cédric notredame (08/12/2015) molecular evolution cédric notredame
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Cédric Notredame (21/04/23)
Molecular Evolution
Cédric Notredame
Cédric Notredame (21/04/23)
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 DataCompatible with
Darwinism
Cédric Notredame (21/04/23)
If each variable locus is influenced by selection,then how can populations be so genetically variable?
Can each variable “locus” influencepopulation fitness?
Genotype: A1A1 A1A2 A2A2
Fitness: 1 1 1-s
What about the total “cost of selection”when ALL these variableloci are taken into account? J.B.S. Haldane
Cédric Notredame (21/04/23)
Neutral Theory of Molecular Evolution
M. Kimura
Genotype: A1A1 A1A2 A2A2
Fitness: 1 1 1
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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 areoften “silent”
Cédric Notredame (21/04/23)
Neutral Theorypostulates thatmuch of the geneticvariation presentin populations isnot influenced byselection--ratherit is a reflection oftwo interactingprocesses:
(1) Mutation(2) Drift
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H = 4Nu/[4Nu + 1], where N = population size and u = mutation rate
(N)
^
(H)
^ Neutral theory predictsa regular relationshipbetween heterozygosityand population size
Cédric Notredame (21/04/23)
The Molecular Clock
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Another prediction of Neutral Theory--Because mutation is regular(or “clocklike”) and because selection does not influence the rate ofdivergence, divergence of DNA and protein molecules in two separatelineages should occur in a REGULAR, clocklike manner
i.e., the longer the time separating two species from their commonancestor, the more divergent will be a given protein or DNA molecule(and this relationship should be LINEAR)
THE MOLECULAR CLOCK HYPOTHESIS
Cédric Notredame (21/04/23)
If most mutations are selectively neutral, we might expect to findthat molecular divergence is “clocklike”. Do we, in fact, see this?
11.21.51.8
22.22.52.8
33.2
Am
ino
Aci
d S
ub
stit
uio
ns/
Sit
e x
10
150 250 350 450 550 650
Independent evolution (MYA)
Amino acid substitutions /site
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Different molecular clocks for different proteins--another prediction
Cédric Notredame (21/04/23)
How Do Sequences Evolve ?
CONSTRAINED Genome Positions Evolve SLOWLY
EVERY Protein Family Has its Own Level Of Constraint
Family KS KA
Histone3 6.4 0Insulin 4.0 0.1Interleukin I 4.6 1.4Globin 5.1 0.6Apolipoprot. AI 4.5 1.6Interferon G 8.6 2.8
Rates in Substitutions/site/Billion Years as measured on Mouse Vs Human (80 Million years)Ks Synonymous Mutations, Ka Non-Neutral.
Cédric Notredame (21/04/23)
Cédric Notredame (21/04/23)
How Can We Compare Sequences ?
G
C
LIV A
F
Aliphatic
Aromatic
Hydrophobic
C
ST
W
YQH
K
R
ED N
Polar
PG
Small
C
Using Knowledge Could Work
But we do not know enough about Evolution and Structure.
Using Data works better.
Cédric Notredame (21/04/23)
How Do Sequences Evolve ?
In a structure, each Amino Acid plays a Special Role
OmpR, Cter Domain
In the core, SIZE MATTERS
On the surface, CHARGE MATTERS
--+
Cédric Notredame (21/04/23)
How Do Sequences Evolve ?
Accepted Mutations Depend on the Structure
Big -> BigSmall ->SmallNO DELETION
--+
Charged -> ChargedSmall <-> Big or SmallDELETIONS
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Alignments and Evolution
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An Alignment is a STORY
ADKPKRPLSAYMLWLN
ADKPKRPKPRLSAYMLWLNADKPRRPLS-YMLWLN
ADKPKRPLSAYMLWLN ADKPKRPLSAYMLWLN
Mutations+
Selection
Cédric Notredame (21/04/23)
An Alignment is a STORY
ADKPRRP---LS-YMLWLNADKPKRPKPRLSAYMLWLN
Mutation
InsertionDeletion
ADKPKRPLSAYMLWLN
ADKPKRPKPRLSAYMLWLNADKPRRPLS-YMLWLN
ADKPKRPLSAYMLWLN ADKPKRPLSAYMLWLN
Mutations+
Selection
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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…
AFGP with (ThrAlaAla)nSimilar To Trypsynogen
N
AFGP with (ThrAlaAla)n
S
Chen et al, 97, PNAS, 94, 3811-16
NOT
Similar to Trypsinogen
Cédric Notredame (21/04/23)
Evolution is NOT Always Divergent
AFGP with (ThrAlaAla)nSimilar To Trypsynogen
AFGP with (ThrAlaAla)nNOT
Similar to Trypsinogen
N
S
SIMILAR Sequences BUT
DIFFERENT origin
Cédric Notredame (21/04/23)
OrthologousAnd
ParalogousGenes
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Cédric Notredame (21/04/23)
Speciation
Duplication
C C ABB A
Orthology and Paralogy
CParalogous C
COrthologous B
Duplication
AA A
COrthologous AandA
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Koonin and the COGs: Best reciprocal BLAST matches
Cédric Notredame (21/04/23)
Koonin and the COGs: Best reciprocal BLAST matches
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Cédric Notredame (21/04/23)
Cédric Notredame (21/04/23)
Cédric Notredame (21/04/23)
Mixing Orthologs and Paralogs leads to
inexact Phylogenetic trees
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0 My
1 My
3 My
2 My
1My
3 My
2 My
Cédric Notredame (21/04/23)
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)