A simple principle concerning the robustness of protein complex activity to changes in gene expression

Abstract

Background: The functions of a eukaryotic cell are largely performed by multi-subunit protein complexes that act as molecular machines or information processing modules in cellular networks. An important problem in systems biology is to understand how, in general, these molecular machines respond to perturbations.

Results: In yeast, genes that inhibit growth when their expression is reduced are strongly enriched amongst the subunits of multi-subunit protein complexes. This applies to both the core and peripheral subunits of protein complexes, and the subunits of each complex normally have the same loss-of-function phenotypes. In contrast, genes that inhibit growth when their expression is increased are not enriched amongst the core or peripheral subunits of protein complexes, and the behaviour of one subunit of a complex is not predictive for the other subunits with respect to over-expression phenotypes.

Conclusion: We propose the principle that the overall activity of a protein complex is in general robust to an increase, but not to a decrease in the expression of its subunits. This means that whereas phenotypes resulting from a decrease in gene expression can be predicted because they cluster on networks of protein complexes, over-expression phenotypes cannot be predicted in this way. We discuss the implications of these findings for understanding how cells are regulated, how they evolve, and how genetic perturbations connect to disease in humans.

Figure 1

Genes with under- but not over-expression phenotypes are enriched amongst protein complexes. Essential genes, genes required for normal growth in rich media and haploinsufficient genes are all enriched amongst the subunits of protein complexes. In contrast genes with over-expression phenotypes are equally represented amongst protein complex subunits and other genes. The graph shows the percentage of genes found in MIPS protein complexes and the percentage of all other genes that have each phenotype. ** Chi square test p < 0.05 for difference between protein complex subunits and all genes.

Figure 2

Genes with under- but not over-expression phenotypes cluster into individual protein complexes. Genes with essential functions (A), genes required for normal growth in rich media (B), and haploinsufficient genes (C) are arranged amongst protein complexes very differently to the random expectation. In contrast genes with over-expression phenotypes are arranged much more randomly (D). The graphs show the observed number of complexes in each of ten bins defined by the proportion of subunits having each phenotype. These are compared to the expected values (the mean of 100,000 randomisations). ** Bins significantly different from random at a 5% FDR (Benjamini-Hochberg method).

Figure 3

Genes sensitive to a reduction in expression level, but not to over-expression are enriched amongst both the core and peripheral subunits of protein complexes. Percentages of genes with essential, overexpression or haploinsufficient phenotypes among different structural components of protein complexes as defined by Gavin et al. (2006). The percentages of all genes are shown for comparison. Inset: schematic representation of the overlap between the datasets used. Only 21 genes are found exclusively in modules, so we did not test these as a separate category. ** Fisher's exact test p < 0.0001 for difference between genes with the particular phenotype and all genes without that phenotype.

Figure 4

A simple principle concerning the robustness of protein complex activity. The results presented here suggest that protein complex activity in eukaryotic cells is in general robust to an increase, but not to a decrease in the expression levels of individual subunits.