title: Nonlinear regulation enhances the phenotypic expression of trans-acting genetic polymorphisms.
abstract: BACKGROUND
  Genetic variation explains a considerable part of observed phenotypic variation in gene expression networks. This variation has been shown to be located both locally (cis) and distally (trans) to the genes being measured. Here we explore to which degree the phenotypic manifestation of local and distant polymorphisms is a dynamic feature of regulatory design.
  
  
  RESULTS
  By combining mathematical models of gene expression networks with genetic maps and linkage analysis we find that very different network structures and regulatory motifs give similar cis/trans linkage patterns. However, when the shape of the cis-regulatory input functions is more nonlinear or threshold-like, we observe for all networks a dramatic increase in the phenotypic expression of distant compared to local polymorphisms under otherwise equal conditions.
  
  
  CONCLUSIONS
  Our findings indicate that genetic variation affecting the form of cis-regulatory input functions may reshape the genotype-phenotype map by changing the relative importance of cis and trans variation. Our approach combining nonlinear dynamic models with statistical genetics opens up for a systematic investigation of how functional genetic variation is translated into phenotypic variation under various systemic conditions.
authors.affiliation: Centre for Integrative Genetics (CIGENE), Norwegian University of Life Sciences, As, Norway. rne.gjuvsland@cigene.no
authors.forename: Arne B
authors.initials: AB
authors.lastname: Gjuvsland
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Hayes
authors.forename: Theo H E
authors.initials: TH
authors.lastname: Meuwissen
authors.forename: Erik
authors.initials: E
authors.lastname: Plahte
authors.forename: Stig W
authors.initials: SW
authors.lastname: Omholt
mesh_terms: D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000235:genetics; D008040:Genetic Linkage / Q000235:genetics; D005838:Genotype; D008957:Models, Genetic; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics; D049490:Systems Biology