title: POEM: Identifying Joint Additive Effects on Regulatory Circuits.
abstract: BACKGROUND
  Expression Quantitative Trait Locus (eQTL) mapping tackles the problem of identifying variation in DNA sequence that have an effect on the transcriptional regulatory network. Major computational efforts are aimed at characterizing the joint effects of several eQTLs acting in concert to govern the expression of the same genes. Yet, progress toward a comprehensive prediction of such joint effects is limited. For example, existing eQTL methods commonly discover interacting loci affecting the expression levels of a module of co-regulated genes. Such "modularization" approaches, however, are focused on epistatic relations and thus have limited utility for the case of additive (non-epistatic) effects.
  
  
  RESULTS
  Here we present POEM (Pairwise effect On Expression Modules), a methodology for identifying pairwise eQTL effects on gene modules. POEM is specifically designed to achieve high performance in the case of additive joint effects. We applied POEM to transcription profiles measured in bone marrow-derived dendritic cells across a population of genotyped mice. Our study reveals widespread additive, trans-acting pairwise effects on gene modules, characterizes their organizational principles, and highlights high-order interconnections between modules within the immune signaling network. These analyses elucidate the central role of additive pairwise effect in regulatory circuits, and provide computational tools for future investigations into the interplay between eQTLs.
  
  
  BACKGROUND
  The software described in this article is available at csgi.tau.ac.il/POEM/.
authors.affiliation: Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University Tel Aviv, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Botzman
authors.affiliation: Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University Tel Aviv, Israel.
authors.forename: Aharon
authors.initials: A
authors.lastname: Nachshon
authors.affiliation: Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University Tel Aviv, Israel.
authors.forename: Avital
authors.initials: A
authors.lastname: Brodt
authors.affiliation: Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University Tel Aviv, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Gat-Viks
keywords: additive effects; eQTL; gene modules; immune signaling network; pairwise effects