Hunter B. Fraser,^1* Aaron E. Hirsh,^2* Lars M. Steinmetz,³ Curt Scharfe,³ Marcus W. Feldman²

High-throughput screens have begun to reveal the protein interaction network that underpins most cellular functions in the yeast Saccharomyces cerevisiae. How the organization of this network affects the evolution of the proteins that compose it is a fundamental question in molecular evolution. We show that the connectivity of well-conserved proteins in the network is negatively correlated with their rate of evolution. Proteins with more interactors evolve more slowly not because they are more important to the organism, but because a greater proportion of the protein is directly involved in its function. At sites important for interaction between proteins, evolutionary changes may occur largely by coevolution, in which substitutions in one protein result in selection pressure for reciprocal changes in interacting partners. We confirm one predicted outcome of this process--namely, that interacting proteins evolve at similar rates.

¹ Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
² Center for Computational Genetics and Biological Modeling, Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA.
³ Stanford Genome Technology Center, Palo Alto, CA 94306, USA.
^*   These authors contributed equally to this work.

   To whom correspondence should be addressed. E-mail: hunter{at}ocf.berkeley.edu

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Mol. Biol. Evol.
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PNAS 110, E678-E686
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Increased Genome Sampling Reveals a Dynamic Relationship between Gene Duplicability and the Structure of the Primate Protein-Protein Interaction Network.

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Assessing Determinants of Exonic Evolutionary Rates in Mammals.

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Exploring the Differences in Evolutionary Rates between Monogenic and Polygenic Disease Genes in Human.

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The Two AGPase Subunits Evolve at Different Rates in Angiosperms, yet They Are Equally Sensitive to Activity-Altering Amino Acid Changes When Expressed in Bacteria.

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Assessing the Determinants of Evolutionary Rates in the Presence of Noise.

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Global eQTL Mapping Reveals the Complex Genetic Architecture of Transcript-Level Variation in Arabidopsis.

M. A. L. West, K. Kim, D. J. Kliebenstein, H. van Leeuwen, R. W. Michelmore, R. W. Doerge, and D. A. St. Clair (2007)
Genetics 175, 1441-1450
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Rapid Evolution Exposes the Boundaries of Domain Structure and Function in Natively Unfolded FG Nucleoporins.

D. P. Denning and M. F. Rexach (2007)
Mol. Cell. Proteomics 6, 272-282
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Gene loss rate: a probabilistic measure for the conservation of eukaryotic genes.

E. Borenstein, T. Shlomi, E. Ruppin, and R. Sharan (2007)
Nucleic Acids Res. 35, e7
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Impact of Transcriptional Properties on Essentiality and Evolutionary Rate.

J. K. Choi, S. C. Kim, J. Seo, S. Kim, and J. Bhak (2007)
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BIOCHEMISTRY: Proteins in a Small World.

T. O. Yeates and M. Beeby (2006)
Science 314, 1882-1883
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Relating Three-Dimensional Structures to Protein Networks Provides Evolutionary Insights.

P. M. Kim, L. J. Lu, Y. Xia, and M. B. Gerstein (2006)
Science 314, 1938-1941
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Flux control and excess capacity in the enzymes of glycolysis and their relationship to flight metabolism in Drosophila melanogaster.

W. F. Eanes, T. J. S. Merritt, J. M. Flowers, S. Kumagai, E. Sezgin, and C.-T. Zhu (2006)
PNAS 103, 19413-19418
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Origins and impact of constraints in evolution of gene families.

B. E. Shakhnovich and E. V. Koonin (2006)
Genome Res. 16, 1529-1536
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Impacts of Gene Essentiality, Expression Pattern, and Gene Compactness on the Evolutionary Rate of Mammalian Proteins.

B.-Y. Liao, N. M. Scott, and J. Zhang (2006)
Mol. Biol. Evol. 23, 2072-2080
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Protein Evolution Is Faster Outside the Cell.

K. Julenius and A. G. Pedersen (2006)
Mol. Biol. Evol. 23, 2039-2048
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A rapid genome-scale response of the transcriptional oscillator to perturbation reveals a period-doubling path to phenotypic change.

C. M. Li and R. R. Klevecz (2006)
PNAS 103, 16254-16259
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Global topological features of cancer proteins in the human interactome.

P. F. Jonsson and P. A. Bates (2006)
Bioinformatics 22, 2291-2297
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Structural Determinants of the Rate of Protein Evolution in Yeast.

J. D. Bloom, D. A. Drummond, F. H. Arnold, and C. O. Wilke (2006)
Mol. Biol. Evol. 23, 1751-1761
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Unifying measures of gene function and evolution.

Y. I Wolf, L. Carmel, and E. V Koonin (2006)
Proc R Soc B 273, 1507-1515
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