Edward J. Dick Jr., 3 Kurt Benirschke, and Ajit Varki1

31 Pages·2011·1.95 MB·English

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-mail]rcnahldifCTorernnaiitanerian,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.