Estimating the size of the human interactome

Abstract

After the completion of the human and other genome projects it emerged that the number of genes in organisms as diverse as fruit flies, nematodes, and humans does not reflect our perception of their relative complexity. Here, we provide reliable evidence that the size of protein interaction networks in different organisms appears to correlate much better with their apparent biological complexity. We develop a stable and powerful, yet simple, statistical procedure to estimate the size of the whole network from subnet data. This approach is then applied to a range of eukaryotic organisms for which extensive protein interaction data have been collected and we estimate the number of interactions in humans to be Ϸ650,000. We find that the human interaction network is one order of magnitude bigger than the Drosophila melanogaster interactome and Ϸ3 times bigger than in Caenorhabditis elegans.evolutionary systems biology ͉ network inference ͉ network sampling theory ͉ network evolution O ne of the perhaps most surprising results of the genomesequencing projects was that the number of genes is much lower than had been expected and is, in fact, surprisingly similar for very different organisms (1, 2). For example, the nematode Caenorhabditis elegans appears to have a similar number of genes as humans, whereas rice and maize appear to have even more genes than humans. It was then quickly suggested that the biological complexity of organisms is not reflected merely by the number of genes but by the number of physiologically relevant interactions (1, 3). In addition to alternative splice variants (4), posttranslational processes (5), and other (e.g., genetic) factors influencing gene expression (6, 7), the structure of interactome is one of the crucial factors underlying the complexity of biological organisms. Here, we focus on the wealth of available protein interaction data and demonstrate that it is possible to arrive at a reliable statistical estimate for the size of these interaction networks. This approach is then used to assess the complexity of protein interaction networks in different organisms from present incomplete and noisy protein interaction datasets.There are now fairly extensive protein interaction network (PIN) datasets in a number of species, including humans (8, 9). These have been generated by a variety of experimental techniques (as well as some in silico inferences). Although these techniques and the resulting data are (i) notoriously prone to false positives and negatives (10, 11), and (ii) result in highly idealized and averaged network structures (12), such interaction datasets are increasingly turning into useful tools for the analysis of the functional (e.g., ref. 13) and evolutionary properties (14) of biological systems. In particular, in Saccharomyces cerevisiae we are beginning to have a fairly complete description of the protein interaction network that is accessible with current experimental technologies; the recent high-quality literaturecurated dataset of Reguly et al. (15) provides us w...

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