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GE46CH07-Anholt ARI 13August2012 9:25 E V I E R W Review in Advance first posted online S on August 28, 2012. (Changes may still occur before final publication online and in print.) E I C N N A D V A Genetics of Aggression Robert R.H. Anholt1,2,3,∗ and Trudy F.C. Mackay2,3 1DepartmentofBiology,2DepartmentofGenetics,and3W.M.KeckCenterforBehavioral Biology,NorthCarolinaStateUniversity,Raleigh,NorthCarolina27695-7617; email:[email protected];[email protected] y. ws.orguse onl vienal eo ualrpers ww.ann12. For m w15/ o0/ oaded frerst on 1 Annu.Rev.Genet.2012.46:145–64 Keywords ownlAmh gTehneetA.annnnuuaallRreevviieewwso.foGrgeneticsisonlineat behavioralgenetics,neurogenetics,complextraits,gene-brain 46. Detts - Thisarticle’sdoi: behavior,comparativegenomics net. 2012.Massachus A1C0lol.p1r1yigr4hi6gt/hsatnre(cid:2)ncsuerr2ev0ve1-d2gebnyeAt-n1n1u07al1R1-e1v5ie5w51s.4 AAgbgsrtersasicotn mediates competition for food, mating partners, and v. Gey of 0066-4197/12/1201-0145$20.00 hhaiebriatractshieasn.dI,nhamumonangs,saobcniaolrmanalimagaglsr,esesisotanbilsisahheasllmstaabrkleofdnoemuirnoapnscye- nnu. Reniversit ∗Correspondingauthor cohniaatnricunddiseorlrydienrgsganendectiacnsbuesceelpictiibteildityb.yIednevnitriofynimngenthtaelgfaecnteotriscaacrtcihnig- AU y tecturethatpredisposestoaggressivebehaviorinpeopleischallenging b because of difficulties in quantifying the phenotype, genetic heterogeneity,anduncontrolledenvironmentalconditions.Studiesonmice have identified single gene mutations that result in hyperaggression, contingent on genetic background. These studies can be comple- mented by systems genetics approaches in Drosophila melanogaster, in which mutational analyses together with genome-wide transcript analyses, artificial selection studies, and genome-wide analysis of epistasishaverevealedthatalargesegmentofthegenomecontributes to the manifestation of aggressive behavior with widespread epistatic interactions.Comparativegenomicanalysesbasedontheprincipleof evolutionarilyconservationareneededtoenableacompletedissection oftheneurogeneticunderpinningsofthisuniversalfitnesstrait. 145 Changes may still occur before final publication online and in print GE46CH07-Anholt ARI 13August2012 9:25 “Itisbettertobefearedthanloved,ifyoucannot of aggression are also harmful, as they divert beboth.” energy from other essential activities, such as Niccolo´Machiavelli(1469–1527) foraging; and they may carry a reproductive Sexualselection: cost (86) and a high risk for injury or death. atypeofnatural selectioninwhich Thus,onecanpostulatethataggressionisatrait membersofonesex AGGRESSION:AUNIVERSAL under stabilizing selection (Figure 1), a hy- choosemateswith FITNESSTRAIT pothesisthathasbeencorroboratedbystudies particularfeatures onspeciesasdiverseaswaterstriders(39)and AggressionasaQuantitativeTrait Stabilizingselection: baboons(86)(Seesidebar,GroupAggression). selectionthatselects Aggressivebehaviorenablesindividualstosur- Fromageneticsperspective,aggressionisa againstextreme vive by allowing them to compete for limited quantitativetrait,themanifestationofwhichis phenotypicvaluesand favorsintermediate resources. Among social animals, aggressive attributabletomultiplesegregatinggenesthat valuesofatrait, displaysservetoestablishhierarchiesinwhich aresensitivetotheenvironment(40).Heritabil- therebyreducing the most dominant individuals have priority ityestimatesforaggressivebehaviorinpeople y. phenotypicvariation ws.orguse onl Hpreorpiotartbioilnityo:fthe adcocmesisnatnocefosotdatuasndremfleacttinsgfitpnaerstsn,efresm. Baleecsauarsee ainreagsetundeyraollfy3h–i1g0h-,yeraarn-goilndgDfurotcmh t0w.5in1s–0(5.772) vienal phenotypicvariation expectedtoselectdominantmalesaspreferred and 0.37–0.57 in a study of adult twins (124). eo mating partners. Morphological characteris- Itshouldbenoted,however,thatnonadditive ww.annualr12. For pers tgheanteitsicexvparlaiaintieodnby tianisctssre,iccsoautncedhvairasyusacblhoaandraydc/taoerrrmivsooticrca,slstdihziaseptsloaefyrsva,enctaalsenpresr,vooxalinvedes gaosernwsehetailcrlevadasreisaxhtpaieorrenidefnroocrmesc,doaorrmreeillnaitkaenedlcyeetanonvdiirneoflpnaimstteaesneists-s, m w15/ forfitnessassessmentbymatingpartners(67). timates of heritability in humans by unknown o0/ wnloaded frmherst on 1 Iuhnaiedlresaeerdlce,hcaitegiosgnprer(es6sv7iev)ne.tTbsethhheeavenisoetaerbdilsfisoohrfmtceonennuttinnodufeesrdoscaeigxa--l aafogmrgooruetshnsetisvres(p4b0eec).hieaHsv,iiiognrhclhuhadevirneitgaabmlsilooitnybkeeeeysntsi(m4o1abt)se,esdrvofeogdrs oA gressionandassociatedriskofinjury.Whereas (98),mice(115),andbirds(33).Theseheritabil- 46. Detts - low levels of aggression may be detrimental ityestimatesshowthatasubstantialproportion 2012.achus tosurvivaland/orprocreation,excessivelevels oisfdpuheentootygpenicetviacrivaatrioiantioinn.agCgornessseiqvueebnethlya,vrioer- et. ass sponsetoartificialselectionforeitherincreased nM Rev. Gesity of GROUPAGGRESSION orarpdideacnredafsoerdmasgtghreebssaisviesfobrehsuacvcioerssfiuslgdeonmereasltliy- Annu. Univer Otorggeatnhiezretdoadgegfreenssdioonraomccounpgystoecrirailtoinrsye,citss,reinmwinhiiscchengtrooufphsuwmoarnk coaftiBoenl.yTaehvi’ssisRiullsussiatrnatseidlvbeyrtfhoexecsl,aswsihciecxhamafpteler by warfare(oritsmorebenevolentsurrogate,teamsports),inwhich selection for tameness retained their docile coordinatedactionagainstoutsidersisshapedbysociallyaccept- characteristicswhenselectionwasnolongerap- ableculturalnormsimposedonanunderlyingsusceptibilityfor plied,indicatingtheremovalfromthepopula- aggression.Socialinsects,suchasantsandhoneybees,formso- tionofallelesthatpredisposetoaggression(9). cieties in which only the queen is reproductively active. Such Environmentaleffectsonaggressioninclude societies, often considered a super organism, have divisions of internal effects, i.e., regulation by hormones, laborinwhichcertainindividualsarededicatedtodefendingthe and external effects, determined by the physi- queenandpreparedtosacrificethemselvestoensurethesurvival cal environment (e.g., stress) and, in the case oftheircloselyrelatedsiblingsorworktogethertoaggressively of aggression, other individuals in the society invadenewterritories.Selfandnonselfdiscriminationinantwar- (Seesidebar,HormonalRegulationofAggres- fareismediatedbypheromonalcuescomposedofcuticularhy- sion). Effects that arise when the genotype of drocarbons(49,53).Thisrepresentsanexampleofamechanism oneindividualmodifiestheexpressionoftraits forindirectgeneticeffects. inanotherindividualhavebeencoinedindirect genetic effects (77). Previous experiences and · 146 Anholt Mackay Changes may still occur before final publication online and in print GE46CH07-Anholt ARI 13August2012 9:25 developmental conditions can also affect the Fitness expressionofaggression. The significant heritability of aggressive behavior presents a favorable scenario for identifying quantitative trait loci (QTLs) Injury risk Social dominance thataffectaggressionbylinkagemappingand Grooming Survival associationanalyses.Tounderstandthegenetic architecture of aggression, it is necessary to Parental care Aggression Predator defense addressthefollowingquestions.Whatarethe Foraging Resource access genes that contribute to aggressive behavior? Reproductive cost Mating priority How do these genes interact in functional ensembles? How do polymorphisms within a Costs Benefits subsetofthesegenescontributetophenotypic variation?Howdogeneticensemblesthatme- y. views.orgnal use onl drtieioasnptesona(pdghgtreoensosctihvyaepnibcgeephslaaivsnitoicerintwyv)ii,trhoainnnmdaenhnotiwanldaicvnoiddnudtaio-l FSagcigghureemrsesait1viecbreephraevsieonrtaastiiotnreolfattehsetboafilatnnceessb.etweencostsandbenefitsfor eo whatextentdodifferentgenotypesvaryintheir ualrpers responsestodifferentenvironments(genotype- ww.ann12. For bwye-aerngvuireotnhmateinttisindtifefircauctltio(nifsn)?otInimtphoisssribevleie)wto, m w15/ obtain answers to these complex questions by wnloaded fromherst on 10/ ewthxeactlaudsivnivoteeclgaytreasttaeuscdoyhmiunpmgaarhanutimvgeeanngeetpniocospmusilctaustdiaoipenpssr,owaaincthhd HTcohuOenRtreeMrlpaatOirotNnisnAhfiiLpshRb,e1Et1wG-ekeUentLoatAegsgTtroeIssOtseiroNonnOea—nFdisAtewGsetGollsetResrtEaobSnlSeis—IhOeodrN.iItns oA studiesonmodelorganisms. 46. Detts - msuilctse,inartoemrriattoizriaatliobnehoafvtieosrtso(s1te2r1o)n.Ieninrattos,etshtreoegsetrnoignetnhreebcreapitnorreβ- 2012.achus PathologicalAggressioninPeople hasbeenassociatedwithaggressivebehavior(87),whereasexper- et. ass Abnormal expression of aggressive behavior imentsemployingvirallydeliveredshRNAshowsomeevidence nM Annu. Rev. GeUniversity of iiadsnnisjdaueracyssoue,msb.snmtSaetonuuncrdoeicpeoassnybocsuehnsqeiaut,theraeninccrdeeldonaitfesiouotrrrndaosuedhrmeispg,aetbniaceeltrcbwaortehaievionnel msfbotyuerdctihhineeacsnreoeissnatmsreeossdgtfreoaongrggarergenecgserrsepeivcsteesoinproetnαossrin(ak1gnm0ao2iicn)c.kesotEdujsuittsrvpmoelgnaicyeielneshserxameuvceaeeldpsdhitaoiotmrew–donm,rptienhhdaiipstamateersstd-;, by genetic variation and neurodegeneration- trogenreceptorαincreasesmaleaggressionbutdecreasesfemale aggression,whereastheoppositepatternisobservedfortheestro- related aggression have focused primarily on genreceptorβ(23).Additionalhormonalsystemsthatcontribute Alzheimer’s disease. Physical aggression and toaggressionhavebeenimplicatedbystudiesonvolesandcich- agitation occur in a variable portion (20%– lidfishes.Amongprairievoles,avariablelengthmicrosatellitein 65%) of patients diagnosed with probable thepromoterregionofthevasopressin1areceptorregulatesre- Alzheimer’sdiseaseandareemotionallystress- ceptorlevelexpressionandisassociatedwithanxiety-relatedand ful for family members and caregivers. The socialbehaviors(50).However,thiscorrelationdoesnotholdup genetic factors that determine comorbidity acrossthevolephylogeny(44).IntheAfricancichlidfishAsta- of aggression with neurodegeneration remain totilapiaburtoni,administrationofasomatostatinantagonistin- largely unknown. Difficulty in obtaining creasedaggression,whereasanagonistreducedaggression(110). sufficiently large sample sizes and phenotypic Somatostatinreceptorgeneexpressionwasnegativelycorrelated heterogeneity have prevented large-scale withaggressivedisplays(111). linkage studies and genome-wide association studies and have limited genetic studies to www.annualreviews.org • GeneticsofAggression 147 Changes may still occur before final publication online and in print GE46CH07-Anholt ARI 13August2012 9:25 association analyses of single candidate genes. and exhibitionism. Affected individuals were Such studies have focused on a small number deficientintheactivityofmonoamineoxidase of genes either previously known to be asso- A(MAOA),acentralenzymeinthecatabolism Quantitativetrait ciated with Alzheimer’s disease or implicated ofbiogenicamines,becauseofapointmutation locus(QTL): a chromosomalregion inaggression.Alzheimer’sdiseasepatientsho- in the eighth exon of the MAOA gene, which thatharborsoneor mozygousfortheapolipoproteinEe4allelewere changed a glutamine to a termination codon. moregeneswithalleles reported to be more susceptible to aggressive Thiswasthefirstdemonstrationthatbioamine thatcontributeto episodes(25,114),butthisobservationwasnot metabolismmaybecriticalintheregulationof phenotypicvariation replicatedinapopulationwithalargersample impulsiveaggression.Subsequentstudieshave Linkagemapping: size(1,120patientsversus∼100–400patients) corroborated the association between MAOA locatingquantitative (54).Severalstudieshaveexaminedassociation polymorphisms and aggression in humans traitlocibylinkageto polymorphicmarker ofAlzheimer’sdisease–relatedaggressionwith (56,71),mice(12),andrhesusmonkeys(83). lociwithinafamilyor polymorphismsintryptophanhydroxylase(24), Thediscoverythatbioaminesignalingmay amappingpopulation serotonin 5HT-2A and 5HT-2C receptors play a critical role in modulating aggressive y. derivedfromcrosses ws.orguse onl bAestswoeceiantiionbnraendalliynseiss: (150,69,11)1,3a)n,dbutthtehesseerosttoundiinesthraanvespboeretenrc(o5n,tr9o2-, bceenhtarvailorneduirreocttreadnsamttiettnetrioinnvtoolvseedroitnonainggarsesa- vienal identificationof versialbecauseoflowstatisticalpower. sion, as lower levels of serotonin were related eo Studies on the catechol-O-methyl transferase toincreasedaggression.Apolymorphisminthe ww.annualr12. For pers qasptsuhasaetoinncstotiiaittctyaaetpldievdweibfiftetertharweiatenelconeciin (bgCreeOtwsMseioeTnn)itnhgesecVnheaizl1ho5apv8heMreiendtiecpnsot(il1fiy0me9do).raTpnhhiaessmMsoaecntia/dMtiaogen-t pl(oSrnLogmC6aoAltlee4rl)er)heagosifobnteh(eernesfaeesrrsoroetcodinatitoneadtsrwtahniteshpshoaogrtrgetrrveesgsreisonunes m w15/ genotypesat genotype has lower enzyme activity and is andawiderangeofneuropsychiatricdisorders o0/ polymorphicmarkers wnloaded frmherst on 1 tnTharatytuprsaetolgppreohgpaauntleatinioan aiincssscoidcaeinandtceedaolwcfoitshhuoihlciiicgdshee(ar8tlt0ee,vme8pls5ts)o.finaTgshgcerhseieszsoiopstnhurdaeinned-s (s7es9I)h.naveadimdiptiloicnatetoddsoeproamtoinnien,,ngoerenpeitnicepahnrainlye-, oA hydroxylase: the should be viewed with caution, however, andGABAneurotransmittersinaggression(72, 2012.46. Dachusetts - ripnaatttehh-welimabyiiotoisnfygsneterhonetztoyicnmine bicnoencadguietsnieodnoesfr,,thanpeadstmiehnaelttlershoaimgsetponlreeyit,syizeeonsf,vipdrsiofyfncemhreieanntcrteaicsl 7ype5ria)m.r-Aaorlydstcuaaddroyelgebisvacseeerndstasonandnds2e5alfs3sreteespsamochretensrtsosfifdr2eo9nm8tifi219e5d6- et. ass thatattachesa manifestations. Furthermore, interpretations anassociationofexternalizingbehaviorwitha nM hydroxylgrouptothe e Rev. Gsity of aCmaitneochaocild-Otr-ympteotphhyaln ogefnsetsudfoiersnoenuroppoaltyhmoolorgpyh-irsemlasteidnacgagnrdesidsiaotne vmaorirapbhleismnuimnbtheertthainrddeemxornepoefathte(VdoNpTamRi)npeoDly4- Annu. Univer tgrraonuspf–etrraasnes:fearrminegthyl acroerrceolamtiopnlesx,waitshitdiisseadsieffisctuatltustofrodmisccriamusianlaittye rgeocuespftoorrth(DeRshDo4r)taglelenlee.oIfntdhievsideuroatlsonhinomtroaznys-- by enzymeinvolvedinthe ontheaggressivephenotype. porter and carrying the DRD47r variant had breakdownof higherscoresforaggressionand/ordelinquent catecholamine behaviorthanothercombinationsoftheseloci neurotransmitters, includingdopamine, THEGENETICSOFAGGRESSION (51). This is a rare example of a demonstra- epinephrine,and INHUMANPOPULATIONS tion of epistasis in a human association study, norepinephrine inwhichtheeffectoftheshortalleleofthesero- ImplicationofBioamines Monoamineoxidase tonintransporterismodifiedbyapolymorphic (MAOA): anenzyme Thefirstmajorbreakthroughtoshedlighton siteintheDRD4gene(Seesidebar,Epistasis). thatinactivates the neurogenetic basis of human aggression monoamines,such came in 1993 from a study on a large Dutch asnorepinephrineand Genotype-by-Environment serotonin,by family (11). Several males in this family Interactions catalyzingtheir showed borderline mental retardation and oxidation abnormal violent behavior, which included Aggression,likemostbehaviors,isplastic,and impulsive aggression, arson, attempted rape, itsmanifestationdependsontheenvironment. · 148 Anholt Mackay Changes may still occur before final publication online and in print GE46CH07-Anholt ARI 13August2012 9:25 Furthermore, this phenotypic plasticity may dependonthegenotype(Figure2).Following EPISTASIS the identification of risk alleles for aggressive behavior of the MAOA and serotonin trans- Epistasis occurs when the action of one gene is modified by porter genes, it became clear that the effects oneorseveralothergenes,resultinginnonadditivephenotypic of these alleles were dependent on previous effects. Such modifiers can be enhancers or suppressors. The experience.Astudyonalargesampleofboys analysis of epistatic interactions, especially higher-order inter- with a history of childhood maltreatment actions,isstatisticallychallengingunderconditionsinwhichthe showedthattheVNTRatthepromoterofthe geneticbackgroundcannotbepreciselycontrolled,asisthecase MAOAgeneisassociatedwithviolentbehavior formosthumangeneticsstudies.Consequently,humangenetics onlyinindividualswhowereabusedaschildren studieshavemostlybeenrestrictedtotheresolutionofadditive (13, 60). Maltreated children with high levels effects. In Drosophila melanogaster, the genetic background can of this enzyme were less likely to develop be controlled precisely, and large numbers of individuals can antisocial problems than maltreated children be reared under controlled environmental conditions. Analysis y. ws.orguse onl wFuitrhthleorwslteuvdeilessorfeMpoArtOedAtehxaptretshsiisonge(n3o5,ty5p6e)-. oexftednosuivbeleephiesttaesrioszfyogrooulfsacPt-oerlyembeehnatviionrs(e4r2ti,o9n9)l,isnteasrtlheabseshhaovwionr vienal by-environment interaction is gender specific (123),andaggression(129),andsuppressingepistasisofnaturally eo (56) and that extreme cases of maltreatment segregating modifiers of transposon-tagged genes that affect ualrpers overshadowed the differences between alter- startlebehavior(122),olfactorybehavior,sleepphenotypes,and ww.ann12. For ncaarteeMcoAuOldAmalilteilgeaste(12th0e).Ienffeacdtdsitioofn,stpraersesnotanl wwaidkeinspgreaacdtiveiptyisthasaissbiseeangedneemraolnfsetartautereda(c1r0o5s)s.pIhtyilsa,liiknecllyudtihnagt m w15/ behavioral outcomes in female carriers of the humans,inwhichitmaybeanunderlyingcauseforthemissing o0/ wnloaded frmherst on 1 MaroctrAievOditAtyh(ea6sl1ele)o.lebAswesrtivuthadtyioloonwns.rRmhheoesnusuossammmoionnnekkeeyoysxsimdthaisrae-t hefafeflrlesicttassbhioolifrttymocaofnnyeuxnlpodlcariiuntmihn,agtthctehooenbtrtsioebtruavltaetoiotbonsectrhovametdpthlgeeexnatdertdaiiicttiovvnaarroiiaafttiitoohnne oA were reared under adverse social conditions (70,128).Thus,itisreasonabletopredictthatinpeople,asin 46. Detts - (small social groups versus large interactive flies, the genetic underpinnings of aggressive behavior involve 2012.achus gthreoyupcsa)rwrieerdetmheorMeaAgOgrAesasilvleel,eescpoercreiaslplyonwdhineng epistaticnetworksofpleiotropicgenes. et. ass tolowlevelsofenzymeactivity(59). nM e Rev. Gsity of actiAonsiemffielacrt gheansobteyepne-rbeyp-oenrtveidrofnomretnhteisnhtoerr-t theGMenAoOtyApean-bdy-SeLnCv6irAo4nmalelneltesinotneraagcgtiroensssioonf Annu. Univer atrnadnslopnorgtearllegleenpeo.lyHmeorrep,hpisemopoleftwheithseroontoenoinr hliakveelynboetcabueseenoufntihveersloalwlysrteaptilsitciactaeldp.oTwheirsoisf by two copies of the short allele exhibited more some studies; differences in ethnicity, age, depressivesymptomsasaresultofstressfullife and sex of the study subjects; and different experiences than did individuals homozygous environmental factors analyzed to determine for the long allele (14, 62). Associations of genotype-by-environment effects. Confound- Externalizing promoter polymorphisms of the serotonin ingfactorsofotherneuropsychiatricinfluences behavior: behavior transportergenewithaggressivebehaviorhave of allelic variants at these loci introduce a thatdirects problematicenergy beenreportedinsomecases(48,74,107),but furtherconfoundingelementintheinterpreta- outwardandis associations with suicidal behavior (which can tionofgenotype-by-environmentinteractions. expressedas be considered a form of self-aggression) have Genotype-by-environment interactions to- aggression,defiance, beencontroversial(10,96,112).Also,cocaine getherwithgeneticbackgroundeffectspresent bullying,vandalism, dependence did not affect differences in major complicating factors for larger-scale theft,andother sociallyunacceptable aggressive behavior among African-American genome-wide association studies in human actions individualswithalternativealleles(88). populations. www.annualreviews.org • GeneticsofAggression 149 Changes may still occur before final publication online and in print GE46CH07-Anholt ARI 13August2012 9:25 a b e e u u val Genotype 1 val c c Genotype 1 pi pi y y ot ot n n e e h h P P Genotype 2 Genotype 2 Environment 1 Environment 2 Environment 1 Environment 2 views.orgnal use only. FIgenneigtnveuiorrrtaoyecnptm2ieosen.ns(atbs)ebPtuwhteetneonottthyhpeeiscgapemnlaeosmetixcetietaynn.td,Prhtehesenuloetntiynvpgiricoinnvmpalauerenasltl.seThlirhfeteafcbotlriuobenoatnnhodrgmreensdo.ct(byo)ploGersesinnroetpthyrepesetew-nboty-ddeiinffffveeirrreeonnnttment eo ualrpers interaction.Phenotypicvaluesareaffecteddifferentlyforbothgenotypesinthetwoenvironments.The ww.ann12. For gpenehnveionrtooytnpymepieicnndvtai1clu,atereeodsufblttyhinethggeeinnbolcutreyopsliseninienghdoaicfsaritdeeaedcntbtiiyocnathlnpeohrreemndsol.tinypeiicsvsaulbusetsanintiealnlyvihroignhmeernintse1navnirdon2m,wehnetr2eathsathnein m w15/ o0/ et. 2012.46. Downloaded frassachusetts - Amherst on 1 CAPWtbtoheosheeahspnnaeosutlrecildesleriaeaooansfitcttignioioapoineltoninsianlvsnyefSmdoltytrvrouairionGdmplsiheppeeniolnssitmrcobtiaensmetrehHideanav-niuiWnogdmrep,inMadiretenesiAdsiOecsnlpAeocaosrihdttiaihonvanget mocdnitfnraifieoaifadenftsmkiedipveopreisetnhdceonieuinstcfirnatoedeucloussciidtftgryfimiyubehpcisecaiut.ctokslawIuteninnlbedtaiofeajturoendgcvqcrdiemituvrsieathetatiunhotottaoitmnonoilfli,nyyocsggugeatierghnemnnpnrioddaspoemseDoutosrrsepuNas-dassiiw,tibAsfglfiaaaedestemnraentaemdpooanllmespecotsvlehboeoeese---sfl, nM theyrepresentonlythetipoftheicebergofa e Rev. Gsity of cmoimnepsleaxggnreeusrsoivgeenbeethicavairocrh.iHteuctmuraentshtautddieesteorn- wsigidneifimcaunlctiep.leTtheessteingdatuhnrteisnhgolcdhaflolernsgteatsishtiacvael Annu. Univer tmhoesgtleyneotnicseoxfcevsiosilveentabgeghraevssioiornharvaethceernttehraend cieosrroanlleadggtrheessmioanjoirnittoyoafsheaurmchanfogretnheetilcosssttukedy- by on the genetic underpinnings that contribute underthestreetlight,astheycontinuetofocus mostly on a small number of well-established to phenotypic variation in the normal range candidate genes related to bioamine function of aggression in the human population, with and metabolism. Advances in understanding phenotypesencompassingthefullspectrumof thecomplexgeneticarchitectureofaggressive shyness, assertiveness, chronic suppressed or behavior will benefit from the recruitment overt anger, intimidating behavior, and incli- of model organisms in which the phenotype nation toward violence. As with most studies can be accurately quantified and the genetic of neuropsychiatric disorders, quantification backgroundandenvironmentalconditionscan of aggression relies on questionnaires or, in bepreciselycontrolled.Comparativegenomic thecaseofstudiesonchildren,interviewswith studies can discover evolutionarily conserved parents or teachers. Nevertheless, the pheno- principles and orthologous genes and genetic typic complexity of aggression, with its many networks that are associated with aggression manifestations and multiplicity of triggers, acrossphyla. · 150 Anholt Mackay Changes may still occur before final publication online and in print GE46CH07-Anholt ARI 13August2012 9:25 INSIGHTSINTOTHEGENETICS recorded. Aggression in mice is mediated via OFAGGRESSIONFROMMODEL neural pathways similar to those in people ORGANISMS (Figure 3) (82). Furthermore, similar neuro- transmittersareimplicatedinthemanifestation GeneticsofAggressioninMice of aggressive behavior (82). Mice with a dele- Aggressive behaviors in mice can be readily tion of the MAOA gene show enhanced quantifiedbythenumberofattacksandattack intermale aggression as adults (90, 101). duration when mice are placed in various Serotonin suppresses aggressive behavior situations of social confrontation (76). In the (20, 74), whereas dopaminergic (94, 117) resident-intruderassay,aresidentmaledefends and noradrenergic (72) mechanisms enhance his territory (i.e., home cage) by attacking an aggression. Modulation of aggression by intruder.Maternalaggressionofafemalewith serotonin is, however, dependent on the type pupsagainstastrangemalecanalsobereadily ofserotoninreceptorthatisactivated(47,82). Malemicethatlackthe5-HT1Breceptorshow y. ws.orguse onl vienal Chemical Visual and auditory eo cues social cues, stress ualrpers ww.ann12. For Rodent brain m w15/ o0/ oaded frerst on 1 Orbitofrontal Hippocampus wnlmh Olfactory cortex 46. Doetts - A bulbAccessory sLeapteturaml 2012.achus olfactory bulb Boefd t hneu cstleriuas net. Mass terminalis Periaqgureeyductal e v. Gy of Resit Paraventricular nnu. niver nucleus AU by hypAonttheariloamr ic Medial area amygdala Inhibitory inputs Aggression Figure3 Brainregionsimplicatedinaggressivebehaviorinrodents.Chemosensoryinputscantriggeraggressionthroughtheolfactoryand accessoryolfactorysystems,whereasvisualandacousticinput,adversesocialinteractions,andstressgenerallyelicitaggressionin humans.Inrodents,chemosensorysignalsactivatethemedialamygdala,whichsendsprojectionstothelateralseptum,thebednucleus ofthestriaterminalis,andtheanteriorhypothalamus.Projectionsfromtheseregionstotheperiaqueductalgrayresultintheexpression ofaggression.Inhibitoryinputs(dashedlines)canmodulateaggression.Projectionsfromtheorbitofrontalcortextotheamygdalainhibit aggression.Optogeneticstimulationofneuronsintheventrolateralsubdivisionoftheventromedialhypothalamuselicitsindiscriminate aggressivebehaviorinmalemice(66).Patientswithorbitofrontalcorticallesionsarepronetouninhibitedaggressivebehaviors(fora moredetaileddescriptionofneuralmechanismsofaggression,seeReference82). www.annualreviews.org • GeneticsofAggression 151 Changes may still occur before final publication online and in print GE46CH07-Anholt ARI 13August2012 9:25 high levels of aggression (100), whereas mice prevents signaling via V2R receptors and treated with a 5-HT1A receptor antagonist resultsinincreasedaggression(16). show reduced aggression (8). Raising synaptic The genetic analysis of aggression in mice Homologous serotonin levels by deleting the serotonin hasemployedtwoapproaches:QTLmapping recombination: breakageandreunion reuptaketransporterviahomologousrecombi- and analysis of single gene mutations. In the betweenhomologous nationalsolowersaggressivebehavior(52,65). former approach, an aggressive strain of mice lengthsofDNA,used Thediverseeffectsofserotoninimplicatemul- (e.g., BALB/cJ) is crossed with a nonaggres- inknockoutmiceto tipleneuralcircuitsthatorchestrateaggressive sive strain (e.g., A/J), and linkage analysis is generatedefective behavior. performed in an F2 population. Such a study allelesofthetarget gene Although internal hormonal factors identified chromosomal regions that harbor influence the propensity for aggression, envi- geneswithallelicvariantsassociatedwithvaria- ronmentaltriggerscanelicitacuteexpressionof tioninaggressionbetweentheparentalstrains aggressivebehaviorsthroughactivationofthe (31). However, these studies are limitedin endocrinesystem.Theseenvironmentalsignals that the mapping population is derived from y. ws.orguse onl abryepphriemroamriloyncehermeciecpaltocrusesinthathtearveormeceorgonniazseadl orenllaytivtweloylpimarietnedtalsasmtrpaliensofanndatuthraulspchaepntoutryepsiac vienal organ,achemosensoryorganlocatedabovethe variation.Ithasbeendifficulttoidentifycausal eo palatethatmediatesthereceptionofchemical alleleswithinlargechromosomalQTLregions ualrpers signals that provide social information about inmice.Testingtheeffectofknockoutsofevery ww.ann12. For kpirnesshenipceorofgepnrdeedratoorrsin(f5o8rm, a7t8io,n10ab8o).utVt1hRe cnaontdfiedaastiebglee.nTewheithCinolsluabchoraartievgeioCnriossgse,nwerhailclhy m w15/ pheromone receptors are G-protein-coupled consists of inbred lines derived from an ad- o0/ wnloaded frmherst on 1 abrepycicesapmltaovlrolsmmtheoralotencsuaigsleanlsalnfoveuiuanrodGniis2n,aaunrrdeinaeerxep(6rae3cs)ts.ievVdat2beRdy vmcoaonmucmesedunisntittryearirncerssoosausnrpdcoepifsuolrabtheiiiognnhg-orfgeeesnoigleuhrtatitodenidffQearTsenLat oA receptors constitute a class of pheromone mapping(22),holdsgreatpromisefortheiden- 46. Detts - receptors related to metabotropic glutamate tificationofnarrowerQTLregions(6)butmay 2012.achus rbeacseapltloaryseranodfatrheeevxopmreessreodnabsyalnoerugraonn.sTinhtehsee stillInfaslltusdhioerstcoofmidpelenmtifeynintagrycatuosQalTalLlemlesap(7p3in).g net. Mass receptors signal via G0 and recognize peptide approaches,severalsingle-genemutationshave e Rev. Gsity of lhigisatnocdos,minpcaltuibdiilnitgybarnetaikgdeonws(n1p7r).oMduicctesionfwmhaijcohr bAesepnoindteannteiofiuesdmthuattatrieosnultthiantlhaycpkseraafgugnrcetsisoionnal. Annu. Univer tthioenTcoRmP2pocnheanntnoefl,vaomceenrtornalassailgnnaelutrroannss,dwuca-s gasentehefofiretrhceenmuuctleaanrt,reshceopwteodrNexRtr2eEm1e,khnyopwern- by removed by homologous recombination were aggression(125),whichcouldbesuppressedby no longer aggressive in the resident-intruder introductionofafunctionalhumanhomologof assayandhadlostgenderdiscrimination,show- theNR2E1gene(1).Similarly,aknockoutmu- ingsimilarmatingbehaviortowardmalesand tation of the neuronal nitric oxide synthetase females(104).Furthermore,removalofalarge generesultedinmicethatrelentlesslyattacked cluster of 16 genes that encode vomeronasal even opponents who had surrendered or dis- V1R receptors resulted in reduced maternal played no interest in fighting and that killed aggression, indicating that one or more of their cage mates (81). Interestingly, maternal the deleted receptors interact with chemical aggressionagainstmaleintruderswasreduced cues that elicit maternal aggression (27). V2R inthesemice(46),whereasneuronalnitricox- receptors have been implicated in male-male idesynthetaseexpressionwasincreasedinmice aggressiontriggeredviamajorurinaryproteins selected for high maternal aggression (45). It (17). Tissue-specific deletion of the G hasbeensuggestedthatabnormalbehaviorsin α0 subunit through homologous recombination the neuronal nitric oxide synthetase knockout · 152 Anholt Mackay Changes may still occur before final publication online and in print GE46CH07-Anholt ARI 13August2012 9:25 mice may be due to compromised serotoner- and in mice but can be accomplished in the gicneurotransmission(20).Subsequently,ahu- powerfulD.melanogastergeneticmodel. man association study, which included 1,308 Attention patients with personality disorder, familial or deficit/hyperactivity AggressioninFlies:Enabling adult attention deficit/hyperactivity disorder disorder(ADHD): a SystemsGenetics (ADHD),suicideattempters,andcriminalof- familyofneurological fenders along with 1,954 controls, revealed a Drosophila presents a powerful model for the disordersthatprevent anindividualfrom promoterpolymorphismintheNOS-Igeneas- dissectionofcomplextraits,includingaggres- regulatingactivity sociatedwithimpulsivity,includinghyperactive sion, because large numbers of individuals level,inhibiting andaggressivebehaviors(93).Thisstudycon- of the same genotype can be reared rapidly behavior,andfocusing firmedearlierstudieswithsmallersamplesizes, under controlled environmental conditions ontasks which implicated polymorphisms and haplo- and without regulatory restrictions. The first Ethogram: a typesintheNOS-IandNOS-IIIgenesinsuici- documentation of aggression in flies and its diagrammatic dalbehaviorinCaucasians(97)andapolymor- relation to mating behavior was reported in depictionofa ws.orguse only. cpohmismpleitnedthseui3c(cid:4)i-dUesToRfJoafptahneesNeOmSe-nI(g2e6n).ewith 1to9o7k5 mbyorDeotwhan&2v5onyeSacrhsilbcehfeorre(3D2)r,osbouphtiliat behavioralrepertoire vienal As is often found with single-gene muta- materialized as a model organism for the eo tions, the effects of both the null mutation in systematic genetic dissection of aggressive ualrpers neuronalnitricoxidesynthetaseandthefierce behavior (21). This required the development ww.ann12. For mgruotuantido.nTwheerehyinpfleruaegngcreedssibvye gpehneentoictypbeacko-f oeifthqeruavnidtietaottiavpeingme(2a8su)roers doirfecatgogbressesrivoantiobnys m w15/ the neuronal nitric oxide synthetase knockout offliesfightinginthepresenceofadecapitated o0/ wnloaded frmherst on 1 atChll5ee7leBCL5w/7a6BsJLga/be6noJel-it1sih2c9ebdabcaakfcgtkergroruobnuadcnkd(c6r4to)os.sSitnihmgeilfparruolrmye, foinefmvfooalloveedd(d21ekp)icrkoivirnagtai,ofncoho(ad3s7idn).rgoA,pgwlgeirtnegassftitveherrebaaetph,eaarviniooddr, oA the hyperaggressive phenotype of the fierce inextremecases,boxing,inwhichflieswould 46. Detts - mutation was attenuated in the B6129F1 tusslewhileholdingoneanotherwiththefront 2012.achus g(1e2n5e)t.icTbahceksgerofiunnddincgosmpilalurestdrawteiththCa5t7BgLen/6esJ lsehgosw.eEdthsoegxruaaml sdidmocourpmheinsmtinignthfiegshetibneghasvtyiolerss et. ass that contribute to aggression are subject to betweenmalesandfemales(84)inaccordance nM e Rev. Gsity of mbaocdkuglraotuionndsb,yunmdeordsicfioerrinsginthdeinffoertieonnttgheanteatgic- wobitsherbveehdafvoiorrvailrtduimalloyrpevheisrmyobtehtewrebeenhtahveiosrex(4es) Annu. Univer gfrroemssivaegbeenheatviicorairschaitpehcetunroetytpheatthcaotnesmisetsrgoesf asinvdeminotesrtaqcutiaonntistactainvebteramitos.dMulaatlee-dmbaylepargevgiroeus-s by ensembles of interacting genes. Disruption of experience and social context (89, 126), and certain components within such an ensemble subgroupsofneuronsofthesexuallydimorphic caneitherunleashahyperaggressivephenotype neuronalcircuitthatexpressesthemale-specific or can be buffered by other members of the form of the sex determination gene fruitless geneensembletoattenuatethemutationalef- havebeenimplicatedasonecomponentofthe fect.StudiesonDrosophilamelanogastermutants nervous system essential for mediating inter- incontrolledwild-derivedgeneticbackgrounds maleaggression(15,18,116).Similartostudies have shown that epistatic modifiers that seg- in people, serotonin has been implicated as a regateinnaturetendtoreducethemagnitude neurotransmitter that mediates aggression in of newly arising mutations (105, 122). The Drosophila(2,30).Inaddition,octopamine,the identificationofgeneticnetworksthatunderlie fly counterpart of norepinephrine expressed complexbehavioraltraitsandtheidentification in a subgroup of neurons that project to the of epistatic interactions on a genome-wide subesophagealganglion(15,55,127),andneu- scale are currently still impractical in people ropeptideF(30)modulateaggressioninflies. www.annualreviews.org • GeneticsofAggression 153 Changes may still occur before final publication online and in print GE46CH07-Anholt ARI 13August2012 9:25 Artificialselectionforincreasedaggression underlies aggressive behavior (37). The large implicated a cytochrome P450, Cyp6a20, in number of genes implicated in aggression is mediating aggressive behavior (29). Further consistent with the large mutational target Falsediscovery experiments showed that social experience evidentfromastudyinwhichascreenof170co- rate: theexpected proportionoffalse modulatesexpressionlevelsofCyp6a20andthat isogenicP-elementinsertionlinesidentified57 positivesamongall Cyp6a20expressionlevelsareinverselyrelated genes(∼35%)withaberrantaggressivebehav- significantresults tolevelsofaggressivebehavior(119).Expres- iorcomparedwiththecontrol(38).Thesestud- sion of Cyp6a20 in support cells of olfactory iesindicatethatalargesegmentofthegenome sensillasuggestedthattheactivityofCyp6a20 contributes to the manifestation of aggressive might be related to regulating pheromone behavior,anobservationthatislikelytoapply sensitivity that triggers intermale aggression across phyla, and underscores the importance (119). The pheromone 11-cis-vaccenylacetate of defining how individual loci interact in ge- elicits male-male aggression via the Lush neticnetworkstogainanunderstandingofthe odorant-binding protein and the Or67d complexgeneticunderpinningsofaggression. y. ws.orguse onl ocids-ovraacnctenreyclaecpettoarte(1a1re8)m, aonddultahteedefbfeycotslfoacft1o1ry- ensTemwboleaspporfoagcehneesshtahvaetbmeeendiuasteedatgogirdeessnitoinfy, vienal neurons expressing the Or65a receptor (68). onebasedoncovariantexpressionoftranscripts eo Furthermore, masculinization of females by and the other based on epistatic interactions. ualrpers expressing transgenes that are components of Microarray expression analysis of 40 inbred ww.ann12. For tphreodsuexcidnegteormeninoactyitoenspealtihciwteadyinattpahcekrsomraothneer- wshioldw-edderitvheadt thDerotsroapnhsiclariptmomelaeniosgahstiegrhlylingee-s m w15/ thancourtshipfrommales(43).Theseobserva- netically intercorrelated and organized as 241 o0/ wnloaded frmherst on 1 tasiigoggnnrsaelssihsniogvweinbthtehahetapvmihooerur,osaemnvaoolnomagleosruiogsnnataoslasplchoarengrotarnmig.ogneer btforiaornlaosgcggriicrpeatslslsyi(v7me).beeaThnhainevgiolfiurn,leasmnadordreeugvlearsestsolsyifodcniovovefarrpgiheanne-tt oA Theartificialselectionexperimentthatled notypicvaluesandtranscriptabundancelevels 46. Detts - to the identification of Cyp6a20 had limited followedbyclusteringanalysisoftheresiduals 2012.achus pwoitwhelrowbehcaeutesreoigteenmeiptylocyoemdpaobseadseopfoapmuilxattuiorne rtaeivneianlged26a6gneonvoemltircansisgcnriaptutsraesosofcmiaotedduwleisthcoang-- et. ass of different Canton S laboratory strains and gression(Figure4)(34).Aswithdifferentially nM e Rev. Gsity of abidsiirnegclteiosneallecsteeldectrieopnlicfartoem(2a9)h.etIenrocgoennteroasuts, eagxpgrreesssseiodntsrealnecsctiroipntslinaems,ocnogvalroiawn-ttarnadnschriigpht-s Annu. Univer bparesessipoonpualnaatliyosnesfoclolonwtreadstibnyg mduicprloicaartreayhiegxh- sapnadnmaanwyidareevthareieptryodoufctbsioolfocgoicmapluptraoticoensasellsy, by and low aggression lines revealed differential predictedgenesofyetunknownfunctions(34). expression of as many as 1,539 transcripts at The first evidence for extensive epistasis a stringent false discovery rate (>0.001), pro- in the genetic architecture for aggression in vidingaglimpseofthegeneticcomplexitythat Drosophila came from gene mapping studies −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→ Figure4 Modulesofcorrelatedtranscriptsassociatedwithaggressivebehavioramonggenome-widetranscriptionalprofilesfrom40inbred wild-derivedDrosophilamelanogasterstrains.(a)Heatmapofcorrelatedprobesetsorganizedasmodules,usingmodulatedmodularity clustering(MMC)(103).Phenotypicvalueswereregressedontranscriptabundancelevels,andtheresidualsofsignificantregressions wereclusteredintomodulessothatmemberswithineachmodulearemorehighlycorrelatedwitheachotherthanwiththoseoutside themodule.Thediagramshowspairwisecorrelationsbetween133transcriptsandthestrengthofcorrelationswithinthemodules decreasesdownthediagonal.Highlycorrelatedmodulesappearinred.(b)Anetworkviewofthemosthighlycorrelatedmodules,in whichtheedgesrepresentcorrelatedtranscriptsandthecolorcodesofthenodesrepresentthedifferentmodulesinpanela.Figure usedwithpermissionfromReference34. · 154 Anholt Mackay Changes may still occur before final publication online and in print