Epistasis in a Model of Molecular Signal Transduction 英文参考文献.docVIP

EpistasisinaModelofMolecularSignalTransduction AlainPumir1,BorisShraiman2* 1LaboratoiredePhysique,EcoleNormaleSupe′rieure deLyon,Lyon,France,2KavliInstituteforTheoreticalPhysicsandDepartmentofPhysics,UniversityofCalifornia, SantaBarbara,California,UnitedStatesofAmerica Abstract Biological functions typically involve complex interacting molecular networks, with numerous feedback and regulation loops. How the properties of the system are affected when one, or several of its parts are modified is a question of fundamental interest, with numerous implications for the way we study and understand biological processes and treat diseases.Thisquestioncanberephrasedintermsofrelatinggenotypestophenotypes:towhatextentdoestheeffectofa genetic variation at one locus depend on genetic variation at all other loci? Systematic quantitative measurements of epistasis–thedeviationfromadditivityintheeffectofallelesatdifferentloci–onagivenquantitativetraitremainamajor challenge.Here,wetakeacomplementaryapproachofstudyingtheoreticallytheeffectofvaryingmultipleparametersina validated model of molecular signal transduction. To connect with the genotype/phenotype mapping we interpret parameters of the model as different loci with discrete choices of these parameters as alleles, which allows us to systematically examine the dependence of the signaling output – a quantitative trait – on the set of possible allelic combinations. We show quite generally that quantitative traits behave approximately additively (weak epistasis) when allelescorrespondtosmallchangesofparameters;epistasisappearsasaresultoflargedifferencesbetweenalleles.When epistasisisrelativelystrong,itisconcentratedinasparsesubsetoflociandinloworder(e.g.pair-wise)interactions.Wefind thatfocusingoninteractionbetweenlocithatexhibitstrongadditiveeffectsisanefficientwayofidentifyingmostofthe epistasis.Ourmodelstudydefinesatheoreticalframeworkforinterpretationofexperimentaldataandprovidesstatistical predictionsforthestructureofgeneti