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Science 298 (5594): 824-827

Copyright © 2002 by the American Association for the Advancement of Science

Network Motifs: Simple Building Blocks of Complex Networks

R. Milo,1 S. Shen-Orr,1 S. Itzkovitz,1 N. Kashtan,1 D. Chklovskii,2 U. Alon1*

Complex networks are studied across many fields of science. To uncover their structural design principles, we defined "network motifs," patterns of interconnections occurring in complex networks at numbers that are significantly higher than those in randomized networks. We found such motifs in networks from biochemistry, neurobiology, ecology, and engineering. The motifs shared by ecological food webs were distinct from the motifs shared by the genetic networks of Escherichia coli and Saccharomyces cerevisiae or from those found in the World Wide Web. Similar motifs were found in networks that perform information processing, even though they describe elements as different as biomolecules within a cell and synaptic connections between neurons in Caenorhabditis elegans. Motifs may thus define universal classes of networks. This approach may uncover the basic building blocks of most networks.

1 Departments of Physics of Complex Systems and Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel 76100.
2 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
*   To whom correspondence should be addressed. E-mail: urialon{at}weizmann.ac.il



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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
Social structures depend on innate determinants and chemosensory processing in Drosophila.
J. Schneider, M. H. Dickinson, and J. D. Levine (2012)
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   Abstract »    Full Text »    PDF »
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A. M. Middleton, E. Farcot, M. R. Owen, and T. Vernoux (2012)
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   Abstract »    Full Text »    PDF »
Digital clocks: simple Boolean models can quantitatively describe circadian systems.
O. E. Akman, S. Watterson, A. Parton, N. Binns, A. J. Millar, and P. Ghazal (2012)
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   Abstract »    Full Text »    PDF »
Combinatorial control of diverse metabolic and physiological functions by transcriptional regulators of the yeast sulfur assimilation pathway.
A. A. Petti, R. S. McIsaac, O. Ho-Shing, H. J. Bussemaker, and D. Botstein (2012)
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   Abstract »    Full Text »    PDF »
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D. B. Chklovskii and C. I. Bargmann (2012)
Science 337, 416-417
   Abstract »    Full Text »    PDF »
High-cost, high-capacity backbone for global brain communication.
M. P. van den Heuvel, R. S. Kahn, J. Goni, and O. Sporns (2012)
PNAS 109, 11372-11377
   Abstract »    Full Text »    PDF »
Implications of functional similarity for gene regulatory interactions.
K. Glass, E. Ott, W. Losert, and M. Girvan (2012)
J R Soc Interface 9, 1625-1636
   Abstract »    Full Text »    PDF »
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J. Anderson, N. Strelkowa, G.-B. Stan, T. Douglas, J. Savulescu, M. Barahona, and A. Papachristodoulou (2012)
EMBO Rep. 13, 584-590
   Full Text »    PDF »
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E. Karsenti (2012)
Mol. Biol. Cell 23, 2403-2406
   Abstract »    Full Text »    PDF »
Evolutionary significance of metabolic network properties.
G. Basler, S. Grimbs, O. Ebenhoh, J. Selbig, and Z. Nikoloski (2012)
J R Soc Interface 9, 1168-1176
   Abstract »    Full Text »    PDF »
Network-theoretic classification of parallel computation patterns.
S. Whalen, S. Engle, S. Peisert, and M. Bishop (2012)
International Journal of High Performance Computing Applications 26, 159-169
   Abstract »    PDF »
Computational Approaches for Analyzing Information Flow in Biological Networks.
B. Kholodenko, M. B. Yaffe, and W. Kolch (2012)
Science Signaling 5, re1
   Abstract »    Full Text »    PDF »
Keystones in a Tangled Bank.
T. M. Lewinsohn and L. Cagnolo (2012)
Science 335, 1449-1451
   Abstract »    Full Text »    PDF »
Evolutionary Conservation of Species' Roles in Food Webs.
D. B. Stouffer, M. Sales-Pardo, M. I. Sirer, and J. Bascompte (2012)
Science 335, 1489-1492
   Abstract »    Full Text »    PDF »
Merging Systems Biology with Pharmacodynamics.
R. Iyengar, S. Zhao, S.-W. Chung, D. E. Mager, and J. M. Gallo (2012)
Science Translational Medicine 4, 126ps7
   Full Text »    PDF »
The rate of change in Ca2+ concentration controls sperm chemotaxis.
L. Alvarez, L. Dai, B. M. Friedrich, N. D. Kashikar, I. Gregor, R. Pascal, and U. B. Kaupp (2012)
J. Cell Biol. 196, 653-663
   Abstract »    Full Text »    PDF »
Biological network motif detection: principles and practice.
E. Wong, B. Baur, S. Quader, and C.-H. Huang (2012)
Brief Bioinform 13, 202-215
   Abstract »    Full Text »    PDF »
Commentary: The epigenotype--a dynamic network view of development.
E. Jablonka and E. Lamm (2012)
Int. J. Epidemiol. 41, 16-20
   Full Text »    PDF »
Computing graphlet signatures of network nodes and motifs in Cytoscape with GraphletCounter.
C. Whelan and K. Sonmez (2012)
Bioinformatics 28, 290-291
   Abstract »    Full Text »    PDF »
PINA v2.0: mining interactome modules.
M. J. Cowley, M. Pinese, K. S. Kassahn, N. Waddell, J. V. Pearson, S. M. Grimmond, A. V. Biankin, S. Hautaniemi, and J. Wu (2012)
Nucleic Acids Res. 40, D862-D865
   Abstract »    Full Text »    PDF »
A Novel Method of Transcriptional Response Analysis to Facilitate Drug Repositioning for Cancer Therapy.
G. Jin, C. Fu, H. Zhao, K. Cui, J. Chang, and S. T. C. Wong (2012)
Cancer Res. 72, 33-44
   Abstract »    Full Text »    PDF »
Decompositions of large-scale biological systems based on dynamical properties.
N. Soranzo, F. Ramezani, G. Iacono, and C. Altafini (2012)
Bioinformatics 28, 76-83
   Abstract »    Full Text »    PDF »
Computing global structural balance in large-scale signed social networks.
G. Facchetti, G. Iacono, and C. Altafini (2011)
PNAS 108, 20953-20958
   Abstract »    Full Text »    PDF »
Motifs emerge from function in model gene regulatory networks.
Z. Burda, A. Krzywicki, O. C. Martin, and M. Zagorski (2011)
PNAS 108, 17263-17268
   Abstract »    Full Text »    PDF »
A Perimotor Framework Reveals Functional Segmentation in the Motoneuronal Network Controlling Locomotion in Caenorhabditis elegans.
G. Haspel and M. J. O'Donovan (2011)
J. Neurosci. 31, 14611-14623
   Abstract »    Full Text »    PDF »
JMassBalance: mass-balanced randomization and analysis of metabolic networks.
G. Basler and Z. Nikoloski (2011)
Bioinformatics 27, 2761-2762
   Abstract »    Full Text »    PDF »
Systems Biology--Biomedical Modeling.
E. A. Sobie, Y.-S. Lee, S. L. Jenkins, and R. Iyengar (2011)
Science Signaling 4, tr2
   Abstract »    Full Text »    PDF »
Introduction to Network Analysis in Systems Biology.
A. Ma'ayan (2011)
Science Signaling 4, tr5
   Abstract »    Full Text »    PDF »

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