title: Uncovering disease mechanisms through network biology in the era of Next Generation Sequencing.
abstract: 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.
authors.affiliation: Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM), DCEXS, Pompeu Fabra University (UPF). C/Dr. Aiguader, 88. 08003- Barcelona, Spain.
authors.forename: Janet
authors.initials: J
authors.lastname: Piñero
authors.affiliation: Departamento de Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires. Pabellón 1, Ciudad Universitaria, Buenos Aires, Argentina.|Instituto de Física de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas. Pabellón 1, Ciudad Universitaria, Buenos Aires, Argentina.
authors.forename: Ariel
authors.initials: A
authors.lastname: Berenstein
authors.affiliation: Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM), DCEXS, Pompeu Fabra University (UPF). C/Dr. Aiguader, 88. 08003- Barcelona, Spain.
authors.forename: Abel
authors.initials: A
authors.lastname: Gonzalez-Perez
authors.affiliation: Departamento de Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires. Pabellón 1, Ciudad Universitaria, Buenos Aires, Argentina.|Instituto de Física de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas. Pabellón 1, Ciudad Universitaria, Buenos Aires, Argentina.|Laboratorio de Biología de Sistemas Integrativa, Fundación Instituto Leloir, Buenos Aires, Argentina.
authors.forename: Ariel
authors.initials: A
authors.lastname: Chernomoretz
authors.affiliation: Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM), DCEXS, Pompeu Fabra University (UPF). C/Dr. Aiguader, 88. 08003- Barcelona, Spain.
authors.forename: Laura I
authors.initials: LI
authors.lastname: Furlong
mesh_terms: D019295:Computational Biology / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009369:Neoplasms / Q000235:genetics