Achim Tresch Computational Biology Gene Center Munich
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Transcript of Achim Tresch Computational Biology Gene Center Munich
Achim TreschComputational BiologyGene Center Munich
(The Sound of One-Hand Clapping)
Modeling Combinatorial Intervention Effects in Transcription Networks
The Question
(Japanese Kōan)
If two hands clap and there is a sound; what is the sound of one hand?
If two hands clap and there is a sound; what is the sound of one hand?
Kōan
A paradoxical anecdote or riddle, used in Zen Buddhism to demonstrate the inadequacy of logical reasoning and to provoke enlightenment.
Synthetic Genetic Interactions
modified after Collins, Krogan et al., Nature 2007
How to define “Interaction“ mathematically?
Synthetic Genetic Array
ΔA
GrowthYA of single manipulation of A
ΔBGrowthYB of single manipulation of B
ΔA ΔB
Growth YAB
of double manipulation of A and B
Synthetic Genetic Interactions
ΔB
ΔA
ΔA ΔB
Phenotype Measurement YA
of single perturbation
Phenotype Measurement YB
of single perturbation
Phenotype Measurement YAB
of double perturbation
How to define “Interaction“ mathematically?
The interaction score SAB is a function
of the two single perturbations and the combined perturbation,
SAB = SAB (YA ,YB ,YAB )
Synthetic Genetic Interactions
Common Interaction Scores
Common choices for f :
f = min(YA ,YB ) (v. Liebig´s minimum rule for plant growth)
f = YA ·YB (chemical equilibrium a + b ↔ ab , [a][b] = [ab])
f = YA + YB (log version of YA ·YB )
f = log2[(2YA - 1)(2YB - 1) + 1] (essentially the same as YA + YB )
Define an expected phenotype of the double perturbation as a function f(YA ,YB ) of the single perturbation phenotypes YA and Yb. The interaction score SAB is then the deviation from the expected phenotype
SAB = YAB - f(YA ,YB )
Interaction Scores are not very reliable
Results crucially depend on f
Mani, Roth et al., PNAS 2007
Synthetic Genetic Interactions
Pan, Boeke et al., Cell 2006
Cartoon by Van de Peppel et al, Mol. Cell 2005
Collins, Krogan et al., Nature 2007
Breakthrough: Combine a set of weak predictors to create a strong predictor (guilt by association = correlation of interaction scores)
Synthetic Genetic Interactions
Costanzo M, Myers CL, Andrews BJ, Boone C, et al.: Science 2010
Take home message: Two components are likely to interact (physically) whenever they have the same interaction partners
Screening for TF interactions
ΔA
One manipulation
High dimensionalreadout
If two hands clap and there is a sound; what is the sound of one hand?
If two hands clap and there is a sound; what is the sound of one hand?
Genetic interactions from one perturbation
Harbison, Fraenkel, Young et al. Nature 2004MacIsaac, Fraenkel et al. BMC Bioinformatics 2006
Ansari et al., Nature Methods 2010Berger, Bulyk et al., Nature Biotech 2006
a) From ChIP binding experiments
b) From protein binding arrays, followed by PWM-based predictions
Step 1: Construct a transcription factor - target graph
Genetic interactions from one perturbation
Step 1: Construct a transcription factor - target graph
Intersection size of target sets of TF1 and TF2 can be used alone to assess TF cooperativity. (Beyer, Ideker et al., PlOS Comp. Biol 2006)
Genetic interactions from one perturbation
~2.000 target genes
118 transcription factors
Graph obtained from MacIsaac et al. (BMC Bioinformatics 2006)
Established Methods for the detection of univariate TF activity :
GSEA (Subramanian, Tamayo PNAS 2005)
Globaltest (Goemann, Bioinformatics 2004)
MGSEA (Bauer, Gagneur, Nucl. Acids Res. 2010)
and many more …
Step 2: Combine TF-target information and expression data
Common Idea: A TF is active if its set of target genes shows significantly altered expression.To quantify this, various tests are constructed.
gene 4time
Antagonistic interaction of TF 1+2
TF 1+2 active
Genetic interactions from one perturbation
gene 1
TF 1 TF 2 Synthesis rates during salt stress
gene 2
TF 1 is active
gene 3
TF 2 is active
Binding sites
TF1
TF1
TF2
TF2
Step 3: Given TF1 and TF2, group genes into 4 interaction classes
Genetic interactions from one perturbation
gene 1
TF 2 is inactivegene 3
TF 1 is inactivegene 2
TF 1 TF 2 Synthesis rates during salt stressBinding sites
time
Synergistic interaction of TF1+2
gene 4TF 1+2 active
Step 3: Given TF1 and TF2, group genes into 4 interaction classes
Genetic interactions from one perturbation
Our interaction score for the pair (T1,T2) is then β12.
TF2) and TF1 of target a is (
TF2) of target a is (
)TF1 of target a is (
~ )inducednot is (
)induced is (log
12
2
1
0
gInd
gInd
gInd
gP
gP
Step 4: Use these 4 groups to define an interaction score
(for all genes g)
For any pair of transcription factors T1 and T2, we perform a logistic regression.
Genetic interactions from one perturbation
),()()(~ . . . 211222110 gTFTFIndgTFIndgTFInd
gene 1
gene 3
gene 2
gene 4time
TF 1 is active
TF 2 is active
Antagonistic interaction
010
020
012210
Example:
0 ~
00
10 ~
20 ~
12210 ~ TF 1+2 active
Step 4: Use these 4 groups to define an interaction score
TF 1 TF 2Binding sites
0)()( 1010012
Application: Osmotic stress in yeast
Use the guilt by association trick to construct an interaction matrix for all transcription factors using only a two group microarray comparison!
Inclusion criterion: only TFs with >70 targets
Miller, Tresch, Cramer et al., Mol. Syst. Biol. 2010, in revision
„One hand clapping“
Validation with BioGRID database:
Application: Osmotic stress in yeast
Among 84 TFs under consideration (with enough targets), 3486 potential interactionsExist. Only 97 interactions are recorded.
Application: Osmotic stress in yeast
Single interactions scores don‘t work well
Profile correlations do work
Validation with BioGRID database:
Genetic interactions from one intervention
One hand clapping can be applied to: Microarray data, Pol II ChIP data, nascent RNA data
3 stress responses: osmotic stress NaCl, osmotic stress KCl, heat shock
(Mitchell, Pilpel at al. Nature 2009):
Application to a similar dataset leads to similar results:
Acknowledgements
20
Gene Center Munich:
Patrick CramerDietmar Martin
Björn Schwalb
Sebastian Dümcke
My Answer
Two hands clap and there is a sound; what is the sound of one hand?
Two hands clap and there is a sound; what is the sound of one hand?
It is similar for transcription factors that interact.It is similar for transcription factors that interact.
Zen BiologySystems Buddhism