Animal evolution during domestication: the domesticated ...bio156/Papers/PDFs/Bioessays 2009 Trut.pdf · Animal evolution during domestication: the domesticated fox as a model Lyudmila

A n im a l e v o l u ti o n d uri n g d o m e sti c ati o n :t h e d o m e sti c ate d f o x a s a m o d e lLyudm il a Trut ,* Irin a O sk in a , a nd A n a st a s iy a K h arl a mov aInstitute of C ytology and G ene tics, S iberian Branch of Russian A cademy of S ciences, Novosibirsk, Russia

W e re v i e w t h e e v o l u ti o n o f d o m e sti c a n im a l s , e m p h a s i z-i n g t h e effe ct o f t h e e arli e st ste p s o f d o m e sti c ati o n o n itsc o u rs e . U s i n g t h e first d o m e sti c ate d s p e c i e s , t h e d o g( C a n i s fa m ili ari s), f o r ill u strati o n , w e d e s cri b e t h e e v o l u-ti o n ary p e c u li ariti e s d u ri n g t h e h i st ori c a l d o m e sti c ati o n ,s u c h a s t h e h i g h l e v e l a n d w i d e ra n g e o f d i v ers ity . W es u g g e st t h at t h e pr o c e s s o f e arli e st d o m e sti c ati o n v i au n c o n s c i o u s a n d l ater c o n s c i o u s s e l e cti o n o f h u m a n-d e fi n e d b e h a v i o ra l tra its m a y a c c e l erate p h e n o ty p i c v ar-i ati o n s . T h e re v i e w i s b a s e d o n t h e re s u lts o f a l o n g-terme x p eri m e n t d e s i g n e d t o re p ro d u c e e arl y m a m m a li a nd o m e sti c ati o n i n t h e s il v er f o x (V u l p e s v u l p e s) s e l e cte df o r ta m e a b ility o r a m e n a b ility t o d o m e sti c ati o n . W ed e s cri b e c h a n g e s i n b e h a v i o r, m or p h o l o g y a n d p h y s i o l-o g y t h at a p p e are d i n t h e f o x d uri n g its s e l e cti o n f o rta m e a b ility , w h i c h w ere s i m il ar t o t h o s e o b s erv e d i nt h e d o m e sti c d o g . B a s e d o n t h e d ata o f t h e f o x e x p eri-m e n t a n d s u rv e y o f re l e v a n t d ata , w e d i s c u s s t h e d e v e l-o p m e n ta l, g e n eti c a n d p o s s i b l e m o l e c u l ar g e n eti cm e c h a n i s m s u n d erl y i n g t h e s e c h a n g e s . W e a s cri b e t h ec a u s ati v e r o l e i n e v o l u ti o n ary tra n sf orm ati o n o f d o m e s-ti c a n im a l s t o t h e s e l e cti o n f o r b e h a v i or a n d t o t h en e uro s p e c i fi c re g u l at ory g e n e s it affe cts .

K e y w o rd s : anima l domestica tion; behavior; deve lopmenta lra tes; evolution; morphologica l diversity; regula tory system;se lection

D o m e sti c ati o n i n e v o l u ti o n aryterm s – fro m D arw i n t o t h e pre s e n t d a y

It is well known tha t D arwin has focused much a ttention ondomestica tion as the process during which striking varia tionarises. Although believing tha t the range of changes in anydirection may be different, he admitted tha t the ‘‘tendency togeneral variability is unlimited’’(1). H e repe a tedly raised thequestion why domestic animals are so variable. In his analysisof the causes of varia tion under domestica tion, D arwin thoughtthe changes to be exclusively due to environmental influences.H e maintained tha t the sta te of the parent organism during

fertiliz a tion or embryonic development has profound effects onthe characteristics of the offspring. D arwin emphasiz ed tha t theconstitution of the organism will largely determine the kind ofchanges induced by the environment, and acknowledged theoccurrence of peculiarities as being due to unknown laws actingon individual constitution.

B esides environmenta l influences on varia tion, D arwinnoted the e ffects of crosses and inbre eding known in his timefrom the experience of anima l bre eders. R e lying on the irobserva tions, D arwin presented vivid examples of the resultsof bre eding se lection apparent in a compara tive ly shor t time.However, he a lso assigned a gre a t role to unconsciousse lection acting on anima ls for thousands of ye ars. B ecausea ll our domestic anima ls have be en first exposed todomestica tion a t very remote periods, it is unknown whenanima ls star ted to change and a t wha t ra tes. D arwinma inta ined tha t anima ls continued to be variable for longperiods a fter the ir e arly domestica tion, suggesting tha t thee arly domestica tes were even more variable than the nowexisting ones, and proposed tha t the capacity to become morevariable under domestica tion is common to a ll species.

D arwin a lso ra ised the problem of similarity be twe en thechanges observed in dif ferent domestic anima ls. H e regardedcerta in fe a tures shared by many domestic species as theresult of the ir domestica tion.

D arwin’s observa tions and conclusions on varia tion underdomestica tion hold true today. T he evolutionary peculiaritiesof domestica tion, such as the wide phenotypic diversity ofdomestica t es, rema in puz z ling. Inde ed, the varia tion range ofcerta in tra its within a domestic species occasiona lly exce edstha t within whole families or even orders.(2–5) Morphologica lvaria tion in dogs, our e arliest domestica tes, is most illustra tivein this respect ( F ig. 1).

A ccording to conventiona l gene tic theory, rare (10 5–10 6

per gene per genera tion) random muta tions are the mostcommon mechanisms of phenotypic changes.(6) T he diver-gence of the dog from the wolf might have happened some12,000–15,000 ye ars ago,(3,7,8) which is a short span of timeon the evolutionary sca le. N everthe less, variability hasaccumula ted a t immense ra tes which are incommensura tewith random muta tions. T here fore, the na ture and sources ofthe varia tion under domestica tion are intriguing.

Another ha llmark fe a ture of varia tion under domestica tionis its similar pa ttern in dif ferent domestic mamma lian

D O I 10.1002/bies.200800070 My fa v o rite a n im a l

*C o rre s p o n d e n c e t o : L. Trut, Institute of C ytology and G ene tics, S iberianBranch of Russian A cademy of S ciences, Lavrentieva ave, 10, 630090,Novosibirsk, Russia .E-ma il: trut @ bione t.nsc.ru

B io E ssays 31:349–360, 2009 Wiley Periodicals, Inc. 349

species.(9,10) When subjected to domestica tion, anima lswhose evolutionary pa thways did not cross, started to evolvein the same direction. T hey a ll lost the species-specific wild-type behaviora l response to humans. T he activity of the irreproductive system became enhanced and re la tive lyuncoupled from the environmenta l photoperiod, and theya ll, unlike the ir wild ancestors, acquired the capacity to bre edin any se ason and more often than once a ye ar.(10,11) Incontrast, the activity of the hypotha lamic–pituitary–adrena l(H PA) axis, the key hormona l regula tor of adapta tion to stress,became a ttenua ted in the very few domestica tes studied inthis respect.(12–14) The same morphologica l changes, first interms of overa ll body siz e and its proportions and a lso color,length, and texture of the coa t, appe ared in many domes-tica tes.(2,3–5,7,8,11) Some of these a ttributes (white spotting,floppy e ars, curly ta ils) have be en aptly ca lled the morpho-logica l markers of domestica tion ( F ig. 2). It se ems unlike lytha t these similar trends of morphologica l and physiologica ltransforma tion of different domestic anima ls depend onhomology-independent muta tions of structura l homologousgenes. T he Russian evolutionary biologist B e lya ev hassuggested more than 50 ye ars ago tha t domestica tion mightinvolve other mechanisms tha t contribute to phenotypicvaria tion, ma inly changes in the activity of genes regula tingdeve lopment.(2,15,16)

During evolution the same phenotypic changes can begenera ted through different deve lopmenta l pa thways under-la in by dif ferent genes. However, there may be deve lopmenta lprocesses underla in by key genes with many regula toryfunctions which under certa in recurring se lective conditionsmay most like ly be targe ted by se lection. A ccording toB e lya ev, the crucia l se lective factor during e arly domestica tionwas the new socia l environment, i. e ., the first encounter of awild species with humans. This extreme ly stressful se ttingrendered the behavior – tolerance, docility toward humansand the corre la ted stress resistance – the ma in targe t ofse lection. In his opinion, the genes tha t control behaviora lvaria tion play a key regula tory role during deve lopment.B e lya ev there fore suggested tha t behaviora l varia tion was thecausa tive varia tion during domestica tion. A ccording to his lineof thought, the re la tionship be twe en behaviora l varia tion andtransforma tion of domestic anima ls would become moreinte lligible when domestica tion would be traced from thebeginning, i. e ., when this process would be reproducedexperimenta lly. Such a sophistica t ed mode l was se t up usingsilver foxes (Vulpes vulpes) a t the Institute of C ytology andG ene tics, Novosibirsk, Russia , about 50 ye ars ago.(16–19)

B e lya ev was the initia tor of this experiment. There were twore asons why silver foxes were given pre ference for experi-menta l domestica tion. O ne was the close taxonomic re la tion-

Figure 1. Variability range in dogs for A : body siz e (C hinese crested, pekingese and bullmastiff). B : body shape (greyhound and E nglishbulldog). C : coa t types (ha irless terrier and komondor).

Figure 2. R epresenta tives of different families and orders show the most specific morphologica l markers of domestica tion, white spotting onthe he ad (t o p ro w) and floppy e ars (b o tt o m ro w): A : Horse (Equus caballus): O rder Perissodactyla, family Equidae, bre ed Russian he avydraught horse. B : C ow (Bos taurus): O rder Artiodactyla, family Bovidae, bre ed Aberde en-Angus (t o p), banteng (b o tt o m). C : P ig (Sus scrofadomestica): O rder Artiodactyla, family Suidae, bre ed V ie tnamese hybrid (t o p), Landrace (b o tt o m). D: She ep (Ovis): O rder Artiodactyla, familyBovidae, bre ed Romanov (t o p), ba lbas (b o tt o m). E : Dog (Canis familiaris): O rder Carnivora, family Canidae, bre ed Boston terrier (t o p), pug(b o tt o m). F : R abbit (Oryctolagus cunticulus): O rder Lagomorpha, family Leporidae, bre ed Holland white-black (t o p), G erman ram (b o tt o m).

My fa v orite a n i m a l L. Trut e t a l.

350 B io E ssays 31:349–360, 2009 Wiley Periodicals, Inc.

ship be twe en the fox and the dog; the other was tha t cagebre eding of foxes had a lre ady be en star ted a t the beginningof the 20th century. T hus, by the onse t of the experiment,captive foxes had a lre ady be en subjected to rigorousse lection for adapta tion to the new socia l environment. T hisconsiderably facilita ted the long life experiment and reducedits dura tion.

D e v e l o p m e n t o f t h e e x p e rim e n ta lm o d e l o f d o m e sti c ati o n

A lthough silver foxes had be en farm-bred for about 50 ye arsbe fore our experiment, they re ta ined the standard morpho-logica l phenotype, se asona l pa ttern of bre eding specific to thefoxes of na tura l popula tions, and the wild-type aggressive(growing and biting) or avoidance response to humans.(20)

F igures 3A– C shows the polymorphism of the expression ofthese behaviora l responses in foxes of large farm-bredpopula tions. A ltoge ther severa l thousands foxes were testeda t fur farms. In the behaviora l test, the experimenterapproached the home cage, tried to open it and monitoredthe expression of the response. This observa tiona l test washighly reproducible. About 10% of farm foxes displayed thewild-type responses very we akly or not a t a ll ( F ig. 3 C). O fthese foxes, 100 fema les and 30 ma les were chosen fromdifferent farm-bred popula tions as the initia l parenta lgenera tion for se lection for tolerance towards humans ordocility, then for tame ability. The fox popula tion was out-bre eding.(20)

The ra tiona le of the experiment was tha t subjection of anexperimenta l fox popula tion to se lection for a singlebehaviora l tra it, tame ability, is sufficient for domestica tion tooccur, and the experimenta l design followed this ra tio-na le.(20,21) The rese archer tested the tame ability during thetime-dosed contacts with pups on the basis of the ir responsesto hand fe eding and to a ttempts to touch or pe t them. A ll thepups underwent time-dosed contacts for 2.0–2.5 months.T hose pups tha t continued to show aggressive-avoidanceresponses despite the contacts were discarded from theexperimenta l popula tion. T he pressure of se lection was veryrigorous: less than 10% of the most tame individua ls of everygenera tion were used as parents of the next genera tion.(17–21)

A s a result of such rigorous se lection, the of fspring exhibitingthe aggressive and fe ar avoidance responses were e limina tedfrom the experimenta l popula tion in just two to thre egenera tions of se lection.

In the fourth se lected genera tion, there appe ared pups tha tresponded to humans by dog-like ta il wagging. The offspringof the next se lected genera tions displayed more and moredog-like behavior. In the sixth genera tion, there appe aredpups tha t e agerly sought contacts with humans, not onlywagging, but a lso whining, whimpering, and licking in a dog-like manner. Such foxes were assigned to the ‘‘e lite ofdomestica tion’’ ( F ig. 3 D E F ). E lite pups constituted only 1.8%(4 of the tota l 213 foxes) in the sixth genera tion of se lection,17.9% (66 of 379) in the tenth and 35% (503 of 1438) in thetwentie th genera tion. In the thirtie th genera tion, the propor-tion of e lite pups was as high as 49%, (804 of 1641).(19) By2005/2006 a lmost a ll the foxes of the domestica t ed popula tion

Figure 3. B ehavior of foxes of the farm-bred popula tions (t o p ro w) and of the popula tion se lected for tame ability (b otto m ro w): A : A fox showingthe aggressive response to humans; B : A fox showing the avoidance response to humans; C : A fox we akly expressing the wild-type aggressive-avoidance response to humans; D– F : Domestica ted foxes referred to the behaviora l e lite. F : from left to right: Prof. K . G . Lark (University of Utah, S altLake C ity), Prof. L.N . Trut (Institute of C ytology and G enetics, Novosibirsk), Prof. G .M. Acland (C ornell University, Ithaca) with domestic foxes.

L. Trut e t a l. My fa v orite a n im a l


were assigned to the behaviora l e lite. Q uantita tive differencesbe twe en the behavior of e lite foxes are now estima ted usingvideo records of behaviora l tests. From these records, fiftymost informa tive behaviora l parame ters (for example fre-quency of wagging, specific voca liz a tions, posture of body,and its communica tive parts such as ta il, e ars, and others)were ana ly z ed by the principa l component ana lysis(P C A).(22,23) This sta tistica l me thod identifies the quantita tivephenotypic varia tion in tameness as line ar combina tions ofcorre la ted parame ters or principa l components (P C s).(24)

These new integra ted independent tra its are gene tica llyana ly z able phenotypes.(25,26)

Throughout the experiment, a ltoge ther 10,500 foxes wereused as parents. A ll in a ll, about 50,000 of fspring wereobta ined and tested for the ir amenability to domestica tion.(19)

The result of this directiona l se lection is impressive: a uniquedomestic fox behaving very similar to another species, thedomestic dog, has be en deve loped through me thodica llyapplied se lection.

M u ltifa c ete d re s u lts

The rigorous se lection of the silver fox sole ly for tame abilitybrought about corre la ted changes in cer ta in fe a tures ofbehavior, physiology, and morphology.

Thus, the rise of the dog-like ability of foxes to ‘‘re ad’’human socia l cues, for example gestures and glances, was anotewor thy change in the ir behavior. Domestic foxes becamemore skillful than farm-bred foxes in using human cues forcoping with the man-made environment not only during brie fexperimenta l tests and se lection procedures, but a lso duringda ily routine care.(27)

The most impor tant physiologica l consequence of foxdomestica tion is the transforma tion of the se asona l repro-ductive pa ttern. T he ma ting se ason of foxes in na ture as we llas a t fur farms occurs only once a ye ar during incre asing ofdaylight (January to March). In some gene a logica l groups offoxes tha t were more advanced with regard to tameness,sexua l activity and ma ting were observed outside the limits ofthe bre eding se ason (Table 1),(20,28) which is norma llystrongly restricted by na tura l se lection.(11) Moreover, a fewvixens have even ma ted twice a ye ar. The tota l number ofanima ls exhibiting changes in the ir reproductive pa ttern wassma ll throughout the ye ars of the experiment. However, the iremergence among the tame foxes is of crucia l impor tance.R eproduction se asona lity is under strong se lective con-stra int.(11) Varia tions in the ma ting da tes of anima ls within thema ting se ason are ma inly due to environmenta l factors. A s aconsequence, direct se lection for ma ting timing during these ason is ine f fective and does not change the limits of thebre ading period. However, the da ta in Table 1 suggest tha t thecapacity to bre ed a t any time throughout the ye ar, which is

characteristic of domestic anima ls, might have occurred as acorre la ted consequence of se lection for tame ability.

T he consequences of se lection for behavior are thought-provoking ( F ig. 4). In the foxes of the domestica tedpopula tion, severa l morphologica l tra its tha t mirror dogmorphologica l fe a tures began to appe ar a t different frequen-cies (Table 2). T he changes in standard coa t color pa tternappe ared e arlier than the other changes, name ly in the 8th–10th se lected genera tion. Specific pieba ld S tar spotting ( F igs.4 F and 5A , B) and brown mottling on the background ofstandard silver-black color ( F ig. 5 C) are the most typica lpa tterns. T he S tar spotting is de termined by the incomple te lydominant autosoma l S tar muta tion.(29) The gene control ofbrown mottling in foxes is still uncle ar. In dogs, it is controlledby one of the muta tions a t the Agouti locus. A ccording tocultura l-historica l evidence, similar changes in coa t coloroccurred in e arly dogs.(8)

In the domestica ted foxes, morphologica l aberra tions suchas floppy e ars and curly ta ils occurred in addition to changesin standard coa t color. These morphologica l tra its are a lsocharacteristic of many domestica tes, particularly dogs( F igs. 4 F –J). A t the more advanced steps of se lection,changes in the parame ters of the ske le ta l system began toarise. T hey included shor tened legs, ta il, snout, upper jaw,and widened skull ( F ig. 4).

Some of the phenotypic changes appe ared not only in thedomestica t ed foxes, but a lso in those foxes of the farm-bredpopula tions tha t were not subjected to se lection for tame-ability (Table 2). T he above observa tions suggest a re la tionbe twe en se lection for tame ability and the appe arance of asubse t of phenotypic changes characteristic of domesticanima ls. T he appe arance of some phenotypic changes in thefoxes of the nonse lected popula tions is not a t variance withthis suggestion. T hese popula tions have be en bred incaptivity for about a hundred ye ars, during which they havebe en inevitably subjected to se lection for adapta tion tocaptivity or amenability to domestica tion. The ana lysis of thissubse t in terms of traditiona l quantita tive gene tics ofcorre la ted variability is difficult.(30) In fact, strong se lectionpressure on any quantita tive tra it, especia lly on those havingadaptive significance, bre aks down the gene tic system kept inba lance by preceding evolution and, as a consequence,inevitably le ads to the appe arance of deviants from thephenotypic me ans whose reproductive capacity is reduced.C er ta inly, the corre la ted responses of any popula tion to anyse lection depend on the structure of its gene tic pool, andthere fore they are, in a sense, unique, and irreproducible.However, domestica tion of different popula tions of onespecies, different species or even orders is, as we ll asse lection of foxes for tame ability, consistently associa ted withthe same morphologica l, and physiologica l changes. T hisremarkable para lle lism can be hardly regarded as usua lcorre la ted responses to se lection for any quantita tive tra it. In



addition, the reproductive performance of a ll anima ls underdomestica tion improved, in contrast to wha t happened in thecase of the corre la ted responses in terms of traditiona lquantita tive gene tics.(30)

The inbre eding coe fficients of the popula tion wereestima ted on the basis of its reproductive performance(19,20)

and of a se t of randomly chosen polymorphic microsa te llitemarkers(31) a t different stages of se lection; the coe fficientva lues were not sma ller than 0.02 and never gre a ter then 0.07in both the domestica ted and farm popula tions. Theseestima tes indica t e tha t the probability of appe arance ofchanges due to stochastic fixa tion of the a lle les pre-existing inthe initia l popula tion and controlling e ach and every observedphenotypic change was very low.

F ina lly, it is unlike ly th a t the ch a ng e s in the dome stica t edfoxes were a result of ra ndomly arise n n ew muta tions. T hus,in th e sa me litter of ph enotypica lly st andard parents a ndeven in the sa m e of fspring of p arents assign e d to th e t am ee lite , severa l dif fere nt ch a ng e s in the st a nd ard phe notyp eappe ared ( F ig. 5A). T his is incomp a tibl e with th e mut a tion a lna ture of those ch ange s. T h e re sults of the ge ne tic an a lysisof morphologica l ch ange s are a lso incompa tibl e with thevi ew th a t e ach ph e notypic a lt era tion is due to a single

inde p end ent g en e , sinc e the of fspring of p arents with on e oranoth er morphologica l a ltera tion showed , contrary toexp e ct a tion, quite dif ferent morpholog ic a l ch ang es. O nlyth e S tar de pigm ent a tion ph enotype show ed an inde p end entge n e tic ba sis. T he results of ge ne tic an a lysis of th e otherph e notypic ch ang es de monstra te d th a t a common g en e ticba sis m ay underlie the se t of dif fere nt morphologica lab erra tions. A ll this strongly sugg ests th a t the phe notypicvaria tion within the dome stica t ed fox popula tion m ay resultfrom ch a ng e s in th e re gula tion of deve lopm ent by the keyge n es ca us e d by se le ction for t am e a bility.(18–20)

A s s o c i ati o n b et w e e n p h e n o ty p i c c h a n g e sa n d d e v e l o p m e n ta l rate

The associa tion be twe en the newly genera ted tra its andchanges in the deve lopmenta l ra t es of domestic foxes isnoteworthy. C er ta in behaviora l and morphologica l changesare corre la tes of de layed deve lopment of norma l tra its. T heemotiona l expression of positive responses to human,widened skulls, shor tened snouts, floppy e ars, curly ta ilsare a ll juvenile tra its tha t certa in domestica ted individua ls

T a b l e 1. The time course of ma ting in the tame foxes showing extrase asona l sexua l activity. The circles next to the order number of ma lesindica te the ir ma tings in the ye ars when they ma ted outside the bre eding se ason. W hite circles, sterile ma ting; black circles, fertile ma ting.

Ma l e10

O ct10

N o v15

N o v20

N o v25

N o v30

N o v10

D e c15

D e c25

D e c30

D e c10

J a n20

J a n30

J a n10

F e b20

F e b28

F e b10

Mar30

Mar5

A pr30

A pr5

Ma y10

Ma y15

Ma y

1 * 2 *3 * 4 * 5 *6 7 8 * 9 *** *** * * * * 10 * 11 * * * *** *12 * * *** * 13 * * * *** 14 ** * 15 ** **16 * * * * * * 17 * * *18 * 19 ** * *20 21 *22 *23 * * 24 * 25 * 26 * * * 27 * 28 29

Ma ting se ason



re ta in to adulthood.(3,32,33) D e lay in deve lopmenta l ra tes wasobserved as e arly as during embryonic morphogenesis. A sa lre ady noted, the specifica lly loca ted S tar depigmented spotsare the specific markers of domestica tion ( F igs. 2 and 5). It wasshown tha t re tarda tion of the deve lopment (prolifera tion andmigra tion from the neura l crest) of the embryonic precursors ofme lanocytes, or primary me lanoblasts, is the mechanismunderlying depigmenta tion.(34) This re tarda tion le ads to theabsence of me lanocytes from specific are as of the coa t and,hence, to its depigmenta tion.

T he shifts in the timing of deve lopment brought about byse lection of foxes for tame ability have a neotenic-liketendency; the deve lopment of individua l soma tic tra its isdece lera ted, while sexua l ma tura tion is acce lera ted. H igher

leve ls of sexua l hormones in the plasma and incre asedgonada l we ight during the prepuber ta l period are indica tors ofe arlier sexua l ma tura tion of tame foxes. Judging by these

Figure 4. A schema tic representa tion of the results of the fox domestica tion experiment. A : Transforma tion of fox behavior resulting fromse lection for tame ability. L eft: a fox of the farm-bred popula tion not se lected for behavior. Foxes of this popula tion show the typica l aggressiveresponse to humans. Ri g h t: a fox of the experimenta l domestica ted popula tion. The dog-like behavior of foxes of this popula tion is the result ofmany ye ars of se lection for tame ability. B – E : A ctivity of the H PA axis in farm-bred and domestica ted foxes. F arm-bred foxes are shown in grey, thedomestica ted in red. B : Hypotha lamic C R F (C R F mR N A/18SmR N A) and pituitary POMC (POMCmR N A/18SmR N A) gene expression, as we ll asA C T H (pg/ml) and cortisol (mg/dl) leve ls in farm-bred and domestica ted foxes. C : Age-re la ted changes in plasma cortisols leve l in farm-bred anddomestica ted foxes: 1) farm-bred foxes exhibiting aggressive responses to humans, 2, 3) foxes of the domestica ted popula tion with low (2) andhigh (3) domestica tion scores. D: Tota l time of locomotion, an indica tor of explora tory behavior, and plasma cortisol leve ls in farm-bred anddomestica ted foxes a t the age of 1–2 months: locomotion is plotted on the graph; plasma cortisol leve ls are represented as bars. E : P lasmacortisol in silver foxes during pregnancy and lacta tion. F –J: Dog-like morphological changes arisen in foxes of the domestica ted popula tion:F : S imilarity of coa t depigmenta tion be twe en dogs and foxes: L eft, border collie; Ri g h t, tame fox. G : Ta il carriage, curly ta il: L eft, IslandskF arehund; R i g h t, tame fox. H: E ars are floppy and face skull is widened in some pups of tame foxes: L eft, pug; Ri g h t, tame fox pup. I: Long jaw(e longa tion of the lower jaw), characteristic of the E nglish bulldog, occurs among tame foxes: L eft, E nglish bulldog; Ri g h t, tame fox. J: E longa tionof face skull in certa in dog bre eds and tame foxes: L eft, Pharaoh hound, Ri g h t, tame fox.

T a b l e 2. Frequencies of phenotypic changes newly arisen in foxpopula tions.

Tra its

F re q u e n c y i n p o p u l atio n s

D o m e sti c ate d F arm-bre d

S tar 1.24 10 1 0.71 10 2

Brown mottling 0.45 10 2 0.9 10 3

F loppy e ars 0.23 10 2 0.17 10 3

Shortened ta ils 0.14 10 2 0.2 10 3

C urly ta ils 0.94 10 1 0.8 10 2



parame ters, tame foxes re ach sexua l ma turity, on average,one month e arlier than the ir farm-bred counterpar ts.(35) Manyrese archers regard the neotenic tendency of deve lopment asa mechanism of evolutionary transforma tion of domesticanima ls. However, the causes of the emergence of thistendency during domestica tion rema in uncle ar.(8,32,33,36) O urfox experiment demonstra ted tha t neotenic shifts in deve l-opmenta l ra te may arise as a corre la ted consequence ofse lection for tame ability, i. e ., socia l adapta tion to humans.The point is tha t there is a sensitive socia liz a tion period inmamma ls when they explore the ir environment and ge t usedto par ticular socia l factors.(37,38) This period starts e arly withthe functioning of the sense organs and the forma tion oflocomotion, and enables the anima l to le arn about itssurroundings and to form a ttachments. T he ma tura tion ofthe neurophysiologica l substra te of the fe ar responsehampers socia liz a tion. Incre asingly fe arful pups star t to avoidthe impact of socia l factors, thus limiting the ir furthersocia liz a tion. It was found tha t se lection of foxes fortame ability slowed down the deve lopment of the fe arresponse and shifted it to la ter da tes. In foxes tha t werenot se lected for tame ability, the explora tory activity (estima tedon the basis of locomotion in an unknown se tting) becamesharply reduced by the age of 45 days or so when fe ar wasfirst manifested.(39) This reduction was lacking in the tamefoxes until the age of four months.(19) Q uite plausibly,re tarda tion of the deve lopment of the neurophysiologica lsubstra te of fe ar is just one of the numerous manifesta tions ofthe regula tory e f fects of genes tha t a ffect deve lopmenta lra tes and are targe ted by se lection for domestica tion. Itcannot be excluded tha t these genes perform a broaderfunction by regula ting the deve lopmenta l ra t es of other tra its.

N e ur o e n d o cri n e c h a n g e s u n d erd o m e sti c ati o n

Which puta tive genes a f fecting the deve lopmenta l ra te maypossibly be involved in se lection for domestica tion? Weassumed tha t some of these genes might perhaps control the

glucocor ticoid ( G C) sta tus in anima ls. This assumption isbased on the close associa tion be twe en socia l behavior andthe forma tion of the G C sta tus; the reduction in explora toryactivity, which, as noted above, se ts an end to the sensitivesocia liz a tion period, was found to be corre la ted with a rise inplasma cortisol leve ls during e arly postna ta l deve lopment.(40)

In the tame pups, whose socia liz a tion period was longer, thisrise occurred la ter ( F ig. 4D). Not only the ra t e of socia ldeve lopment, but a lso of the embryonic precursors ofme lanocytes were found to be associa ted with the G Csta tus.(41,42) These observa tions suggested tha t G C s mayfunction as coordina tors of the parame ters characteriz ing thetiming of deve lopment. E vidence exists tha t during embry-ogenesis G C s may have an inhibitory e f fect on ce llprolifera tion and thereby promote ce ll transition to differentia-tion, which is the next step of e arly deve lopment.(43–46)

O nly few studies were concerned with the function ofglucocorticoids under domestica tion. It has be en reported tha tdomestica tion of grey ra ts is associa ted with a decre ase in thewe ight of adrenals, changes in the ir morphology and a ltera-tions in the glucocorticoid synthesis under basal conditions andstress or under the effect of exogenous adrenocorticotropichormone (A C T H).(12,13) C omparison of domestic guine a pigswith their wild ancestors reve aled a decre ase in the stressresponse of the H PA axis in domestica tes.(14) It is ofimportance tha t the function of the H PA axis decre ased infoxes with advancing se lection for tameness. We started thecompara tive analysis of the H PA axis from genera tion 10 ofse lection for tame behavior. In this genera tion, the levels ofplasma glucocorticoids in the tame foxes were significantlylower in a ll se asons of the ye ar compared with the farm-bredfoxes.(47) The hormone levels decre ased with advancingse lection. B asa l cortisol levels in the blood of the domestica tedfoxes in genera tion 20 were a lmost two-fold lower than of thenon-domestica ted foxes, and stress-induced levels were about30% lower. In genera tion 45, basa l and stress-induced bloodcortisol leve ls in foxes of the tame popula tion were a lreadythre e- and five-fold lower than in the farm-bred foxes.(48) Theseda ta suggest tha t genes controlling plasma glucocorticoidswere possibly the targe ts during se lection for tameability.

Figure 5. Specific markers of domestica tion. A : Two different phenotypic changes in an Ss he teroz ygote: the S tar depigmenta tion and a floppyright e ar. B : Homoz ygote for the Star muta tion (SS). C : Phenotypic similarity be twe en brown mottling in fox and dog.



In the foxes se lected for domestica tion, the activity of theH PA axis is reduced a t a ll leve ls ( F igs. 4B– E ). This includesthe tota l G C s pool, the adrena l G C production in vitro, thebasa l A C T H leve l in plasma , and the adrena l response tostress.(49,50) The expression of the pro-opiome lanocortin(P O M C) gene, whose prote in product includes A C T Hand b-endorphin in the pituitary, was a lso reduced, andthe expression of corticotropin-re le asing hormone (C R H), there le asing factor for A C T H , tended to decre ase in thehypotha lamus.(51) It is a lso impor tant tha t in the tame foxesthe tota l G C pool in the blood was considerably decre asedduring pregnancy and lacta tion.(52,53) A s a consequence, theentire embryonic and e arly postna ta l deve lopment of the tameof fspring proce eded on the background of lower ma terna lG C s. G iven the multifarious e f fects of G C s on deve lop-ment,(54) the impact of the ir changes on deve lopmenta lprocesses is evident. They are directly associa ted with theexpression of the G C receptor ( G C R) gene, whose promoterregion has a complex structure. T he multiple and tissue-specific promoters provide fine regula tion of changes in G C Rgene expression in dif ferent e arly environments.(55,56) Mostimpor tantly, the G C R gene expression in the hippocampus, abra in structure modula ting the regula tion of behavior andactivity of the H PA axis and in the fronta l cortex, is higher in thedomestic anima ls.(57) Thus, the e ffects of se lection for tamebehavior on the H PA axis are manifest a t a ll leve ls, rangingfrom phenotypic parame ters to the expression of the C R H,P O M C , and G C R genes.

Domestica tion a lso a f fects the deve lopmenta l neurotrans-mitter systems. T he role of neurotransmitters in the regula tionof deve lopment has be en discussed(58) and recently reva l-ua ted.(59) The serotonin system of the bra in deserves specia la ttention with re ference to domestica tion. Its contribution tothe inhibition of aggressiveness in anima ls, including foxes,has recently be en discussed in B ioessays.(60) T he studies ofthe bra in’s serotonin system showed tha t the domestica tedfoxes differed from the farm-bred by higher leve ls of serotoninand its ma in me tabolite 5-hydroxyindol ace tic acid in anumber of bra in structures. D if ferences in the activities ofmonoamine oxidase, the principa l enz yme in serotonindegrada tion, and of tryptophan hydroxylase, the keyenz yme in serotonin synthesis, were a lso demonstra ted. Itwas shown tha t the activity of tryptophan hydroxylase washigher in the tame than in the non-tame foxes. T he higheractivities of this key enz yme and the higher leve ls of serotoninin the bra ins of domestica t ed foxes agre e we ll with the da taconcerning the inhibitory influence of serotonin on a numberof aggressive types of behavior.(49,60) Thus, it is impor tant toemphasiz e the role of serotonin in deve lopment. Previous(58)

and recent(61) publica tions have shown tha t serotonin acts asa multifarious signa l molecule tha t is impor tant duringdeve lopment and capable of e liciting a cascade of geneactiva tions.

D e sta b ili z i n g s e l e c ti o n a s a p o s s i b l ea c c e l erat or o f e v o l u ti o n ar ytra n sf orm ati o n o f d o m e sti c a n i m a l s

Surveying the observa tions made during the course ofexperimenta l fox domestica tion, B e lya ev found no sa tisfac-tory explana tion within the traditiona l gene tic framework andcame to the ide a of destabiliz ing se lection as a factor ofdomestica tion.(16) A s destabiliz ing se lection B e lya ev desig-na ted se lection causing destabiliz a tion of regula tory systemscontrolling deve lopment and, hence, destabiliz a tion of themorphologica l and physiologica l organiz a tion stabiliz ed byprevious na tura l se lection.(62) Under domestica tion, se lectionfor particular behaviora l fe a tures accomplishes the destabi-liz ing function. B e lya ev regarded the se lection for just thesefe a tures as a ma jor acce lera tor of the evolutionary transfor-ma tion of domestic anima ls. It appe ars like ly tha t destabiliz ingse lection can a f fect anima ls a t any organiz a tiona l leve l,whose popula tions experience se lection pressure on beha-viora l tra its. Illustra tive examples of multiface ted conse-quences of se lection for behavior(63,64) were reported even inDrosophila .(65,66,67) The evolutionary role of se lection forbehavior would incre ase gre a tly in the case of highlyorganiz ed mamma ls, because the ir phenotypic manifesta tionof behaviora l tra its involves much more regula tory neuro-transmitters and neurohormona l re la tionships.(62)

The evolutionary function of destabiliz ing se lection isthe reverse to tha t of stabiliz ing se lection.(68) S tabiliz ingse lection acts a lways in an environment with which aspecies has coped we ll; this le ads to stabiliz a tion ofdeve lopment to form a phenotype tha t is optima l under thiscondition. S tabiliz ing se lection acts by suppressing the e f fectsof muta tions tha t disrupt deve lopment and a lter the norma lphenotype, or even by e limina ting them. It ma inta insvariability within the optimum range of the evolutionaryestablished norm, but it does not produce variabilitybeyond the phenotype of the species. Ana lysis of thee ffects of se lection for behavior on deve lopment andvariability in our fox mode l demonstra ted tha t it sharplydestabiliz ed the corre la ted deve lopmenta l systems and led toan incre ase in phenotypic varia tion. Wha t mechanisms can beinvolved in this process? And wha t is the na ture of thechanges in the specific genes tha t are induced by destabiliz-ing se lection?

It appe ars plausible tha t the phenotypic nove lties in theexperimenta l fox popula tion could be due to changes in geneactivity, large ly in its epigene tic modifica tion. Hormona lchanges under domestica tion may result in e ither genesilencing or gene activa tion. In this context, the above-mentioned S tar phenotype ( F ig. 5), which appe ars repe a tedlya t high frequencies (10 1–10 2) in the popula tion of tamefoxes and which is de termined by the incomple te ly dominantS gene, is of impor tance.(29) S egrega tion ana lysis of



of fspring from crosses be twe en S s he teroz ygotes for thisgene demonstra ted a shor tage of S S homoz ygotes. Thisshor tage cannot be accounted for by se lective embryonic,z ygotic, and game tic morta lity. Some foxes tha t were provento be S S homoz ygotes have the he teroz ygous phenotype (S s)and the inheritance pa ttern characteristic of he teroz ygotes. Itwas assumed tha t one of the two homologous mutant S tara lle les became functiona lly inactive. A lso, cases of bir th ofhomoz ygotes in crosses be twe en a he teroz ygous and astandard parent have be en documented (unpublished da ta).This suggests the reverse process of activa tion of a wild-type‘‘silent’’ a lle le in rare he teroz ygotes for the S tar gene. A similarphenomenon of heritable gene inactiva tion/re activa tion hasbe en described for the kinked ta il character in the mousecontrolled by the dominant A xin-fused gene, the phenotypicexpression of which is extreme ly variable, to the extent tha tsome of its carriers have a norma l phenotype.(69) Subsequentstudies showed tha t the absence of the kinked ta il phenotypecorre la tes with the leve l of D N A me thyla tion in a re tro-transposon within A xin F u.(70) Moreover, the epigene ticmodifica tion of the mutant kinked a lle le of both ma terna land pa terna l deriva tion passes me iosis, i. e ., it does notundergo reprogramming during game togenesis.(70)

In the mouse, another example of inheritance of epigene ticmodifica tion in the Agouti locus, which controls wild-type coa tcolor, has be en described. The A vy a lle le be ars a transposoninsertion. T he number of viable ye llow phenotypes wasre la ted to the me thyla tion pa ttern of this insertion.(71–74) TheAgouti locus is implica t ed to be involved in brown mottling inthe dog. T his prompts to study the Agouti locus a t themolecular leve l in the domestica ted fox to reve a l whe ther thelocus possess structura l components tha t can act as e f fectivecarriers of me thyla tion marks.

Me thyla tion of the D N A promoter regions is implica t ed as amechanism of the epigene tic a ltera tion in gene expression;me thyla tion is re la ted to the transcriptiona l silencing ofregula ted genes, while hypome thyla tion is re la ted to the irtranscriptiona l activity. A s to the S tar muta tion in foxes, it isunknown whe ther its activity changes a t the transcriptiona lleve l or a t subsequent steps of gene product conversion. Itmay be specula ted tha t the se lection-re la ted gene tic changesin the regula tory neurohormona l system of the domestica tedfoxes could induce changes in the expression of many otherdownstre am genes, thereby causing phenotypic destabiliz a-tion. However, only limited changes in gene expression in foxbra in have be en shown so far.(51,75) A s indica ted above, thesechanges involve a lso genes of the H PA axis.(48,51) Thissuggests tha t behaviora l as we ll as morphologica l andphysiologica l changes in the domestic foxes may dependon changes in the expression of a very sma ll number of bra ingenes with many regula tory downstre am e f fects.

It is of interest tha t the expression profiles of the bra in-specific genes showed remarkable dif ferences be twe en

domestic dogs and the ir closest wild re la tives, wolves(C anis lupus) and coyotes ( C anis la trans).(76) In dogs, themost prominent changes in gene expression occurred in thehypotha lamus, which is a biologica lly important, evolutionaryconserved bra in structure as we ll as a modula tor of behaviora land neuroendocrine responses to environmenta l agents.C omparisons of the differences in gene expression be twe enwolves and coyotes, which have be en separa ted for 2 MyrB P,(77) have demonstra ted tha t the differences are minima land tha t the expression profiles of the hypotha lamic genes inthe wild canids are conserved. T his is in striking contrastwith the variable expression of these genes in dogs andwith the differences be twe en dogs and wild canids. It couldnot be ruled out tha t se lection for tame behavior during12,000–15,000 ye ars of dog domestica tion acce lera teddivergence of gene expression in the bra in, as postula tedby the authors.(76)

M o l e c u l ar g e n eti c im p li c ati o n s f orp h e n o ty p i c c h a n g e s u n d er d o m e sti c ati o n

A s ye t, little is known about the corre la tion be twe en theexpression leve ls of specific genes and phenotypic variabilityin particular tra its. However, some da ta indirectly indica te tha tthis re la tion does exist. For example, it is known tha t codingregions abound with presumably noncoding simple sequencerepe a ts (S S Rs). It is curious tha t ha lf of these repe a ts clusterin regions conta ining one or severa l genes playing a key role indeve lopment.(78) This suggests tha t they are impor tant for theregula tion of expression of these key deve lopmenta l genes.T he ir a ltered regula tion may be implica ted as the ma jorsource of changes in many genes under the ir control. Thus, ithas be en shown tha t varia tion in the number of tandemrepe a ts in two such genes, Runx-2 and A lx-4, may be re la tedto the varia tion in ske le ta l tra its in dogs.(79) Varia tion ra t es inthe number of tandem repe a ts in genes for neurotransmittersand the ir receptors may be involved in de termining varia tionsin behavior.(80) The varia tion in the number of repe a ts canexce ed by far tha t of point muta tions. This suggested tha tvaria tion in the length of tandem repe a ts may be apredominant source of rapid morphologica l evolution andtha t the repe a ts associa ted with the deve lopmenta l genesincre ase the pace of evolution.(79)

In addition to S S Rs, phenotypic varia tion may beinfluenced by canid-specific sma ll interspersed nucle are lements (SIN E s).(81) Both se em to be often present a tpositions influencing gene expression.(82,83) B sp repe a tssimilar to canine SIN E s have be en de tected in the foxgenome, in which they may potentia lly perform regula toryfunctions.(84,85) The presence of S S R , SIN E , or B sp e lementsin the genes of the hormona l and neurotransmitter systemsmay have impor tant consequences. C hanges in the ir



expression may be implica ted in changes in the expression ofmany genes under the ir control.

The molecular gene tic mechanisms underlying thebehaviora l and morphologica l tra its of the now existingdog bre eds may not, however, reflect the gene tic na ture ofthe e arly changes brought about by domestica tion. Thedomestic fox is there fore a unique mode l of the gene ticevents of e arly domestica tion. A t the IC& G fur farm, foxesare me thodica lly se lected not only for domestica tion, i. e .,e limina tion of the aggressive genes, but a lso in the oppositedirection — for re tention and enhancement of the expressionof aggressive behavior. A s a result, a popula tion ofaggressive foxes has a lso be en se t up. This popula tion,toge ther with the domestica ted one, serves as va luableresource for gene tic studies of e arly domestica tion.

It shou ld be note d a ga in th a t an intriguing cons e qu e nc eof dom estic a tion — historica l of the dog and exp erim e nt a l ofthe silver fox — were the ne wly aris en morphologica lvaria tions. This is a m a z ing with resp ect to th e tra its ofthe ske le ta l syst em th a t de fin e body siz e and conform a tion.We are now ra ising th e impor t ant evolution ary qu e stion ofwhe ther b eh aviora l and morpholog ic a l tra its are inte gra t eda t the ge nomic leve l, i. e . , whe th er th ere exist loci which co-regula t e morpholog ic a l-b eh aviora l tra its. We have st ar t edres e arch in this dire ction in collabora tion with th e Universityof U t ah (Prof. Lark) a nd th e C orn e ll University (Prof.Ackla nd and Dr. Kukekova). T he P C A a ppro ach was use dfor ge n e tic disse ction not on ly of compl ex be haviora l tra itsas above but a lso of ske le ta l tra its.(86 ,87) This a ppro achreve a led se ts of corre la t ed para me ters (P C s) which arestructuring variability. D if fere nc es be twe en ta m e , aggre s-sive , a nd control popula tions were expre ss ed in t erms of theP C s. T he P C s b eh ave d as ind ividu a l ph enotype s in these gre ga ting g en era tions from the Ta m e Aggre ssive crossand the subse qu ent b ackcross es, a s we re por t ed .(22 ,23 ,86)

Thus, the s e ph enotype s were appropria t e for mol ecularge ne tic a na lysis. S e arch for the loci for be havior a ndmorphology, a long with the ir common loci, is of currentint erest, be ca us e co-se gre ga tion of som e of the ir P C ssugge sts tha t th ey may sh are cer ta in loci. C onstruction ofthe m e iotic ma p of th e ge nom e of the fox was followed byge ne tic ma pping of the loci for th e P C s,(88) which will beus e d to fur th er study th e co-regula tion of morphology a ndbe havior.

C o n c l u s i o n s

We proce eded on the assumption tha t regula tory changes ingene activity may genera t e the remarkable leve l of diversityand its similar pa tterns among domestic anima ls. T heseregula tory changes were presumably caused by se lection ofanima ls for specific behavior, name ly tame ability as a

marker of tolerance and successful adapta tion to the humansocia l environment. The experimenta l mode l of domestica-tion, as a kind of forced evolution, was deve loped bysystema tica lly applying se lection for tame ability on silverfoxes.

The founders of the se lected popula tion were chosen fromlarge farm-bred popula tions. T hey represented the gene ticvariants tha t had reproductive success and showed thewe akest wild-type aggressive-avoidance response tohumans. Such foxes had undoubtedly be en under na tura land artificia l se lection for tame ability through a ll the ye ars ofcage bre eding. However, this se lection did not a ffect thestandard morphologica l and physiologica l phenotype of thefoxes in a ll popula tions we studied. We succe eded in rapidlyse tting up a unique popula tion of domestic foxes following thee ffect of rigorous se lection pressure for tame behavior. T hebehaviora l pa tterns of these foxes are dog-like. T hese foxesa lso have a range of morphologica l and physiologica l tra itsa ttributable to domestic anima ls. T he fox domestica tionexperiment demonstra ted tha t this se lection a f fected thegenes controlling the neurohormona l sta tus. Some of thegenes responsible for the associa tion be twe en tame abilityand hormona l and transmitter leve ls might have be en broughttoge ther and become fixed by 8–10 se lected genera tions.T he ir fixa tion might have modified the activity of many otherdownstre am genes, thereby destabiliz ing and shifting timingof deve lopment, and uncovering some of the phenotypica llyhidden potentia lities of the genome. This me ans tha t theinteractions be twe en gene tic variants a ltered during se lectionmight have produced new pa tterns of gene expression andnew phenotypes.

D ifferent molecular mechanisms are implied in thephenotypic expression of non-expressing genes and the irepigene tic modifica tion. T hey include non-coding sequencesand me thyla tion–deme thyla tion of the regula tory regions ofgenes. Wha tever the molecular mechanisms of changes ingene activity under domestica tion, the results suggest tha tthese changes could be produced by se lection for tame ability.

In the light of the results of the fox domestica tionexperiment, the similar pa tterns of behaviora l as we ll asmorphologica l and physiologica l transforma tion in foxes, dogsand other domestica tes are suggested to be the result ofse lection for tame ability. T his se lection is thought to be thecausa tive and universa l mechanism for evolutionary trans-forma tion of domestic anima ls.

A c k n o w l e d g m e n ts : The authors thank Anna F ade eva fortransla tion of the manuscript from Russian into E nglish andYeka terina O me lchenko for technica l assistance. NIH grants #1R03 T W 008098-01, # R01 MH 077811-01, and the Programsof B asic R ese arch of the R A S Presidium ‘‘B iodiversity and genepool dynamics’’ and ‘‘Molecular and C e ll B iology’’.



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