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Molecular Evolution

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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

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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

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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”

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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

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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

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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

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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

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OrthologousAnd

ParalogousGenes

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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

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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

3 My

2 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)