Mapping the Environmental Fitness Landscape of a Synthetic Gene Circuit 英文参考文献.docVIP

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Mapping the Environmental Fitness Landscape of a Synthetic Gene Circuit 英文参考文献.doc

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Mapping the Environmental Fitness Landscape of a Synthetic Gene Circuit 英文参考文献

MappingtheEnvironmentalFitnessLandscapeofa SyntheticGeneCircuit DmitryNevozhay1.,RhysM.Adams1.,ElizabethVanItallie2,MatthewR.Bennett2,Ga′borBala′zsi1* 1DepartmentofSystemsBiology,TheUniversityofTexasMDAndersonCancerCenter,Houston,Texas,UnitedStatesofAmerica,2DepartmentofBiochemistryandCell BiologyandInstituteofBiosciencesandBioengineering,RiceUniversity,Houston,Texas,UnitedStatesofAmerica Abstract Geneexpressionactualizestheorganismalphenotypesencodedwithinthegenomeinanenvironment-dependentmanner. Amongallencodedphenotypes,cellpopulationgrowthrate(fitness)isperhapsthemostimportant,sinceitdetermines howwell-adaptedagenotypeisinvariousenvironments.Traditionalbiologicalmeasurementtechniqueshaverevealedthe connectionbetweentheenvironmentandfitnessbasedonthegeneexpressionmean.Yet,recentlyitbecameclearthat cellswithidenticalgenomesexposedtothesameenvironmentcandifferdramaticallyfromthepopulationaverageintheir geneexpressionanddivisionrate(individualfitness).Forcellpopulationswithbimodalgeneexpression,thisdifferenceis particularly pronounced, and may involve stochastic transitions between two cellular states that form distinct sub- populations.Currentlyitremainsunclearhowacellpopulation’sgrowthrateanditssubpopulationfractionsemergefrom themolecular-levelkineticsofgenenetworksandthedivisionratesofsinglecells.Toaddressthisquestionwedeveloped and quantitatively characterized an inducible, bistable synthetic gene circuit controlling the expression of a bifunctional antibiotic resistance gene in Saccharomyces cerevisiae. Following fitness and fluorescence measurements in two distinct environments(induceraloneandantibioticalone),weappliedacomputationalapproachtopredictcellpopulationfitness and subpopulation fractions in the combination of these environments based on stochastic cellular movement in gene expressionspaceandfitnessspace.Wefoundthatknowingthefitnessandnongenetic(cellular)memoryassociatedwith specific gene expression states were necessary for predicting the overall