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Summary on similarity search
or
Why do we care about far homologies ?
A protein from a
new pathogenic
bacteria.
We have no idea
what it does
A protein from a
model organism.
We know its function
in one organism but
not in another
(arrestin)
A protein related
to a disease
-Completely
unknown function
-May have
A different function
related to the disease
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retinol-binding
protein
apolipoprotein D
odorant-binding
protein
RBP4 and obesity
retinol-binding
protein
apolipoprotein D
odorant-binding
protein
Scoring matrices let you focus on the big (or small) picture
PAM250
PAM30
retinol-binding
retinol-binding
protein
protein
Blosum80
Blosum45
PSI-BLAST generates scoring matrices
more powerful than PAM or BLOSUM
retinol-binding
protein
Phylogenetic trees
Phylogeny is the inference of evolutionary relationships.
Traditionally, phylogeny relied on the comparison of morphological
features between organisms. Today, molecular sequence data are
mainly used for phylogenetic analyses.
One tree of life A sketch Darwin made
soon after returning from his voyage on
HMS Beagle (1831–36) showed his thinking
about the diversification of species
from a single stock (see Figure, overleaf).
This branching, extended by the concept
of common descent,
Phylogeny in Greek =the origin of the tribe
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Haeckel (1879)
Pace (2001)
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Molecular phylogeny uses trees to depict evolutionary
relationships among organisms.
These trees are based upon DNA and protein sequence data
Human
Gorilla
Chimpanzee
Chimpanzee
Gorilla
Orangutan
Orangutan
Human
Molecular analysis:
Chimpanzee is related more closely
to human than the gorilla
Pre-Molecular analysis:
The great apes
(chimpanzee, Gorilla & orangutan)
Separate from the human
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What can we learn from
phylogenetics tree?
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Determine the closest relatives of one organism
in which we are interested
• Was the extinct quagga more like a zebra or a horse?
Which species are closest to Human?
Gorilla
Human
Chimpanzee
Chimpanzee
Orangutan
Gorilla
Human
Orangut
an
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Human Evolution
Neanderthals
Modern
Man
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Help to find the relationship between the
species and identify new species
Example Metagenomics
A new field in genomics aims the study the genomes
recovered from environmental samples.
A powerful tool to access the wealthy biodiversity of
native environmental samples
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Discover new species in the ocean
106 cells/ ml seawater
107 virus particles/ ml seawater
>99% uncultivated microbes
Discover new species in our own gut
The total number of genes in the various species represented in
our internal microbial communities (microbiome) likely exceeds
the number of our human genes by at least two orders of magnitude.
Suez et al, Nature 2014
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How to discover new species?
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Extracting Phylogenetic Trees of known species
A
?
B
C
D
Finding relationships between the unknown and known species
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Phylogenetic Tree Terminology
• Graph composed of nodes & branches
• Each branch connects two adjacent nodes
R
F
E
A
B
C
D
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Phylogenetic Tree Terminology
Un-rooted tree
Rooted tree
Human
Chimp
Chicken
Gorilla
Chicken
Gorilla
Human Chimp
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Rooted vs. unrooted trees
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3
1
2
1
2
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How can we build a tree with
molecular data?
-Trees based on DNA sequence (rRNA)
-Trees based on Protein sequences
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Basic algorithm for
constructing a rooted tree
Unweighted Pair Group Method using Arithmetic Averages
(UPGMA)
Assumption: Divergence of sequences is assumed
to occur at a constant rate  Distance to root is equal
Sequence
Sequence
Sequence
Sequence
a
b
c
d
ACGCGTTGGGCGATGGCAAC
ACGCGTTGGGCGACGGTAAT
ACGCATTGAATGATGATAAT
ACACATTGAGTGTGATAATA
a
b
c
d
Moving from Similarity to Distance
Sequences
Sequence
Sequence
Sequence
Sequence
a
b
c
d
ACGCGTTGGGCGATGGCAAC
ACACATTGAGTGTGATCAAC
ACACATTGAGTGAGGACAAC
ACGCGTTGGGCGACGGTAAT
Distances *
Dab = 8
Dac = 7
Dad = 5
Dbc = 3
Dbd = 9
Dcd = 8
Distance Table
a
b
c
d
a
0
8
7
5
b
8
0
3
9
c
7
3
0
8
d
5
9
8
0
* Can be calculated using different distance metrics
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Constructing a tree starting from a STAR model
a
a b c d
a 0 8 7 5
b 8 0 3 9
c 7 3 0 8
d 5 9 8 0
b
d
c
Step 1:Choose the nodes with the shortest distance and fuse them.
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Step 2: recalculate the distance between the rest of the
remaining sequences (a and d) to the new node (e)
and remove the fused nodes from the table.
a
b
c
d
a
0
8
7
5
b
8
0
3
9
c
7
3
0
d
5
9
8
a
8
a
d
a
0
5
d
5
0
e
6
7
0
e
6
7
0
c,b e
d
a
c
D (ea) = (D(ac)+ D(ab)-D(cb))/2
e
d
D (ed) = (D(dc)+ D(db)-D(cb))/2
b
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Step 3: In order to get a tree, un-fuse c and b by
calculating their distance to the new node (e)
a
c
a
a
0
d
5
e
6
d
e
5
6
0
7
7
0
Dce
e
d
Dde
b
!!!The distances Dce and Dde are calculated assuming
constant rate evolution
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Next…
We want to fuse the next closest nodes
c
a
d
e
a
d
e
0
5
6
5
0
7
6
7
0
Dce
e
f
a,d
Dde
b
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Finally
We need to calculate the distance between e and f
c
f
e
f
0
4
e
4
0
a
Dcee
Dde
b
f
Daf
Dbf
d
D (ef) = (D(ea)+ D(ed)-D(ad))/2
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From a Star to a tree
a
b
f
e
d
b
c
a
d
c
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IMPORTANT !!!
•Usually we don’t assume a constant mutation rate
and in order to choose the nodes to fuse we have to
calculate the relative distance of each node to all other
nodes .
Neighbor Joining (NJ)- is an algorithm which is
suitable to cases when the rate of evolution varies
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Human Evolution Tree
UPGMA
Neighbor Joining
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The down side of phylogenetic trees
- Using different regions from a same alignment
may produce different trees.
Problems with phylogenetic trees
1Bacillus
7Burkholderias
3Pseudomonas
5Aeromonas
6Lechevaliera
2E.coli
Salmonella
4
0 .2
Problems with phylogenetic trees
Bacillus
1
7 Burkholderias
5 Aeromonas
1Bacillus
3
5
Aeromonas
Pseudomonas
3Pseudomonas
7Burkholderias
6
6Lechevaliera
Lechevaliera
2 E.coli
4Salmonella
2E.coli
4
Bacillus
3Pseudomonas
7 Burkholderias
5 Aeromonas
6Lechevaliera
2 E.coli
4 Salmonella
Salmonella
3Pseudomonas
1
5
Aeromonas
7
Burkholderias
1 Bacillus
6Lechevaliera
2E.coli
4 Salmonella
Problems with phylogenetic trees
• What to do ?
Bootstrapping
A.We create new data sets by sampling N positions with
replacement.
B.We generate 100 - 1000 such pseudo-data sets.
C.For each such data set we reconstruct a tree, using the
same method.
D.We note the agreement between the tree reconstructed
from the pseudo-data set to the original tree.
Note: we do not change the number of sequences !
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Bootstrapped tree
Less reliable Branch
1Bacillus
83
58
3Pseudomonas
7Burkholderias
5Aeromonas
6Lechevaliera
2E.coli
100
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Highly reliable
branch
0 .2
4Salmonella
Stimulating questions
• Do DNA and proteins from the same gene
produce different trees ?
• Can different genes have different
evolutionary history ?
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