Transcript Revolution - Tel Aviv University

1: Introduction
Introduction to Bioinformatics
Fall 2009-2010
1: Introduction
Administration
Teachers:
Dr. Tal Pupko
Dr. Eran Halperin
Dr. Iftach Nachman
[email protected]
[email protected]
[email protected]
Reception hours:
Please set a meeting by email.
1: Introduction
Course Website
http://bioinfo.tau.ac.il/~intro_bioinfo/
WHAT ARE THE QUESTIONS IN
THE EXAMS?
1: Introduction
Requirements
Final exam – 100%
1: Introduction
Exercise course
•
•
•
•
"‫"כלים בביואינפורמטיקה‬
Each student participates once in 2 weeks:
Sunday 16:00-18:00
Monday 12:00-14:00
Monday 14:00-16:00
Computer classroom Sherman 03
TAs:
Nimrod Rubinstein
Osnat Penn
Daiana Alaluf
[email protected]
[email protected]
[email protected]
1: Introduction
Goals
To familiarize the students with research
topics in bioinformatics, and with
bioinformatic tools
Prerequisites
• Familiarity with topics in molecular biology
(cell biology and genetics)
• Basic familiarity with computers & internet
1: Introduction
Ask, Ask, Ask!!
"‫"אין הביישן למד‬
1: Introduction
What is Bioinformatics
• “The analysis of biological information
using computers and statistical
techniques.
• The science of developing and utilizing
computer databases and algorithms to
accelerate and enhance biological
research “
www.niehs.nih.gov/dert/trc/glossary.htm
1: Introduction
Gregor Mendel
laws of inheritance,“gene”
Watson and Crick Genome
Project
DNA Discovery
1866
1953
2003
1: Introduction
Genome
Project
2003
1: Introduction
(Slide from Prof. Ron Shamir)
1: Introduction
Bioinformatics
The marriage of Computer Science and Biology
• Organize, store, analyze, visualize genomic data
• Utilizes methods from Computer Science,
Mathematics, Statistics and Biology
(Slide from Prof. Ron Shamir)
1: Introduction
(Slide from Prof. Ron Shamir)
Bioinformatics
• At the convergence of two revolutions: the ultrafast growth of biological data, and the information
22 Aug 2005:
revolution
100,000,000,000 bases
Biology is becoming an information science
1: Introduction
Bioinformatics – a short CV
• Born ~1990
• Grown rapidly.
• Experience: essential part of modern life
science and medicine
• Now a separate multidisciplinary scientific
area
• Is one of the cornerstones of 21st Century
medical and biological research
(Slide from Prof. Ron Shamir)
1: Introduction
The Bioinformatics Actors
•Academic research: where it all started
•Biotechnology companies
•Big Pharmas and big AgBio
•National and international centers
Find me gene (gin?)
1: Introduction
(Slide from Prof. Ron Shamir)
Bioinformatics in Israel
• World class player in
research
• Ranked 2-3 in absolute
number of papers in the
most prestigious and
competitive conferences
• Maintaining our
competitive global
position is nontrivial
1: Introduction
Bioinformatics in TAU
• TAU is the Israeli leader in the field…
(Slide from Prof. Ron Shamir)
1: Introduction
What do bioinformaticians study?
• Bioinformatics today is part of almost
every molecular biological research.
• Just a few examples…
1: Introduction
Example 1
• Compare proteins with similar sequences (for
instance –kinases) and understand what the
similarities and differences mean.
1: Introduction
Example 2
• Look at the genome and predict where
genes are (promoters; transcription
binding sites; introns; exons)
1: Introduction
Example 3
• Predict the 3-dimensional structure of a
protein from its primary sequence
Ab-initio
prediction –
extremely
difficult!
1: Introduction
Example 4
• Correlate between gene expression and
disease
A gene chip – quantifying gene
expression in different tissues
under different conditions
May be used for personalized
medicine
1: Introduction
Computational biology –
revolutionizing science at the
turn of the century.
1: Introduction
Three studies using bioinformatics
which impacted science
1. Classifying life into domains
2. Predicting drug resistance in HIV and
personalizing drug administration
3. Solving the mystery of anthrax
molecular biology
1: Introduction
Revolutionizing the Classification of Life
1: Introduction
In the very beginning
•Life was classified as
plants and animals
•When Bacteria were discovered
they were initially classified as plants.
•Ernst Haeckel (1866) placed all unicellular
organisms in a kingdom called Protista,
separated from Plantae and Animalia.
1: Introduction
1: Introduction
When electron microscopes were developed, it was
found that Protista in fact include both cells with and
without nucleus. Also, fungi were found to differ from
plants, since they are heterotrophs (they do not
synthesize their food).
Thus, life were classified to 5 kingdoms:
LIFE
Procaryotes
Plants
Animals
Protists
Fungi
1: Introduction
Later, plants, animals, protists and fungi were
collectively called the Eucarya domain, and the
procaryotes were shifted from a kingdom to be a
Bacteria domain.
Domains
Kingdoms
Bacteria
Plants
Eucarya
Animals
Protists
Fungi
Even later, a new Domain was discovered…
1: Introduction
rRNA was sequenced from a great
number of organisms to study phylogeny
•The translation apparatus is universal and
probably already existed in the “beginning”.
1: Introduction
Carl R. Woese and rRNA phylogeny
1: Introduction
A distance matrix was computed for each two
organisms. In a very influential paper, they showed
that methanogenic bacteria are as distant from
bacteria as they are from eucaryota (1977).
1: Introduction
One sentence about methanogenic
“bacteria”
“There exists a third kingdom which, to date, is
represented solely by the methanogenic bacteria,
a relatively unknown class of anaerobes that
possess a unique metabolism based on the
reduction of carbon dioxide to methane”.
These "bacteria" appear to be no more related to
typical bacteria than they are to eucaryotic
cytoplasms.“
1: Introduction
From sequence analysis only, it was thus
established that life is divided into 3:
Bacteria
Archaea
Eucarya
1: Introduction
The rRNA phylogenetic tree
1: Introduction
Revolutionizing HIV treatment
1: Introduction
There are very efficient drugs for HIV
Many viruses in blood
DRUG,
+a few days
A few viruses in blood
Many viruses in blood
DRUG,
+a few more days
1: Introduction
Explanation: the virus mutates and some viruses
become resistant to the drug.
Solution 1: combination of drugs (cocktail).
Solution 2: not to give drugs for which the virus is
already resistant. For example, if one was infected
from a person who receives a specific drug.
The question: how do one knows to which drugs the
virus is already resistant?
1: Introduction
Sequences of HIV-1 from patients who were treated
with drug A:
AAGACGCATCGATCGATCGATCGTACG
ACGACGCATCGATCGATCGATCGTACG
AAGACACATCGATCGTTCGATCGTACG
Sequences of HIV-1 from patients who were never
treated with drug A:
AAGACGCATCGATCGATCGATCTTACG
AAGACGCATCGATCGATCGATCTTACG
AAGACGCATCGATCGATCGATCTTACG
1: Introduction
drug A+
AAGACGCATCGATCGATCGATCGTACG
ACGACGCATCGATCGATCGATCGTACG
AAGACACATCGATCGTTCGATCGTACG
drug AAAGACGCATCGATCGATCGATCTTACG
AAGACGCATCGATCGATCGATCTTACG
AAGACGCATCGATCGATCGATCTTACG
This is an easy example.
1: Introduction
drug A+
AAGACGCATCGATCGATCGATCGTACG
ACGACGCATCGATCGATCGATCGTACG
AAGACACATCGATCATTCGATCATACG
drug AAAGACGCATCGATCTATCGATCTTACG
AAGACGCATCGATCTATCGATCTTACG
AAGACGCATCGATCAATCGATCGTACG
This is NOT an easy example. This is an example of
a classification problem.
1: Introduction
2006: Five machine learning tools were compared:
•Decision trees
•Linear regression
~80% accuracy
•Linear discriminant analysis
•Neural networks
•Support vector regression
1: Introduction
Revolutionizing our understanding of the
anthrax molecular mechanism
1: Introduction
•Anthrax is a disease whose causative agent is the
gram positive Bacillus anthracis.
•It infects mainly cattle, swine, and horses but it
can also infect humans.
•Humans are infected from milk or meat from
infected animals.
•In humans it causes skin problems, in cattle –
fatal blood poisoning.
1: Introduction
•A vaccine was found by Pasteur.
•Koch was the first to isolate the bacterium.
•Airborne anthrax, such as that induced by
weaponized strains used for
bioterrosrism is almost
always fatal in humans
(respiratory distress,
hemorrhage).
1: Introduction
How does the bacterium Bacillus anthracis work?
It secretes three proteins: protective antigen (PA),
edema factor (EF), and lethal factor (LF).
PA monomer first binds to a host-cell surface
receptor. This binding triggers proteolytic cleavage
(a part of the N terminus is cut out).
The (remaining) PA monomers oligomerize,
forming heptamers.
1: Introduction
LF and EF bind the heptamer and the entire
complex is internalized into an endosome.
The acidity in the endosome causes a
conformational change in the complex, thus it
penetrates the endosome membrane and forms a
pore.
The story continues…
1: Introduction
Researchers from the group of David Baker
wanted to know how LF and EF
bind to the heptameric PA.
They used a method called
docking…
1: Introduction
This is where the two proteins interact!
1: Introduction
Once they had a prediction, they performed
mutagenesis experiments. Changing residues in the
predicted interface cancelled the binding.
1: Introduction
How does docking work? Each 3D conformation is
given a score. The pair with the best score is chosen.
1: Introduction
Challenges: what is the best score?
How to go over as many conformations as possible?
How to take into account that proteins are flexible?