title: Directed mammalian gene regulatory networks using expression and comparative genomic hybridization microarray data from radiation hybrids.
abstract: Meiotic mapping of quantitative trait loci regulating expression (eQTLs) has allowed the construction of gene networks. However, the limited mapping resolution of these studies has meant that genotype data are largely ignored, leading to undirected networks that fail to capture regulatory hierarchies. Here we use high resolution mapping of copy number eQTLs (ceQTLs) in a mouse-hamster radiation hybrid (RH) panel to construct directed genetic networks in the mammalian cell. The RH network covering 20,145 mouse genes had significant overlap with, and similar topological structures to, existing biological networks. Upregulated edges in the RH network had significantly more overlap than downregulated. This suggests repressive relationships between genes are missed by existing approaches, perhaps because the corresponding proteins are not present in the cell at the same time and therefore unlikely to interact. Gene essentiality was positively correlated with connectivity and betweenness centrality in the RH network, strengthening the centrality-lethality principle in mammals. Consistent with their regulatory role, transcription factors had significantly more outgoing edges (regulating) than incoming (regulated) in the RH network, a feature hidden by conventional undirected networks. Directed RH genetic networks thus showed concordance with pre-existing networks while also yielding information inaccessible to current undirected approaches.
authors.affiliation: Signal and Image Processing Institute, University of Southern California, Los Angeles, California, USA.
authors.forename: Sangtae
authors.initials: S
authors.lastname: Ahn
authors.forename: Richard T
authors.initials: RT
authors.lastname: Wang
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Park
authors.forename: Andy
authors.initials: A
authors.lastname: Lin
authors.forename: Richard M
authors.initials: RM
authors.lastname: Leahy
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lange
authors.forename: Desmond J
authors.initials: DJ
authors.lastname: Smith
mesh_terms: D000818:Animals; D055028:Comparative Genomic Hybridization / Q000379:methods*; D006224:Cricetinae; D030541:Databases, Genetic; D053263:Gene Regulatory Networks; D051379:Mice; D008957:Models, Genetic; D015233:Models, Statistical; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D040641:Quantitative Trait Loci; D021101:Radiation Hybrid Mapping; D012044:Regression Analysis; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D014157:Transcription Factors