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PM06CH16-Varki ARI 10December 2010 12:17 Biomedical Differences Between Human and Nonhuman Hominids: Potential Roles for Uniquely Human Aspects of Sialic Acid Biology g or s. w viey. Nissi M. Varki,1 Elizabeth Strobert,2 ualree onl Edward J. Dick Jr.,3 Kurt Benirschke,1 ns w.annal u and Ajit Varki1 wo ded from w11. For pers Te12CYmreaearininklt:ieenvsragNfroCkarietaAindoctmneaaridnl,e@UPmruniicmcivsReadtr.eeessidetRuyaeroscefhaCarcnahldifCTorernnaiitanerian,tgESmiannoADryniteUhgrnooi,vpLeoragseJitonyly,l,aA,GtCllayancltiofaob,riGonlieoaog9ryg2iR0a9e33s0e-a00r62c82h7;and wnloa01/26/ R3Seosueathrcwhe,sStaNnaAtinotnoanliPo,riTmeaxtaesR78es2e4a5r-c0h5C49enter,SouthwestFoundationforBiomedical Doon 5-393. Diego Annu.Rev.Pathol.Mech.Dis.2011.6:365–93 Keywords 6:36San FirstpublishedonlineasaReviewinAdvanceon chimpanzees,humanevolution 11.a - November8,2010 Dis. 20aliforni TDihseeaAseninsuoanllRineeviaetwpoaftPhoatlh.aonlonguya:lMreevciheawnsi.somrsgof AAlbthsotruagchthumans are genetically very similar to the evolutionar- Mech. y of C T10h.1is1a4r6t/icalnen’sudreovi:-pathol-011110-130315 ily related nonhuman hominids (chimpanzees, bonobos, gorillas, and Rev. Pathol. by Universit CA15lol5pr3yi-gr4hig0th0s6tr/e(cid:2)1cse1r2/v00e21d218b-0y3A6n5n$u2a0l.0R0eviews. ouiccunraarilrnqceugodeunltddyauinhtrsiuio)nm,ngsac.hnoSumdomimpffaaeenrradeetinifvvfcoeeelrsuesitnntiocutendhs.ieeaHsrineocsdwuiudgeeevgnteeocrse,tamnaanaatdnos/yumorrcipcasreanilvsnieconhrtgiatnbynegoeufesmbxtpihbolaeamtrineoedocd--f u. either by these changes or by known environmental factors. Because n n A chimpanzeeswerelongconsideredmodelsforhumandisease,itisim- portant to be aware of these differences, which appear to have been deemphasized relative to similarities. We focus on the pathophysi- ology and pathobiology of biomedical conditions that appear unique tohumans,includingseveralspeculativepossibilitiesthatrequirefur- ther study. We pay particular attention to the possible contributions of uniquely human changes in the biology of cell-surface sialic acids and the proteins that recognize them. We also discuss the metabolic incorporationofadiet-derivednonhumansialicacid,whichgenerates anovelxeno-autoantigenreaction,andchronicinflammationknownas xenosialitis. 365 PM06CH16-Varki ARI 10December 2010 12:17 INTRODUCTION NHHsforresearch(3).Apartfromtheseissues, humans appear to have several surprising dif- Mammalssuchasrodentsarefrequentlyusedas ferencesintheseverityand/orincidenceofdis- Sialicacids: generic experimental models for research into human easesandpathologiesthatcannotbeexplained termforafamilyof disease. However, the shared common ances- sugarswithacommon torofhumanswiththesespeciesexistedmany by environmental factors (4–9). Although this 9-carbonbackbone; situationposesachallengetotranslatingNHH tensofmillionsofyearsago(Mya)(1),allow- theyaretypically studies into the human condition, it also pro- ing ample time for genetic differences to de- foundattheoutermost vides an opportunity because of the extreme endofglycanchains, velopandprobablyexplainingthemultiplein- genetic similarities to humans (we are more whichdecorateallcell stanceswhereinmousestudiesdonottranslate surfacesinvertebrates well into studies on humans. Primate models closelyrelatedtoNHHsthanmiceandratsare andso-calledhigher toeachother). areconsideredmorerepresentative.However, invertebrates Inthisreview,weinterfacetheexistingback- even among primates, our common ancestor org with Old World monkeys was ∼25 Mya (2). ground and knowledge base regarding NHH s. diseases with our own ongoing research, in w Our closest evolutionary cousins are the so- ualreviee only. claasl,leadndgroeraatnagpuetsa(ncsh),imwiptahnwzeheosm,bwoneosbhoarse,gmoorirle- wtwheiecnh whuemhaanves faonudndNmHuHltsipwleitdhiffreergeanrcdestobea- ww.annonal us rmeacnenhtocmoimnimdso(nNaHncHesst;oserset(h2)e.sTidheebsaerennotnithleud- faacmidisly(10o–f1c2e)l.l-Wsuerfparceesesnutgianrtserkenstoiwngnbaiosmsieadliic- m wpers UpdatedClassificationofAfricanPrimates)are calconditions,emphasizingthedefinite,prob- ed fro1. For tmhaunsdoifsteeansec.oHnosiwdeerveedr,tthheerbeeasrtemmoadneylfissfcoarlahnud- aabnlde,NaHndHpsoasnsidblceondsififdeerrenpcoetsenbteiatwliemenplhicuamtioannss wnload01/26/1 ethicalissuesthatcurrentlyconstraintheuseof fporroporuiartesi.alWiceacrieda–lrizeelattehdatressiaelaircchacwidh–erreelaatepd- Doon changesareprobablynottheprimarycausefor 5-393. Diego UPDATEDCLASSIFICATION mareosmtaonfytohtehedrifgfeerneentcicesdidffiescreunssceeds.bAetlwsoe,enthheure- 6:36San OFAFRICANPRIMATES mans and NHHs (13) that we do not con- 11.a - sider here due to lack of space. Additionally, Dis. 20aliforni TmhoenkAefyrisc,aanpOesl,danWdohruldmparnims.aAtpeseswienretutrrandwiteiorenaslulybccllaassssiififieeddiinnttoo wtoecroemalipzaerethtahtevemryanliyttloethweorrkcohmasplbeexenaspdeocntes Rev. Pathol. Mech. by University of C lbdptehoirsfaenfstveeoirrhobeauuonpmsscel,eyaossnrc(iasslnainaasmgmsruieofiatreanbpndgahsssso,iecaalpaonnlagddlryyagg,taoibebrlembiyhlo.loaanMdvss)ii).oofiBarde,nedeadcrnnafogdugrrsfemeeuanontoofcamaftpipogiepcsnrsae,(rmachethunaiakmtmpleyaepsnm.aistnTawczrhlekeeueerassder,, oFilsfieuficcnmtgaailtenlyildo-ycno,iansswnyodsleauutrckaihonnrnetoiaswbubsoletadttshcwy.ea-ettbeyinlmnadthoiionunnmogsaamsncpicseghcahaintfirdicdailNettieeHmrsHotahdsse--. u. thereisanemergingnewclassification(170)inwhichtheterm In deciding which biomedical conditions n An hominoidorHominoideacontinuestobeusedforallapesand anddiseasestodiscuss,wechosetobeinclusive; humans and the lesser apes continue to be classified as Hylo- weevenmentionmanyspeculativepossibilities. batidae. The term hominid has been expanded to include not Thereasonsforthisapproacharetwofold.First, only humans but also the other great apes. The most distantly giventherelativelyfewNHHsincaptivitythat relatedgreatape(theorangutan)isclassifiedasPonginae.The havebeenstudiedtodate,thereisapotentialfor AfricangreatapesarenowclassifiedasHomininaeandhumans observationalbiasinonedirectionortheother. asHominini.Thesenewclassificationsarestillunderdiscussion Second, given that support of chimpanzee re- andhavenotyetbeenacceptedbyallinvestigatorsinthefield. searchbytheNationalInstitutesofHealthwas Forthepurposesofthisreview,wereplacethetermgreatapes, meant to provide models for human disease, whichisnolongertaxonomicallyvalid,withthetermnonhuman the tendency in published studies has been to hominids(NHHs). emphasizethesimilarities,ratherthanthedif- ferences, between NHHs and humans. Thus, 366 Varkietal. PM06CH16-Varki ARI 10December 2010 12:17 someoftheapparentdifferenceshavebeendoc- However, understanding these disease differ- umented only minimally and/or not formally encesrepresentsagreatopportunity.Ifhumans reported.Althoughthisreviewdescribesboth and NHHs are genetically so similar, any ge- definitivefactsandhighlyspeculativeconsider- neticexplanationsfordiseasedifferencesshould ations,westrivethroughouttomakeclearwhen be within reach. Such information could be our comments are true, likely, or speculative. collectedsimplybystudyingbothNHHsand We first mention biomedical conditions that humans in a similar fashion, and the results canbeplausiblyexplainedbyanatomicaldiffer- wouldbenefitthecareortreatmentofallthese encesbetweenhumansandotherhominids.We species. thenlistdiseasesandbiomedicalconditionsthat apparently cannot be explained by anatomical BIOMEDICALDIFFERENCES differences. The latter are classified into defi- BETWEENHUMANSAND g nite,probable,andpossibledifferencesonthe or NONHUMANHOMINIDSTHAT s. basis of the amount and type of information w viey. available. CANPROBABLYBEEXPLAINED ualree onl BYANATOMICALFACTORS nnus Somediseasesthatdifferbetweenhumansand w.anal NONHUMANHOMINIDSARE NHHscanbeexplainedbyanatomicaldiffer- wo GENETICALLYVERYSIMILAR m wpers TOHUMANSBUTMAYNOTBE ences.Thefollowingsectionsfocusonsuchdif- wnloaded fro01/26/11. For GCAsOOmMOenDMtioOMneNOdDHabEUovLMeS,AhFuNOmRDanIsSSOaEreMArSEeEmSarkably ftcehoreuelnddicseeexsa.pslIeanianneaditc.thheinasntaantocem,iwcaelbdrififeeflryendceessctrhibaet Doon similartoNHHsfromthegeneticperspective. 5-393. Diego Ithnedseeedo,thweershhoamreidniadscommomreornecaennctelsytothrawnitmhiaclel SHiunmuasnitisskull bones have four air-containing 6:36San and rats did with each other: Our common sinus spaces lined by epithelium that secretes 11.a - ancestor with the orangutan lived ∼13 Mya, mucus(14).Thereasonfortheprominenceof Dis. 20aliforni tthheatcwhiimthpathnezegeoarnildlath∼e8bMonyoab,oan∼d6tMhaytaw(i2t)h. sliignhutseens tihnehwuemigahntsoisf tuhneknskouwllnd;uitrinmgayupbreightot Rev. Pathol. Mech. by University of C Fcstchplouoeerrscrteteiherecersttmr;omtwogtoehrrgeeueoa,shrtetiuahlNlmpeaesHacsnhaHiinsmldisnnpioenoaasrnlgotazeenneaggetdhue-br(atsaontenaneasxorotb(ehn2oeoa).lcmslilTdaitcdhehaebrulealisyers, pdphinouluygsrmtibonuaefgrnteahfs,apbeoceyrsie-aiincplthruamo.nsedaAasutylothchemtaresonylfpaa(b1tewiuv5voin)et.ldlhuTyat,mnhisoteoinncdeauipulrsiilyaeta.hstciHehmnlaigoaunwysmgoeesuvilsmiennirnd--, u. entitledUpdatedClassificationofAfricanPri- inflammationresultingfromallergiesorinfec- n An mates). Despite these facts, there are remark- tions causes mucosal swelling. This swelling ablesimilaritiesamongtheNHHsandobvious blocks the exit channels for mucus, resulting differences from humans not only in general ininflammationandchronicsinusitis—abane phenotypebutalsointhepattern,severity,and for modern humans. Predisposing factors in- incidenceofvariousdiseases(4–9). cludeciliaryimpairment,allergy,nasalpolypo- Given these close genetic similarities, sis,andimmunedeficiency.Treatmentisaimed NHHs (particularly chimpanzees) were as- atreducingmucosalinflammationandswelling, sumedtobegoodmodelsforhumandiseases. controllinginfection,andrestoringaerationof As mentioned above, this may be why the ex- the nasal and sinus mucosa (14). In general, tant literature is rather biased toward report- NHHshavesmallerornonexistentsinuses.For ing instances in which similarities are present example, frontal sinuses in chimpanzees and and pays limited attention to differences. gorillas tend to be smaller than in humans, www.annualreviews.org • DifferencesBetweenHumanandNonhumanHominids 367 PM06CH16-Varki ARI 10December 2010 12:17 and orangutans do not have these sinuses at the larynx with a “lockup” of the epiglottis– all (16). Perhaps for this reason and/or be- soft palate region—all factors that contribute causeofdifferentialgravitationalforcesarising to obstructive sleep apnea (20). This problem fromhumans’uprightposture,chronicsinusi- mayalsoprecipitateoraggravatethemetabolic tisanditscomplicationsappearuncommonin syndrome,whichischaracterizedbyhyperten- NHHs. sionandaprediabeticstate(22).Metabolicsyn- dromerespondstoweightlossand/ortreatment withcontinuouspositiveairwaypressureduring AirSacInfections nocturnalsleep. Unlikehumans,allNHHshaveairsacs,which are extensions of the pharyngeal pouches of BackDisorders the upper airways. These sacs are best de- g veloped and most obvious in the orangutan. Takentogether,currentevidenceindicatesthat or s. Althoughtheairsacsmayassistinsoundpro- theonsetofbipedaluprightpostureinthehu- w viey. duction,theirfunctionisunknown.Giventheir man lineage may have occurred 6–7 Mya— ualree onl locationandconnectivitytotheupperairways, relatively soon after the time of our common nnus theyarepronetoinfections,whichcanbeacute ancestor with the chimpanzee-bonobo clade w.anal or chronic. Cultures of such infected sacs can (23, 24). As a consequence, the cervical, tho- wo m wpers yieldentericorganisms,andtreatmentwithan- racic,andlumbarvertebraeofthehumanskele- ed fro1. For tHiboiwoteivcsera,nsdurirgriicgaaltdiornainisaogeftemnasyucbceesnsefucels(s1a7r)y. taorendneovtelporpeesednvtenintraNl(HloHrdso.tOict)hceurrvaantuatroemstihcaatl wnload01/26/1 (e1q8u,iv1a9le).ntHoufmthaenssedstoruncotutrheas.ve an anatomical aclletesraaptipoenasruonfivqeuretetborhauemaanndss(2u5p,p2o6rt).inUgpmriguhs-t Doon walking imposes stresses and strains the spine 5-393. Diego SleepApnea afancdtobraiaclkcmauussecslefso,rwthheichchcroonnticribbuatcektpoaimnualntid- 6:36San Humans commonly suffer from obstructive injury syndromes suffered by many humans. 11.a - sleepapnea,whichischaracterizedbyperiodic Evidently,despitetheevolutionoffullyupright Dis. 20aliforni cceiastseadtiownithofsnborerainthginangdduupripnegraslierwepayanodbsatrsusoc-- bfuiplleydaadljurustnendintogo>u2rnMoyvael(p27o)s,tuwree.arestillnot Rev. Pathol. Mech. by University of C tpdooirfroooetnohms.fenTionoEhtethninssegetrsleiwymsmnhitdathbormuotbhmlmeledaeaoelcshgpoai((mds22e0r1mme)),c.oiewFcnnaiofttcelfhytaoottbbruheserecessoiueotmcxyfhcNe(e2apmH0st)oitH.ohrIneest OTcahubessetudeptarringicahrtaronpwodsitnPugereorifontfhahteauplmeDlavniicfafioncucutelsletttoi.erHssoalwso- u. anatomyoftheskull,differencesinplacement everuntil∼2Mya,thisnarrowingprobablydid n An oftheforamenmagnum,andadescendedlar- notposeanobstetricproblem,becausethesize ynx as compared with NHHs have been pro- ofthebrainandheadremainedapproximately posedascontributors(20).Theepiglottisand thesameasthoseofthechimpanzee.Beginning oropharyngealregioninhumansmaynothave at ∼2 Mya, and continuing up to a few hun- evolvedspecificmusculaturetomaintainthedi- dredthousandyearsago,thesizeofthehuman lationofthepharynxneededduringsleep.Also, brain increased continuously. Thus, although whenhumansassumedanuprightpostureand humanfetusesarebornbothwithunfusedskull acquiredtheabilitytospeak,anatomicchanges sutures and before brain growth is complete, occurred, such as shortening of the mandible they still face great difficulty passing through and descent of the larynx, klinorhynchy (pos- the maternal pelvic canal (28, 29). This diffi- terior migration of the facial skeleton under culty partly explains the very prolonged labor the skull), and protrusion of the tongue into ofhumanscomparedwiththatofchimpanzees, 368 Varkietal. PM06CH16-Varki ARI 10December 2010 12:17 anditcausesperinataltraumatobothmother malanatomy.Ofthevariouskindsofhernias, andnewborn.Detailsregardingtheseissuesare some are probably aggravated by the upright notcoveredhere. posture of humans and the resulting increase inpressureintheabdominalcavity.Inpartic- ular,aninguinalherniainvolvesprotrusionof SuddenInfantDeathSyndrome peritonealadiposetissue,andsometimesparts Sudden infant death syndrome (SIDS) is a oftheviscera,throughtheinguinalligamentin diagnosisofexclusion.Itoccursinsleepinghu- humans. This condition is observed more of- maninfantsunderoneyearofage,anditscause ten in males than in females. In both humans is unknown. Most such deaths occur between andNHHswithinguinalhernias,thereisade- twoandsixmonthsofage.Theoriesproposed fect of the posterior rectus muscle sheath and include a delayed response to arousal; poorly apoorlydevelopedtransversalisfascia(33).In g developedcardiorespiratorycontrol;immature humans,thegravitationaleffectsofuprightpos- or s. upper airways; and prone positioning of the tureprobablyincreasethefrequencyofherni- w viey. infant in the crib, especially on a soft surface. ationthroughtheinguinalcanal(33). ualree onl Other factors include maternal smoking, low nnus birth weight, young maternal age, inadequate w.anal prenatalcare,upperrespiratoryinfections,fatty Hemorrhoids wo m wpers acid oxidation disorders, and so on. Interest- Hemorrhoidsaredilatedveinsintheanorectal ed fro1. For iinngfalny,tucnotsilletehpeinagdvwenatsotfhceivniloizramti,ona,nmdoSthIDerS- rceognisotnipathtiaotnuisnuvaolllyvinregsustlrtafirnoinmgldounrgi-nsgtabnodwinegl wnload01/26/1 alopwpetahrissttorabdeitriaorne.iTnhhuusn,tSerI-DgSathmearyerbsewahtolefoasl-t mtalovpermesesunrtes,awnhdicchomcapuesnessationrcyredaisleadtioinntorafrtehce- Doon partlytheconsequenceofthemodern,falseno- loose-walled venules. Hemorrhoids may also 5-393. Diego taipoanrtthfraotmittishbeemstoftohretrhbeeignifnannitntgoalteaanrneatorlsyleaegpe adruirsienfgropmreignncarnecaysedorinftrroam-abidnocmreiansaeldprveesnsouures 6:36San (30).Regardless,agreatreductioninSIDShas pressuressecondarytolivercirrhosis.Thiscon- 11.a - been achieved by advising parents to position dition is not commonly observed in NHHs, Dis. 20aliforni bthaabniesfaocne-tdhoewirnb,aicnksth(seupcrinibe(p3o1s)i;tioagna),inr,atthheirs pverogebtaabbllyebdeiceatu(swehoicfhthmeiirnihmigizhe-sficboenrsftriupiattiaonnd) Rev. Pathol. Mech. by University of C acwaledachdrcvieiicpdchmueenbioastlnviacceulolrayhnwlestesa.rmilaUgtrhohynttohtfooofefirrrttcehuiidnaantleasibftnoterfouilaaynnat,detdrsdvainirtmseoeooleaddtpgheeiaearsiotrnihsndsfetha(sa3tnhvi2tnee-) ad(3nr4od)s/.toartipcerphraepsssubreeccaauuseseodftbhyeulapcrkigohfthpigohsthuyre- u. natural evolutionary norm of mother-infant VaricoseVeins n An cosleeping. SIDS has not been formally Varicose veins are superficial, enlarged, reported in NHHs, in whom mother-infant bulging, tortuous veins visible on the skin cosleepingisthenorm.However,occasionally surface, typically in the lower legs (35), that neonatal NHHs are found dead in situations are usually a result of poor valve function where not enough information is known to within the veins. The enlarged veins are establishacauseofdeathortoruleSIDSinor visible under the skin and are associated with out. heredity, pregnancy, age, obesity, chronic venous insufficiency, or localized pathologies that cause blockages to flow. Complications InguinalHernias include local thromboses and rupture, which Aherniaisanabnormalprotrusionofanorgan lead to bruising and hemorrhaging under or structure that should be confined by nor- the skin. Areas of intimal hyperplasia and www.annualreviews.org • DifferencesBetweenHumanandNonhumanHominids 369 PM06CH16-Varki ARI 10December 2010 12:17 smooth muscle proliferation—and sometimes BIOMEDICALDIFFERENCES areas of atrophy and reduced elastic content, BETWEENHUMANSAND upregulationofmatrixmetalloproteinases,and NONHUMANHOMINIDSTHAT N-glycolylneuraminic dysregulated smooth muscle apoptosis—have ARENOTEXPLAINEDBY acid(Neu5Gc): nonhumansialicacid beenobserved.Althoughthecausesofvaricose ANATOMICALFACTORS thatdiffersbyone veins are multifactorial, hydrostatic pressure Biomedical differences between humans and oxygenatomfromthe due to upright posture contributes and may NHHsthatcannotbeexplainedbyanatomical humansialicacid explain why this condition is uncommon in N-acetylneuraminic differencesaremoreintriguing(4,5,7–9,42). NHHs. acid(Neu5Ac);it In the following sections, we divide the can- cannotbesynthesized didate conditions into definite, probable, and byhumancells possibledifferences.Thesecategoriesweresug- becauseofamutation WoundHealing gestedbyourownresearchandexperience,bya thatoccurredinthe g or humanancestors Although the difference between human and surveyoftheliterature,andbydiscussionswith ws. ∼2–3Mya.Itcan NHH wound healing has not been precisely others with expertise (see Acknowledgments). e nualrevise only. bifnreotcomohmtuhemeinadncieottripssoureasted dwoocuunmdsenotfedm,oanckoemyms aonndobNseHrvHastiotennidstthoathtehael Aofgacihni,mppearnhzaepessbeascamusoedoeflsthfeorhihstuomryanofdtihseeaussee, ww.anonal u rsuaptuidrilny,gwfohrecrleoassuhreuamnadntawkoeuanlodnsgotfitmenertoeqhueiarle. eraxtthanertltihtearnatduirffeetreenndcsest,oseomipnhtahsiiszecassimeitlhaeritaibe-s m wpers This difference could be due to the anatomi- senceofpublishedliteratureisnotevidencefor ed fro1. For caanldanNdHhHistoslkoignic(a3l6d)i,ffienrcelnucdeinsgbedtwiffeeernenhcuemsainn tehraelaobfstehnecseecoofnadditiifofenrsebnycec.atTegaobrlye;1ealcihstisssdeivs-- d1 wnloa01/26/ hphaiorl,osguyb.cIunttaenreesotuinsgflayt,,aamndouswseewatitghlaanhdummaonr-- cussedfurtherbelow. 5-393. DoDiego on gliekneedaelfseoctdienmtohnesstiraaltiecsadceidla–ymedodwifoyuinngdhCeMalAinHg UONFISQIAULEILCYAHCUIDMBAINOLFOEAGTYU: RES 11.6:36a - San (37),althoughthemechanismisunknown. MTOECBHIOAMNEISDTIICCACLODNIFNFEECRTEINOCNESS? Dis. 20aliforni AcneVulgaris Tcluhdeirnegamreanuyntdhoautbhtaevdelyyemtatonyberedaissoconvs,ereind-, Rev. Pathol. Mech. by University of C At(lto3iimocs8nne)ebe.stIahitcssaiehtsaoooccuuhcoslcamdlureearmsrcsiotomrennerosgiezsoiretonudnctposbhtmyieavmfnteahdcoheenuai,nlmpnyvpeaoiecnnlkavars,eadkasninoncbdleelcssooooccnefmkndpeetiid---s fooeoonbwfrcsnteehtrsherveeebsbdeenitaoobwrlneoceathgewn,nyaewteohonefummhhsiiaucaavamlnielcsabfnaaoisocnuimdandnsdeNddamiNHncudaHHlltsidHsipailfislefni.ecIrdtneaienfcrfoicemduer–r-ss u. sebaceoussweatglands,closedcomedones,in- recognizing proteins. These differences are n An flammatorypapules,andsoon.Acne-likeskin summarizedinTable2,anddetailedaccounts eruptions have not been reported in NHHs. can be found elsewhere (10–12). Given that Although the reason for this discrepancy is fewerthan60genesareinvolvedinsialicacid unknown, it may again relate to anatomical biology,ourfindingthatmorethan10ofthem differences between human and NHH skin, showhuman-specificchanges(12)suggeststhat particularlywithregardtothetypeanddistri- this system represents a “hot spot” in human butionofsweatglands(36,39).Aroleformilk evolution. A dramatic change in the sialic consumptionhasbeensuggested(40).Itwould acids of human cell surfaces, which occurred beinterestingtoknowwhetherthebacterium approximately ∼2–3 Mya, is characterized by commonly found in acne lesions (Propioni- Alu-mediated inactivation of the CMAH gene bacterium acnes) (41) is specifically adapted to thatcaused(a)alossofsynthesisofthecommon humans. mammalian sialic acid N-glycolylneuraminic 370 Varkietal. PM06CH16-Varki ARI 10December 2010 12:17 Table1 Apparentdifferencesbetweenhumansandnonhumanhominids(NHHs)intheincidenceandseverityof biomedicalconditionsaandthepotentialroleofsialicacidbiologychanges Medicalcondition Humans NHHs Potentialrolesofsialicacidbiologychanges Definitedifferences Myocardialinfarction Common Veryrare LowSiglecs:increasedimmunereactivity? DietaryNeu5Gcaccumulationinendotheliumandatheromas Interstitialmyocardialfibrosis Rare Common Differentpatternsofcardiacsialylation? Plasmodiumfalciparummalariainfection Susceptible Resistant Neu5Acisthepreferredmerozoiteligand Sexuallytransmittedbacterialdiseases Common Veryrare BacterialNeu5AcengagesSiglecs? HIVinfectionprogressingtoAIDS Common Veryrare LowSiglecs:increasedimmunereactivity? Foamyvirus(spumavirus)infection Rare Common Didanti-Neu5Gcantibodieseliminate? Probabledifferences g or HumaninfluenzaAsusceptibility Variable Oftenmild α2-6-linkedSiasonupperairways s. w LowSiglecs:increasedimmunereactivity? e viy. HepatitisB/Clatecomplications Variable Oftenmild LowSiglecs:increasedreactivity? ualree onl Alzheimer’sdiseasepathology Common Rare Siglecexpressioninmicroglia? ns ww.anonal u ENpeiuth5eAlcia-lexcpanrecsesrisn(gcabraccitneorimalaps)athogens CCoommmmoonn RRaarree?? NExecue5sGsecnidnocgaerncoinuosmSiagslec-1ligands? m wpers BacterialNeu5AcengagesinhibitorySiglecs? ed fro1. For PPrreeetecrlammlpasbioar CCoommmmoonn RRaarree?? S—iglec-6expressioninplacenta d1 wnloa01/26/ Rheumatoidarthritis Common RPaorses?ibledifferLeonwceSsiglecs:increasedimmunereactivity? 5-393. DoDiego on Bronchialasthma Common Rare? NLoewu5SGigcleinc:jionicnrtes?asedimmunereactivity? 11.6:36a - San EHayrdlyatfiedtiafolrwmasmtaogelarpregnancy CCoommmmoonn RRaarree?? —— Dis. 20aliforni EFenmdoamleeitrroinosdiseficiency CCoommmmoonn RRaarree?? N—eu5Gcinendometrium? Rev. Pathol. Mech. by University of C MaatEhcxaiedcjoluprd(rpeNesscydeuciushre5siaaoGsterrcdici)sffdieaairlseniencdacseeas(scdbiu)detaoNno-baavcicoecutusymalnnuaetlouaCmrtaioiocmmanlimdnioofifcenfrenc((e1isnR.2Aa)b.rSebI?rAGevnLiaEtiaoCdn1ds:3iNt—,ieouSn5IaAGlc,LNnEo-aCnc1egt4eyl,nneeautnricadmionSuiIctGaccoLidmE;NCee1uo65f)Gc,N-glycolylneuraminicacid. u. acid(Neu5Ac).Thistransformationappearsto the CMAH mutation is that Neu5Gc derived n n have been followed by a variety of (probably fromthediet(particularlyfoodsofmammalian A linked) changes in other sialic acid–related origin) can become incorporated into human genes, including increased expression of tissues, particularly endothelia and epithelia. α2-6-linked Sias (probably due to increased ThisNeu5Gc-accumulationprocesscanoccur expressionoftheST6GALIgene)andmultiple despite the presence of a broad spectrum of Sialicacid– changes in genes encoding Sia-recognizing circulating anti-Neu5Gc antibodies, and the recognizing immunoglobin-likelectins(Siglecs),including combinationmayleadtochronicinflammation immunoglobin-like binding-specificitychanges(inSiglec-5,-7,-9, (12). In the following sections on biomedical lectins(Siglecs): constitutethelargest -11,and-12),geneconversion–basedsequence differences between NHHs and humans, we knownfamilyofsialic changes (in Siglec-11), expression-pattern mentionpossibleconnectionstotheseuniquely acid–recognizing changes (in Siglec-1, -5, -6, and -11), and in- human changes in sialic acid biology. Several proteins stancesofdeletionorpartialpseudogenization of these possibilities require much further www.annualreviews.org • DifferencesBetweenHumanandNonhumanHominids 371 PM06CH16-Varki ARI 10December 2010 12:17 Table2 Human-specificchangesinsialicacidbiology–relatedgenesa Gene Human-specificchanges Possibleconsequencesforhumans CMAH Human-specificAlu-mediateddeletion LossofNeu5GcandexcessofNeu5Acexpressiononcellsurfaces eliminatesexon6,resultinginframe-shiftand Correspondingeffectsonpathogenrecognitionandinvasion truncatedinactiveenzyme MetabolicincorporationofNeu5Gcfromdiet,despite anti-Neu5Gcantibodies SIGLEC1 IncreasedendogenousNeu5Ac-richligandsin IncreasedlikelihoodofmaskingbyendogenousNeu5Ac-rich humans;enhancedfrequencyandbroader ligands? expressionpatterninmacrophages AlteredphagocytosisofNeu5Ac-expressingpathogens? Increaseduptakeofhypersialylatedvirusesbymacrophages? SIGLEC5 ExpressionsuppressedonTcells;likely HyperresponsivephenotypeofhumanTcells restorationofessentialarginineresiduefor PossibleroleinpropensityfordiseasesassociatedwithTcell g sialicacidrecognition activation or s. InteractionswithgroupBStreptococcustypeIaβprotein? w e viy. SIGLEC14 Likelyrestorationofessentialarginineresidue Lossofleukocyteactivatorypotentialinhomozygousnull nualrese onl fpoorpsuialalitcioancipdorlyecmoogrnpihtiiosnm;fusion/deletion individuals? nu w.anal SIGLEC6 Placentaltrophoblastexpression Expressionlevelsincreasewithprogressoflabor wo ed from w1. For pers SIGLEC7and AminoacidchangesinV-setdomain;adjusting EE(nxaphhraeunsmcseiaodnn-ssuispsecfuceirpfitthcibedirliisuteypartseoeg)Nuleaute5dAicn-epxrpereecslsaimngpspiaathogensthat wnload01/26/1 SSIGIGLLEECC191 HoufmNaenu-5spGeccitfiocNgeenu5eAcocnrveecorsgionnit;ionnew Adltaemrepdeninitnenraactteiolenuskoofcmytiecrroesgplioanwsiivtehnneessu?ralcells? Doon expressioninbrainmicroglia Alteredresponseofmicrogliatoinfections? 5-393. Diego SIGLEC12 Haurgminanin-espreecsiifiducem”ufotartisoianliocfa“ceidssreenctoiaglnition Unknown 6:36San SIGLEC13 Human-specificdeletion Unknown 11.a - SIGLEC16 Human-specificinactivatingmutation; Alteredinteractionsofmicrogliawithneuralcells? Dis. 20aliforni ST6GAL1 Inpcorpeualsaetdioenxpproelsysmioonrpohfism APrltoetreecdtiroenspfroonmseaovfiamniicnrfloguleinaztaovinirfuescetsio,wnsh?ichpreferα2-3sialic Mech. y of C vSaiarαio2u-s6cGelallβty1p-e4sGlcNAcβ1terminiin awchidiclhinpkraegfeers,αa2n-d6ssuisacliecpaticbidililtiynktoagheusmaninfluenzaviruses, Rev. Pathol. by Universit aFordetails,seeReferences11raensde1a2r.cAhb,barnevdiamtioanns:yNoetuh5Aerc,,Nu-narceetlyaltneedurafamcintoicrascaidr;eNeu5tGhoc,uNg-hgltycotloylnebueramcinaircdaicoidv.ascular disease that u. likelytobeoperative. manifestedeitherassuddendeathduetoheart n An attacksorasaslowerdeathduetoprogressive heart failure (5, 43, 44). Older studies often DEFINITEBIOMEDICAL assumed that cardiovascular disease was a DIFFERENCESBETWEEN human-chimpanzee similarity, although some HUMANSANDNONHUMAN studies noted different pathologies (45, 46). A HOMINIDS more detailed comparison (47) indicates that the two diseases are indeed completely differ- CardiovascularDisease:Myocardial ent. Human cardiovascular disease is caused InfarctionVersusInterstitial primarily by progressive atherosclerosis, in MyocardialFibrosis which deposition of low-density lipoprotein– The most common cause of death in both derivedcholesterolcausesgradualblockadeof humans and captive chimpanzees was long arteries, especially the coronary blood supply 372 Varkietal. PM06CH16-Varki ARI 10December 2010 12:17 to the heart. When complete blockage of Human Chimpanzee coronary arteries occurs acutely, it causes the typical human heart attack, also known as a myocardial infarction. When ischemia to the E) myocardium occurs gradually, it gives rise to & H progressive,congestiveheartfailure. al ( Although NHHs suffer from a moderate m r o degree of atherosclerosis in captivity and can N beinducedtohavemoreseverediseasevialipid feeding (48, 49), atherosclerosis only rarely leadstoblockageofcoronaryarteries(although blockage of cerebral blood vessels leading to g stroke can occur). There is one report of E) or & ualreviews.e only. aoRcecgcloeunrsiitlolanreianwnaawlsyhsiidscehtbeycctoersdoevneaarrtaylnagetrchoreourpposssyclsehr(5oo0wti)cs. Fibrotic (H nnus that early reports of sudden cardiac death or w.anal cardiomyopathyinNHHswereduetodiffuse wo m wpers fibrosis that affected the myocardium; such ed fro1. For ilongteicrsatliltyiaqlumiteyodcifafredreianltfifrbormositshe(IhMuFm)ainsdpiastehaose- 5-393. DownloadDiego on 01/26/1 (iiisnntFudmdigaidclauleanrntNieefesdHs1ettha)Hstahe(ts4i,tt3(hhpp,ieraso4rrt4btyai,aspcbue4all7yoah,rfealp5yaria1rstti)inh.naogtFmtloaufacrgrloktyeh—msie)srtacahoanacnmdthaiamlstny,hosgaainesst Masson’s trichrome 6:36San inthecardiacrhythm—orasprogressiveheart 11.a - failureduetolossofmyocardialfunction. Rev. Pathol. Mech. Dis. 20by University of Californi FcSgchoaeeeiurmtcasTsorttemth,nhsdedouwti,nscshh,weoeyaftrhohsocyierenso?miramseiTrtiymtoahttrfaohehetnaahIfitMtterwhNrshuFootuHmsqmcmouaHlbeaneynrssssoetsftdiroteooivrdrcneimonedbsoilsnotoitondfcfortkiiefaNusfiqgcgncuehHeurteealHtnmtvththetsaliloyec?t. Coronary artery u. answer, but our analysis reveals differences in 500 µm n An terminalglycosylationofsialicacidsandother Figure1 glycansinthemyocardiumofthehumanversus Inhumansandnonhumanhominids,differentpathologiesleadtocardiac chimpanzee heart,andthereisadditionalevi- disease.Shownarehistologicalcomparisonsbetweenhumanandchimpanzee denceforahigherdensityofsmallbloodvessels heartsandcoronarybloodvessels.(Top)Hematoxylinandeosin(H&E)stains ofnormalmyocardiumsectionsfromhumansandchimpanzeesappearvery in the human myocardium as well as more fi- similar.(Topmiddle)Anexampleoffibrosisimmediatelysurroundingblood brousseptaeinthenormalNHHmyocardium vessels,asobservedinsomehumanhearts,andanexampleofextensive (Figure2)(47).Regardingthesecondquestion, interstitialmyocardialfibrosisinachimpanzeeheart.(Bottommiddle)Collagen the likely explanation is that atherosclerosis fibrosisismoreclearlyseenwithMasson’strichromestain.(Bottom) in humans is more severe than in NHHs, Atheroscleroticcoronaryarterytypicallyobservedinhumans(notethe subendothelialplaques),comparedwithatypicaluninvolvedcoronaryarteryin althoughbothgroupssharemanyofthesame achimpanzee,asobservedusingMasson’strichromestain.Reproducedwith riskfactors(47,52–56).Ourworkonsialicacids permissionfromReference47. suggests two possibilities that may contribute www.annualreviews.org • DifferencesBetweenHumanandNonhumanHominids 373 PM06CH16-Varki ARI 10December 2010 12:17 Human Chimpanzee anti-Neu5Gc antibodies that can react with these immunogenic epitopes. In vitro studies usinghumanendothelialcellsfedwithNeu5Gc supportthenotionthatexposureofhumanen- al dothelium expressing Neu5Gc to human sera G A2 bearing anti-Neu5Gc antibodies can trigger UEαc1- complement-mediated activation, monocyte u F adhesion,andinflammation(59)—mechanisms thatarecommontobothearlyatherosclerosis andlatestagesoflesionprogression.Ourstud- iessuggestpossiblemechanismstobeexplored, althoughadditionalexplanationsremainlikely. c) ws.org NAGal(NA ualreviee only. SαSia2-6 PHluamsmanomdiaulamriafaislccaipuaserdubmyvMariaoluasrPialasmodium nnus parasitesthatinvadeerythrocytes.Plasmodium w.anal sporozoitesareinjectedfromsalivaryglandsof wo m wpers themosquitovectorintothehostbloodstream, Downloaded froon 01/26/11. For MAHαSia2-3Gal wtasahusnherdefnmareceveeerrtenohlrzteeeuoaycaisetleelpmydst.oudrlebMtssiatpcreolkorynoyizininoengrittyhotetheshpertmaobhtcieo.nyOcdtyebftslett,ohosoeidnavvnsvaatdarrrdeiiooiaanuurmgess 5-393. Diego Pgrlaesamteosdtiuvmirulpeanrcaesitiens,huPm. afnalsc;ipiatruismknhoawsnthaes 6:36San 500 µm Lectin malignantmalariabecauseitisresponsiblefor 11.a - Figure2 most malaria deaths worldwide. Interestingly, Dis. 20aliforni Ustaniinqiuneglyofhhuimstaonloegxipcarellsysinoonrmpaatlt–earpnpseoafrginlygcmanysoicnarcdariadliaseccmtiounscslefr:olemcthinumans tinhischpimarpaasintzeeedso(e6s0)n,oatndcaiutseappseevaerrsetodibseeaosef Rev. Pathol. Mech. by University of C apraFcehngaucgtadcotilαenungrst1noni-nionsz2fhieiGnnugslm(athyUleβcuarEonmm1pA-hair4n)noo,GamtwalelnicSihnndNiisaicd;cαAhhsac2.rniβm-eSd6ch;pGoMSoagwaananmlznaβiezcbk1aeeuri-scame4utGaeseymrxnolmacicugmNairrnreapAdnalilacseaigβfsslughosculefeuoncmttstiiyetinaposriginnoecgssnal(iuluSdNtlsNueiin-encAlsitginin)in,Unk(-wMesltetdhhxaAieigcenHhlsuyienr)cq,ogaupwnaehenuiccseh roiPbtefo.sltarhtptehirivocecehhculeuiysnmarorsnpweodacris,ne?nzaoTetfesohsirmyeiaeginamliardnsor,sgeotaosrgtrlgoioimlaglnaai(sic6tsae1mildn).catAahtWnfaordtihncidalaiynta(ftt6eewec2nati)ssss. u. recognizesSiaα2-3Galterminionvariousglycoconjugates(74,75).Theresults Investigatorsinitiallybelievedthatthetwopar- Ann shownaretypicalofthoseobservedin11humanand7chimpanzeesamples. asitesspeciatedatthesametimethatthehuman Threegorillaandfourorangutansamplesyieldedresultssimilartothoseofthe chimpanzeesections.ModifiedwithpermissionfromReference47. andchimpanzeelineagessplit,whichoccurred ∼6 Mya (62). However, this hypothesis does to this difference. First,we found that human notaccordwithP. falciparumbeingarecently lymphocytes are more reactive than those of evolved pathogen. A potential explanation for chimpanzees (57, 58), which may represent a this paradox, which relates to our work on potential mechanism for accelerating the in- sialicacids,wasrecentlyputforward. flammationobservedinhumanatherosclerotic Sialicacidsarecriticalcomponentsofbind- lesions. Second, we observed incorporation ing targets on erythrocytes that are used by of the nonhuman sialic acid Neu5Gc into the P.falciparummerozoites,andthemajorcarriers endothelial cells of humans (Figure 3) (59), of sialic acids (the glycophorins) are rapidly which occurs in the presence of circulating evolving (63). The EBA-175 major binding 374 Varkietal.

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Abstract. Although humans are genetically very similar to the evolutionar- ily related nonhuman hominids (chimpanzees, bonobos, gorillas, and orangutans), comparative studies suggest a surprising number of uniquely human differences in the incidence and/or severity of biomed- ical conditions.
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