoglobus fulgidus -- oil well souring
• Thermotoga maritima -- energy from plant biomass
• Deinococcus radiodurans -- radiation resistant, bioremediation
• Methanobacterium thermoautotrophicm -- methane producer
• Pyrobaculum aerophilum -- thermophile (100NC)
• Aquifex aeolicus VF5 -- deep branching lineage
Microbial Genome Program
Sequencing in progress --
• Pyrococcus furiosus -- model hypothermophile
• Clostridium acetobutylicum -- biotech & waste remediation
• Shewanaella putrefaciens -- bioremediation
• Pseudomonas putida -- bioremediation
• Thiobacillus ferroxidans -- CO2 fixation
• Desulfovibrio vulgaris -- bioremediation
• Caulobacter crescentus -- bioremediation
• Chlorobium tepidum -- carbon management
• Dehalococcoides ethenogenes -- bioremediation
• Carboxydothermus hydrogenoformans -- H2 production
Challenges and
Opportunities
Private and public sector
sequencing efforts are
about to drive the
genome project into……

Information Overload!!!
What is Bioinformatics?
Bioinformatics is :
• the use of computers (and persistent data
structures) in pursuit of biological research.
• an emerging new discipline, with its own
goals, research program, and practitioners.
• the sine qua non for 21st-century biology.
• The most significantly underfunded
component of 21st-century biology
• all of the above.
Visualising Genome
Information
What is Genome Annotation?
The Process of Adding Biology Information and
Predictions to a Sequenced Genome Framework
Increasing Volume of Data
:
A Biological Data Deluge
• Between now and 2003, over 50,000 new human genes and
proteins.
• 100,000 new genes and proteins from genome sequencing
of microbes and model organisms.
• Variants will be found or manufactured at high throughput
(mutants, normal population variants, man-made constructs, homologues
determined in many species from gene-specific environmental screens).
• If 40,000 per year, > 3,000 per month, >100 per day
• In just 1997, about 12,000 genes and proteins were
discovered
Paradigm Shift in Biology
The new paradigm, now emerging, is that all
the ‘genes’ will be known (in the sense of
being resident in databases available
electronically), and that the starting point of a
biological investigation will be theoretical. An
individual scientist will being with a
theoretical conjecture, only then turning to
experiment to follow or test that hypothesis.

Walter Gilbert. 1991. Towards a paradigm shift in biology. Nature, 349:99.


Call for Change
Among the many new tools that are or will be
needed (for 21st century biology), some of
those having the highest priority are :
• bioinformatics
• computational biology
• functional imaging tools using biosensors and biomakers
• transformation and transient expression technologies
• nanotechnologies
Impact of Emerging Technologies on the Biological Sciences: Report of a
Workshop. NSF-supported workshop, held 26-27 June 1995, Washington, DC.
Human Resources Issues

Elbert Branscomb : “You must recognize that


some day you may need as many computer
scientists as biologists in your labs.”
Craig Venter : “At TIGR, we already have
twice as many computer scientists on our
staff.”
Exchange at DOE workshop on high-throughput sequencing.
Fundamental Dogma

Although a few databases already exist


to distribute molecular information,

the post-genomic era will need many


more to collect, manage, and publish
the coming flood of new findings
Base Pairs in Genbank
Projected Base Pairs
Current Situation
• Computational Infrastructure for processing genome
sequences geared for 2 million bases pairs per day
• New sequencing technology (whole genome shotgun) has
changed the landscape
• Raw data must be processed not just finished clones
• Data generation Jan 1 1999 - 30 million per day, mid-1999
- 1 billion bases per week.
• Most comprehensive analyses will be beyond capabilities
of all but a few sites
Private Sector Genome
Research
Current Situation
• Computational Infrastructure for processing genome
sequences geared for 2 million bases pairs per day
• New sequencing technology (whole genome shotgun) has
changed the landscape
• Raw data must be processed not just finished clones
• Data generation Jan 1 1999 - 30 million per day, mid-1999
- 1 billion bases per week.
• Most comprehensive analyses will be beyond capabilities
of all but a few sites
Biological Data:
High Complexity and
Large Scale
Computational Biology
in the High-Throughput Era
The Genome and Beyond

• Scientific Challenges
• Algorithmic Challenges
• Computational Challenges
IT-Biology Synergism
• Physics needs calculus, the method for
manipulating information about statistically
large numbers of vanishingly small,
independent, equivalent things.
• Biology needs information technology, the
method for manipulating information about
large numbers of dependent, historically
contigent, individual things
Moore’s Law : The Statement

Every eighteen months, the number of


transistors that can be placed on the chip
doubles.

- Gordon Moore, co-founder of Intel


Biosciences that
canonly be addressed with
significantly enhanced
1. Computational
Full genome-genome comparisons Power
2. Rapid assessment of polymorphic genetic variations
3. Complete construction of orthologous or paralogous groups of genes
4. Structure determination of large macromolecular assemblies/complexes
5. Dynamically simulation of realistic oligomeric systems
6. Rapid structural/topological clustering of proteins
7. Prediction of unknown molecular structures; Protein folding
8. Computer simulation of membrane structure and dynamic function
9. Simulation of genetic networks and the sensitivity of these pathways to
component stiochiometry and kinetics
10.Integration of observations across scales of vastly different dimensions
and organization to yield realistic environmental models for basic
biology and societal needs
General Scope of Introductory
Bioinformatics
• Database Searching
• Sequence Alignment
• Gene finding
• Functional Genomics
• Protein Classification
• Phylogenetic inference
Analogy
• 1980s Gene Cloning, rDNA technology -
Revolutionised biological and medical
research changing it into engineering -
genetic engineering
• 1990s Biocomputing and Bioinformatics -
Revolutionised biomedical research and
turned it into an informational science
• 2000s The next generation ???
Acknowledgements
• Dr John Wooley, Dept of Energy, USA, for
his ppt report on DOE's projected research
expenditure and the overview of
bioinformatics (copyright)
• Colleagues at BIC