生理学与基因组学走向系统生物学

1ActaPhysiologicaSinica,February25,2006,58(1):1-4*Correspondingauthor.Tel:[phone];Fax:[phone];E-mail:[e-mail]:towardsystemsbiologyAllenW.Cowley,Jr.,MingyuLiangDepartmentofPhysiology,MedicalCollegeofWisconsin,Milwaukee,Wisconsin53226,USAAbstract:Thelasttenyearshaveseenanunprecedentedmergeofphysiologyandgenomics.Whilethefieldofphysiologicalgenomicsisstillveryyoung,theintroductionoftheconceptofsystemsbiologypromisestopropelphysiologicalgenomicstoawholenewlevel.Inthisbriefarticle,weoutlinedsomeofthegreatopportunitiesandchallengesforphysiologistsatthisexcitingtimeofphysiologicalsciences,andusedourownexperiencefromthelasttenyearsasanexampletodiscusshowwecouldexpandandgobeyondthecombinationofphysiologyandgenomicstoachieveasystemsunderstandingofbiology.Keywords:physiology;genomics;systemsbiology生理学与基因组学：走向系统生物学AllenW.Cowley,Jr.,梁明瑜威斯康星医学院生理学系，密尔沃基，威斯康星州53226，美国摘要：近十年来，生理学与基因组学达到了空前的融合。尽管生理基因组学还是一个非常年轻的研究领域，系统生物学概念的引入必将推进生理基因组学达到全新的水平。本文概要地叙述了这个令人振奋的生理科学的新时代给生理学家带来的机遇和挑战，并以我们自己近十年来的经验为例，讨论了怎样通过扩展和延伸生理学与基因组学的结合，从而对生物学得到系统的理解。关键词：生理学；基因组学；系统生物学中图分类号：Q4Physiologicalgenomics:anexampleWhentheHumanGenomeProjectwasinitiatedin1991,itwasnotclearwhereitwouldlead.Itwassuchanunprec-edentedundertakingintherealmofbiologicalsciencesthatonecouldnothelpwonderingaboutitsoutcomes.Al-thoughitisnowhardtobelieve,itwasnotatallobviousatthattimehowthissequencewouldbeused,iftheentiregenomecouldactuallybesequenced.Itwasnotlongbeforesomeofusbeganthinkingthatiftheseteamsofmoleculargeneticengineersweresuccess-fulinsequencingtheentiregenome,thenexttaskwouldbeevenmoreformidable-attachingfunctiontothetensofthousandsofgeneswithinthehumangenome.Inotherwords,thegenomehadtobelinkedtophysiology.Thusthenewfieldofphysiologicalgenomicsbegan.By1995,wehadassembledaresearchgroupattheMedicalCollegeofWisconsin(MCW)()tobegintomapimportantfeaturesofcardio-vascularandrenalfunctiontothegenomesofhumansandrats,startingwiththedeterminantsofbloodpressure.Theetiologyofhypertensionremainsoneofthegreatestenig-masinclinicalmedicine,withtheage-adjustedprevalencerisingbynearlyfivepercentagepointsoverthepast15yearstoapproximately30%oftheentirepopulationintheUS[5].Theratisanexcellentmodelforthestudyofmanyaspectsofhumandisease,includinghypertension[6].ThisworkwaspropelledintoaproductionmodebyourcollaborationwithDr.HowardJ.JacobofourMCWgroup().Dr.Jacobhaddevelopedapanelofgeneticmarkersfortheratthatspannedtheentirege-nomeandcouldbeusedforchromosomallocalizationoftraitsinrats.ByutilizinganF2crossoftheBrownNor-ActaPhysiologicaSinica,February25,2006,58(1):1-42way(BN)ratandtheDahlsalt-sensitive(SS)rat,weana-lyzed239phenotypesand219genotypesin325rats,gen-eratingapproximately17milliondatapoints.Thisdatasetenabledustomap81phenotypesonto19chromosomesandcreatedthefirstlarge-scalephysiologicalgenomicmaplinkingcardiovascularfunctionstotheratgenome[12].Sub-sequentanalysisindicatedsignificantgenderdifferencesinthesemaps[11](Fig.1).Toovercomesomeofthelimitationsofgeneticlinkageanalyses,Dr.JacobandourgroupbeganaProgramforGenomicApplicationsthatwassupportedbytheNationalHeartLungandBloodInstituteoftheNationalInstitutesofHealth.Thegoalwastogeneratecompletepanelsofconsomicratsderivedfromcombinationsofinformativeratmodels.Aconsomicratishomogeneousinallitsallelestooneratstrain,exceptforonechromosomethatisho-mogeneousforanotherratstrain(Fig.2).Fromthisresearch,acompletepanelof22consomicstrainsofSSwithBNsubstitutionsaswellasacompletepanelofFawnHoodedratswithBNsubstitutionshasbeencreated.Ithasbecomearenewablenationalresourceforstudyingtheimpactofallelicvarianceuponnormalfunctionanddisease.Utilizingtheseconsomicrats,wehavemeasured327physi-ologicalparametersin13740rats,andtheoutcomesarefreelyavailableat[3,4,7].Buildingonthesuccessoftheconsomicpanelswebuilt,wehavenowgeneratedpanelsofcongenicratsinwhichonlysmallsegmentsofachromosomearesubstituted.Anon-redundantpanelofcongenicratswithsegmentsofSSchromosome13substitutedwithBN13wasselected,basedonphenotypiccriteria,fromoverlappingcongenics.Weareutilizingthisnon-redundantpanelofcongenicstofurthernarrowchromosomalregionsthatcontaingeneticvariationsinfluencingbloodpressuresaltsensitivityandotherimportantphenotypes.Toestablishcause-effectrelationshipsbetweenanyse-quencevariationswithphenotypicdifferences,itisneces-sarytomanipulatespecificallythegeneorgenesidentifiedbycorrelativestudies.Severalapproacheshaveprovedsuccessfulforthisprocess,oneofwhichisdevelopmentoftransgenicrats