evidence of selection on genomic gc content in bacteria · 2011. 4. 11. · at gc = 1 . four-fold...

Evidence of Selection on Genomic GC Content in Bacteria!

Falk Hildebrand!Axel Meyer!

Adam Eyre-Walker!

Genomic G+C content!

Genomic GC content!

Codons!

123!ATA CCC!CTA CCT!

Non-synonymous

Synonymous

2-fold : TTT TTC

4-fold : CCT CCC CCA CCG

Variation!

0 20 40 60 80 1000.000

0.005

0.010

0.015

0.020

0.025

0.030

GC3

0 20 40 60 80 100

0.01

0.02

0.03

0.04

0.05

GC12

Correlations!

0.0 0.2 0.4 0.6 0.8 1.00.0

0.2

0.4

0.6

0.8

1.0

GC12

GC3

Explanations!

•  Mutation bias!•  Suoeka (1961) & Freese (1962)!•  Intrinsic and/or extrinsic!

•  Selection!•  Many authors!

•  Biased gene conversion!•  Anonymous referees!

Evidence of selection!

•  Escherichia coli!•  Mutation pattern!

•  273 GCAT versus 131 ATGC!•  Predicted GC content = 0.32!•  Observed GC content = 0.50!•  Observed GC at neutral sites = 0.58!

Lynch (2007) Origins of genome architecture

Test of mutation bias!

•  If GC content is!•  Due to mutation bias alone!•  Stationary!•  And the infinite sites assumption holds!

•  Then!•  # GCAT mutations = # ATGC mutations!

Orienting mutations!

Strain 1 ACT GCT TTG GCT TTA TGG!Strain 2 ACT GCT TTG GCT TTA TGA!Strain 3 ACT GCT TTG GCT TTA TGG!Strain 4 ACT GCT TTC GCT TTA TGA!Strain 5 ACC GCT TTC GCT TTA TGG!Strain 6 ACT GCT TTG GCT TTA TGG!

TC GC GA

GCAT = 1 ATGC = 1

Four-fold synonymous sites!

Genomic GC

GC4!

Data!

•  Popset!•  Keyword “bacteria”!•  8 or more sequences from same species!•  149 bacterial species!

•  8 phyla, 15 classes and 77 genera!•  1 or more genes!•  10 or more synonymous polymorphisms!•  4-fold diversity < 0.1!

Overall result!

No. of SNPs!

GCAT! 11045!

ATGC! 8309!

P

Bias versus GC4!

Z = GCAT

GCAT

No. species! Z > 0.5! P-value!GC-rich! 82! 69!

Phylogenetic distribution!Phylum! Class! No. of species! GC4 range! Mean Z

(GC40.34)!

Actinobacteria! Actinobacteria! 3! 0.64-0.93! no species! 0.64!

Bacteroidetes! Bacteroidetes! 3! 0.12-0.46! 0.43! 0.36!

Chlamydiae+! Chlamydiae! 2! 0.21-0.30! 0.45! no species!

Cyanobacteria! Chroococcales! 2! 0.38-0.51! no species! 0.53!

Cyanobacteria! Nostocales! 3! 0.26-0.31! 0.45! no species!

Cyanobacteria! Oscillatoriales! 2! 0.41! no species! 0.38!

Cyanobacteria! Stigonemales! 1! 0.40! no species! 0.59!

Firmicutes! Bacilli! 27! 0.085-0.68! 0.44! 0.58!

Firmicutes! Clostridia! 5! 0.050-0.28! 0.34! no species!

Proteobacteria! Alphaproteobacteria! 16! 0.099-0.94! 0.43! 0.65!

Proteobacteria! Betaproteobacteria! 6! 0.66-0.96! no species! 0.67!

Proteobacteria! delta/epsilon! 6! 0.15-0.99! 0.49! 0.78!

Proteobacteria!Gammaproteobacteria! 62! 0.095-0.95! 0.50! 0.66!

Spirochaetes! Spirochaetes! 7! 0.12-0.60! 0.45! 0.54!

Tenericutes! Mollicutes! 4! 0.023-0.24! 0.33! no species!

Potential problems!

•  Infinite sites assumption!

•  Sequencing error!

Zpred!

Z-Zpred!

No. of species! Z-Zpred > 0! P-value!

GC-rich! 82! 61!

Potential problems!

•  Infinite sites assumption!

•  Sequencing error!

Sequencing error!

No. of species! Z > 0.5! P-value!

GC-rich! 82! 60!

Explanations!

•  Non-stationary base composition!•  Selection for translational efficiency!•  Biased gene conversion!•  Selection upon base composition!

Non-stationary base composition!

Explanations!


Selection on codon usage!

Amino Acid! Codon! High usage! Low usage!Phenylalanine! UUU! 0.22! 0.71!

UUC! 0.78! 0.29!

Valine! GUU! 0.46! 0.36!GUC! 0.09! 0.19!GUA! 0.24! 0.23!GUG! 0.21! 0.23!

Translational efficiency!

No. of species! Z > 0.5! P-value!

GC-rich! 31! 29!

Explanations!


Biased gene conversion!

A T

C G

A G

C T

C G

C G

Four gamete test!

G A!G T!C A!

G A!G T!C A!C T!

No recombination Recombination


No. species! Z > 0.5! P-value!

GC-rich! 28! 19! 0.087!

GCAT! ATGC! P-value!

No. of SNPs! 1079! 844!


GC AT -w w

if New >> 1 BGC effective if New


r / m! p-value!

GC4! -0.076! 0.67!

GC4pred! -0.115! 0.52!

34 species with estimate of r / m Vos & Didelot (2009) ISME J.


θ r / m! p-value!

GC4! 0.039! 0.83!

GC4pred! -0.031! 0.86!

€

πsrm

= 2Neurm

= 2Nerk

Explanations!


Selection on GC content!

€

H(x) = J(x)J(x)dx0

1∫

€

J(x) = eSx xV −1(1− x)U −1

€

S = 2Nes U = 2Neµ(1− f ) V = 2Neµf f = v /(u + v)

GC AT uµ

vµ +s -s

Selection on GC content!

2 4 6 8 10

0.6

0.7

0.8

0.9

1.0Zpred

S

Selection on GC4!

0.2 0.4 0.6 0.8 1.0

0.2

0.4

0.6

0.8

1.0

Zobs

Zpred

Selection on GC4!

0.2 0.4 0.6 0.8 1.0

0.2

0.4

0.6

0.8

1.0

Zobs

Zpred

f = α + β GC4

f = 0.2 + 0.35 GC4

Selection on GC4!f = α + β GC4

f = 0.2 + 0.35 GC4

0.2 0.4 0.6 0.8 1.0

0.25

0.30

0.35

0.40

0.45

0.50

0.55

f

GC4

Selection on genomic GC!

Genomic GC

GC4!

Correlates!

•  Genome size!•  positive correlation!

•  Lifestyle!•  higher GC in free living!

•  Aerobiosis!•  higher GC in aerobic!

•  Nitrogen utilization!•  higher GC amongst N fixers!

•  Temperature !•  higher amongst thermophiles?!

Environmental meta-genomics!

Foerstner et al. (2005) EMBO Reports

Environmental meta-genomics!

Thanks!

Falk Hildebrand Axel Meyer

Mitochondrial DNA!

•  488 animal datasets!

Group! Percentage!Mammals! 30!

Birds! 12!Fish! 23!

Insects! 16!Crustacea! 7!Molluscs! 12!

Mitochondrial DNA!

0.0 0.2 0.4 0.6 0.8 1.0

1

2

3

4

GC content

Z versus GC4!

0.2 0.4 0.6 0.8 1.0

0.2

0.4

0.6

0.8

1.0

Z

GC content

Z-Zpred versus GC4!

0.1 0.2 0.3 0.4 0.5 0.6

0.4

0.2

0.0

0.2

0.4

Z-Zpred

GC4

r=0.11, p=0.02

Evidence of selection II!

•  Phylogenetic analyses!•  Mycobacterium leprae (Lynch 2007)!•  Escherichia coli (Balbi et al. 2009)!•  (5 pathogenic bacteria (Hershberg and

Petrov 2010))!•  Excess of GC AT!

evidence of selection on genomic gc content in bacteria · 2011. 4. 11. · at gc = 1 . four-fold...

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