Construction of regulatory networks using expression time-series data of a genotyped population

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 48; pp. 19436 - 19441
• Main Authors: Yeung, Ka Yee, Dombek, Kenneth M, Lo, Kenneth, Mittler, John E, Zhu, Jun, Schadt, Eric E, Bumgarner, Roger E, Raftery, Adrian E
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29-11-2011; National Acad Sciences
• Subjects: Algorithms; Bayes Theorem; Bayesian networks; Binding sites; Binding Sites - genetics; Biochemistry; Biological Sciences; Children; DNA; Drug regulation; drugs; Gene expression; Gene Expression Regulation, Fungal - genetics; Gene Regulatory Networks - genetics; Genes; Genetic Variation; Genomics; Genotype & phenotype; Inference; Logistic Models; Metabolic Networks and Pathways - genetics; Models, Biological; Molecular biology; mutants; P values; Physical Sciences; RNA; Time Factors; Time series; Transcription Factors - genetics; Yeasts
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1116442108

The inference of regulatory and biochemical networks from large-scale genomics data is a basic problem in molecular biology. The goal is to generate testable hypotheses of gene-to-gene influences and subsequently to design bench experiments to confirm these network predictions. Coexpression of genes in large-scale gene-expression data implies coregulation and potential gene–gene interactions, but provide little information about the direction of influences. Here, we use both time-series data and genetics data to infer directionality of edges in regulatory networks: time-series data contain information about the chronological order of regulatory events and genetics data allow us to map DNA variations to variations at the RNA level. We generate microarray data measuring time-dependent gene-expression levels in 95 genotyped yeast segregants subjected to a drug perturbation. We develop a Bayesian model averaging regression algorithm that incorporates external information from diverse data types to infer regulatory networks from the time-series and genetics data. Our algorithm is capable of generating feedback loops. We show that our inferred network recovers existing and novel regulatory relationships. Following network construction, we generate independent microarray data on selected deletion mutants to prospectively test network predictions. We demonstrate the potential of our network to discover de novo transcription-factor binding sites. Applying our construction method to previously published data demonstrates that our method is competitive with leading network construction algorithms in the literature.