journal.pcbi.1007587.pdf 1,80MB
1000 Titel
  • Host factor prioritization for pan-viral genetic perturbation screens using random intercept models and network propagation
1000 Autor/in
  1. Dirmeier, Simon |
  2. Dächert, Christopher |
  3. van Hemert, Martijn |
  4. Tas, Ali |
  5. Ogando, Natacha |
  6. van Kuppeveld, Frank |
  7. Bartenschlager, Ralf |
  8. Kaderali, Lars |
  9. Binder, Marco |
  10. Beerenwinkel, Niko |
1000 Erscheinungsjahr 2020
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2020-02-10
1000 Erschienen in
1000 Quellenangabe
  • 16(2):e1007587
1000 Copyrightjahr
  • 2020
1000 Lizenz
1000 Verlagsversion
  • |
  • |
1000 Ergänzendes Material
  • |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • Genetic perturbation screens using RNA interference (RNAi) have been conducted successfully to identify host factors that are essential for the life cycle of bacteria or viruses. So far, most published studies identified host factors primarily for single pathogens. Furthermore, often only a small subset of genes, e.g., genes encoding kinases, have been targeted. Identification of host factors on a pan-pathogen level, i.e., genes that are crucial for the replication of a diverse group of pathogens has received relatively little attention, despite the fact that such common host factors would be highly relevant, for instance, for devising broad-spectrum anti-pathogenic drugs. Here, we present a novel two-stage procedure for the identification of host factors involved in the replication of different viruses using a combination of random effects models and Markov random walks on a functional interaction network. We first infer candidate genes by jointly analyzing multiple perturbations screens while at the same time adjusting for high variance inherent in these screens. Subsequently the inferred estimates are spread across a network of functional interactions thereby allowing for the analysis of missing genes in the biological studies, smoothing the effect sizes of previously found host factors, and considering a priori pathway information defined over edges of the network. We applied the procedure to RNAi screening data of four different positive-sense single-stranded RNA viruses, Hepatitis C virus, Chikungunya virus, Dengue virus and Severe acute respiratory syndrome coronavirus, and detected novel host factors, including UBC, PLCG1, and DYRK1B, which are predicted to significantly impact the replication cycles of these viruses. We validated the detected host factors experimentally using pharmacological inhibition and an additional siRNA screen and found that some of the predicted host factors indeed influence the replication of these pathogens.
1000 Sacherschließung
lokal Dengue virus
lokal Genetic screens
lokal Genetic networks
lokal ssRNA viruses
lokal Viral replication
lokal RNA interference
lokal Hepatitis C virus
lokal Small interfering RNA
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
1000 (Academic) Editor
1000 Label
1000 Förderer
  1. FP7 Food, Agriculture and Fisheries, Biotechnology |
1000 Fördernummer
  1. -
1000 Förderprogramm
  1. ERASysAPP-30
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer FP7 Food, Agriculture and Fisheries, Biotechnology |
    1000 Förderprogramm ERASysAPP-30
    1000 Fördernummer -
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6423906.rdf
1000 Erstellt am 2020-11-02T12:40:37.157+0100
1000 Erstellt von 218
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1000 Bearbeitet von 25
1000 Zuletzt bearbeitet Fri Nov 06 09:15:16 CET 2020
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