Reconstructing the molecular function of genetic variation in regulatory networks

Roni Wilentzik, Chun Jimmie Ye, Irit Gat-Viks*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Over the past decade, genetic studies have recognized hundreds of polymorphic DNA loci called response QTLs (reQTLs) as potential contributors to interindividual variation in transcriptional responses to stimulations. Such reQTLs commonly affect the transduction of signals along the regulatory network that controls gene transcription. Identifying the pathways through which reQTLs perturb the underlying network has been a major challenge. Here, we present GEVIN (“Genome-wide Embedding of Variation In Networks”), a methodology that simultaneously identifies a reQTL and the particular pathway in which the reQTL affects downstream signal transduction along the network. Using synthetic data, we show that this algorithm outperforms existing pathway identification and reQTL identification methods. We applied GEVIN to the analysis of murine and human dendritic cells in response to pathogenic components. These analyses revealed significant reQTLs together with their perturbed Toll-like receptor signaling pathways. GEVIN thus offers a powerful framework that renders a comprehensive picture of disease-related DNA loci and their molecular functions within regulatory networks.

Original languageEnglish
Pages (from-to)1699-1709
Number of pages11
JournalGenetics
Volume207
Issue number4
DOIs
StatePublished - Dec 2017

Keywords

  • EQTL
  • Gene expression
  • Immune dendritic cells
  • Regulatory networks

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