in memory of john maynard smith

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In memory of John Maynard Smith

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In memory of John Maynard Smith. Phenotypic variability is omnipresent in nature. It takes all the running you can do to keep in the same place. If you want to get somewhere else, you must run at least twice as fast. Lewis Carroll, 1871. environmentally. intraspecific. induced adaptation. - PowerPoint PPT Presentation

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Page 1: In memory of John Maynard Smith

In memory of

John Maynard Smith

Page 2: In memory of John Maynard Smith

Phenotypic variability is omnipresent in nature

Page 3: In memory of John Maynard Smith

It takes all the running you can do to keep in the same place

If you want to get somewhere else, you must run at least twice as fast

Lewis Carroll, 1871

Page 4: In memory of John Maynard Smith

A B A B A B••••• •

intraspecific variability

environmentally induced adaptation

Lamarckian Paradigm

A B A B BA• • • • ••

Darwinian Paradigm

natural selection

natural selection

Page 5: In memory of John Maynard Smith

Darwinian evolution : variability, selection, transmission

time

Num

ber

of c

opie

s

Adaptives mutations : 0 1 2 3 4 5 6

Can be applied to any «amplifiable  information» (Dawkins, 1976, « the selfish gene »)

Page 6: In memory of John Maynard Smith

Different types of MUTATIONS

Neutral

Lethal

Deleterious

Adaptives

10 -5

10 -4

10 -8

wildtype

mutS+

Mutator

mutS-

10 -3

10 -2

10 -6

Estimated total mutation rate for bacteria1 mutation / 300 genomes replicated

An invariant in evolution of DNA !? (Drake rule)

Page 7: In memory of John Maynard Smith

Mechanisms controlling the maintenance of genetic information

nucleotide pool

DNA repair

Fidelity of synthesis

post-replication control

Page 8: In memory of John Maynard Smith

Photoactivation Repair in E. coli

• Exposing UV treated cells to blue light results in a reversal of the thymine dimer formation

• Enzyme, photoactivation repair enzyme (PRE) absorbs a photon of light (from blue light) and is able to cleave the bond forming the thymine dimer.

• Once bond is cleaved, DNA is back to normal

Page 9: In memory of John Maynard Smith

Like other repair systemIt is conserved throughout evolution, conserved from bacteria (where first discovered)to man where they are involved in a variety of disease

Excision Repair

Page 10: In memory of John Maynard Smith

Xeroderma Pigmentosum & Nucleotide Excision Repair

• Xeroderma pigmentosum (XP)- is a rare genetic disorder that predisposes an individual to skin abnormalities

– Individuals lose the ability to undergo NER• UV radiation exposure leads to reactions from freckling and skin

ulceration to skin cancer

– Studies suggest many different genes may be involved in excision repair

– XP-variant is encoding a lesion by-pass DNA polymerase (SOS)

Page 11: In memory of John Maynard Smith

By-pass polymerasescan lead to error free or error prone (mutagenic) synthesis depending on the lesion

Page 12: In memory of John Maynard Smith

Oxidation of guanine lead to transversion

Page 13: In memory of John Maynard Smith

The Mismatch Repair System

ExoI, ExoVII, RecJ, UvrD, PolIII, SSB, Ligase

CH3

MutSMutL

CH3

MutH

Mismatch repair system• corrects replication errors • ensures global genomic stability • prevent tumour formation

Mismatch site

GATC-site

Page 14: In memory of John Maynard Smith

High polymorphism of mutation rates in commensal and pathogenic Escherichia coli natural isolates

7060 6550 5540 4530 3525201510501E-9

1E-8

1E-7

1E-6

1E-5

Frequency of mutations to Rif in mutator strains

Strain number

mutS-

mutS-

mutL-

mutL-

R

Commensals FranceCommensals MaliCommensals Croatia

UTIbacteremiapusneonatal meningitis

haemolytic-uremicsyndrome

I. Matic, M. Radman, F. Taddei, B. Picard, C. Doit, E. Bingen, E. Denamur and J. ElionScience (1997) vol. 277 p. 1833

mutS-

Page 15: In memory of John Maynard Smith

The frequencies of mutator among E. coli vary

with the associated pathologies

Denamur J. bacteriol. 2002

Page 16: In memory of John Maynard Smith

Number of virulence factors correlates with in vivo virulence

Picard Infect.Immun. 2001

only in non-mutator strains

Page 17: In memory of John Maynard Smith

Mutation rates are higher among strains with

intermediate virulence

Picard Infect.Immun. 2001

Page 18: In memory of John Maynard Smith
Page 19: In memory of John Maynard Smith

1E-05

1E-04

1E-03

1E-02

1E-01

1E+00

0 5000 10000 15000

Temps (générations)

Modélisation des mutateurs

Nature (1997) 387 700-702

Time (generations)

Mut

ator

fre

quen

cyModelling mutators frequencies during adaptation to a new environment

Page 20: In memory of John Maynard Smith

Tenaillon Genetics (1999)

Selecting for mutators is easier in larger population

Page 21: In memory of John Maynard Smith

Tenaillon Genetics (1999)

When mutation is rate limiting large population adapt much faster

log (population size)

Page 22: In memory of John Maynard Smith

Tenaillon Genetics (1999)

Mutator can speed up adaptation (even when rare)

log (population size)

Page 23: In memory of John Maynard Smith

Kiss meI ’m germ-

free

An in vivo model: an animal with a controled microbial flora

Giraud

Page 24: In memory of John Maynard Smith

Evolution of population size

mutS+

days

log

(pop

ulat

ion

size

)8,8

9,0

9,2

9,4

9,6

9,8

10,0

10,2

0 5 10 15 20

mutS+

mutS- mutS-

Mutator bacteria adapt faster to a new environment

Giraud Science 2001

Page 25: In memory of John Maynard Smith

Time (Days)

Mea

n lo

g(m

utat

or/w

ild t

ype)

0 1 2 3 4 5 6 7 8 9 10

-5

-4

-3

-2

-1

0

1

2

3

4

5

The initial population size influence the outcome of the competition

mutS-/mutS+

mutS-/ 50 mutS+

mutS-/ 50 000 mutS+

Giraud et al Science 2001

Page 26: In memory of John Maynard Smith

The population threshold for mutator victory

is 1/(mutation rate)

Mutator victory threshold is frequency independentLe Chat

Page 27: In memory of John Maynard Smith

The victory is stochastic with a constant expected gain

Le Chat

Page 28: In memory of John Maynard Smith

Once adaptation is achieved the mutator advantage is reduced

Mea

n l

og

(mu

tato

r/w

ild

typ

e)

-1

-0.5

0

0.5

1

1.5

2

2.5

3

3.5

0 1 2 3 4 5 6 7 8 9 10Time (Days)

Naive

adapted

Giraud et al Science 2001

Page 29: In memory of John Maynard Smith

WT+Mut MutWT

Mutators & migration in vivo

-1

0

1

2

3

0 2 4 6 8 10Days

Log

(mut

S- / m

utS+

)

-1

0

1

2

3

0 2 4 6 8 10Days

Log

(mut

S- / m

utS+

)The benefit of the mutator is reduced in presence of migration

Page 30: In memory of John Maynard Smith

Controlling migration timing in vitro

WT Mut

0 12 24

hours

migration

24 h

migration

24 h

media: LB + Spc

Mut : mutS-

15 18 21

V VV V

Le Chat

Page 31: In memory of John Maynard Smith

55,5

66,5

77,5

88,5

99,510

9 12 15 18 21 24

log

(C

FU

)

Mutator population adapt faster

mutator

nonmutator

The benefit of the mutator disappears if adaptation is over before migration

"migration"

-0,5

0

0,5

1

1,5

2

2,5

3

9 12 15 18 21 24lo

g (

mu

tato

r/W

T)

Page 32: In memory of John Maynard Smith

Mutator bacteria suffer from genetic amnesia

mutS- ancestormutS+ ancestor

Days post inoculum

Mean % of auxotrophs

100 150 200 250 3000

510

15

202530

ndnd

Emergingmutator

non mutator

Giraud et al Science 2001

Page 33: In memory of John Maynard Smith

23456789

1011

0 5fos spc

4 mice

10 15

Impact of antibiotic treatments on mutation rates

Log

(po

pula

tion

size

)

20fos spc fos spc

23456789

1011

0 5 10 15 20

1 mouse

2023456789

1011

0 5 10 15

1 mouse

Rpopulation Rif

Page 34: In memory of John Maynard Smith

fosspc

time

Day 0 : inoculation

Measures of population sizes

streptomycinNalidixic acid

23456789

1011

0 5 10 15 20

1 mouse

fos spc20

23456789

1011

0 5 10 15

1 mouse

fos spc

Page 35: In memory of John Maynard Smith

str + nal

Impact of mutation rates on bacterial survival to antibiotic treatments

2

3

4

5

6

7

8

9

1011

0 5 10

Log

( p

opul

atio

n si

ze)

non mutator

mutator

Page 36: In memory of John Maynard Smith

How many antibiotics should be used against mutator bacteria ?

Percentage of treatment failure

Number of antibiotics administered simultaneously

Ancestral genotype1 2 3

Antimutator (mutS+) 100 0 (+17*) n.d.

Mutator (mutS-) n.d. 70 0

*emerging mutator (2 mutS-)

Giraud AAC (2002)

Page 37: In memory of John Maynard Smith

Denamur J. bacteriol. 2002

Mutator bacteria are more likely to become antibiotic resistant

Page 38: In memory of John Maynard Smith

Non mutator (A) and mutator (B) phenotypes on antibiograms

Denamur et al J. bacteriol 2002

Page 39: In memory of John Maynard Smith

Mutators are abundant and more antibiotic resistant among P. aeruginosa infecting Cystic Fibrosis patients

Oliver Science (2000)

Mutator (CF)

Non-mutator (CF)

Non-CF

Page 40: In memory of John Maynard Smith

Resistance accumulate 3 times faster in patients colonised by mutators

MutatorNon mutator

delay (days)

Pro

babi

lity

of

incr

ease

d re

sist

ance

Moumile

Page 41: In memory of John Maynard Smith

Mutator can speed up cellular evolution

time

Cel

l num

ber

time

Cel

l num

ber Mutator sub-population

Adaptives mutations

0 1 2 3 4 5 6

Page 42: In memory of John Maynard Smith

The bacterial Red Queen

Page 43: In memory of John Maynard Smith

Why change ?Population geneticsGodelle Gouyon Brown Maynard-Smith

Change where ?Microbial ecology Fons

Who changes ?Molecular epidemiologyBinguen Denamur Picard Brisabois Berche

A network approach of bacterial variability

GiraudLechatBambou

B. ToupanceO. TenaillonJ-B André

Duriez

Change what?Bio-informaticsRocha

Who has changed ?Molecular PhylogenyLecointre Darlu

How to change ? Molecular biology Matic Radman Vulic Dionisio BjedovBregeon Leroy Hayakawa Sekiguchi Dukan

Change when ?transcriptome analysis Knudsen Cerf

Phenotypic variabilityLife History Stewart Madden Lindner Paul Gabriel Fontaine Depaepe Bredèche Mosser

Moumile

Diard

Page 44: In memory of John Maynard Smith

www.necker.fr/tamara/

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Page 45: In memory of John Maynard Smith

Hyper-recombination phenotypes of

mismatch repair mutants

Denamur Cell (2000)

Page 46: In memory of John Maynard Smith

BB

A

A

Holliday junction

Splice

Patch

+

+

Homologous Recombination

• exchange of DNA 1strands to form heteroduplex DNA

• cleavage of Holliday junction at A or B

• religation to recombinant products

A: splice products B: patch products

Page 47: In memory of John Maynard Smith

The barrier to recombination is DNA sequence divergence

Vulic PNAS (1997)

Page 48: In memory of John Maynard Smith

Holliday junction

Splice

Patch

+

+

Homeologous Recombination

• divergent sequences do not recombine efficiently

• mismatch repair prevents formation of recombination intermediates

• in mismatch repair deficient background homeologous recombination proceeds to generate mosaic genes and genomes

mismatch +mismatch -

Page 49: In memory of John Maynard Smith

Effect of Mismatch Repair System on InterspeciesRecombination

Page 50: In memory of John Maynard Smith

Inhibition of Mismatch Repair System

• increases homeologous recombination to the level of homologous recombination and thus allows interspecies recombination

• allows broadest genetic variability in vivo

• broad area of applications• generation of novel low molecular weight entities• generation of modified and optimised macromolecules• generation of (micro)organisms with desired properties

Page 51: In memory of John Maynard Smith

Homeologous Recombination In Vivo

Mosaic Genes Mosaic Genomes

Mosaic Proteins Mosaic Pathways

A

D

B

CC´´

D´´

Novel Products

Page 52: In memory of John Maynard Smith

The bacterial Red Queen

Page 53: In memory of John Maynard Smith

Why change ?Population geneticsGodelle Gouyon Brown Maynard-Smith

Change where ?Microbial ecology Fons

Who changes ?Molecular epidemiologyBinguen Denamur Picard Brisabois Berche

A network approach of bacterial variability

GiraudLechatBambou

B. ToupanceO. TenaillonJ-B André

Duriez

Change what?Bio-informaticsRocha

Who has changed ?Molecular PhylogenyLecointre Darlu

How to change ? Molecular biology Matic Radman Vulic Dionisio BjedovBregeon Leroy Hayakawa Sekiguchi Dukan

Change when ?transcriptome analysis Knudsen Cerf

Phenotypic variabilityLife History Stewart Madden Lindner Paul Gabriel Fontaine Depaepe Bredèche Mosser

Moumile

Diard

Page 54: In memory of John Maynard Smith

www.necker.fr/tamara/

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Page 55: In memory of John Maynard Smith

Most genes in E. coli genome have a common history

Denamur Cell (2000)

Page 56: In memory of John Maynard Smith

Phylogenetic trees of mismatch repair genes show horizontal transfers

Denamur Cell (2000)

Page 57: In memory of John Maynard Smith

Inferred horizontal transfers in mutU gene

Denamur Cell (2000)

Page 58: In memory of John Maynard Smith

Inferred horizontal transfers in mutS gene

Denamur Cell (2000)

Page 59: In memory of John Maynard Smith

Horizontal transfers are more abundant in mismatch repair genes

Denamur Cell (2000)

Page 60: In memory of John Maynard Smith

Hyper-recombination phenotypes of

mismatch repair mutants

Denamur Cell (2000)

Page 61: In memory of John Maynard Smith

Hyper-rec phenotypes of mutator genes correlate with their sequence mosaicisms

Denamur Cell (2000)

Page 62: In memory of John Maynard Smith

Mutator bacteria suffer from genetic amnesia

mutS- ancestormutS+ ancestor

Days post inoculum

Mean % of auxotrophs

100 150 200 250 3000

510

15

202530

ndnd

Emergingmutator

non mutator

Giraud et al Science 2001

Page 63: In memory of John Maynard Smith

Role of mutator in adaptive evolution

Page 64: In memory of John Maynard Smith

The bacterial Red Queen

Page 65: In memory of John Maynard Smith

Why change ?Population geneticsGodelle Gouyon Brown Maynard-Smith

Change where ?Microbial ecology Fons

Who changes ?Molecular epidemiologyBinguen Denamur Picard Brisabois Berche

A network approach of bacterial variability

GiraudLechatBambou

B. ToupanceO. TenaillonJ-B André

Duriez

Change what?Bio-informaticsRocha

Who has changed ?Molecular PhylogenyLecointre Darlu

How to change ? Molecular biology Matic Radman Vulic Dionisio BjedovBregeon Leroy Hayakawa Sekiguchi Dukan

Change when ?transcriptome analysis Knudsen Cerf

Phenotypic variabilityLife History Stewart Madden Lindner Paul Gabriel Fontaine Depaepe Bredèche Mosser

Moumile

Diard

Page 66: In memory of John Maynard Smith

www.necker.fr/tamara/

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Page 67: In memory of John Maynard Smith

How to adapt to predictable

impredictability ?

Page 68: In memory of John Maynard Smith

start stop

ORF

duplication

deletionconversion

Recombination between close repeats

Recombination between SSR

st art stop

ORF

XXXXXX XXXXXXXX

delet ion

XXXX

duplicat ion

Localized mutators

Rocha Nucleic Acid Research (2002)

x y

x x x

x x y

Page 69: In memory of John Maynard Smith

Close direct repeats

gene500 bp 500 bp

1 2

1 2

1 2

L < 1000 ntObserved

Observed in 1000 random sequences

of equal length and 3-tuple composition

ObservedExpected = 1.9Over-represented classes:

• Recombination, repair• Transcription, RNA degradation

• Translation• Transport proteins

Page 70: In memory of John Maynard Smith

Close direct repeats.

5

10

0 10 20 30Number of close repeats in gene

0

gene500 bp 500 bp

1 2

1 2

1 2

L < 1000 ntStress response

genes

All E. coli K12genes

Rocha NAR (2002)

Page 71: In memory of John Maynard Smith

aab

bcccc

dddd e

eff

gg h

hh

hhh

iii

i

jjkk ll

dnaA

position (kb)

a ab b b

b

c c c

cd

d

e

eg

g

h hi

ij

j

k k

l l

m

mn n

o

op p

q

qr rf

f

betB

b

b

c

c c c

c

c

c d de ef

f f

g g

h

h hm m

n

n oop pl

l

k kj

ji

i a a

mutS

a

abb

cc c

d dd d d

d

d de e

csgA

a

a

b

b

c c

d d e ef

f g gh

h

i

i

i

j j

k

k

k

n n n n n q q

p

p

o

o m m l

lmutL

a

a

a

a

a a

a

a

f

f

g g

h

he e

ee

ee

e e

e

e

e

e

e e

e

ed

d

d d dc c b

b baceF

a

a b b b bc

c

c c

c

c

c

c c

f

f g

gm m

p

p p

q

qr rs

su u

v v t t

o oo

n

n

n n

n

ll l lkj j

i

ih

h

e

ed dsbcC

a a

b

b

bc c

c

e e

e

f

f

i iik kl ln no op p

lamB

a a

bc cd dfg h il mnj e

b bcd d df gh i l mo o k kje

cyoE

a

ab

b bc c c c

c

d

d

f fj ji ih hg g

e e

cyoC

a

ab b bc c d d

e

ef fg g

g

i i

h

h

sodB

0

0

0

0

00

0 0

0 0

1

2 4

3

position (kb)0 3

gene

occurrence of the repeat

b repeat label

21 21

21

21

21

21

21 31

1

1

Rocha NAR (2002)