Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Logo for

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

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Rapid reorganization of the transcriptional regulatory network after genome duplication in yeast.
G. C. Conant (2009)
Proc R Soc B
   Abstract »    Full Text »    PDF »
Analyzing biological network parameters with CentiScaPe.
G. Scardoni, M. Petterlini, and C. Laudanna (2009)
Bioinformatics 25, 2857-2859
   Abstract »    Full Text »    PDF »
Network analyses in systems pharmacology.
S. I. Berger and R. Iyengar (2009)
Bioinformatics 25, 2466-2472
   Abstract »    Full Text »    PDF »
Proteome-wide Prediction of Signal Flow Direction in Protein Interaction Networks Based on Interacting Domains.
W. Liu, D. Li, J. Wang, H. Xie, Y. Zhu, and F. He (2009)
Mol. Cell. Proteomics 8, 2063-2070
   Abstract »    Full Text »    PDF »
An investigation into the population abundance distribution of mRNAs, proteins, and metabolites in biological systems.
C. Lu and R. D. King (2009)
Bioinformatics 25, 2020-2027
   Abstract »    Full Text »    PDF »
Hub genes with positive feedbacks function as master switches in developmental gene regulatory networks.
C. H. Seo, J.-R. Kim, M.-S. Kim, and K.-H. Cho (2009)
Bioinformatics 25, 1898-1904
   Abstract »    Full Text »    PDF »
Understanding Modularity in Molecular Networks Requires Dynamics.
R. P. Alexander, P. M. Kim, T. Emonet, and M. B. Gerstein (2009)
Science Signaling 2, pe44
   Abstract »    Full Text »    PDF »
Scale-Free Networks: A Decade and Beyond.
A.-L. Barabasi (2009)
Science 325, 412-413
   Abstract »    Full Text »    PDF »
Disentangling the Web of Life.
J. Bascompte (2009)
Science 325, 416-419
   Abstract »    Full Text »    PDF »
Structure discovery in PPI networks using pattern-based network decomposition.
P. Bachman and Y. Liu (2009)
Bioinformatics 25, 1814-1821
   Abstract »    Full Text »    PDF »
Systematic analysis of synchronized oscillatory neuronal networks reveals an enrichment for coupled direct and indirect feedback motifs.
C.-Y. Dong, J. Lim, Y. Nam, and K.-H. Cho (2009)
Bioinformatics 25, 1680-1685
   Abstract »    Full Text »    PDF »
The assembly and disassembly of ecological networks.
J. Bascompte and D. B. Stouffer (2009)
Phil Trans R Soc B 364, 1781-1787
   Abstract »    Full Text »    PDF »
Synthesis of orthogonal transcription-translation networks.
W. An and J. W. Chin (2009)
PNAS 106, 8477-8482
   Abstract »    Full Text »    PDF »
The effect of network topology on the stability of discrete state models of genetic control.
A. Pomerance, E. Ott, M. Girvan, and W. Losert (2009)
PNAS 106, 8209-8214
   Abstract »    Full Text »    PDF »
Combinatorial Regulation by a Novel Arrangement of FruA and MrpC2 Transcription Factors during Myxococcus xanthus Development.
S. Mittal and L. Kroos (2009)
J. Bacteriol. 191, 2753-2763
   Abstract »    Full Text »    PDF »
Semantic web for integrated network analysis in biomedicine.
H. Chen, L. Ding, Z. Wu, T. Yu, L. Dhanapalan, and J. Y. Chen (2009)
Brief Bioinform 10, 177-192
   Abstract »    Full Text »    PDF »
Insights into the Organization of Biochemical Regulatory Networks Using Graph Theory Analyses.
A. Ma'ayan (2009)
J. Biol. Chem. 284, 5451-5455
   Abstract »    Full Text »    PDF »
From the Cover: Model of genetic variation in human social networks.
J. H. Fowler, C. T. Dawes, and N. A. Christakis (2009)
PNAS 106, 1720-1724
   Abstract »    Full Text »    PDF »
Inferring malaria parasite population structure from serological networks.
C. O Buckee, P. C Bull, and S. Gupta (2009)
Proc R Soc B 276, 477-485
   Abstract »    Full Text »    PDF »
Superfamily phenomena and motifs of networks induced from time series.
X. Xu, J. Zhang, and M. Small (2008)
PNAS 105, 19601-19605
   Abstract »    Full Text »    PDF »
Ordered cyclic motifs contribute to dynamic stability in biological and engineered networks.
A. Ma'ayan, G. A. Cecchi, J. Wagner, A. R. Rao, R. Iyengar, and G. Stolovitzky (2008)
PNAS 105, 19235-19240
   Abstract »    Full Text »    PDF »
The Protein Interaction Network of the Epithelial Junctional Complex: A System-Level Analysis.
L. Paris and G. Bazzoni (2008)
Mol. Biol. Cell 19, 5409-5421
   Abstract »    Full Text »    PDF »
Signatures of combinatorial regulation in intrinsic biological noise.
A. Warmflash and A. R. Dinner (2008)
PNAS 105, 17262-17267
   Abstract »    Full Text »    PDF »
Wired for Sex: The Neurobiology of Drosophila Mating Decisions.
B. J. Dickson (2008)
Science 322, 904-909
   Abstract »    Full Text »    PDF »
Analysis of regulatory network topology reveals functionally distinct classes of microRNAs.
X. Yu, J. Lin, D. J. Zack, J. T. Mendell, and J. Qian (2008)
Nucleic Acids Res. 36, 6494-6503
   Abstract »    Full Text »    PDF »
Building trophic modules into a persistent food web.
M. Kondoh (2008)
PNAS 105, 16631-16635
   Abstract »    Full Text »    PDF »
Small-scale copy number variation and large-scale changes in gene expression.
Y. Mileyko, R. I. Joh, and J. S. Weitz (2008)
PNAS 105, 16659-16664
   Abstract »    Full Text »    PDF »
High-Quality Binary Protein Interaction Map of the Yeast Interactome Network.
H. Yu, P. Braun, M. A. Yildirim, I. Lemmens, K. Venkatesan, J. Sahalie, T. Hirozane-Kishikawa, F. Gebreab, N. Li, N. Simonis, et al. (2008)
Science 322, 104-110
   Abstract »    Full Text »    PDF »
A C. elegans genome-scale microRNA network contains composite feedback motifs with high flux capacity.
N. J. Martinez, M. C. Ow, M. I. Barrasa, M. Hammell, R. Sequerra, L. Doucette-Stamm, F. P. Roth, V. R. Ambros, and A. J.M. Walhout (2008)
Genes & Dev. 22, 2535-2549
   Abstract »    Full Text »    PDF »
Models and computational strategies linking physiological response to molecular networks from large-scale data.
F. Ortega, K. Sameith, N. Turan, R. Compton, V. Trevino, M. Vannucci, and F. Falciani (2008)
Phil Trans R Soc A 366, 3067-3089
   Abstract »    Full Text »    PDF »
Cascading failure and robustness in metabolic networks.
A. G. Smart, L. A. N. Amaral, and J. M. Ottino (2008)
PNAS 105, 13223-13228
   Abstract »    Full Text »    PDF »
Unraveling transcriptional regulatory programs by integrative analysis of microarray and transcription factor binding data.
H. Li and M. Zhan (2008)
Bioinformatics 24, 1874-1880
   Abstract »    Full Text »    PDF »
Automatic decomposition of kinetic models of signaling networks minimizing the retroactivity among modules.
J. Saez-Rodriguez, S. Gayer, M. Ginkel, and E. D. Gilles (2008)
Bioinformatics 24, i213-i219
   Abstract »    Full Text »    PDF »
Inferring causal relationships among different histone modifications and gene expression.
H. Yu, S. Zhu, B. Zhou, H. Xue, and J.-D. J. Han (2008)
Genome Res. 18, 1314-1324
   Abstract »    Full Text »    PDF »
Geometric constraints on neuronal connectivity facilitate a concise synaptic adhesive code.
S. Itzkovitz, L. Baruch, E. Shapiro, and E. Segal (2008)
PNAS 105, 9278-9283
   Abstract »    Full Text »    PDF »
Biomolecular network motif counting and discovery by color coding.
N. Alon, P. Dao, I. Hajirasouliha, F. Hormozdiari, and S. C. Sahinalp (2008)
Bioinformatics 24, i241-i249
   Abstract »    Full Text »    PDF »
PRINCESS, a Protein Interaction Confidence Evaluation System with Multiple Data Sources.
D. Li, W. Liu, Z. Liu, J. Wang, Q. Liu, Y. Zhu, and F. He (2008)
Mol. Cell. Proteomics 7, 1043-1052
   Abstract »    Full Text »    PDF »
A review on models and algorithms for motif discovery in protein-protein interaction networks.
G. Ciriello and C. Guerra (2008)
Brief Funct Genomic Proteomic
   Abstract »    Full Text »    PDF »
From the Cover: Nonrandom connectivity of the epileptic dentate gyrus predicts a major role for neuronal hubs in seizures.
R. J. Morgan and I. Soltesz (2008)
PNAS 105, 6179-6184
   Abstract »    Full Text »    PDF »
Intrinsic noise, dissipation cost, and robustness of cellular networks: The underlying energy landscape of MAPK signal transduction.
S. Lapidus, B. Han, and J. Wang (2008)
PNAS 105, 6039-6044
   Abstract »    Full Text »    PDF »
Fitting a geometric graph to a protein-protein interaction network.
D. J. Higham, M. Rasajski, and N. Przulj (2008)
Bioinformatics 24, 1093-1099
   Abstract »    Full Text »    PDF »
From individual Wnt pathways towards a Wnt signalling network.
H. A Kestler and M. Kuhl (2008)
Phil Trans R Soc B 363, 1333-1347
   Abstract »    Full Text »    PDF »
Protein networks in disease.
T. Ideker and R. Sharan (2008)
Genome Res. 18, 644-652
   Abstract »    Full Text »    PDF »
Disrupted small-world networks in schizophrenia.
Y. Liu, M. Liang, Y. Zhou, Y. He, Y. Hao, M. Song, C. Yu, H. Liu, Z. Liu, and T. Jiang (2008)
Brain 131, 945-961
   Abstract »    Full Text »    PDF »
Transcriptional Networks Inferred from Molecular Signatures of Breast Cancer.
R. Tongbai, G. Idelman, S. H. Nordgard, W. Cui, J. L. Jacobs, C. M. Haggerty, S. J. Chanock, A.-L. Borresen-Dale, G. Livingston, P. Shaunessy, et al. (2008)
Am. J. Pathol. 172, 495-509
   Abstract »    Full Text »    PDF »
The evolutionary dynamics of the Saccharomyces cerevisiae protein interaction network after duplication.
A. Presser, M. B. Elowitz, M. Kellis, and R. Kishony (2008)
PNAS 105, 950-954
   Abstract »    Full Text »    PDF »
YEASTRACT-DISCOVERER: new tools to improve the analysis of transcriptional regulatory associations in Saccharomyces cerevisiae.
P. T. Monteiro, N. D. Mendes, M. C. Teixeira, S. d'Orey, S. Tenreiro, N. P. Mira, H. Pais, A. P. Francisco, A. M. Carvalho, A. B. Lourenco, et al. (2008)
Nucleic Acids Res. 36, D132-D136
   Abstract »    Full Text »    PDF »
Spontaneous emergence of modularity in cellular networks.
R. V Sole and S. Valverde (2008)
J R Soc Interface 5, 129-133
   Abstract »    Full Text »    PDF »
DIA-MCIS: an importance sampling network randomizer for network motif discovery and other topological observables in transcription networks.
D. Fusco, B. Bassetti, P. Jona, and M. Cosentino Lagomarsino (2007)
Bioinformatics 23, 3388-3390
   Abstract »    Full Text »    PDF »
Coordination logic of the sensing machinery in the transcriptional regulatory network of Escherichia coli.
S. C. Janga, H. Salgado, A. Martinez-Antonio, and J. Collado-Vides (2007)
Nucleic Acids Res. 35, 6963-6972
   Abstract »    Full Text »    PDF »
Characterization of Pancreatic Transcription Factor Pdx-1 Binding Sites Using Promoter Microarray and Serial Analysis of Chromatin Occupancy.
D. M. Keller, S. McWeeney, A. Arsenlis, J. Drouin, C. V. E. Wright, H. Wang, C. B. Wollheim, P. White, K. H. Kaestner, and R. H. Goodman (2007)
J. Biol. Chem. 282, 32084-32092
   Abstract »    Full Text »    PDF »
Topological Analysis of Large-scale Biomedical Terminology Structures.
M. E. Bales, Y. A. Lussier, and S. B. Johnson (2007)
J. Am. Med. Inform. Assoc. 14, 788-797
   Abstract »    Full Text »    PDF »
Small-World Anatomical Networks in the Human Brain Revealed by Cortical Thickness from MRI.
Y. He, Z. J. Chen, and A. C. Evans (2007)
Cereb Cortex 17, 2407-2419
   Abstract »    Full Text »    PDF »
Exploring biological network structure using exponential random graph models.
Z. M. Saul and V. Filkov (2007)
Bioinformatics 23, 2604-2611
   Abstract »    Full Text »    PDF »
Characterization of an Eppin Protein Complex from Human Semen and Spermatozoa.
Z. Wang, E. E Widgren, R. T Richardson, and M. G O'Rand (2007)
Biol Reprod 77, 476-484
   Abstract »    Full Text »    PDF »
Evidence for the existence of a robust pattern of prey selection in food webs.
D. B Stouffer, J. Camacho, W. Jiang, and L. A Nunes Amaral (2007)
Proc R Soc B 274, 1931-1940
   Abstract »    Full Text »    PDF »
Circuit Motifs for Spatial Orientation Behaviors Identified by Neural Network Optimization.
N. A. Dunn, J. S. Conery, and S. R. Lockery (2007)
J Neurophysiol 98, 888-897
   Abstract »    Full Text »    PDF »
Network structure of cerebral cortex shapes functional connectivity on multiple time scales.
C. J. Honey, R. Kotter, M. Breakspear, and O. Sporns (2007)
PNAS 104, 10240-10245
   Abstract »    Full Text »    PDF »
Mixture models and exploratory analysis in networks.
M. E. J. Newman and E. A. Leicht (2007)
PNAS 104, 9564-9569
   Abstract »    Full Text »    PDF »
Variable gene expression in eukaryotes: a network perspective.
P. J. Wittkopp (2007)
J. Exp. Biol. 210, 1567-1575
   Abstract »    Full Text »    PDF »
Getting connected: analysis and principles of biological networks.
X. Zhu, M. Gerstein, and M. Snyder (2007)
Genes & Dev. 21, 1010-1024
   Abstract »    Full Text »    PDF »
NetMatch: a Cytoscape plugin for searching biological networks.
A. Ferro, R. Giugno, G. Pigola, A. Pulvirenti, D. Skripin, G. D. Bader, and D. Shasha (2007)
Bioinformatics 23, 910-912
   Abstract »    Full Text »    PDF »
Understandable Complexity.
J. Stelling (2007)
Sci. STKE 2007, pe9
   Abstract »    Full Text »    PDF »
Approaches for Extracting Practical Information from Gene Co-expression Networks in Plant Biology.
K. Aoki, Y. Ogata, and D. Shibata (2007)
Plant Cell Physiol. 48, 381-390
   Abstract »    Full Text »    PDF »
Regulation of yeast oscillatory dynamics.
D. B. Murray, M. Beckmann, and H. Kitano (2007)
PNAS 104, 2241-2246
   Abstract »    Full Text »    PDF »
Topological Determinants of Epileptogenesis in Large-Scale Structural and Functional Models of the Dentate Gyrus Derived From Experimental Data.
J. Dyhrfjeld-Johnsen, V. Santhakumar, R. J. Morgan, R. Huerta, L. Tsimring, and I. Soltesz (2007)
J Neurophysiol 97, 1566-1587
   Abstract »    Full Text »    PDF »
Regulation of HDAC9 Gene Expression by MEF2 Establishes a Negative-Feedback Loop in the Transcriptional Circuitry of Muscle Differentiation.
M. Haberland, M. A. Arnold, J. McAnally, D. Phan, Y. Kim, and E. N. Olson (2007)
Mol. Cell. Biol. 27, 518-525
   Abstract »    Full Text »    PDF »
Rediscovering secondary structures as network motifs--an unsupervised learning approach.
B. Raveh, O. Rahat, R. Basri, and G. Schreiber (2007)
Bioinformatics 23, e163-e169
   Abstract »    Full Text »    PDF »
Biological network comparison using graphlet degree distribution.
N. Przulj (2007)
Bioinformatics 23, e177-e183
   Abstract »    Full Text »    PDF »
CellCircuits: a database of protein network models.
H. C. Mak, M. Daly, B. Gruebel, and T. Ideker (2007)
Nucleic Acids Res. 35, D538-D545
   Abstract »    Full Text »    PDF »
Resolution limit in community detection.
S. Fortunato and M. Barthelemy (2007)
PNAS 104, 36-41
   Abstract »    Full Text »    PDF »
Small-World Networks and Functional Connectivity in Alzheimer's Disease.
C. Stam, B. Jones, G Nolte, M Breakspear, and P. Scheltens (2007)
Cereb Cortex 17, 92-99
   Abstract »    Full Text »    PDF »
A robust measure of food web intervality.
D. B. Stouffer, J. Camacho, and L. A. N. Amaral (2006)
PNAS 103, 19015-19020
   Abstract »    Full Text »    PDF »
Resources for integrative systems biology: from data through databases to networks and dynamic system models.
A. Ng, B. Bursteinas, Q. Gao, E. Mollison, and M. Zvelebil (2006)
Brief Bioinform 7, 318-330
   Abstract »    Full Text »    PDF »
Unraveling transcription regulatory networks by protein-DNA and protein-protein interaction mapping.
A. J.M. Walhout (2006)
Genome Res. 16, 1445-1454
   Abstract »    Full Text »    PDF »
The tYNA platform for comparative interactomics: a web tool for managing, comparing and mining multiple networks.
K. Y. Yip, H. Yu, P. M. Kim, M. Schultz, and M. Gerstein (2006)
Bioinformatics 22, 2968-2970
   Abstract »    Full Text »    PDF »
Deciphering the Underlying Mechanism of Specification and Differentiation: The Sea Urchin Gene Regulatory Network.
S. Ben-Tabou de-Leon and E. H. Davidson (2006)
Sci. STKE 2006, pe47
   Abstract »    Full Text »    PDF »
Modelling protein-protein interaction networks via a stickiness index.
N. Przulj and D. J Higham (2006)
J R Soc Interface 3, 711-716
   Abstract »    Full Text »    PDF »
Feed-Forward Loop Circuits as a Side Effect of Genome Evolution.
O. X. Cordero and P. Hogeweg (2006)
Mol. Biol. Evol. 23, 1931-1936
   Abstract »    Full Text »    PDF »
Graph-based methods for analysing networks in cell biology.
T. Aittokallio and B. Schwikowski (2006)
Brief Bioinform 7, 243-255
   Abstract »    Full Text »    PDF »
Graemlin: General and robust alignment of multiple large interaction networks.
J. Flannick, A. Novak, B. S. Srinivasan, H. H. McAdams, and S. Batzoglou (2006)
Genome Res. 16, 1169-1181
   Abstract »    Full Text »    PDF »
An unusual Zn-finger/FH2 domain protein controls a left/right asymmetric neuronal fate decision in C. elegans.
R. J. Johnston Jr, J. W. Copeland, M. Fasnacht, J. F. Etchberger, J. Liu, B. Honig, and O. Hobert (2006)
Development 133, 3317-3328
   Abstract »    Full Text »    PDF »
A High Efficiency Strategy for Binding Property Characterization of Peptide-binding Domains.
E. Song, S. Gao, R. Tian, S. Ma, H. Huang, J. Guo, Y. Li, L. Zhang, and Y. Gao (2006)
Mol. Cell. Proteomics 5, 1368-1381
   Abstract »    Full Text »    PDF »
Cross-species analysis of biological networks by Bayesian alignment.
J. Berg and M. Lassig (2006)
PNAS 103, 10967-10972
   Abstract »    Full Text »    PDF »
Network motif identification in stochastic networks.
R. Jiang, Z. Tu, T. Chen, and F. Sun (2006)
PNAS 103, 9404-9409
   Abstract »    Full Text »    PDF »
From the Cover: Modularity and community structure in networks.
M. E. J. Newman (2006)
PNAS 103, 8577-8582
   Abstract »    Full Text »    PDF »
Observations on related ecological exponents.
T. R. E. Southwood, R. M. May, and G. Sugihara (2006)
PNAS 103, 6931-6933
   Abstract »    Full Text »    PDF »
Manufacturing Relations: An Empirical Study of the Organization of Production Across Multiple Networks.
A. Lomi and P. Pattison (2006)
Organization Science 17, 313-332
   Abstract »    PDF »
FANMOD: a tool for fast network motif detection.
S. Wernicke and F. Rasche (2006)
Bioinformatics 22, 1152-1153
   Abstract »    Full Text »    PDF »
The LEAFY target LMI1 is a meristem identity regulator and acts together with LEAFY to regulate expression of CAULIFLOWER.
L. A. Saddic, B. Huvermann, S. Bezhani, Y. Su, C. M. Winter, C. S. Kwon, R. P. Collum, and D. Wagner (2006)
Development 133, 1673-1682
   Abstract »    Full Text »    PDF »
Efficient estimation of graphlet frequency distributions in protein-protein interaction networks.
N. Przulj, D. G. Corneil, and I. Jurisica (2006)
Bioinformatics 22, 974-980
   Abstract »    Full Text »    PDF »
Mapping cis-acting regulatory variation in recombinant congenic strains.
P. D. Lee, B. Ge, C. M. T. Greenwood, D. Sinnett, Y. Fortin, S. Brunet, A. Fortin, M. Takane, E. Skamene, T. Pastinen, et al. (2006)
Physiol Genomics 25, 294-302
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882