Download - Detecting topological patterns in protein networks Sergei Maslov Brookhaven National Laboratory
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Detecting topological patterns in protein
networks
Sergei MaslovBrookhaven National Laboratory
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What defines a complex system? Complex system has many interacting
components (1011 neurons, 104 types of proteins, 106 routers, 109 web pages)
All components are different from each other
Systems traditionally studied by physics also have many interacting components (1023 electrons in a superconductor)
But they are all the same!
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Networks in complex systems
The simplest question about a complex system: who interacts with whom?
The answer can be visualized as a network
Network is the backbone of a complex system
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Why study the topology of complex networks?
Lots of easily available data: that’s where the state of the art information is (at least in biology)
Large networks may contain information about basic design principles and/or evolutionary history of the complex system
This is similar to paleontology: learning about an animal from its backbone
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Complex networks are the right description when things are
interconnected
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Internet
From Y. Tu, “How robust is the Internet?” , Nature 406, 353 (2000)
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Hierarchy of bio-networks Metabolic network: production of necessary
chemical compounds Binding network: enzymes bind to their
substrates in a metabolic network and to other proteins to form complexes
Regulatory network: turns on and off particular groups of proteins in response to signals
HIGHER LEVELS: cell-to cell communication (e.g. neurons in a brain), food webs, social networks, etc.
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Protein binding network
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Transcription regulatory networks
Prokaryotic bacterium:
E. coli
Single-celled eukaryote: S. cerevisiae
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General properties Densely interconnected Not very modular: functional
modules talk to each other Have many random features Few proteins (hubs) interact with
a lot of neighbors: but most – with just one
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in- and out-degree of nodes
Out-degreeKout=5
In-degreeKin=2
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How many transcriptional regulators are out there?
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Fraction of transcriptional regulators in bacteria
from Stover et al., Nature (2000)
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From E. van Nimwegen, Trends in Genetics, 2003
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Complexity of regulation grows with complexity of
organism
NR<Kout>=N<Kin>=number of edges NR/N= <Kin>/<Kout> increases with N <Kin> grows with N
In bacteria NR~N2 (Stover, et al. 2000) In eucaryots NR~N1.3 (van Nimwengen, 2002)
Networks in more complex organisms are more interconnected then in simpler ones
Life is not just a bunch of independent modules!
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Complexity is manifested in Kin distribution
E. coli vs. S. cerevisiae vs. H. sapiens
0 5 10 15 2010
0
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N(K
in)
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A B
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Beyond degree distributions:How is it all wired together?
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Central vs peripheral network architecture
central(hierarchical)
peripheral(anti-
hierarchical)From A. Trusina, P. Minnhagen, SM, K. Sneppen, Phys. Rev. Lett. (2004)
random
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Correlation profile Count N(k0,k1) – the number of links
between nodes with connectivities k0 and k1
Compare it to Nr(k0,k1) – the same property in a random network
Qualitative features are very noise-tolerant with respect to both false positives and false negatives
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Correlation profile of the protein interaction network
R(k0,k1)=N(k0,k1)/Nr(k0,k1) Z(k0,k1) =(N(k0,k1)-Nr(k0,k1))/Nr(k0,k1)
Similar profile is seen in the yeast regulatory network
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Some scale-free networks may appear similar
In both networks the degree distribution is scale-free P(k)~ k- with ~2.2-2.5
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But: correlation profiles give them unique identities
InternetProtein interactions
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How to construct a proper random network?
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Null-model of a network Distribution of degrees is non-
random: the degree of every node has to be conserved in a random network
Other topological properties may be also conserved as well: The extent of modularity (by function,
sub-cellular localization, etc.) Small motifs (e.g feed-forward loops)
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Randomization
given complex network random
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Edge swapping (rewiring) algorithm
Randomly select and rewire two edges
Repeat many times
SM, K. Sneppen, Science (2002)
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Metropolis rewiring algorithm
Randomly select two edges Calculate change E in “energy function”
E=(Nactual-Ndesired)2/Ndesired
Rewire with probability p=exp(-E/T)
“energy” E “energy” E+E
SM, K. Sneppen:preprint (2002),Physica A (2004)
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How do protein networks evolve?
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Gene duplication
Pair of duplicated proteins
Shared interactions
Pair of duplicated proteins
Shared interactions
Right after duplication
After some time
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Yeast regulatory network
SM, K. Sneppen, K. Eriksen, K-K. Yan 2003
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100 million years ago
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Network properties of self-binding proteins
AKA homodimers
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There are just TOO MANY homodimers
• Null-model • Pself ~<k>/N• Ndimer=N Pself
= <k>• Not surprising ashomodimers have many functional roles
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Network properties around homodimers
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Fly: two-hybrid data Human: database data
Likelihood to self-interact vs. K
Pself~0.05, Pothers~0.0002 Pself~0.003, Pothers~0.0002
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What we think it means? In random networks pdimer(K)~K2 not ~K like our
empirical observation K is proportional to the “stickiness” of the
protein which in its turn scales with the area of hydrophobic residues on the surface # copies/cell its’ popularity (in datasets taken from databases) etc.
Real interacting pair consists of an “active” and “passive” protein and binding probability scales only with the “stickiness” of the active protein
“Stickiness” fully accounts for higher than average connectivity of homodimers
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Summary Living cells contain many complex protein
networks Networks in more complex organisms are more
interconnected Most have hubs – highly connected proteins Hubs often avoid each other (networks are anti-
hierarchical) Networks evolve by gene duplications There are many self-interacting proteins.
Probability to self-interact linearly scales with the degree K.
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Collaborators: Kim Sneppen – U. of Copenhagen Kasper Eriksen – U. of Lund Koon-Kiu Yan – Stony Brook Ilya Mazo, Jaroslav Ispolatov, Anton
Yuryev – Ariadne Genomics
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THE END
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Protective effect of duplicates
Gu, et al 2003Maslov, Sneppen,
Eriksen, Yan 2003
Yeast Worm
Maslov, Sneppen, Eriksen, Yan 2003
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Protein interaction networks
SM, K. Sneppen, K. Eriksen, K-K. Yan 2003
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What shapes the topology of protein networks?
Duplication-divergence models CAN account for their basic topological features
BUT: functional organization dominates: Most pairs with many shared interactions
are NOT homologs Hubs are not caused by mult. duplications
Functional organization is more important than duplication-divergence
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Genome-wide protein networks
Nodes - proteins Edges – interactions between
proteins Bindings (physical interactions) Regulations (transcriptional, protein
modifications, etc.) Etc, etc, etc.
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Correlation profile of the yeast regulatory network
R(kout, kin)=N(kout, kin)/Nr(kout,kin) Z(kout,kin)=(N(kout,kin)-Nr(kout,kin))/ Nr(kout,kin)
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YPD full regulatory network O <-2 standard deviations O > 2 standard deviations
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2.65 0.1
2.55 0.25inK
2.65 0.1inK
Regulators:
Workhorse:
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Amplification ratios
• A(dir): 1.08 - E. Coli, 0.58 - Yeast • A(undir): 10.5 - E. Coli, 13.4 – Yeast• A(PPI): ? - E. Coli, 26.3 - Yeast
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Two-hybrid experiment
To test if A interacts with B create two hybridsA* (with Gal4p DNA-binding domain) and B* (with Gal4p activation domain)
High-throughput: all pairs among 6300 yeast proteins are tested: Uetz, et al. Nature (2000), Ito, et al., PNAS (2001).
Gal4-activated reporter gene, say GAL2::ADE2Gal4-binding domain
A* B*
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1 3 10
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Prolexsys 2-hybrid daatset for Human
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DIP core correlation profile
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Protein binding networks
Two-hybrid nuclear
Database (DIP) core set
S. cerevisiae
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SM, K. Sneppen, K. Eriksen, K-K. Yan 2003
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Pathway vs. network paradigm
Pathway Network
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How to deal with feedback loops?
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Propagation of signals often involves feedback loops Feedback could be used as a checkpoint
that the signal reached its destination: The main direction of information flow
ABC “Weak” feedback signal CA
Some closed loops like ABCA are not used to send feedback but to regulate periodic processes: Cell cycle Circadian rhythms
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Finding the feedback links
Feedback links go against the main direction of the information flow
Feedback edge
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Algorithm Goal: remove the smallest number of
edges to make the network feedback-free Solution:
Randomly assign hierarchy weights Hi to all nodes. Links ij such that Hi<Hj are candidate feedback links
Try to switch Hm and Hn on randomly selected nodes m,n. Accept if this switch reduces the number of feedback links. If increases – accept with a small probability (a la Metropolis)
The final network obtained by removing feedback links is feedback-free
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Bow-tie diagram
SCC:93
nodes
In:96 nodes
wormholes
dangling ends and isolated components
Out:553nodes
Human protein modification network: 1100 nodes
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Feedback loops in human protein-modification network
Removal of only 48 out of 2200 edges makes human protein modification network feedback-free
Most links are “reproducible”: rerunning experiment gives almost the same answer
Run algorithm 10 times. Each time record all upstream-downstream relations. Look for reproducible relationships: the correspond to main direction of the information flow
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MAPK signalingInhibition of apoptosis
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Gene disruptions in yeast
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100
101
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103
104
100
101
102
brazma out degree
his
tog
ram
Repercussions of gene deletions
Number of proteins affected by a single gene deletion
Total number of proteins in yeast genome
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Data from Ariadne Genomics
Homo sapiens
Total: 120,000 interacting protein pairs extracted from PubMed as of 8/2004