Computational Biology

Introduction, Basic Biology

Q
Nives Skunca
Slides prepared by Dr. Christophe Dessimoz
19/21 September 2012

This week
Course introduction
Basic Biology

perturbation

Reality
observation

Catalogue

observation
observation

Nature

Georg Dionysius Ehret's illustration of Linnaeus's

sexual system of plant classification, 1736

Model
formulate/select

recreate life
synthetic biology

take it apart
in vitro
obs.

obs.

obs.
perturb.

Validate on
real data
obs.

perturb.

f(x)

Validate
Estimate
by simulation

prediction

Learning Outcomes

Understand basic concepts of molecular

biology

Understand and apply fundamental

models, algorithms, data structures, and
computational techniques to answer
biological questions

Wide range of topics, but special focus on

biological sequences and their evolutionary
context.

Topics
Molecular Genetics
Gene Evolution
Genome Evolution
Mass Spectrometry
Codon Bias

Modeling
Dynamic programming
Markov models
Least squares
Maximum Likelihood
Optimization
Heuristics
Simulation

Organization

Lecture

Wed 13-14 (CAB G52), Fri 13-15 (ML F34)

Prof. Gonnet will hold the lectures

Exercises:

Thu 14-16 (CAB H56), starting this week

If you do not have a nethz account, ask
Stefan Zoller as soon as possible.

Teaching Assistants

Stefan Zoller
Nives Skunca

Date
Sept. 19/21

Topic
Course Introduction; Basic Molecular
Biology
Sept. 26/28 Markov models/String Alignment I
Oct. 3/5
String Alignment II (indels, estimating
distances)
Oct. 10/12
Substitution Matrices
Oct. 17/19
Approximate Alignment Methods;
Statistics of Pairwise Alignments
Oct. 24/26
Phylogeny I
Oct.31/Nov.2 Phylogeny II
Nov. 7/9
Phylogeny III
Nov. 14/16 Multiple Sequence Alignments
Nov. 21/23 Synthetic Evolution; Evaluation of
Estimators
Nov. 28/30 Current research; Mass profiling
Dec. 5/7
Dec. 12/14
Dec. 19/21

Orthology/Lateral Gene Transfer

Codon bias
Genome Rearrangements

Lecturer
NS
GHG
GHG
GHG
GHG
GHG
GHG
GHG
AS
DD/GHG
Guests/
GHG
NS
SZ
GHG

Course Grade & Credits

Participation in the exercises is strongly

encouraged, but not mandatory

Written Exam

During winter session

3 hours
Only support materials are 2 A4 pages
(4 sides), personally handwritten.

Course Homepage
http://www.cbrg.ethz.ch/education/CompBiol

Course details
Schedule
Slides
Exercises

Darwin

Interpreted language based on Maple

Available for download mac and linux

(http://www.cbrg.ethz.ch/darwin)

Environment for bioinformatics, can do

sequence management, mathematics,
alignments, trees, drawing, etc.

Biorecipes
www.biorecipes.com

A collection of real
problems with coded
solutions in the
Darwin language

Darwin input in green

Darwin output in red

Other materials

Slides can be downloaded from the

course homepage.

Additional notes and references will be

made available as well.

Basic Biology
Slides of this part are largely
based on material from
Dr. Gina Cannarozzi

Basic Principles

Universality of life on earth: water,

carbon-based biochemistry; genetic
material; genetic code (largely) universal.
common origin!
Life is compartmentalized: cells are
fundamental units of structure,
function, organization
Self-replicating
Capable of Darwinian evolution

10 m
Cryptomonadales
Encyclopedia of Life
(eol.org)

So what is life?
Living organisms undergo metabolism,
maintain homeostasis, possess a capacity
to grow, respond to stimuli, reproduce
and, through natural selection, adapt to
their environment in successive
generations.

What about endospores? viruses? mules? priests?

prions? computer viruses?

In biology, there are exceptions to almost every rule.

Inside a Cell
Prokaryote

http://www.osovo.com/diagram/prokaryoticcelldiagram.htm

~2 m

Eukaryote

http://www.biologycorner.com/resources/cell.gif

10-30 m

Relevant components

Ribosomes translate mRNA into proteins.

Mitochondria (eukaryotes) have their own
DNA and are a result of early inclusion of proteobacteria into a eukaryotic cell.
Chloroplasts (plants, protists) have their own
DNA as a result of early inclusion of
cyanobacteria into a eukaryotic cell.
Plasmids (bacteria) are short pieces of circular
DNA in multiple copies; nonessential; get
transferred between bacteria.

Genome
chromosome

chromatin
histone

Genome: all the genetic

material of an organism.

The genome consists of

genes and non-coding
regions.

Genes consist of
regulatory regions,
intron, exons,
untranslated regions

http://www.scfbio-iitd.res.in/tutorial/geneorganization.html

Escherichia coli

Homo sapiens

23 chromosome pairs
1 circular chromosome
1 plasmid (multiple copies)
~4.6 million base pairs
~3.9 million
coding bases (85%)
4132 protein-coding genes
172 RNA (tRNA, rRNA,etc)
578 pseudogenes

~3 billion base pairs

~50 million coding bases (1.5%)
~21,000 protein-coding genes
~294,000 exons
~60,000 different transcripts
~6,000 pseudogenes
~4,800 RNA genes
~2,900 RNA pseudogenes

DNA
Deoxyribonucleic acid

Double helix
Backbones: phosphate and
deoxyribose , directed
(5 3), antiparallel

34
(3.4 nm)

Connection: 4 bases Adenine,

Thymine, Cytosine, Guanine.
A-T and C-G are paired by
hydrogen bonds (relatively weak)

3.3
(0.33 nm)
Wikipedia

DNA Bases
PuRines
PYrimidines
C G: 3 H-bonds
A T: 2H-bonds
Wikipedia

Hydrogen Bond

X-H Y where X,Y is

an electronegative
atom (typically N,O,F)

Responsible for high

boiling point of water
(each H20 can have
up to 4 H bonds)

Central dogma of
molecular biology

Wikipedia

DNA Replication

Wikipedia

Polymerase can only add bases from 53

(DNA is read 3 5)

Movie time!
Replication visualized:

http://www.wehi.edu.au/education/wehitv/molecular_visualisations_of_dna/

End of day 1

RNA

Single stranded (can form structure)

microRNA: short nucleotides (~22 nts)

which regulate gene function

Uracil instead of Thymine

mRNA: messenger RNA, for translation
rRNA: subunit of ribosome
tRNA: specific for one amino-acid,
selectively bind to codon via ribosome.

http://www.pdb.org/pdb/static.do?
p=education_discussion/
molecule_of_the_month/pdb15_2.html

Transcription

Transcription factors bind to promoter sites at

the 5 regulatory region.

RNA polymerase, binds to the complex.

Genes can be on either strand, but direction of

growing mRNA sequence is always 5 3

Working together, they open the DNA double

helix.

Roger Kornberg
Nobel Prize Chemistry 2006

The chain shown in grey is RNA polymerase,

with the portion that clamps on the DNA
shaded in yellow. The DNA helix being
unwound and transcribed by RNA
polymerase is shown in green and blue, and
the growing RNA stand is shown in red.
http://med.stanford.edu/featured_topics/nobel/kornberg/release.html

Post-transcriptional
modifications (Eukaryotes)

5 Cap
Poly-A tail
Splicing (removal of introns)

Research questions: Where are the introns? Where are the

coding sequences? Where are the stop and start of
transcription? Where are the binding sites for the transcription
factors that control when transcription takes place?

Alternative Splicing

Humans: >50% of genes have splice variants.

Dscam gene in D. melanogaster: 95 alternative
exons can express 38,016 different mRNAs through
alternative splicing.

Translation

Wikimedia
Commons

The Genetic Code

Proteins

Participate in most (all?) cellular processes

Encoded in DNA

Made of 20 amino-acids (+ occasionally a

cofactor, such as metal ion, heme, ATP, etc.)

Alberts et al., Essential cell biology: an introduction to the

molecular biology of the cell, Garland 1996

Functions of Proteins

...

Amino
Acids

Only sidechains
differ (red)

Sidechains have
diverse chemical
properties
(charge, size, pH,
hydrophobicity, ...)

Wikimedia
Commons

Peptide Bond

G. Cannarozzi

Proteins
have a 3D
structure

Wikimedia Commons

Biological sequences
How are they identified?
Where are they stored?

Next Generation Sequencing

Unidentified protein
extracted from gel

Proteomics
MDISTLTASEEIE
MEIDAEEIEIMAT
IDLAEDLISLFM
DDMFSSIDLESI
NFEIFNSSDIDSI
NIDLESIEEIEIMF
EEIEIMATIFNSS
DIDIMMDIMMD
SINFEIFNSSDIDI
MMDATIDLAED
LISLFMDDMFSS
IDLESINFEIFNSS

Split into fragments

of 5-10 amino acids

. . . AEDLISLFMDDM . . .

Determine mass
using MS (Mass
Spectrometry)

Determine amino
acid sequence and
compare with sequence database

Sequence
Database
Jiang Long, Science Creative
Quarterly Image Bank

Protein Identified

Growth of sequence databases

Number of sequences x 10^7

2.0

Protein Data Bank

8QL3URW.%6ZLVV3URW
UniProtKB/TrEmbl

1.5

1.0

0.5

0
2000

2002

2004

2006
Year

2008

2010

2012

Getting Sequences

Ensembl
...

e.g. GenBank File

e.g. GenBank
File

e.g. GenBank File

Evolution

Darwinian Evolution

Start from an initial population

Repeat:
reproduce and mutate randomly
natural selection: fittest individuals
survive and have descendants
selects good mutations
sometimes: a branching occurs (e.g.
speciation, duplication)

Not only the good

characters survive

Genetic drift (random sampling)

Population bottleneck
Founder effect

Genetic hitchhiking (neutral or mildly

deleterious alleles linked to positively
selected gene)

Species Evolution
Diane Dodds fruit fly experiment

Speciation: the
evolutionary process by
which new species arise

Can occur from

geographic isolation or
barriers, new niche
entered, animal
husbandry
http://evolution.berkeley.edu/evolibrary/article/_0_0/evo_45

Genome Rearrangements
e.g. Human vs. Dog

Krzywinski et al. Circos: an information aesthetic for comparative genomics. Genome Research (2009) vol. 19 (9) pp. 1639-45

Example: recombination
among E. coli strains

Mau et al. Genome Biology 2006 7:R44

Whole genome duplications

Gene Evolution

Point mutations

Kunkel, 2004, The Journal of Biological Chemistry

Point mutations
Purines

Pyrimidines

Insertion/deletion

Lateral Gene
Transfer

Wikipedia

http://www.scq.ubc.ca/attack-of-the-superbugs-antibiotic-resistance/

Recombination

Gene Evolution

Mutation (base substitution)

Insertion/Deletion
Transposition (horizontal transfer)
Recombination
Gene loss or gene duplication
Splicing pattern mutations

Evolutionary Distances
How can we quantify the amount of evolution
between two subjects?

Time since divergence

Number of common traits.
Edit distance (minimum # of elementary
operations to transform one object into the
other)
...

Desirable properties
distance estimable without knowing history
metric properties (e.g. triangle inequality)

Markovian Evolution
Markov Model: every site evolves independently,
probability of mutation only depends on present
state (no memory), probabilities of mutation are
expressed by transition matrix.
A

M1=

A
C
G
T

C G

0.900

0.033

0.033

0.033

0.033

0.900

0.033

0.033

0.033

0.033

0.900

0.033

0.033

0.033

0.033

0.900

After one unit of evolution, the

probability that an A mutates into a
C is given by the corresponding
entry in the matrix:
p(AC | d=1) = M1[AC] = 0.033

http://gi.cebitec.uni-bielefeld.de/people/boecker/bilder/tree_of_life_new.gif

Augustin Augier,
Arbre Botanique
(1801)

Lamarck, Philosophie Zoologique , 1809

Darwin, Notebook B, 1837

Edward Hitchcock, Elementary Geology, 1840

Haeckel, The Evolution of Man, 1879

rRNA was used by Woese (1987) to group early life forms into
three kingdoms

NO

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