title: Identification of critical paralog groups with indispensable roles in the regulation of signaling flow.
abstract: Extensive cross-talk between signaling pathways is required to integrate the myriad of extracellular signal combinations at the cellular level. Gene duplication events may lead to the emergence of novel functions, leaving groups of similar genes - termed paralogs - in the genome. To distinguish critical paralog groups (CPGs) from other paralogs in human signaling networks, we developed a signaling network-based method using cross-talk annotation and tissue-specific signaling flow analysis. 75 CPGs were found with higher degree, betweenness centrality, closeness, and 'bowtieness' when compared to other paralogs or other proteins in the signaling network. CPGs had higher diversity in all these measures, with more varied biological functions and more specific post-transcriptional regulation than non-critical paralog groups (non-CPG). Using TGF-beta, Notch and MAPK pathways as examples, SMAD2/3, NOTCH1/2/3 and MEK3/6-p38 CPGs were found to regulate the signaling flow of their respective pathways. Additionally, CPGs showed a higher mutation rate in both inherited diseases and cancer, and were enriched in drug targets. In conclusion, the results revealed two distinct types of paralog groups in the signaling network: CPGs and non-CPGs. Thus highlighting the importance of CPGs as compared to non-CPGs in drug discovery and disease pathogenesis.
authors.affiliation: Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, Budapest, Hungary.|Department of Genetics, Eotvos Lorand University, Budapest, Hungary.|Earlham Institute, Norwich Research Park, Norwich, UK.
authors.forename: Dezso
authors.initials: D
authors.lastname: Modos
authors.affiliation: Gut Health and Food Safety Programme, Institute of Food Research, Norwich Research Park, Norwich, UK.|Faculty of Medicine and Health, University of East Anglia, Norwich, UK.|Department of Gastroenterology, Norfolk and Norwich University Hospitals, Norwich, UK.
authors.forename: Johanne
authors.initials: J
authors.lastname: Brooks
authors.affiliation: Department of Genetics, Eotvos Lorand University, Budapest, Hungary.
authors.forename: David
authors.initials: D
authors.lastname: Fazekas
authors.affiliation: Department of Genetics, Eotvos Lorand University, Budapest, Hungary.|Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Ari
authors.affiliation: Department of Genetics, Eotvos Lorand University, Budapest, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Vellai
authors.affiliation: Department of Medical Chemistry, Semmelweis University, Budapest, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Csermely
authors.affiliation: Department of Genetics, Eotvos Lorand University, Budapest, Hungary.|Earlham Institute, Norwich Research Park, Norwich, UK.|Gut Health and Food Safety Programme, Institute of Food Research, Norwich Research Park, Norwich, UK.
authors.forename: Tamas
authors.initials: T
authors.lastname: Korcsmaros
authors.affiliation: Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, Budapest, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Lenti
mesh_terms: D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D006801:Humans; D009928:Organ Specificity; D015398:Signal Transduction / Q000187:drug effects; D057188:Workflow