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1、LeadingEdgeEssayGeneticHeterogeneityinHumanDiseaseJonMcClellan1,*andMary-ClaireKing2,*1DepartmentofPsychiatry2DepartmentsofMedicineandGenomeSciencesUniversityofWashington,Seattle,WA98195-7720,USA*Correspondence:drjack@uw.edu(J.M.),mcking@uw.edu(M.-C.K.)DOI10.1016/j.c
2、ell.2010.03.032Strongevidencesuggeststhatraremutationsofsevereeffectareresponsibleforasubstantialportionofcomplexhumandisease.Evolutionaryforcesgeneratevastgeneticheterogeneityinhumanillnessbyintroducingmanynewvariantsineachgeneration.Currentsequencingtechnologiesoff
3、erthepossibilityoffindingraredisease-causingmutationsandthegenesthatharborthem.“EveryunhappyfamilyisunhappyinitsAnEvolutionaryPerspectivetions,smallinsertionsanddeletions,ownway,”wroteTolstoyinAnnaKar-Thegeneticbasesofdiseaseinmod-andlargercopynumbermutationsenina.To
4、lstoywasreflectingontheindi-ernhumansreflectthearchitectureand(McKernanetal.,2009).Mostoftheseviduallyuniquenatureofhumantragedy.evolutionofthehumangenome.Theold-mutationslikelyhavenofunctionalsig-Wesuggestthatthisprinciplealsocap-esthumanallelesoriginatedinAfrica,in
5、nificanceandpersistbychanceintheturesthemisfortuneofhumandisease.parallelwiththedevelopmentofourspe-absenceofselectivepressure.Incon-Thatis,fromtheperspectiveofgenetics,cies,millionsofyearsbeforepeoplefirsttrast,mutationswithdeleteriouseffects,wesuggestthatcomplexhum
6、andiseasemigratedoutofAfrica50,000to60,000eitheronviabilitybeforereproductionorisinfactalargecollectionofindividuallyyearsago(Cavalli-Sforzaetal.,1994;onfertility,arelessfrequentlytransmit-rare,evenprivate,conditions.Disentan-Cavalli-SforzaandFeldman,2003)(Fig-tedtos
7、ubsequentgenerations.Bythisglingtheparadoxesembeddedinthisure1A).Theseancientpolymorphismsreasoning,itshouldbenosurprisethatideawillbethesubjectofthisEssay.aresharedbyallhumanpopulationsseveremutationsassociatedwithearly-Inmolecularterms,wesuggestandaccountforapproxi
8、mately90%ofonsetdiseasearedisproportionatelyofthathumandiseaseischaracterizedhumanvariation.Thesepolymorphismsrecentoriginandarethe
