title: The role of the interactome in the maintenance of deleterious variability in human populations.
abstract: Recent genomic projects have revealed the existence of an unexpectedly large amount of deleterious variability in the human genome. Several hypotheses have been proposed to explain such an apparently high mutational load. However, the mechanisms by which deleterious mutations in some genes cause a pathological effect but are apparently innocuous in other genes remain largely unknown. This study searched for deleterious variants in the 1,000 genomes populations, as well as in a newly sequenced population of 252 healthy Spanish individuals. In addition, variants causative of monogenic diseases and somatic variants from 41 chronic lymphocytic leukaemia patients were analysed. The deleterious variants found were analysed in the context of the interactome to understand the role of network topology in the maintenance of the observed mutational load. Our results suggest that one of the mechanisms whereby the effect of these deleterious variants on the phenotype is suppressed could be related to the configuration of the protein interaction network. Most of the deleterious variants observed in healthy individuals are concentrated in peripheral regions of the interactome, in combinations that preserve their connectivity, and have a marginal effect on interactome integrity. On the contrary, likely pathogenic cancer somatic deleterious variants tend to occur in internal regions of the interactome, often with associated structural consequences. Finally, variants causative of monogenic diseases seem to occupy an intermediate position. Our observations suggest that the real pathological potential of a variant might be more a systems property rather than an intrinsic property of individual proteins.
authors.affiliation: Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.
authors.forename: Luz
authors.initials: L
authors.lastname: Garcia-Alonso
authors.affiliation: Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain Bioinformatics of Rare Diseases (BIER), CIBER de Enfermedades Raras (CIBERER), Valencia, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Jiménez-Almazán
authors.affiliation: Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Carbonell-Caballero
authors.affiliation: Medical Genome Project, Genomics and Bioinformatics Platform of Andalusia (GBPA), Seville, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Vela-Boza
authors.affiliation: Medical Genome Project, Genomics and Bioinformatics Platform of Andalusia (GBPA), Seville, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Santoyo-López
authors.affiliation: Medical Genome Project, Genomics and Bioinformatics Platform of Andalusia (GBPA), Seville, Spain Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocio/Consejo Superior de Investigaciones Científicas/University of Seville, Seville, Spain Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Seville, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
authors.affiliation: Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain Bioinformatics of Rare Diseases (BIER), CIBER de Enfermedades Raras (CIBERER), Valencia, Spain Medical Genome Project, Genomics and Bioinformatics Platform of Andalusia (GBPA), Seville, Spain Functional Genomics Node, (INB) at CIPF, Valencia, Spain jdopazo@cipf.es.
authors.forename: Joaquin
authors.identifier: http://orcid.org/0000-0003-3318-120X
authors.initials: J
authors.lastname: Dopazo
mesh_terms: D000483:Alleles; D059472:Exome; D015723:Gene Library; D014644:Genetic Variation; D005828:Genetics, Population; D015894:Genome, Human; D023281:Genomics / Q000379:methods*; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D011487:Protein Conformation; D060066:Protein Interaction Maps; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics
keywords: exome sequencing; interactome; mutational load; network analysis; robustness