Nonlinear Fitness Landscape of a Molecular Pathway 英文参考文献.docVIP

NonlinearFitnessLandscapeofaMolecularPathway LiliaPerfeito1,2*,Ste′phaneGhozzi2,JohannesBerg2,KarinSchnetz1,MichaelLa¨ssig2* 1Institutfu¨rGenetik,Universita¨t zuKo¨ln,Cologne,Germany,2Institutfu¨rTheoretischePhysik,Universita¨t zuKo¨ln,Cologne,Germany Abstract Genes are regulated because their expression involves a fitness cost to the organism. The production of proteins by transcriptionandtranslationisawell-knowncostfactor,buttheenzymaticactivityoftheproteinsproducedcanalsoreduce fitness,dependingontheinternalstateandtheenvironmentofthecell.Here,wemapthefitnesscostsofakeymetabolic network,thelactoseutilizationpathwayinEscherichiacoli.Wemeasurethegrowthofseveralregulatorylacoperonmutants in different environments inducing expression of the lac genes. We find a strikingly nonlinear fitness landscape, which depends on theproduction rate andon theactivity rateof the lac proteins. Asimple fitness model ofthe lac pathway, basedonelementarybiophysicalprocesses,predictsthegrowthrateofallobservedstrains.Thenonlinearityoffitnessis explainedbyafeedbackloop:productionandactivityofthelacproteinsreducegrowth,butgrowthalsoaffectsthedensity ofthesemolecules.Thisnonlinearityhasimportantconsequencesformolecularfunctionandevolution.Itgeneratesacliff inthefitnesslandscape,beyondwhichpopulationscannotmaintaingrowth.Inviablepopulations,thereisanexpression barrier of the lac genes, which cannot be exceeded in any stationary growth process. Furthermore, the nonlinearity determineshowthefitnessofoperonmutantsdependsontheinducerenvironment.Wearguethatfitnessnonlinearities, expressionbarriers,andgene–environmentinteractionsaregenericfeaturesoffitnesslandscapesformetabolicpathways, andwediscusstheirimplicationsfortheevolutionofregulation. Citation:PerfeitoL,GhozziS,BergJ,SchnetzK,La¨ssig M(2011)NonlinearFitnessLandscapeofaMolecularPathway.PLoSGenet7(7):e1002160.doi:10.1371/ journal.pgen.1002160 Editor:IvanMatic,Universite′ ParisDescartes,INSERMU1001,France ReceivedNovember11,20