Optimality of Mutation and Selection in Germinal Centers 英文参考文献.docVIP

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Optimality of Mutation and Selection in Germinal Centers 英文参考文献.doc

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Optimality of Mutation and Selection in Germinal Centers 英文参考文献

OptimalityofMutationandSelectioninGerminal Centers JingshanZhang,EugeneI.Shakhnovich* DepartmentofChemistryandChemicalBiology,HarvardUniversity,Cambridge,Massachusetts,UnitedStatesofAmerica Abstract ThepopulationdynamicstheoryofBcellsinatypicalgerminalcentercouldplayanimportantroleinrevealinghowaffinity maturation is achieved. However, the existing models encountered some conflicts with experiments. To resolve these conflicts,wepresentacoarse-grainedmodeltocalculatetheBcellpopulationdevelopmentinaffinitymaturation,which allowsacomprehensiveanalysisofitsparameterspacetolookforoptimalvaluesofmutationrate,selectionstrength,and initialantibody-antigenbindinglevelthatmaximizetheaffinityimprovement.Withtheseoptimizedparameters,themodel iscompatiblewiththeexperimentalobservationssuchasthe,100-foldaffinityimprovements,thenumberofmutations, the hypermutation rate, and the ‘‘all or none’’ phenomenon. Moreover, we study the reasons behind the optimal parameters.Theoptimalmutationrate,inagreementwiththehypermutationrateinvivo,resultsfromatradeoffbetween accumulatingenoughbeneficialmutationsandavoidingtoomanydeleteriousorlethalmutations.Theoptimalselection strength evolves as a balance between the need for affinity improvement and the requirement to pass the population bottleneck. These findings pointtothe conclusionthat germinal centers havebeenoptimized by evolution togenerate strongaffinityantibodieseffectivelyandrapidly.Inaddition,westudytheenhancementofaffinityimprovementduetoB cell migration between germinal centers. These results could enhance our understanding of the functions of germinal centers. Citation: Zhang J, Shakhnovich EI (2010) Optimality of Mutation and Selection in Germinal Centers. PLoS Comput Biol 6(6): e1000800. doi:10.1371/ journal.pcbi.1000800 Editor:ArupK.Chakraborty,MIT,UnitedStatesofAmerica ReceivedJanuary19,2010;AcceptedApril29,2010;PublishedJune3,2010 Copyright:?2010Zhang,Shakhnovich.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeC