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Molecular Evolution
Cédric Notredame
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Molecular Evolution is a rapidly developing field………..
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Phenotypic diversity in populations suggests underlying genetic diversity
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Other molecular level studies reveal even more variation
Nucleotide sequence variation
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Is Modern Genetic Data
Compatible with
Darwinism
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If each variable locus is influenced by selection,
then how can populations be so genetically variable?
Can each variable “locus” influence
population fitness?
Genotype:
Fitness:
A1A1
1
A1A2
1
A2A2
1-s
What about the total “cost of
selection”when ALL these variable
loci are taken into account?
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J.B.S. Haldane
Neutral Theory of Molecular Evolution
Genotype:
Fitness:
A1A1
1
A1A2
1
A2A2
1
M. Kimura
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How Do Sequences Evolve
Each Portion of a Genome has its own Agenda.
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The Genetic Code is Redundant: Third-position codon changes are
often “silent”
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Neutral Theory
postulates that
much of the genetic
variation present
in populations is
not influenced by
selection--rather
it is a reflection of
two interacting
processes:
(1) Mutation
(2) Drift
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^
(H)
Neutral theory predicts
a regular relationship
between heterozygosity
and population size
(N)
^
H = 4Nu/[4Nu + 1], where N = population size and u
= mutation rate
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The Molecular Clock
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THE MOLECULAR CLOCK HYPOTHESIS
Another prediction of Neutral Theory--Because mutation is regular
(or “clocklike”) and because selection does not influence the rate of
divergence, divergence of DNA and protein molecules in two separate
lineages should occur in a REGULAR, clocklike manner
i.e., the longer the time separating two species from their common
ancestor, the more divergent will be a given protein or DNA molecule
(and this relationship should be LINEAR)
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Amino acid
substitutions /site
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Amino Acid Substituions/Site x 10
If most mutations are selectively neutral, we might expect to find
that molecular divergence is “clocklike”. Do we, in fact, see this?
3.2
3
2.8
2.5
2.2
2
1.8
1.5
1.2
1
150
250
350
450
550
Independent evolution (MYA)
650
Different molecular clocks for different proteins--another prediction
Cédric Notredame (29/04/2017)
How Do Sequences Evolve ?
CONSTRAINED Genome Positions Evolve SLOWLY
EVERY Protein Family Has its Own Level Of Constraint
Family
KS
KA
Histone3
Insulin
Interleukin I
a-Globin
Apolipoprot. AI
Interferon G
6.4
4.0
4.6
5.1
4.5
8.6
0
0.1
1.4
0.6
1.6
2.8
Rates in Substitutions/site/Billion Years as measured on Mouse Vs Human (80 Million years)
Ks Synonymous Mutations, Ka Non-Neutral.
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How Can We Compare Sequences ?
Using Knowledge Could Work
C
Aliphatic
L V
I
A G
T
Aromatic
F
Y
W
H
Small
P
G
CC
D
K E
R
S
N
Q
Hydrophobic
Polar
But we do not know enough about Evolution and
Structure.
Using Data works better.
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How Do Sequences Evolve ?
In a structure, each Amino Acid plays a Special Role
+
On the surface,
CHARGE MATTERS
OmpR, Cter Domain
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In the core,
SIZE MATTERS
How Do Sequences Evolve ?
Accepted Mutations Depend on the Structure
Big -> Big
Small ->Small
NO DELETION
+
-
Charged -> Charged
Small <-> Big or Small
DELETIONS
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Alignments and Evolution
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An Alignment is a STORY
ADKPKRPLSAYMLWLN
ADKPKRPLSAYMLWLN
ADKPKRPLSAYMLWLN
Mutations
+
Selection
ADKPKRPKPRLSAYMLWLN
ADKPRRPLS-YMLWLN
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An Alignment is a STORY
ADKPKRPLSAYMLWLN
ADKPKRPLSAYMLWLN
ADKPKRPLSAYMLWLN
Mutations
+
Selection
ADKPKRPKPRLSAYMLWLN
ADKPRRPLS-YMLWLN
Insertion
Deletion
ADKPRRP---LS-YMLWLN
ADKPKRPKPRLSAYMLWLN
Mutation
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Comparing Is Reconstructing Evolution
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Divergeant or Convergeant
Evolution
?
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Evolution is NOT Always Divergent…
Chen et al, 97, PNAS, 94, 3811-16
AFGP with (ThrAlaAla)n
Similar To Trypsynogen
N
S
AFGP with (ThrAlaAla)n
NOT
Similar to Trypsinogen
Cédric Notredame (29/04/2017)
Evolution is NOT Always Divergent
AFGP with (ThrAlaAla)n
Similar To Trypsynogen
N
S
AFGP with (ThrAlaAla)n
NOT
Similar to Trypsinogen
SIMILAR Sequences
BUT
DIFFERENT origin
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Orthologous
And
Paralogous
Genes
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Orthology and Paralogy
Duplication
Ag Ad Aa
Cb Ca
Bb Ba
Ab Aa
Cb Paralogous Ca
Cb Orthologous Bb
Cb Orthologous Ag and Ad
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Speciation
Duplication
Koonin and the COGs: Best reciprocal
BLAST matches
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Koonin and the COGs: Best reciprocal
BLAST matches
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Mixing Orthologs and
Paralogs leads to inexact
Phylogenetic trees
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0 My
1 My
2 My
3 My
1My
3 My
2 My
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Positions are not enough to
infer
Orthology
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Comparative Map of the Human and Mouse Genomes
Human chromosomes
Mouse chromosomes
Similar colored blocks = blocks of conserved synteny
(blocks of similar genes)
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