title: Deciphering molecular circuits from genetic variation underlying transcriptional responsiveness to stimuli.
abstract: Individual genetic variation affects gene responsiveness to stimuli, often by influencing complex molecular circuits. Here we combine genomic and intermediate-scale transcriptional profiling with computational methods to identify variants that affect the responsiveness of genes to stimuli (responsiveness quantitative trait loci or reQTLs) and to position these variants in molecular circuit diagrams. We apply this approach to study variation in transcriptional responsiveness to pathogen components in dendritic cells from recombinant inbred mouse strains. We identify reQTLs that correlate with particular stimuli and position them in known pathways. For example, in response to a virus-like stimulus, a trans-acting variant responds as an activator of the antiviral response; using RNA interference, we identify Rgs16 as the likely causal gene. Our approach charts an experimental and analytic path to decipher the mechanisms underlying genetic variation in circuits that control responses to stimuli.
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. iritgv@post.tau.ac.il
authors.forename: Irit
authors.initials: I
authors.lastname: Gat-Viks
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chevrier
authors.forename: Roni
authors.initials: R
authors.lastname: Wilentzik
authors.forename: Thomas
authors.initials: T
authors.lastname: Eisenhaure
authors.forename: Raktima
authors.initials: R
authors.lastname: Raychowdhury
authors.forename: Yael
authors.initials: Y
authors.lastname: Steuerman
authors.forename: Alex K
authors.initials: AK
authors.lastname: Shalek
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
authors.forename: Ido
authors.initials: I
authors.lastname: Amit
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
mesh_terms: D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics; D003713:Dendritic Cells / Q000378:metabolism / Q000821:virology*; D005260:Female; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D058685:Genetic Pleiotropy; D014644:Genetic Variation; D051379:Mice; D008815:Mice, Inbred Strains; D040641:Quantitative Trait Loci / Q000235:genetics*; D020710:RGS Proteins / Q000235:genetics; D051193:Toll-Like Receptors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D020710:RGS Proteins; C107413:RGS16 protein; D051193:Toll-Like Receptors