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Protein networks as a scaffold for structuring other data Lars Juhl Jensen EMBL Heidelberg

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Page 1: Protein networks as a scaffold for structuring other data

Protein networks as a scaffold for structuring other data

Lars Juhl Jensen

EMBL Heidelberg

Page 2: Protein networks as a scaffold for structuring other data

cell cycle regulation

Page 3: Protein networks as a scaffold for structuring other data
Page 4: Protein networks as a scaffold for structuring other data

Chapter 1

Page 5: Protein networks as a scaffold for structuring other data

interaction networks

Page 6: Protein networks as a scaffold for structuring other data

what is an interaction?

Page 7: Protein networks as a scaffold for structuring other data

functional interactions

Page 8: Protein networks as a scaffold for structuring other data

physical interactions

Page 9: Protein networks as a scaffold for structuring other data

yeast two-hybrid

Page 10: Protein networks as a scaffold for structuring other data

complex pull-down

Page 11: Protein networks as a scaffold for structuring other data
Page 12: Protein networks as a scaffold for structuring other data

high-throughput

Page 13: Protein networks as a scaffold for structuring other data

S. cerevisiae

Page 14: Protein networks as a scaffold for structuring other data

Uetz et al.

Page 15: Protein networks as a scaffold for structuring other data

Ito et al.

Page 16: Protein networks as a scaffold for structuring other data

Gavin et al.

Page 17: Protein networks as a scaffold for structuring other data

Ho et al.

Page 18: Protein networks as a scaffold for structuring other data

Gavin et al.

Page 19: Protein networks as a scaffold for structuring other data

Krogan et al.

Page 20: Protein networks as a scaffold for structuring other data

C. elegans

Page 21: Protein networks as a scaffold for structuring other data

Li et al.

Page 22: Protein networks as a scaffold for structuring other data

D. melanogaster

Page 23: Protein networks as a scaffold for structuring other data

Giot et al.

Page 24: Protein networks as a scaffold for structuring other data

H. sapiens

Page 25: Protein networks as a scaffold for structuring other data

Stelzl et al.

Page 26: Protein networks as a scaffold for structuring other data

Rual et al.

Page 27: Protein networks as a scaffold for structuring other data
Page 28: Protein networks as a scaffold for structuring other data

yeehaa!

Page 29: Protein networks as a scaffold for structuring other data

network topology

Page 30: Protein networks as a scaffold for structuring other data

degree distribution

Page 31: Protein networks as a scaffold for structuring other data
Page 32: Protein networks as a scaffold for structuring other data

scale-free

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hubs

Page 35: Protein networks as a scaffold for structuring other data

essentiality

Page 36: Protein networks as a scaffold for structuring other data

network robustness

Page 37: Protein networks as a scaffold for structuring other data

targeted attacks

Page 38: Protein networks as a scaffold for structuring other data

artefacts

Page 39: Protein networks as a scaffold for structuring other data

self-activating baits

Page 40: Protein networks as a scaffold for structuring other data

highly expressed proteins

Page 41: Protein networks as a scaffold for structuring other data

Han et al.

Page 42: Protein networks as a scaffold for structuring other data
Page 43: Protein networks as a scaffold for structuring other data

can we trust this data?

Page 44: Protein networks as a scaffold for structuring other data

the human interactome

Page 45: Protein networks as a scaffold for structuring other data

(incomplete)

Page 46: Protein networks as a scaffold for structuring other data

yeast two-hybrid

Page 47: Protein networks as a scaffold for structuring other data

1936

13

4

4

1385

65

18465

Stelzl et al. Rual et al.

Small-scale studies

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32

0

3

4

18

4

23

Stelzl et al. Rual et al.

Small-scale studies

Page 49: Protein networks as a scaffold for structuring other data

62 8 39

Small-scale studies

Stelzl et al. Rual et al.

852

17

473

432

69

260

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3.5% and 21% sensitivity

Page 51: Protein networks as a scaffold for structuring other data

the yeast interactome

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five years ago

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yeast two-hybrid

Page 54: Protein networks as a scaffold for structuring other data

1150

117

117

72

4053

118

4469

Uetz et al. Ito et al.

Small-scale studies

Page 55: Protein networks as a scaffold for structuring other data

162

53

34

72

180

29

338

Uetz et al. Ito et al.

Small-scale studies

Page 56: Protein networks as a scaffold for structuring other data

511 189 616

Small-scale studies

Uetz et al. Ito et al.

439

178

759

897

190

1347

Page 57: Protein networks as a scaffold for structuring other data

19% and 12% sensitivity

Page 58: Protein networks as a scaffold for structuring other data

three years ago

Page 59: Protein networks as a scaffold for structuring other data

complex pull-down

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14186

784

1178

287

19492

230

3475

Gavin et al. Ho et al.

Small-scale studies

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2341

125

656

287

2725

42

149

Gavin et al. Ho et al.

Small-scale studies

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4431 1465 5041

Small-scale studies

Gavin et al. Ho et al.

14913

1071

632

8047

517

746

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63% and 41% sensitivity

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what about accuracy?

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Page 66: Protein networks as a scaffold for structuring other data
Page 67: Protein networks as a scaffold for structuring other data

30–50% specificity

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what can we do about it?

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topology-based scoring

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complex pull-down

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log[(N12·N)/((N1+1)·(N2+1))]

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yeast two-hybrid

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-log((N1+1)·(N2+1))

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calibrate against KEGG

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subcellular localization

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filtering

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high-throughput

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high-confidence

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Chapter 2

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expression data

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S. cerevisiae

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synchronized cell culture

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microarray time series

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periodically expressed genes

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S. cerevisiae

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Cho et al.

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Spellman et al.

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yeehaa!

Page 95: Protein networks as a scaffold for structuring other data

Zhao et al.

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Langmead et al.

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Johansson et al.

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Wichert et al.

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Luan and Li

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Lu et al.

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Ahdesmäki et al.

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Willbrand et al.

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Chen et al.

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Qiu et al.

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Ahnert et al.

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Andersson et al.

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no benchmarking

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reanalysis

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benchmarking

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no progress

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no benchmarking

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Chapter 3

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1+2 = 3

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expression data

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protein interactions

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temporal network

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benchmarking

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very low error rate

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discovery tool

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30+ uncharacterized proteins

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detailed function prediction

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novel module

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global statements

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dynamic and static

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CDK–cyclin complexes

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consistent timing

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pre-replication complex

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just-in-time assembly

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how can we test this?

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evolutionary conservation

Page 147: Protein networks as a scaffold for structuring other data

Chapter 4

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more expression data

Page 149: Protein networks as a scaffold for structuring other data

S. cerevisiae

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microarray time series

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periodically expressed genes

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Page 154: Protein networks as a scaffold for structuring other data

S. pombe

Page 155: Protein networks as a scaffold for structuring other data

Rustici et al.

Page 156: Protein networks as a scaffold for structuring other data

(good job)

Page 157: Protein networks as a scaffold for structuring other data

Peng et al.

Page 158: Protein networks as a scaffold for structuring other data

Oliva et al.

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no benchmarking

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no integration

Page 161: Protein networks as a scaffold for structuring other data

reanalysis

Page 162: Protein networks as a scaffold for structuring other data

benchmarking

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Page 164: Protein networks as a scaffold for structuring other data

no progress

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no benchmarking

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no integration

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Page 168: Protein networks as a scaffold for structuring other data

H. sapiens

Page 169: Protein networks as a scaffold for structuring other data

Whitfield et al.

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reanalysis

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benchmarking

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A. thaliana

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Menges et al.

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reanalysis

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benchmarking

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list of genes

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peak times

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Chapter 5

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cross-species comparison

Page 182: Protein networks as a scaffold for structuring other data

orthology assignment

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peak times

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not comparable

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time warping

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Page 187: Protein networks as a scaffold for structuring other data
Page 188: Protein networks as a scaffold for structuring other data

not conserved

Page 189: Protein networks as a scaffold for structuring other data

individual genes

Page 190: Protein networks as a scaffold for structuring other data

just-in-time assembly

Page 191: Protein networks as a scaffold for structuring other data

protein complexes

Page 192: Protein networks as a scaffold for structuring other data

DNA polymerases

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pre-replication complex

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chromatid cohesion

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reproduces what is known

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known differences

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timing has changed

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identity has changed

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self-consistent

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make sense

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protein complexes

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individual genes

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broader perspective

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protein networks

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context

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understanding

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Acknowledgments

Ulrik de LichtenbergThomas Skøt JensenChristian von Mering

Søren BrunakPeer Bork


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