Characterizing the behavior of disease genes in the context of biological networks has the potential to shed light on disease mechanisms, and to reveal both new candidate disease genes and therapeutic targets. Previous studies addressing the network properties of disease genes have produced contradictory results. Here we have explored the causes of these discrepancies and assessed the relationship between the network roles of disease genes and their tolerance to deleterious germline variants in human populations leveraging on: the abundance of interactome resources, a comprehensive catalog of disease genes and exome variation data. We found that the most salient network features of disease genes are driven by cancer genes and that genes related to different types of diseases play network roles whose centrality is inversely correlated to their tolerance to likely deleterious germline mutations. This proved to be a multiscale signature, including global, mesoscopic and local network centrality features. Cancer driver genes, the most sensitive to deleterious variants, occupy the most central positions, followed by dominant disease genes and then by recessive disease genes, which are tolerant to variants and isolated within their network modules.

We received support from UBACyT (20020130100582BA) and MinCyT (PICT2014-2701), ISCIII-FEDER (PI13/00082, CP10/00524), IMI-JU under grants agreements n° 115002 (eTOX), n° 115191 (Open PHACTS)], n° 115372 (EMIF) and n° 115735 (iPiE), resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution, and the EU H2020 Programme 2014-2020 under grant agreements no. 634143 (MedBioinformatics) and no. 676559 (Elixir-Excelerate). The Research Programme on Biomedical Informatics (GRIB) is a node of the Spanish National Institute of Bioinformatics (INB). A.G.-P. is supported by a Ramon y Cajal scholarship funded by the Spanish Ministry of Economy. The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about.