NongeneticinheritanceandtransgenerationalepigeneticsMosheSzyfDepartmentofPharmacologyandTherapeutics,McGillUniversityMedicalSchool,3655SirWilliamOslerPromenade#1309,Montreal,QuebecH3G1Y6,CanadaTheideathatinheritedgenotypesdefinephenotypeshasbeenparamountinmodernbiology.Thequestionremains,however,whetherstablephenotypescouldbealsoinheritedfromparentsindependentlyofthegeneticsequenceperse.Recentdatasuggestthatparentalexperiencescanbetransmittedbehaviorally,throughinuteroexposureofthedevelopingfetustothematernalenvironment,orthrougheitherthemaleorfemalegermline.Thechallengeistodelineateaplausi-blemechanism.Inthepastdecadeithasbeenproposedthatepigeneticmechanismsareinvolvedinmultigener-ationaltransmissionofphenotypesandtransgenera-tionalinheritance.Theprospectthatancestralexperiencesarewritteninourepigenomehasimmenseimplicationsforourunderstandingofhumanbehavior,health,anddisease.EvidencefornongeneticmultigenerationaltransmissionofparentalexperienceNewadaptivephenotypescanemergeasaresultofnaturalselectionofgeneticvariants.Naturalselectionishighlyinefficientandslowinrespondingtoimmediateenviron-mentalchallenges.Itiswellknownthatphysiologicalsystemscanrespondandadapttonewchangesinrealtime,butthequestionremainswhethertherearenonge-neticprocessesthatcouldestablishstablephenotypesandwhetherthesecanbeinheritedthroughgermlinetrans-missionacrossgenerations.Biologicalexampleshavebeendocumentedofphenotypicplasticityemerginginrelativelyfasttime-scales,andoffrequenciesthatareordersofmagnitudehigherthancanbeexplainedbynaturalselec-tion(seee.g.,[1]).Epidemiologicalevidencefromtwoimportantmultigen-erationalstudieshasbroughttotheforetheprospectofepigeneticmemoryofancestraldietarydistressinhumans.First,Pembreyandcolleagues[2–4]examinedrecordsofthemultigenerationalO¨verkalixcohortsinNorthernSwedenusingharvestandbirthanddeathrecords.Varia-tioninthefoodsupplyduringtheearlylifeofpaternalgrandparentswasassociatedwithvariationinmortalityrate(anddiabeticdeaths)intheirgrandchildren.Therewe...
