Adaptations to climate-mediated selective pressures in sheep
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Adap a ions o Clima e-Media ed Selec i e P essu es in Sheep
Feng-Hua L ,
1
Sai Agha,
2,3
Juha Kan anen,
4,5
Licia Colli,
6,7
Syl ie S ucki,
2
James W. Kijas,
8,
S
ephane Joos ,
2
Meng-Hua Li,*
,1
and Paolo Ajmone Ma san
6,7
1
CAS Key Labo a o y o Animal Ecology and Conse a ion Biology, Ins i u e o Zoology, Chinese Academy o Sciences (CAS),
Beijing, China
2
Labo a o y o Geog aphic In o ma ion Sys ems (LASIG), School o A chi ec u e, Ci il and En i onmen al Enginee ing (ENAC), Ecole
Poly echnique F
ed
e ale de Lausanne (EPFL), Lausanne, Swi ze land
3
Depa men o Animal Science, Facul y o Ag icul u e, Ain Shams Uni e si y, Cai o, Egyp ,
4
Bio echnology and Food Resea ch, MTT Ag i ood Resea ch Finland, Jokioinen, Finland
5
Depa men o Biology, Uni e si y o Eas e n Finland, Kuopio, Finland
6
Is i u o di Zoo ecnica, Facol
a di Ag a ia, Uni e si
a Ca olica del Sac o Cuo e, Piacenza, I aly
7
Biodi e si y and Ancien DNA Resea ch Cen e —BioDNA, Uni e si
a Ca olica del Sac o Cuo e, Piacenza, I aly
8
CSIRO Li es ock Indus ies, S Lucia, B isbane, Qld, Aus alia
*Co esponding au ho : E-mail: menghua[email p o ec ed].
Associa e edi o : Yuseob Kim
Abs ac
Following domes ica ion, sheep (O is a ies) ha e become essen ial a med animals ac oss he wo ld h ough adap a ion
o a di e se ange o en i onmen s and a ied p oduc ion sys ems. Clima e-media ed selec i e p essu e has shaped
pheno ypic a ia ion and has le gene ic “ oo p in s” in he genome o b eeds aised in di e en ag oecological zones.
Unlike nume ous s udies ha ha e sea ched o e idence o selec ion using only popula ion gene ics da a, he e, we
conduc ed an in eg a ed coanalysis o en i onmen al da a wi h single nucleo ide polymo phism (SNP) a ia ion. By
examining 49,034 SNPs om 32 old, au och honous sheep b eeds ha a e adap ed o a spec um o di e en egional
clima es, we iden i ied 230 SNPs wi h e idence o selec ion ha is likely due o clima e-media ed p essu e. Among hem,
189 (82%) showed signi ican co ela ion (P0.05) be ween allele equency and clima ic a iables in a la ge se o
na i e popula ions om a wo ldwide ange o geog aphic a eas and clima es. Gene on ology analysis o genes
coloca ed wi h signi ican SNPs iden i ied 17 candida es ela ed o GTPase egula o and pep ide ecep o ac i i ies in
he biological p ocesses o ene gy me abolism and endoc ine and au oimmune egula ion. We also obse ed high linkage
disequilib ium and signi ican ex ended haplo ype homozygosi y o he co e haplo ype TBC1D12-CH1 o TBC1D12.The
global equency dis ibu ion o he co e haplo ype and allele OAR22_18929579-A showed an appa en geo-
g aphic pa e n and signi ican (P0.05) co ela ions wi h clima ic a ia ion. Ou esul s imply ha adap a ions o
local clima es ha e shaped he spa ial dis ibu ion o some a ian s ha a e candida es o unde pin adap i e a ia ion in
sheep.
Key wo ds: adap a ion, clima e-media ed selec ion, genome-wide scans, GTPase egula o , pep ide ecep o , TBC1D12,
sheep.
In oduc ion
En i onmen al he e ogenei y and di e ences in clima ic ac-
o s (e.g., empe a u e and p ecipi a ion) in luence he spa ial
dis ibu ion o pheno ypic and gene ic a ia ion ac oss
popula ions o a a ie y o o ganisms including loblolly
pine, A abidopsis,D osophila, goa , and human (Hancock
e al. 2008;Pa ise e al. 2009;Ecke e al. 2010;
Gonz
alez e al. 2010;Hancock, B achi, e al. 2011;Hancock,
Wi onsky, e al. 2011). The de ec ion o clima e-media ed
selec i e signa u es is hus one o he cen al esea ch
hemes in e olu iona y biology, wi h he po en ial o shed
ligh on he gene ic basis o local adap a ion and specia ion in
esponse o changing clima es (MacCallum and Hill 2006;
Joos e al. 2007). The iden i ica ion o adap i e a ia ion
also holds he p omise o p o iding insigh in o unc ionally
impo an a ian s (see he e iews in Bamshad and Wooding
2003;Nielsen e al. 2007).
To da e, he iden i ica ion o en i onmen -d i en selec ion
has been la gely es ic ed o species wi h inished genome
sequences o model species, such as D osophila and humans
(see he e iew in Oleksyk e al. 2010). These success ul s udies
ha e e ealed examples o clima ic adap a ion in ai s includ-
ing pigmen a ion (Hancock, Wi onsky, e al. 2011), body size
(Ga dne e al. 2011), and he mal esponse (Ka ell e al.
2011). Few published s udies ha e been conduc ed in li e-
s ock, despi e he ac ha many a mya d animal species
ha e a global ange and exhibi pheno ypic di e si y and ad-
ap a ion o dispa a e en i onmen s. One ecen excep ion is
ßThe Au ho 2014. Published by Ox o d Uni e si y P ess on behal o he Socie y o Molecula Biology and E olu ion.
This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion Non-Comme cial License
(h p://c ea i ecommons.o g/licenses/by-nc/4.0/), which pe mi s non-comme cial e-use, dis ibu ion, and ep oduc ion in any
medium, p o ided he o iginal wo k is p ope ly ci ed. Fo comme cial e-use, please con ac jou nals.pe [email protected] Open Access
3324 Mol. Biol. E ol. 31(12):3324–3343 doi:10.1093/molbe /msu264 Ad ance Access publica ion Sep embe 23, 2014
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a s udy o domes ica ed yaks (Bos g unniens;Qiu e al. 2012);
howe e , yaks ha e a es ic ed angecompa edwi ho he
li es ock species. Thus, he ecen a ailabili y o genome-wide
single nucleo ide polymo phism (SNP) se s in li es ock would
allow he iden i ica ion o en i onmen -associa ed selec ion.
Li es ock ha e a popula ion his o y cha ac e ized by do-
mes ica ion and subsequen human-media ed selec ion o
a o able p oduc ion ai s. The compa ison o genomic pa -
e ns o SNP a iabili y, o en be ween di e gen b eeds, has
success ully iden i ied many genomic egions and genes ha
ha e unde gone selec ion sweeps (Gu e al. 2009;Qanba i
e al. 2010;S ella e al. 2010;Ama al e al. 2011). Mos s udies
ha e employed analyses o allele equency di e ences, wi h
measu es such as F
ST
-based ou lie s o long- ange haplo ype
(LRH) es s. Impo an ly, hese analyses ha e p oceeded wi h-
ou he in eg a ion o genomic and en i onmen al da a (Kijas
e al. 2012;Ai e al. 2013;Ramey e al. 2013). As a esul , i is
s ill impossible o link he signa u es o selec ion o speci ic
spa ially a ying selec i e p essu es (e.g., a speci ic en i on-
men al a iable). In ecen yea s, se e al app oaches ha e
been de eloped in landscape genomics o de ec adap a ion
o di e en clima e p essu es by examining co ela ions o he
associa ion be ween SNP alleles and clima e a iables (e.g.,
BayEn in Coop e al. 2010; la en ac o mixed model
(LFMM) in F icho e al. 2013; see also he e iew in Joos
e al. 2013). These app oaches ha e s eng hs and weaknesses
due o di e en implici assump ions in he models. By ap-
plying hese app oaches, se e al s udies ha e succeeded in
sea ching o e idence o gene ic adap a ion o di e en cli-
ma ic p essu es by scanning he genome o en i onmen al
co ela ions in a a ie y o o ganisms (Coop e al. 2010;
Hancock e al. 2010;Meie e al. 2011;Shimada e al. 2011).
Ruminan s such as sheep can be di ec ly a ec ed by cli-
ma e e ec s on he mo egula ion, pas u e quali y, and bio-
mass (Nielsen e al. 2013). Al hough he e is ex ensi e
e idence o pheno ypic a ia ion due o gene ic adap a ion
and/o nongene ic acclima iza ion o di e en clima es in
sheep (Nielsen e al. 2012,2013), he ex en o which his
a ia ion is he esul o gene ic adap a ion a he whole
genome-wide le el is s ill unclea .In he aceo globallychang-
ing clima es ha may a o mo e woody ege a ion (b owse)
a he expense o g asses (Go don and P ins 2008), hese
ques ions a e highly ele an o sheep gene ics and b eeding
(e.g., ma ke -assis ed selec ion and b eeding) o iden i y
b eeds o sheep o p oduce be e de i ed b eeds ha a e
mo e obus ly sui ed o u u e clima es, ha is, ha e inc eased
eed e iciency on no el ege a ion communi ies (Go don
and P ins 2008;F anks and Ho mann 2012;Nielsen e al.
2012,2013).
To he bes o ou knowledge, his is he i s high densi y
SNP genome scan o clima e-induced selec ion in li es ock
ha combines molecula and en i onmen al da a. The aim o
his s udy is o cha ac e ize he gene ic legacy ha cen u ies
o clima e-induced adap a ions ha e impa ed o he sheep
genome by iden i ying genome-wide signa u es o selec ion.
F omada ase o genome-wide(~50K)SNPsin74sheep
popula ions/b eeds ha we e sampled and geno yped wi hin
he sheep HapMap p ojec (h p://www.sheephapmap.o g/
hapmap.php, las accessed June 3, 2014), we selec ed geno-
ypes o 32 old, au och honous sheep b eeds (see ig. 1). We
pe o med a a ie y o selec ion es s using app oaches based
on di e en assump ions (e.g., gene ic di e en ia ion o SNPs,
haplo ype s uc u e, and gene ic–en i onmen al co ela-
ions) and di e en da a se s (genomic da a alone and he
combina ion o genomic and en i onmen al da a). We iden-
i ied a se o candida e SNPs, genes, and co e haplo ypes
unde clima e-d i en adap a ion ha we e en iched in wo
clus e s o gene on ology (GO) e ms ela ed o he biological
p ocesses o ene gy me abolism and endoc ine and au oim-
mune egula ion. These esul s will ad ance ou unde s and-
ing o he gene ic a chi ec u e o clima e-d i en adap i e
e olu ion and a e o signi icance o hei po en ial applica-
ions in unc ional genomics and selec i e b eeding (Joos
e al. 2007), as well as in he c ea ion o conse a ion man-
agemen p og ams (Luika e al. 2003) o cope wi h apid
global clima e change in sheep and o he li es ock.
Resul s
Rela ionships be ween B eeds Based on Clima e
Va iables and Genomic Da a
P incipal componen analysis (PCA) on he basis o clima ic
a iables ( ig. 2Aand B) and he analysis o gene ic ela ion-
ships be ween b eeds was pe o med o iden i y a se o dis-
an ly ela ed b eeds adap ed o ex eme en i onmen s. In
his subse , signa u es o clima ic adap a ion a e expec ed o
be s onge and easie o de ec while spu ious signals due o
common o igins be ween b eeds will be educed.
PCA clus e ed 32 na i e sheep b eeds acco ding o he
en i onmen hey a e adap ed o inhabi (see ig. 3). The
i s wo p incipal componen s (PC1 and PC2) explain
mo e han 69% o he o al a iance (PC1 accoun s o
50.78% and PC2 o 18.31%). PC1 di ides b eeds as a esul
o he con ibu ions o mul iple en i onmen al clima e a i-
ables. This componen ep esen s a syn he ic pa ame e ha
p incipally summa izes he in o ma ion o h ee clima ic a -
iables (supplemen a y able S1,Supplemen a y Ma e ial
online): The numbe o days wi h 40.1 mm o ain pe
mon h (RDO; 18.49%), he pe cen maximum possible sun-
shine (SUN; 17.89%), and he mean diu nal empe a u e
ange in C (DTR; 15.91%). These a e c i ical ac o s o eg-
e a ion g ow h and e es ial p ima y p oduc ion (Nemani
e al. 2003). PC2 and PC3 do no e eal a clea geog aphic
di e gence associa ed wi h en i onmen al a iables (see
ig. 3A). The plo e ealed ha eigh b eeds ha e posi i e
ex eme PC1 alues: Fou b eeds om he Uni ed Kingdom
(Bo de Leice s e , Bo e ay, Sco ish Black ace, and Soay
Sheep), wo om Swi ze land (Swiss Mi o Sheep, Valais
Blacknose Sheep), one om No way (Spael-colo ed Sheep),
and one om Finland (Finnsheep). These ex eme PC1 alues
likely a ise due o high alues o p ecipi a ion and days o
ain all (PR and RDO). Six b eeds ha e PC1 alues a he
nega i e ex eme mainly because o he high alues o em-
pe a u e, sunshine, and dis ibu ion o p ecipi a ion (TMP,
DTR, SUN, and PRCV): One each om I an (A sha ), Tu key
(Ka akas), Cyp us (Cyp us Fa -Tail), India (Indian Ga ole),
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Sou h A ica (Ronde ib A ikane ), and Kenya (Red Maasai)
( ig. 3B).
Gene ic Rela ionship be ween B eeds
A neighbo -ne g aph o D
R
was cons uc ed o explo e he
genomic ela ionship be ween b eeds ( ig. 4). The b eeds
g ouped in o wo main clus e s. One main clus e (clus e
I) included b eeds om Sou h Asia, he Middle Eas , A ica
and Sou h Ame ica, whe eas he o he clus e (clus e II) was
composed o b eeds om Eu ope, New Zealand and he
Uni ed S a es. This g ouping is consis en wi h p e ious ind-
ings conce ning he phylogeog aphy o he examined b eeds
(Kijas e al. 2009,2012). All he b eeds in clus e I showed
nega i e PC1 alues in he PCA plo based on en i onmen al
a iables. Con e sely, no all he b eeds in clus e II showed
posi i e PC1 alues (see igs. 3 and 4). Fu he , all he b eeds
wi h posi i e PC1 alues we e classi ied in o clus e II, bu all
he b eeds wi h nega i e PC1 alues did no belong o clus e
I(see igs. 3 and 4). Among he 15 b eeds loca ed a he
ex emes o PC1 in he PCA plo , 11 we e selec ed o u he
analyses. Fou b eeds we e excluded due o hei sha ed an-
ces y wi h o he b eeds (e.g., Moghani is closely ela ed o
A sha i; Swiss Mi o Sheep is closely ela ed o Engadine Red
Sheep) o high le els o inb eeding (Soay, F
IS
= 0.33; Bo e ay,
F
IS
= 0.28; see supplemen a y able S3,Supplemen a y
Ma e ial online, in Kijas e al. 2012). The e o e, by combining
he esul s o he in e popula ion gene ic ela ionship analysis
and he PCAs, 11 sheep b eeds (A sha i [AFS, I an], Ronde
A ikane [RDA, Sou h A ica], Indian Ga ole [GAR, India],
Ka akas [KRS, Tu key], Red Maasai [RMA, Kenya], Cyp us
Fa -Tail [CFT, Cyp us], Bo de Leices e [BRL, Uni ed
Kingdom], Spael-whi e [NSP, No way], Finnsheep [FIN,
Finland], Engadine Red Sheep [ERS, Swi ze land], and
Sco ish Black ace Sheep [SBF, Uni ed Kingdom]) we e
chosen o genome-wide selec ion es s.
De ec ion o Selec i e Sweeps
In he i s analysis o selec ion, we sea ched o alues o F
ST
ha we e ei he highe o lowe han expec ed a e con ol-
ling o he expec ed gene ic he e ozygosi y (H
E
). This ap-
p oach was applied o he 11 b eeds in he wo clus e s
p esen ed in igu e 5A. The summa y s a is ical me hod
based on simula ed and obse ed pai wise F
ST
alues iden i-
ied a o al o 2,353 SNPs beyond he 95 h pe cen ile o he
empi ical dis ibu ion (see Ma e ials and Me hods) as ou lie s
ac oss he genome ( ig. 5Aand supplemen a y able S2,
Supplemen a y Ma e ial online). As his igu e is app oxi-
ma ely he expec ed numbe o alse posi i es, only egions
ca ying i e consecu i e signi ican (window-a e aged P
alues 0.05) SNPs, an e en ha is highly unlikely o
occu by chance (P<10
8
), we e conside ed o u he anal-
yses. Using his s a egy, we iden i ied 29 sweep egions ha
FIG.1. Geog aphic o igins o he wo ld’s sheep b eeds. Sampling loca ions o he 74 b eeds/popula ions ( o de ails o he b eeds/popula ions, see
supplemen a y able S1,Supplemen a y Ma e ial online, in Kijas e al. [2012] o a h p://www.sheephapmap.o g/hapmap.php,las accessedJune3,
2014) a e indica ed by ed do s. Only he 32 old, au och honous b eeds selec ed in he analyses a e ep esen ed by he codes. Codes in g een (NSP, FIN,
SBF, BRL, ERS) and in blue (CFT, KRS, AFS, GAR, RMA, RDA) ep esen he 2 g oups o 11 b eeds selec ed o he selec ion es s. B eed names as
ep esen ed by he codes a e de ailed in supplemen a y able S8,Supplemen a y Ma e ial online.
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showed signi ican gene ic di e en ia ion be ween he wo
popula ion g oups. We u he iden i ied wo egions a
he mo e s ingen cu o le el o window-a e aged P alues
0.01 (OAR1:119.38–119.80 Mb, OAR4:48.50–48.80 Mb;
able 1). The 29 egions we e dis ibu ed ac oss ch omosomes
OAR1, OAR2, and OAR3. Mos egions (27/29; a e age alues
o
2
<0. 5; able 1) showed gene ally low le els o linkage
disequilib ium (LD) be ween SNPs wi hin a gi en egion. A
agmen on OAR2 was he la ges , ex ending o e 0.35 Mb
( able 1). A o al o 91 genes we e loca ed in o close o hese
egions by aligning he “ a ge egion” o O ine (Texel) e -
sion 3.1 Genome Assembly (see Ma e ials and Me hods).
O he 29 candida e sweep egions ( able 1), h ee o e -
lapped wi h hose p e iously iden i ied in he analysis ha
excluded he conside a ion o en i onmen al pa ame e s
(~10%; OAR2: 51.72–51.95 Mb, OAR6:36.61–36.87 Mb, and
OAR10:30.49–30.70 Mb; see able 1 in Kijas e al. 2012).
These egions spanned six genes (MELK,GNE,SPP1,IBSP,
MEPE,andHMGB1), which we e no biologically and unc-
ionally ele an candida e genes o selec ion in ei he his
s udy o he ea lie s udy. The majo i y o s ong signals was
speci ic o he subse analyzed he e and did no o e lap wi h
hose ound in ea lie wo ldwide analyses, sugges ing ha ue
selec ion p essu es a e mo e localized a he han dis ibu ed
ac oss popula ions. The di e ence could also be due o he
ela i e e ec s o na u al and a i icial selec ions on he sheep
genome, which we e a ge ed by his and he ea lie s udy,
espec i ely.
To sea ch o selec ion obse ed ac oss mul iple b eeds,
pai wise F
ST
ou lie es s we e implemen ed be ween b eeds
belonging o each o he wo g oups. SNP ou lie s we e dis-
ibu ed ac oss he en i e genome, bu none was de ec ed o
be unde di e gen selec ion (P0.05) ac oss all he 30
(5 6) pai wise es s (da a no shown). The numbe o
FIG.2. Clima ic a iable used in he analysis. (A) Maps show he geog aphic pa e ns o he yea ly mean alues o he eigh clima e a iables: Diu nal
empe a u e ange (DTR), numbe o days wi h g ound os (FRS), coe icien o a ia ion o mon hly p ecipi a ion (PRCV), p ecipi a ion in mm/mon h
(PR), numbe o days wi h 40.1 mm o ain pe mon h (RDO), ela i e humidi y (REH), pe cen maximum possible sunshine (SUN), and mean
empe a u e (TMP); (B) a hea map shows he absolu e alues o Spea man’s ank co ela ion coe icien s o he al i ude and annual mean alues o he
eigh clima ic a iables.
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pai wise popula ions ha displayed signi ican di e gence
wi h P alues 0.05 was plo ed ac oss he genome (supple-
men a y ig. S1,Supplemen a y Ma e ial online). These da a
e ealed peaks and oughs whe e selec ion was sha ed ac oss
b eeds and absen o unique o only a small numbe o
b eeds, espec i ely. In o al, 101 SNPs (supplemen a y ig.
S1,Supplemen a y Ma e ial online) we e de ec ed wi h di e -
gen selec ion (P0.05) sha ed by hal (15/30) o he com-
pa isons. The obse a ion ha signals we e no de ec ed
ac oss all he compa isons is expec ed. Adap a ion is due o
he in e ac ion o a numbe o complex ai s, and many
genes a e likely in ol ed in he con ol o each ai . This
indica es ha a high le el o gene ic he e ogenei y is expec ed
and ha b eeds may ha e adap ed o a simila en i onmen
using di e en “genomic s a egies.”
Signa u es o Genomic Adap a ion o Local
En i onmen s
We p ocessed 15,445,710 uni a ia e models (147,102 geno-
ypes 105 en i onmen al pa ame e s). Due o he limi a-
ion o he so wa e in which he P alues p o ided by
FIG.3. PCA o en i onmen al a iables and 32 old, au och honous sheep b eeds. (A) Hea s ips o each o he i s h ee PCs a e shown o he 32
sheep b eeds assigned o he wo gene ic clus e s (I and II; see ig. 4); he wo le e s be o e he b eed codes indica e he coun y o o igin: CH,
Swi ze land; CY, Cyp us; DE, Ge many; ES, Spain; FI, Finland; IE, I eland; ID, Indonesia; IN, India; IR, I an; IT, I aly; KE, Kenya; NO, No way; NZ, New
Zealand; TR, Tu key; TT, T inidad and Tobago; UK, Uni ed Kingdom; US, Uni ed S a es; and ZA, Sou h A ica; (B) he sco e plo s o PC1 e sus PC2 o
he 32 old, au och honous sheep b eeds and he en i onmen al a iables o hei geog aphic o igins. The b eeds in con as ing en i onmen s selec ed
o he selec ion es s a e indica ed in blue and g een, espec i ely. The nine en i onmen al a iables a e mean diu nal empe a u e ange in C, DTR;
numbe o days wi h g ound os , FRS; p ecipi a ion in mm/mon h, PR; he coe icien o a ia ion o mon hly p ecipi a ion in pe cen , PRCV; ela i e
humidi y in pe cen age, REH; pe cen o maximum possible sunshine, SUN; mean empe a u e in C, TMP; and numbe o days wi h 40.1 mm ain pe
mon h, RDO; and al i ude. The small colo ed ci cles ep esen he al i ude o he yea ly mean and mon hly pa ame e s o one o he eigh clima e
a iables ac oss all he 32 b eeds.
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Ma SAM a e limi ed o 1E-20, we did no se a s anda d
con idence le el be o e co ec ing o mul iple compa isons.
Ins ead, we so ed ou he models acco ding o Wald s a is ics
and selec ed he i s app oxima ely 1,000 showing he high-
es alues (~0.06% o he o al models p ocessed). The Wald
s a is ic o he selec ed models anged be ween 14.1 and 21.7
(supplemen a y able S3,Supplemen a y Ma e ial online). O
he nine en i onmen al ac o s, PR (34.19%, 330/965), SUN
(26.73%, 258/965), and RDO (24.97%, 241/965) a e he
p edominan a iables in ol ed in he bes models (supple-
men a y able S3,Supplemen a y Ma e ial online). In pa ic-
ula , o a o al o 32 selec i e SNPs loca ed nea o wi hin he
17 s ong candida e genes (see nex sec ion), 16 (50%, 16/32)
SNPs a e associa ed wi h SUN (supplemen a y able S3,
Supplemen a y Ma e ial online). The LFMM app oach iden-
i ied a o al o 3,756 SNPs showing jzjsco es g ea e han 5
( wo-sided es ; ig. 5Band supplemen a y able S4,
Supplemen a y Ma e ial online). The cu o jzjsco e 45
FIG.4. Gene ic ela ionship be ween he 32 old, au och honous sheep b eeds based on Reynolds’ gene ic dis ance. A me ic o Reynolds’ gene ic
dis ance was used o cons uc a neighbo -ne g aph ela ing he b eeds. The 11 sheep b eeds selec ed o selec ion es s om he wo gene ic clus e s(I
and II) a e indica ed in g een and blue, espec i ely. The codes in he pa en heses indica e hei geog aphic o igins o de elopmen : CH, Swi ze land; CY,
Cyp us;DE,Ge many;ES,Spain;FI,Finland;IE,I eland;ID,Indonesia;IN,India;IR,I an;IT,I aly;KE,Kenya;NO,No way;NZ,NewZealand;TR,Tu key; TT,
T inidad and Tobago; UK, Uni ed Kingdom; US, Uni ed S a es; and ZA, Sou h A ica; he b eed names, as ep esen ed by he codes, a e de ailed in
supplemen a y able S8,Supplemen a y Ma e ial online.
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indica ed signi ican SNP e ec s a he le el o P10
7
a e
applying a s anda d Bon e oni co ec ion o =0.01 and
L=10
5
(, ype I e o ; L, numbe o loci). Among hese, 382
SNPs we e also de ec ed by Ma SAM ( ig. 6Aand supplemen-
a y able S4,Supplemen a y Ma e ial online).
GO En ichmen s and Co e Haplo ypes
We iden i ied 230 o e lapping SNPs ( ig. 6A) among he se-
lec ion es s using app oaches based on di e en models and
assump ions (F
ST
ou lie , Ma SAM, and LFMM). Compa ed
wi h he o e lap expec ed by chance, he e was a signi ican
excess o o e lapping selec i e signals ha we e sha ed be-
ween pai s o app oaches o among all h ee app oaches
(obse ed SNPs n= 230, SNPs expec ed by chance n=4;
P<0.001; ig. 6A). We also de ec ed a signi ican (obse ed
SNPs n=79, SNPs expec ed by chance n= 13.3; P<0.001; ig.
6B) en ichmen o o e lapping signals be ween he SNPs wi h
jzj45 and he SNPs in he 29 candida e sweep egions
( able 1). The 230 o e lapping SNPs we e loca ed ac oss he
en i e genome wi h a la ge numbe o SNPs loca ed on OAR1,
OAR2, OAR3, and OAR4 (supplemen a y able S5,
Supplemen a y Ma e ial online). We ound a o al o 175
candida e genes (supplemen a y able S5,Supplemen a y
Ma e ial online). Two genes (MAPK14 and ANTXR2;
Hancock e al. 2008;Fumagalli e al. 2011)we ep e iously
de ec ed o be associa ed wi h egional a ia ions in clima e
and pa hogens in humans (supplemen a y able S6,
Supplemen a y Ma e ial online). In addi ion, only six genes
we e associa ed wi h g ow h and p oduc ion (POL and
LRRC2;Zhang e al. 2013), ep oduc ion (FSHR and PRL;
Rannikki e al. 1995;Chu e al. 2007,2009,2012), coa colo
(EDNRB;Me allinos e al. 1998;Wilkinson e al. 2013), and a
deposi s (ACSS2;Bichi e al. 2013), as iden i ied by ea lie
gene ic s udies in sheep (supplemen a y ables S5 and S7,
Supplemen a y Ma e ial online) and o he li es ock.
We compa ed he dis ibu ion o gene sizes in he candi-
da e gene se agains he backg ound se , and he
Kolmogo o –Smi no es o signi icance indica ed ha he
dis ibu ion o gene size o he candida e gene se is indeed
signi ican ly la ge (P<0.01; see supplemen a y ig. S2,
Supplemen a y Ma e ial online). A e u he il e ing ou
28 SNPs ha showed s ong LD (
2
40.5) wi h one o
mo e nea by loci in he same genomic egions (o genes),
we ob ained 202 SNPs and 175 ele an candida e genes
(see supplemen a y able S3,Supplemen a y Ma e ial
online). GO en ichmen among he 175 en i onmen ally as-
socia ed candida e genes was e alua ed o e idence o unc-
ional en ichmen in speci ic ca ego ies o biological
p ocesses, molecula unc ions, and KEGG pa hways. O a
o al o 39 GO ca ego ies, we e ealed 13 GO e ms en iched
wi h 17 genes using a h eshold o P<0.05 ( ables 2 and 3).
These GO e ms g ouped in o wo clus e s; one was mainly
ela ed o GTPase ac i i y (clus e A, en ichmen
sco e = 2.18), and he o he was mainly ela ed o pep ide
and chemokine ecep o ac i i y (clus e B, en ichmen
sco e = 1.95), which a e mainly in ol ed in he biological p o-
cesses o ene gy me abolism and endoc ine and au oimmune
egula ion (e.g., insulin, gonado opin- eleasing ho mone, and
o myl pep ide ecep o s). Among he 17 genes implica ed in
clima e-d i en selec ion, nine we e di ec ly ela ed o ene gy
sou ces and ans e s. These genes encode signaling molecules
in ol ed in GTPase ac i a o and egula o ac i i ies, egula-
ion o Ras p o ein signal ansduc ion, such as ARHGEF18,
FIG.5. F
ST
-based ou lie and LFMM selec ion es s. (A) Genome-wide dis ibu ion o [log
10
(1 P)] alues o gene ic di e en ia ion (F
ST
) be ween he
wo g oups o 11 b eeds (P alue is he p obabili y o simula ed F
ST
<sample F
ST
;An ao e al. 2008;supplemen a y able S2,Supplemen a y Ma e ial
online; see also Ma e ials and Me hods) by he LOSITAN p og am (An ao e al. 2008); he ed line indica es he ou lie SNPs beyond he uppe 95 h
pe cen ile, which we e assumed o be unde selec ion; he ceiling o maximum alues a 6 is due o a limi a ion o he calcula ion o P alues, and only
six digi s a e he decimal poin can be calcula ed; (B) genome-wide dis ibu ion o signi icance alues [log
10
(P)] o he co ela ion be ween he
equencies o SNPs and he en i onmen al a iables in he LFMM es ; he ed line indica es he signi icance le el o P<10
7
;(C) egional dis ibu ion
o F
ST
o he SNPs wi hin and a ound he s ong candida e gene TCB1D12;and(D) egional dis ibu ion o jzjsco es o he SNPs wi hin and a ound
he s ong candida e gene TCB1D12; SNP OAR22_18929579 is in yellow, and he wo o he SNPs (OAR22_18924267 and OAR22_19020858) in he co e
haplo ype a e in ed.
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Table 1. Regions unde Clima e-Associa ed Selec ion in he Sheep Genome.
Region Ch . Posi ion (Mb)
( e sion 3.1)
Posi ion (Mb)
( e sion 1.0)
2
Peak SNP (F
ST
) Top SNPs No. o Genes Candida e
Genes
a
1* 1 69.00–69.19 73.58–73.78 0.68 OAR1_73583793 (0.54) 6 2 EVI5
2* 1 105.35–105.70 113.14–113.48 0.20 s47856 (0.43) 9 8
3** 1 119.38–119.80 129.37–129.96 0.41 s70345 (0.58) 5 1
4*
b
2 51.72–51.95 55.31–55.54 0.15 OAR2_55416697 (0.51) 5 2
5* 2 164.90–165.03 174.54–174.66 0.32 OAR2_174558603 (0.61) 5 1
6* 2 184.00–184.30 195.09–195.39 0.39 OAR2_195251529 (0.42) 6 1
7* 2 232.47–232.59 245.55–245.68 0.42 s13779 (0.44) 5 4 NMUR1
8* 2 234.33–234.61 247.47–247.76 0.28 s09024 (0.38) 7 11
9* 3 11.66–11.89 12.24–12.47 0.32 OAR3_12358231 (0.66) 5 2
10* 3 44.11–44.30 47.15–47.35 0.35 OAR3_47149563 (0.46) 5 2
11* 3 106.05–106.36 112.82–113.18 0.28 OAR3_112822823 (0.48) 6 4
12* 3 144.25–144.55 154.11–154.43 0.33 OAR3_154209677 (0.32) 5 3
13* 3 186.59–186.74 200.81–200.98 0.28 OAR3_200805613 (0.54) 5 1
14** 4 48.50–48.80 51.32–51.63 0.37 OAR4_51489408 (0.73) 7 6
15*
b
6 36.63–36.87 40.83–41.04 0.10 OAR6_40955920 (0.33) 5 3
16* 6 115.21–115.56 116.66–117.05 0.25 s65350 (0.44) 7 4
17* 7 6.55–6.87 6.45–6.74 0.15 OAR7_6587255 (0.60) 6 3
18* 7 55.98–56.18 61.90–62.17 0.40 OAR7_61967937 (0.65) 5 2
19* 10 28.71–29.00 28.73–29.04 0.24 OAR10_28772065 (0.47) 6 5
20*
b
10 30.49–30.70 30.54–30.75 0.20 OAR10_30746533 (0.70) 6 1
21* 13 27.24–27.43 30.18–30.37 0.61 s41783 (0.45) 5 2
22* 13 53.41–53.63 58.10–58.35 0.48 s61722 (0.59) 6 10
23* 14 35.21–35.50 36.64–36.94 0.21 s18388 (0.56) 6 4
24* 16 3.36–3.52 3.43–3.63 0.24 s25980 (0.45) 5
25* 17 4.78–5.17 5.30–5.78 0.14 OAR17_5388531 (0.39) 6 2
26* 21 17.85–18.08 20.16–20.40 0.29 OAR21_20371526 (0.39) 8 1
27* 21 45.17–45.37 50.17–50.38 0.25 s48673 (0.43) 5 2
28* 23 26.31–26.64 27.44–27.77 0.22 s11742 (0.37) 5 2
29* 24 33.80–33.96 36.90–37.06 0.24 s43015 (0.64) 5 2
NOTE.—
2
is he a e age LD alue o all he pai wise SNPs wi hin he egions.
a
O e lap o he 17 s ong candida e genes en iched in he GO e ms.
b
O e lapping egions wi h hose p e iously iden i ied in Kijas e al. (2012).
A e age P alue o i e consecu i e SNPs *less han 0.05 and **less han 0.01.
FIG.6. The o e lapping SNPs unde di e en selec ion es s. (A) Numbe s in he in e sec ion egions a e he obse ed o e lapping SNPs be ween wo
me hods o among all h ee me hods; (B) numbe s in he in e sec ion egion a e o e lapping SNPs be ween he 29 candida e sweep egions ( he
window-a e aged P alues 0.05 in he F
ST
-ou lie es ) and LFMM analysis ( jzjsco e 45 in LFMM). Numbe s in pa en heses show he o e lapping
SNPs expec ed by chance i signals we e independen ac oss popula ions. The o al numbe o SNPs is epo ed in he uppe le co ne .
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PLCE1,TBC1D12 and FBXO8, and enzyme ac i a o s, such as
ARAP1,EVI5,CHN1,ALOX5AP and THY1( ables 2 and 3). The
o he eigh genes encode signaling molecules and cell su ace
p o eins implica ed in pep ide and chemokine ecep o ac-
i i ies, such as XCR1,CCR9,CXCR6,EDNRB and NMUR1,and
cy okine–cy okine ecep o in e ac ion pa hways, such as he
pep ide and chemokine ecep o s PRL,IL12RB1,andACVR2A,
which pa icipa e in endoc ine and au oimmune egula o y
p ocesses ( ables 2 and 3).
On he basis o LRH es , he s onges signal among
hose de ec ed in he 17 s ong candida e genes implica ed
in esponse o he local clima ic a ia ion ( ables 2 and 3)
esides wi hin a 92-kb egion ha lies en i ely wi hin he
gene TBC1D12.Onlyin hisgeneco ehaplo ypesshow
signi ican ly (P<0.01; able 4) high ex ended haplo ype ho-
mozygosi y (EHH)/ ela i e EHH (REHH) alues. In TBC1D12,
h ee SNPs de ine ou co e haplo ypes (deno ed TBC1D12-
CH1 o CH4; able 4). The OAR22_18929579-A allele is ca -
ied only on he co e haplo ype TBC1D12-CH1 ( able 4),
which is common (61%) in popula ions unde low empe -
a u e and high p ecipi a ion clima e (wi h posi i e PC1
alues in ig. 3B). TBC1D12-CH1 demons a es clea long-
ange, high LD, as shown in he haplo ype bi u ca ion dia-
g ams ( ig. 7A) and has co espondingly high EHH alues a
long dis ances (EHH 0.8 a he 1-Mb dis ance es ed;
ig. 7B). We u he compa ed he REHH alues o co e
haplo ypes and ound ha TBC1D12-CH1 is a clea ou lie
( ig. 7C) wi h a s a is ically signi ican (P<0.01; able 4)
highe REHH alue han hose o he o he haplo ypes o
compa able equencies.
Tes ing Candida e SNPs and Genes unde Di e gen
Selec ion
We did no obse e la ge allele equency a ia ion in 2,000
andomly selec ed SNPs among he 32 old, au och honous
popula ions (supplemen a y ig. S3A,Supplemen a y Ma e ial
online),whichha eawo ldwide angeo geog aphico igin
and clima e adap a ion. In con as , allele equencies o he
230 o e lapping candida e SNPs showed a la ge ange o a -
ia ion among hese popula ions (supplemen a y ig. S3A,
Supplemen a y Ma e ial online). We also obse ed signi ican
di e ences in he dis ibu ion o Spea man’s ank co ela-
ion coe icien s be ween he 230 candida e SNPs and he
2,000 andomly selec ed loci (supplemen a y ig. S3B,
Supplemen a y Ma e ial online): The dis ibu ion appea s
o be no mal o he 2,000 andom SNPs, whe eas he
alues a e mos ly a he posi i e and nega i e ex emes o
he 230 candida e SNPs. A la ge majo i y (82%, 189/230; da a
no shown) o he 230 candida e SNPs showed signi ican
(P<0.05) co ela ions be ween hei equencies and he
PC1 alues. In pa icula , he equencies o he OAR22_
18929579-A allele and co e haplo ype TBC1D12-CH1 ( able
4)inTBC1D12 showed signi ican (= 0.636, P<0.001;
= 0.756, P<0.001) co ela ion wi h he a ia ion o he
PC1 alue in he popula ions (n= 32). We u he examined
he global dis ibu ion o he allele OAR22_18929579-A
( ig. 8A) and o he haplo ype TBC1D12-CH1 ( ig. 8B)and
ound ha bo h a e a high equency in cold and humid
egions, as no he n Eu ope andUni edKingdom,anda low
equency in high empe a u e and d y egions, as he Nea
Eas , Sou h Asia, and A ica. Ou esul s u he con i med
ha he allele OAR22_18929579-A and he co e haplo ype
TBC1D12-CH1 in he s ong candida e gene TBC1D12 appea
o be unde s ong selec ion in esponse o en i onmen al
s ess.
Discussion
By combining he pa e ns in SNP a ia ion wi h en i onmen-
al a iables,wep esen he esul so agenomescan ha was
used o de ec he signa u es o na u al selec ion in esponse
o clima ic a ia ion. In he genomic egions signi ican ly
Table 2. O e ep esen ed GO Te ms among he 175 Candida e Genes Iden i ied o Be unde En i onmen ally Associa ed Selec ion in Sheep.
Clus e
(en ichmen sco e)
Te m Desc ip ion Genes P alue
Clus e A (2.18) GO:0030695 Molecula unc ion GTPase egula o ac i i y ARAP1,EVI5,ARHGEF18,PLCE1,CHN1,
THY1, TBC1D12, FBXO8
1.9E-03
GO:0060589 Molecula unc ion Nucleoside- iphospha ase
egula o ac i i y
ARAP1,EVI5,ARHGEF18,PLCE1,CHN1,
THY1,TBC1D12,FBXO8
2.3E-03
GO:0008047 Molecula unc ion Enzyme ac i a o ac i i y ARAP1,EVI5,CHN1,ALOX5AP,THY1,
TBC1D12,
4.9E-03
GO:0005096 Molecula unc ion GTPase ac i a o ac i i y ARAP1,EVI5,CHN1,THY1,TBC1D12 7.7E-03
GO:0005083 Molecula unc ion Small GTPase egula o
ac i i y
ARAP1,EVI5,ARHGEF18,THY1,TBC1D12,
FBXO8
8.0E-02
GO:0043087 Biological p ocess Regula ion o GTPase ac i i y ARAP1,EVI5,THY1,TBC1D12 1.7E-02
GO:0046578 Biological p ocess Regula ion o Ras p o ein
signal ansduc ion
ARAP1,EVI5,ARHGEF18,TBC1D12, FBXO8 2.3E-02
Clus e B (1.95) GO:0001653 Molecula unc ion Pep ide ecep o ac i i y XCR1,CCR9,CXCR6,EDNRB,NMUR1 5.0E-03
GO:0008528 Molecula unc ion Pep ide ecep o ac i i y,
G-p o ein coupled
XCR1,CCR9,CXCR6,EDNRB,NMUR1 5.0E-03
GO:0042277 Molecula unc ion Pep ide binding XCR1,CCR9,CXCR6,EDNRB,NMUR1 1.0E-02
GO:0004950 Molecula unc ion Chemokine ecep o ac i i y XCR1,CCR9,CXCR6 1.6E-02
GO:0019956 Molecula unc ion Chemokine binding XCR1,CCR9,CXCR6 1.9E-02
b a04060 KEGG pa hway Cy okine–cy okine ecep o
in e ac ion
XCR1,CCR9,CXCR6,PRL,IL12RB1,ACVR2A 2.8E-02
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compa isons by plo ing he genome agains he numbe o
imes hey show P alue 40.95 in he 30 con as s.
Tes ing o Signa u es o Local Adap a ion
We used Ma SAM 1.0, which was de eloped by Joos e al.
(2008), o de ec he ma ke s associa ed wi h en i onmen al
a iables. Ra he han elying on popula ion gene ics heo e -
ical models, his spa ial analysis app oach uses spa ial coinci-
dence (Goodchild 1996) o ela e he gene ic p o ile o s udy
sheep o he en i onmen al pa ame e s measu ed a he geo-
g aphic coo dina es o hei sampling si es. The da a used o
he analysis a e in he o m o a ma ix, in which each ow
co esponds o an indi idual and o he geog aphic coo di-
na es whe e i was sampled; he columns con ain 1) bina y
in o ma ion(1o 0) o hep esenceo absenceo agi en
SNP allele; and 2) alues o en i onmen al pa ame e s a he
sampling loca ion. The app oach is pe o med a he indi id-
ual geno ype le el, and mul iple uni a ia e logis ic eg ession
analyses a e calcula ed o de e mine he deg ee o associa ion
be ween he equencies o each allele and he alues o he
en i onmen al pa ame e s. The signi icance o he associa-
ions is de e mined wi h a log-likelihood (G) es and a
Wald es (Joos e al. 2007). Bon e oni co ec ion is applied
o co ec o mul iple compa isons (Joos e al. 2008). By
calcula ing he signi icance o he models gene a ed by all
possible pai wise combina ions (allele s. en i onmen al pa-
ame e ), he ma ke s implica ed in he models ha eme ge
as s a is ically signi ican can be de ec ed, and hese loci a e
likely o be unde he selec i e sweeps o en i onmen al
adap a ions.
We u he calcula ed he co ela ions be ween SNPs
and clima e a iables using new algo i hms implemen ed
in he compu e p og am LFMM (F icho e al.2013;a ail-
able om h p://memb es- imc.imag. /E ic.F icho /l mm/
index.h m, las accessed Janua y 1, 2014). The new algo-
i hms, which a e based on popula ion genomics, ecological
modeling and s a is ical lea ning echniques, ha e p o en
o be e icien in sc eening genomes o signa u es o local
adap a ion by dec easing he numbe o alse-posi i e as-
socia ions due o, o example, popula ion s uc u e and
andom e ec s (F icho e al. 2013). Because he en i on-
men al a iables we e mainly ela ed o empe a u e, sun-
ligh and p ecipi a ion a iables and PC1 explained mos o
he o al a iance (50.78%), which g ea ly exceeded ha
explained by PC2 (18.31%), we summa ized he a iables
by using he i s axis o he PCA (see abo e) o all o he
en i onmen al a iables. We applied he LFMM algo i hm
and calcula ed he jzjsco es o all o he SNPs using 100
sweeps o bu n-in and 1,000 addi ional sweeps. We used
K= 3 la en ac o s based on popula ion s uc u e analyses
using he p og am Sma PCA om he EIGENSOFT 5.0
package (h p://www.hsph.ha a d.edu/alkes-p ice/so wa e/,
las accessed Janua y 1, 2014) and he Bayesian clus e -
ing p og am STRUCTURE 2.3.4 (P i cha d e al. 2000;
o he esul s, see supplemen a y ma e ial and ig. S4,
Supplemen a y Ma e ial online).
Candida e SNP Anno a ion, GO, and EHH Analysis
We anno a ed he o e lapping candida e SNPs de ec ed by
he selec ion es s o iden i y candida e unc ional genes
unde selec ion. We in e ed he gene anno a ion o he
mapped in e al om he O ine (Texel) 3.1 Genome
Assembly (h p://www.li es ockgenomics.csi o.au/cgi-bin/
gb owse/oa 3.1/, las accessed June 20, 2014). In his analysis,
we de ined he “ a ge egion” as app oxima ely 5,000 bp up-
s eam and downs eam o he signi ican SNPs ( he genomic
posi ion o signi ican SNP 5,000 bp; see also Li e al. 2013).
Ta ge genes we e also sea ched o be ween wo signi ican
SNPs 1 Mb and iden i ied as candida e genes unde
selec ion.
GO analyses we e u he pe o med using he unc ion
anno a ion clus e ing ool om DAVID Bioin o ma ics
Resou ces 6.7 (a ailable om h p://da id.abcc.nci c .go ,
las accessed July 2, 2014; e.g., Huang e al. 2008,2009).
When assessing e idence o en ichmen om SNP-based
analyses using his app oach, a bias o la ge genes is likely
due o he inc eased p obabili y o inding a signal by chance.
O he 230 candida e SNPs iden i ied abo e, we u he e-
mo ed he SNPs ha showed signi ican (
2
40.5) LDs wi h
one o mul iple o he loci and only conside ed a single signal
om he SNPs showing signi ican LDs be ween each o he .
The DAVID en ichmen analysis was hen based on he SNPs
and candida e genes a e he il e ing. We in ended o de-
e mine which GO ca ego ies a e s a is ically o e ep esen ed
in a se o genes compa ed wi h ha expec ed in andom
posi ions (Fumagalli e al. 2011). We chose bo ine (Bos
au us) known genes as he backg ound se o genes, because
a la ge po ion o he candida e genes we e mapped on a
bo ine a he han o ine genome (see Resul s). All he GO
e m accession numbe s o each gene om he bo ine
genome we e downloaded om Ensembl (h p://www.
ensembl.o g, las accessed July 2, 2014, elease 74); hese
da a included he en i e anno a ion and we e conside ed as
he e e ence se . En iched e ms we e e ie ed wi h a signi -
ican ly highe han expec ed numbe o associa ed genes
using Fishe ’s exac es . Any p edominan unc ional
heme o in e es ing gene se s in he GO hie a chy was
shown i he P alue was less han 0.05.
Candida e genes unde ecen s ong selec ion should
demons a e EHH (Sabe i e al. 2002;Hue a-S
anchez e al.
2013) because o he low numbe o ecombina ions occu -
ing in only a ew gene a ions (Sabe i e al. 2002). We u he
pe o med LRH es s in he wo g oups o popula ions (i.e., 11
popula ions) o iden i y he co e haplo ypes using he SWEEP
so wa e 1.1 (a ailable om: h p://www.b oadins i u e.o g/
mpg/sweep/, las accessed July 10, 2014). We examined he
EHH and REHH alues in he 300 kb ups eam and down-
s eam o each co e egion wi hin he 17 s ong candida e
genes (see Resul s) in ol ed in he GO e ms (Qanba i e al.
2010;Li e al. 2013). A pai o SNPs wi h he uppe 95% CI o
D0= 0.7–0.98 was de ined o be in s ong LD (Gab iel e al.
2002;Qanba i e al. 2010). Co e haplo ypes we e se o include
3 SNPs. All o he haplo ypes in he majo candida e genes
we e di ided in o 20 bins based on hei equencies. We
3339
Adap a ions o Clima e-Media ed Selec ion .doi:10.1093/molbe /msu264 MBE
a Na u al Resou ces Ins i u e Finland (Luke) on Oc obe 6, 2016h p://mbe.ox o djou nals.o g/Downloaded om
compa ed he equencies and REHHs o he co e haplo ypes
in a candida e gene wi h hose ac oss he genome. P alues
we e ob ained by log- ans o ming he REHH alues in he bin
o achie e no mali y. Co e haplo ypes wi h ex eme REHHs
(beyond he 95 h pe cen iles) in he empi ical dis ibu ion
we e conside ed signi ican (Sabe i e al. 2002;Qanba i e al.
2010).
Valida ing heE idence o Candida eSNPsand
Genes unde Selec ion
As ue causal a ian s should display mos signa u es o pos-
i i e selec ion (e.g., high-de i ed allele equencies and long
ex ended haplo ype; e.g., Ande sen e al. 2012;Li e al. 2013),
we u he alida ed hee idence o candida eSNPsand
majo genes unde selec ion as iden i ied abo e. Because a-
o able alleles o candida e genes unde di e gen selec ion
end o ha e g ea e equencies in popula ions wi h highe
ele an ai alues (O and Kim 1998;P i cha d and Di
Rienzo 2010;Tu chin e al. 2012), we es ed he co ela ion
be ween he allele equencies o he 230 candida e SNPs and
PC1 alues o he en i onmen al a iables, which explained
mos (50.78%) o he o al a iance o he en i onmen al
da a, by examining he Spea man’s ank co ela ion coe i-
cien ( ho) and i s s a is ical signi icance in he 21 b eeds (by
excluding he 11 b eeds included in he F
ST
-ou lie selec ion
es s om he 32 ini ially selec ed wo ldwide old, au och ho-
nous sheep b eeds) wi h a wo ldwide ange o geog aphic
o igins and clima es. We compu ed SNP allele equencies
in he popula ion using he PLINK p og am (Pu cell e al.
2007). The same s a is ical es s we e also applied be ween
equencies o he co e haplo ypes o he 17 s ong candida e
genes and he PC1 alues in he 21 popula ions. We u he
examined he dis ibu ions o allele equencies, as well as
hei co ela ion coe icien s wi h PC1, o he 230 candida e
SNPs and 2,000 andomly selec ed loci om he o al SNP se
in he 32 popula ions.
Supplemen a y Ma e ial
Supplemen a y ma e ial, igu es S1–S4,and ables S1–S10 a e
a ailable a Molecula Biology and E olu ion online (h p://
www.mbe.ox o djou nals.o g/).
Acknowledgmen s
The au ho s acknowledge he Eu opean Science Founda ion
(ESF)—Genomic Resou ces P og amme and MTT Ag i ood
Resea ch Finland in e na ional mobili y g an o suppo ing
Meng-Hua Li’s isi o Uni e si
a Ca olica del Sac o Cuo e,
Piacenza, I aly. This wo k was suppo ed by he Chinese
Academy o Sciences ( he 100- alen P og am o he
Chinese Academy o Sciences), he Na ional Na u al Science
Founda ion o China (g an No. 31272413), and he Academy
o Finland (g an Nos. 250633 and 256077) o M.-H.L. The
In e na ional Sheep Genomics Conso ium (h p://www.
sheephapmap.o g) membe s who con ibu ed o his wo k
and/o coau ho s o Kijas e al. (2012) include Juan-Jos
e
A anz, Uni e sidad de Le
on; Geo gios Banos, A is o le
Uni e si y o Thessaloniki; William Ba endse, CSIRO,
Aus alia; Ahmed El Bel agy, Animal P oduc ion Resea ch
Ins i u e; J€
o n Bennewi z, Uni e si y o Hohenheim; Simon
Boi a d, INRA, F ance; S e e Bishop, The Roslin Ins i u e;
Lu z Bunge , Sco ish Ag icul u al College; Jo ge H Cal o,
CITA; An onello Ca a, AGRIS SARDEGNA; Ib ahim Cemal,
Adnan Mende es Uni e si y; Elena Ciani, Uni e si y o Ba i,
I aly; Noelle Cocke , Uni e si y o U ah; B ian Dal ymple,
CSIRO, Aus alia; Da id Col man, Uni e si y o Albe a;
Magali San C is obal, INRA, F ance; Ma ia Sil ia D’And ea,
Uni e si
a degli S udi del Molise; O ma Dis l, Uni e si y o
Ve e ina y Medicine Hanno e ; Co d D €
ogem€
ulle , Ins i u e
o Gene ics, Uni e si y o Be n; Geo g E ha d , Ins i u €
u
Tie zuch und Haus ie gene ik Jus us-Liebig-Uni e si €
a
Giessen; Emma Ey ho sdo i , Ag icul u al Uni e si y o
Iceland; Kimbe ly Gie zen, Illumina Inc., Uni ed S a es o
Ame ica; Elisha Goo wine, The Volcani Cen e ; Vidja S.
Gup a, Na ional Chemical Labo a o y; Oli ie Hano e,
Uni e si y o No ingham; Ben Hayes, Depa men o
P ima y Indus ies Vic o ia, Aus alia; Mike Hea on, USDA;
S e an Hiendlede , Uni e si y o Adelaide; Han Jianlin, ILRI
and CAAS; Ma hew Ken , CiGene; Johannes A. Lens a,
U ech Uni e si y, he Ne he lands; Te y Longhu s , Mea
and Li es ock Aus alia, Runlin Ma, Chinese Academy o
Sciences; Da id MacHugh, Uni e si y College Dublin, Jill
Maddox, Uni e si y o Melbou ne; Massoud Malek, IAEA;
Russell McCulloch; CSIRO, Aus alia; Md. Oma Fa uque,
Bangladesh Ag icul u e Uni e si y; John McEwan,
AgResea ch, In e may Ag icul u al Cen e , New Zealand;
Despoina Mil iadou, Cyp us Uni e si y o Technology;
Ca ole Mo eno, INRA; V Hu on Oddy, Uni e si y o New
England; Samuel Pai a, Gene ic Resou ces and
Bio echnology, Emb apa, B as
ılia, B azil; Josephine
Pembe on, Uni e si y o Edinbu gh; Fabio Pilla, Uni e si
a
degli S udi del Molise; Lae cio R. Po o Ne o, CSIRO,
Queensland, Aus alia; He man Raadsma, Uni e si y o
Sydney, Aus alia; Cy il Robe s, Ca ibbean Ag icul u al
Resea ch and De elopmen Ins i u e; Tiziana Sechi, AGRIS
SARDEGNA; Be and Se in, INRA, F ance; Paul Schee ,
Uni e si y o Texas MD Ande son Cance Cen e ; P adeepa
Sil a, Uni e si y o Pe adeniya; Henne Simiane , Uni e si €
a
G€
o ingen; Jon Sla e, Uni e si y o She ield; Miika Tapio, MTT
Ag i ood Resea ch Finland; Selina Va a hil, Uni e si y o
Texas MD Ande son Cance Cen e ; and Vicki Whan,
CSIRO, Aus alia.
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