3 years ago

Reconstructing the Molecular Function of Genetic Variation in Regulatory Networks.

Irit Gat-Viks, Roni Wilentzik, Chun Jimmie Ye
During the past decade, genetic studies have recognized hundreds of polymorphic DNA loci ('reQTLs') as potential contributors to inter-individual variation in transcriptional response 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, a methodology that simultaneously identifies a reQTL and the particular pathway at 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 (TLR)-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.

Publisher URL: http://doi.org/10.1534/genetics.117.300381

DOI: 10.1534/genetics.117.300381

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