Still Stratus Not Altocumulus: Further Evidence against the Date/Party Hub Distinction

Abstract

Using a small dataset of protein–protein interactions [1], it was proposed that the yeast protein interaction network is made up of two sorts of hubs, party and date, and that these define modularity in the yeast protein interaction network. We found [2], by using several larger high-confidence datasets and appropriate statistical analyses, that we could not support these conclusions. Bertin et al. now invite analysis of a further dataset of protein-protein interactions, which they argue support the party/date distinction. The claimed properties of party and date hubs are not, however, present in this dataset either. In particular, when controlling for important covariables where necessary, there is no evidence for (1) bimodality in partner co-expression, (2) enrichment for similarly localized proteins that physically interact with party hubs, (3) a lower rate of evolution of party hubs, (4) differences in the effects of deletion of date and party hubs, or (5) higher genetic connectivity of date hubs. In sum, all of our prior conclusions remain robust and there is no evidence for distinctive classes of network hubs. It was suggested [1] that some hub proteins operate at the same intracellular place and time with their multiple interactants (as if at a party) while others operate on a one-by-one basis with their numerous partners (as if on a date). Is this distinction informative? Originally, four features were used to the draw a partition between date and party hubs: expression bimodality, localization entropy, network fragmentation, and genetic connectivity [1]. A subsequent analysis suggested a fifth distinction, namely different rates of evolution after control for covariables [3]. Given the small size of the original dataset and the absence of statistical support for some of the assertions, we asked [2] whether these claims were robust. In both the original dataset and in new high-confidence interaction datasets [2], we found we could not support any of the five points of evidence. Bertin et al. now nominate a new dataset, which they argue supports three of the five points of evidence. Bertin et al. first note a curation issue with one of our many datasets, called HC, which inadvertently contains interactions that were, owing to an ambiguity in the literature, supported by a single analysis. We certainly agree that inclusion of the data from [4] and [5] as independent validations was in error, as the data in [5] indeed fully encompasses that of [4] (A-C Gavin, personal communication). However, approximately half of the interactions reported in [4] remain multi-validated by other means. An updated high-confidence dataset that removes this duplication and incorporates more recent interaction data is available here (Dataset S1) and as a download from the BioGRID database (see http://www.thebiogrid.org). Importantly, however, our dataset HCm is unaffected by the above concern as we required validation of an interaction by multiple different methods. The new build of Bertin et al. (called “filtered-HC”) mimics HCm by excluding interactions not multivalidated with different methods. As the results of HCm confirmed those of our other datasets [2], we were surprised by the claim that the date/party distinction is still supported in filtered-HC. Because this dataset provides the most robustly defendable set of interactions, here we re-analyse the filtered-HC network to ask whether it substantiates the date/party distinction.