Introduction to Bioinformatics

1
Introduction to Bioinformatics
1 Introduction
Fall 2009-2010
2
1 Introduction
Administration

• Teachers
• Dr. Tal Pupko talp_at_post.tau.ac.il
• Dr. Eran Halperin heran_at_post.tau.ac.il
• Dr. Iftach Nachman iftachn_at_tauex.tau.ac.il
• Reception hoursPlease set a meeting by email.

3
Course Website
1 Introduction
http//bioinfo.tau.ac.il/intro_bioinfo/
WHAT ARE THE QUESTIONS IN THE EXAMS?
4
Requirements
1 Introduction
Final exam 100
5
Exercise course
1 Introduction
"???? ???????????????"

• Each student participates once in 2 weeks
• Sunday 1600-1800
• Monday 1200-1400
• Monday 1400-1600
• Computer classroom Sherman 03

TAs Nimrod Rubinstein rubi_at_post.tau.ac.il Osna
t Penn penn_at_post.tau.ac.il Daiana Alaluf
dalaluf83_at_gmail.com
6
Goals
1 Introduction

• 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

7
Ask, Ask, Ask!!
1 Introduction

• "??? ?????? ???"

8
What is Bioinformatics
1 Introduction

• 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
9
1 Introduction
Genome Project 2003
Watson and Crick DNA Discovery 1953
Gregor Mendel laws of inheritance,gene 1866
10
1 Introduction
Genome Project 2003
11
1 Introduction
(Slide from Prof. Ron Shamir)
12
Bioinformatics
1 Introduction
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)
13
(Slide from Prof. Ron Shamir)
1 Introduction
Bioinformatics

• At the convergence of two revolutions the
  ultra-fast growth of biological data, and the
  information revolution

22 Aug 2005 100,000,000,000 bases
Biology is becoming an information science
14
Bioinformatics a short CV
1 Introduction

• 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)
15
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?)
16
Bioinformatics in Israel
(Slide from Prof. Ron Shamir)
1 Introduction

• 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

17
Bioinformatics in TAU
1 Introduction

• TAU is the Israeli leader in the field

(Slide from Prof. Ron Shamir)
18
What do bioinformaticians study?
1 Introduction

• Bioinformatics today is part of almost every
  molecular biological research.
• Just a few examples

19
Example 1
1 Introduction

• Compare proteins with similar sequences (for
  instance kinases) and understand what the
  similarities and differences mean.

20
Example 2
1 Introduction

• Look at the genome and predict where genes are
  (promoters transcription binding sites introns
  exons)

21
Example 3
1 Introduction

• Predict the 3-dimensional structure of a protein
  from its primary sequence

Ab-initio prediction extremely difficult!
22
Example 4
1 Introduction

• Correlate between gene expression and disease

A gene chip quantifying gene expression in
different tissues under different conditions May
be used for personalized medicine
23
1 Introduction
Computational biology revolutionizing science
at the turn of the century.
24
Three studies using bioinformatics which impacted
science
1 Introduction

1. Classifying life into domains
2. Predicting drug resistance in HIV and
   personalizing drug administration
3. Solving the mystery of anthrax molecular biology

25
1 Introduction
Revolutionizing the Classification of Life
26
1 Introduction
In the very beginning

• Life was classified as
• plants and animals
• When Bacteria were discoveredthey were initially
  classified as plants.
• Ernst Haeckel (1866) placed all unicellular
  organisms in a kingdom called Protista, separated
  from Plantae and Animalia.

27
1 Introduction
28
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
Fungi
Plants
Animals
Protists
Procaryotes
29
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.
Eucarya
Bacteria
Domains
Fungi
Plants
Animals
Protists
Kingdoms
Even later, a new Domain was discovered
30
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.

31
1 Introduction
Carl R. Woese and rRNA phylogeny
32
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).
33
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.
34
1 Introduction
From sequence analysis only, it was thus
established that life is divided into
3 Bacteria Archaea Eucarya
35
1 Introduction
The rRNA phylogenetic tree
36
1 Introduction
Revolutionizing HIV treatment
37
1 Introduction
There are very efficient drugs for HIV
A few viruses in blood
Many viruses in blood
DRUG, a few days
38
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?
39
1 Introduction
Sequences of HIV-1 from patients who were treated
with drug A AAGACGCATCGATCGATCGATCGTACG ACGACGCA
TCGATCGATCGATCGTACG AAGACACATCGATCGTTCGATCGTACG S
equences of HIV-1 from patients who were never
treated with drug A AAGACGCATCGATCGATCGATCTTACG A
AGACGCATCGATCGATCGATCTTACG AAGACGCATCGATCGATCGATCT
TACG
40
1 Introduction
drug A AAGACGCATCGATCGATCGATCGTACG ACGACGCATCGATC
GATCGATCGTACG AAGACACATCGATCGTTCGATCGTACG drug
A- AAGACGCATCGATCGATCGATCTTACG AAGACGCATCGATCGATCG
ATCTTACG AAGACGCATCGATCGATCGATCTTACG This is an
easy example.
41
1 Introduction
drug A AAGACGCATCGATCGATCGATCGTACG ACGACGCATCGATC
GATCGATCGTACG AAGACACATCGATCATTCGATCATACG drug
A- AAGACGCATCGATCTATCGATCTTACG AAGACGCATCGATCTATCG
ATCTTACG AAGACGCATCGATCAATCGATCGTACG This is NOT
an easy example. This is an example of a
classification problem.
42
1 Introduction

• 2006 Five machine learning tools were compared
• Decision trees
• Linear regression
• Linear discriminant analysis
• Neural networks
• Support vector regression

80 accuracy
43
1 Introduction
Revolutionizing our understanding of the anthrax
molecular mechanism
44
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.

45
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).

46
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.
47
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

48
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

49
1 Introduction
This is where the two proteins interact!
50
1 Introduction
Once they had a prediction, they performed
mutagenesis experiments. Changing residues in the
predicted interface cancelled the binding.
51
1 Introduction
How does docking work? Each 3D conformation is
given a score. The pair with the best score is
chosen.
52
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?