INVESTIGATION
Gene ics o Asci es Resis ance and Tole ance
in Chicken: A Random Reg ession App oach
An i Kause,
1
Sacha an Dalen, and Henk Bo enhuis
Wageningen Uni e si y and Resea ch Cen e, Animal B eeding and Genomics Cen e, De Els 1, 6708 WD, Wageningen,
The Ne he lands
ABSTRACT Resis ance and ole ance a e wo complemen a y mechanisms o educe he de imen al
e ec s o pa asi es, pa hogens, and p oduc ion diseases on hos pe o mance. Using body weigh and
asci es da a on domes ica ed chicken Gallus gallus domes icus, we demons a e he use o andom e-
g ession animal model and co a iance unc ions o es ima e gene ic pa ame e s o asci es esis ance and
ole ance and illus a e he way indi idual a ia ion in esis ance and ole ance induce bo h geno ype e-
anking and changes in a ia ion o hos pe o mance along inc easing asci es se e i y. Tole ance o asci es
displayed significan gene ic a iance, wi h he es ima ed b eeding alues o ole ance slope anging om
s ongly nega i e ( e y sensi i e geno ype) o weakly nega i e (less sensi i e). Resis ance o asci es had
he i abili y o 0.34. Bo h ai s a e hence expec ed o espond o selec ion. The wo complemen a y de ense
s a egies, ole ance and esis ance, we e gene ically independen . Asci es induced changes o he co e-
la ions be ween asci es esis ance and body weigh , wi h he gene ic co ela ions being weak when bi ds
we e asci es- ee bu mode a ely nega i e when bo h heal hy and a ec ed bi ds we e p esen . This likely
esul s because asci es educes g ow h, and hus high asci es incidence is gene ically ela ed o low adul
body weigh . Al hough asci es induced ele a ed pheno ypic and gene ic a iances in body weigh o
a ec ed bi ds, he i abili y displayed negligible changes ac oss heal hy and a ec ed bi ds. Asci es induced
mode a e geno ype e- anking in body weigh , wi h he gene ic co ela ion o heal hy bi ds wi h mildly
a ec ed bi ds being uni y bu wi h se e ely a ec ed bi ds 0.45. This s udy demons a es a no el app oach
o explo ing gene ics o de ense ai s and hei impac on geno ype-by-en i onmen in e ac ions.
KEYWORDS
disease
he i abili y
geno ype-by-
en i onmen
in e ac ion
gene ic ade-o
eac ion no m
esilience
Resis ance and ole ance a e wo complemen a y de ense mechanisms
agains pa hogens and pa asi es. Resis ance is he hos ai ha p e-
en s in ec ion in he fi s place o educes he pe o mance o a pa h-
ogen on a hos ; bo h ac o s educe he pa hogen bu den wi hin a hos
indi idual. Tole ance o in ec ions, in u n, is defined as he abili y o
he hos o limi he impac o a gi en pa hogen bu den on hos heal h,
pe o mance, and ul ima ely on fi ness (Clunies-Ross 1932; Pain e
1958; Simms and T iple 1994; Simms 2000). In a m animal science,
ole ance is some imes called esilience (Ri kin and Dobson 1979;
Albe s e al. 1987; Bisse and Mo is 1996). In addi ion o pa hogens,
ole ance can be assessed agains abio ic ac o s such as hea y me als,
empe a u e, os damage, o agains p oduc ion diseases causing
damage o body issues (Ra agnolo and Misz al 2000a,b; Scha e al.
2002; Ag awal e al. 2004; Kause 2011; Bloemho e al. 2012). In
a med plan and animal species, bo h inc eased esis ance and ole -
ance se e as ways o insu e global ood secu i y.
Tole ance can be analyzed as a eac ion no m in which hos
pe o mance (on y-axis) is eg essed agains an inc easing pa hogen
bu den o abio ic ac o (on x-axis) (Simms 2000). Gene ic a iance in
eg ession slopes is hence he gene ic a iance o ole ance. When
he e is gene ic a ia ion o ole ance, he i abili y o hos pe o -
mance (e.g., g ow h, ep oduc ion, o fi ness) can po en ially change
ac oss inc easing pa hogen bu den (Kause 2011). Fo ins ance, di e g-
ing eac ion no ms imply an exis ence o geno ype-by-en i onmen
in e ac ion ha c ea es inc easing gene ic a iance o hos pe o -
mance. Diseases a e indeed known o induce changes in he i abili y
o hos pe o mance ai s (Cha man ie e al. 2004; Veh iläinen e al.
Copy igh © 2012 Kause e al.
doi: 10.1534/g3.112.002311
Manusc ip ecei ed Decembe 7, 2011; accep ed o publica ion Feb ua y 27, 2012
This is an open-access a icle dis ibu ed unde he e ms o he C ea i e
Commons A ibu ion Unpo ed License (h p://c ea i ecommons.o g/licenses/
by/3.0/), which pe mi s un es ic ed 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.
Suppo ing in o ma ion is a ailable online a h p://www.g3jou nal.o g/lookup/
suppl/doi:10.1534/g3.112.002311/-/DC1.
1
Co esponding au ho : MTT Ag i ood Resea ch Finland, Bio echnology and Food
Resea ch, Biome ical Gene ics, FI-31600 Jokioinen, Finland. E-mail: an i.kause@
m .fi
Volume 2 | May 2012 | 527
2008; Lewis e al. 2009). Mo eo e , c ossing ole ance eac ion no ms
imply geno ype-by-en i onmen in e ac ion ha c ea es geno ype e-
anking in hos pe o mance. Geno ype-by-en i onmen in e ac ions
oge he wi h en i onmen -dependen selec ion o ces p omo e di e -
gen gene ic esponses in di e en en i onmen s (Falcone 1952; Joshi
and Thompson 1995; Kause e al. 2001). Despi e he la ge numbe o
s udies dealing wi h he changes induced by bio ic (e.g., die ) and
abio ic ac o s in gene al (Ho mann and Me ilä 1999; Kause and
Mo in 2001; Cha man ie and Ga an 2005), he e has been only
a limi ed ocus on in ec ion-induced changes in gene ic pa ame e s
and gene ic esponses o selec ion.
Kause (2011) in oduced he use o andom eg essions and
co a iance unc ions o gene ic analysis o ole ance. These me h-
ods allow he es ima ion o gene ic a iance o esis ance and
ole ance and hei gene ic co ela ions wi h o he ai s in a single
mul i ai analysis. Co a iance unc ions allow he es ima ion o
gene ic a iance o hos pe o mance a any poin along he in-
c easing pa hogen bu den ajec o y as well as he deg ee o geno-
ype e- anking be ween any o he poin s, p o iding no el means
o analyze in ec ion-induced geno ype-by-en i onmen in e ac-
ions in hos pe o mance (Ki kpa ick e al. 1990; Calus e al.
2004; Kause 2011). In he p esen s udy, hese me hods we e ap-
plied o he gene ic analysis o asci es esis ance and ole ance in
domes ica ed chicken Gallus gallus domes icus.
Asci es is a me abolic diso de in indi iduals ha ail o ully
supply he demand o oxygen in hei bodies because o a misma ch
be ween ca diopulmona y sys em ou pu and he demands o he
body (Decuype e e al. 2000). Asci es esis ance is he abili y o a bi d
o p e en ending up in a physiological s a e in which he e is a dis-
c epancy be ween oxygen up ake and oxygen equi emen , esul ing
in o e loading o he ca diopulmona y sys em. Chicken compensa e
o hypoxia by ci cula ing mo e blood h ough hea , esul ing in an
enla ged igh en icula . Consequen ly, hea a io, he a io o igh
en icula weigh o o al hea weigh , is used as an indica o o
asci es esis ance, ha is, whe he chicken ha e asci es o no
(Wideman e al. 1998; Balog e al. 2003; Ze ehda an e al. 2006;
and e e ences he ein). Fu he mo e, he occu ence o asci es is
associa ed wi h educed g ow h, hepa ic damage, ansduc ion o fluid
in o abdominal body ca i y, and occasionally dea h (Julian 1998).
Asci es ole ance is he abili y o a bi d o limi he consequences o
a disc epancy be ween oxygen up ake and oxygen equi emen on
ep oduc ion, g ow h, and fi ness. Unde comme cial p oduc ion con-
di ions, he incidence o asci es is low bu significan enough o cause
educed animal wel a e (Julian 1998; Decuype e e al. 2000). To e -
ec i ely s udy asci es, i s incidence can be ele a ed by exposing bi ds
o low empe a u e and inc eased CO
2
le els.
In his s udy, we defined asci es ole ance in chicken as a eac ion
no m o body weigh along an inc easing asci es se e i y, measu ed as
he hea a io. This app oach ollows he defini ion by Simms (2000)
wi h he di e ence ha we a e dealing wi h a p oduc ion disease, no
pa hogens o pa asi es. The concep s o esis ance and ole ance apply
equally well o asci es, bu he s anda d hos -pa hogen co-e olu iona y
in e ac ions (Mau icio e al. 1997; Raushe 2001; Bishop and MacKenzie
2003; Bes e al. 2008) canno be applied o p oduc ion diseases
because asci es does no e ol e in esponse o hos e olu ion. He e
we demons a e he me i o he sugges ed no el s a is ical me hods
(Kause 2011) o gene ic analysis o ole ance. We fi s es ima ed
gene ic a iances and gene ic co ela ions o ole ance, esis ance,
and g ow h pe o mance. These es ima es eflec whe he a lack o
gene ic a iance o gene ic ade-o s limi gene ic imp o emen o
hese ai s. Second, we examined whe he asci es induces geno ype-
by-en i onmen in e ac ions ac oss heal hy and a ec ed bi ds, in
e ms o a iance changes and geno ype e- anking in body weigh .
METHODS
The expe imen was conduc ed a he acili ies o Hend ix Gene ics/
Cobb Eu ope BV, loca ed in Boxmee , The Ne he lands. The
expe imen was pe o med by licensed and au ho ized pe sonnel
unde app o al o Cobb Eu ope BV.
Popula ion s uc u e
The expe imen al o sp ing popula ion consis ed o 7722 pu eb ed
Whi e Plymou h Rock b oile s, o which 3745 we e males and 3977
emales. They descended om 83 si es and 788 dams. Each si e was
ma ed o an a e age o 15.7 dams ( ange, 5-28 dams), and each dam
was ma ed o an a e age o 1.65 si es ( ange, 1-3 si es). Si e2 amily
sizes anged be ween 22 and 209, wi h an a e age o 93 o sp ing pe
si e. The e we e 2677 ances o s in 25 gene a ions, and hey did no
ha e any ai eco ds. Eigh si es wi h ewe han 20 o sp ing we e
emo ed om he da a because la ge amily sizes a e needed o a oid
biased gene ic co ela ion be ween ole ance slope and in e cep and
biased gene ic a iance es ima e in ole ance slope (Mau icio e al.
1997; Ti fin and Raushe 1999; Kause 2011).
Rea ing p ocedu e
Eggs laid by all he dams we e collec ed un il a ba ch wi h a o al o
app oxima ely 1600 chicks we e ob ained, and a o al o fi e ba ches
we e p oduced. The eggs we e indi idually numbe ed along wi h hei
dam code and ans e ed o a common b ooding machine. A he day
o ha ching, he chicks we e sexed, indi idually wing agged, and
g oup housed in wo s ables wi h 14 bi ds/m
2
.Du ing hewhole
expe imen , bi ds had ee ad libi um access o wa e and comme cial
eed wi h 12.970 KJ/kg. Bi ds we e exposed o 23 h o ligh pe day.
To challenge bi ds o asci es, hey we e kep unde cold condi ions
and inc eased CO
2
le els. A he ime o ha ching, empe a u e was held
a 30. Du ing he successi e 11 days empe a u e was g adually educed
o 12. The ea e , he empe a u e was kep a 12un il week 7 when he
expe imen was e mina ed. To inc ease CO
2
le el in he s ables o
app oxima ely 1500 ppm, he en ila ion was educed om day 11
onwa ds. Excep o he CO
2
le el and empe a u e, ea ing condi ions
closely esembled he comme cial p ac ice. Su i al om he fi s body
weigh eco ding a week 2 o he end o he expe imen was 91.0%.
The expe imen wi h he wo s ables was epea ed in fi e successi e
ba ches o o sp ing. Each si e and dam had o sp ing in an a e age o
3.54 ( ange, 1-5) and 2.58 ( ange, 1-5) ba ches, espec i ely.
T ai defini ions
Bi ds we e indi idually weighed a 2 ( ai : BW2) and 7 weeks o age
(BW7). A e BW7 eco ding, bi ds we e eu hanized using CO
2
.A
pos mo em examina ion was pe o med o measu e hea a io: he
pe cen age o igh en icle weigh om o al hea weigh (RATIO).
RATIO was eco ded by 11 di e en people ained o cu ing. Using
andom eg essions, we defined wo addi ional ai s: 7-week body
weigh (BW7) o asci es- ee bi ds ( ai : INTERCEPT) and ole ance
slope o BW7 (SLOPE).
Hea a io is gene ally ag eed o be an indica o ai o asci es,
and bi ds wi h hea a io g ea e han 27% o 30% a e asci ic
(Wideman e al. 1998; Balog e al. 2003; Ze ehda an e al. 2006; and
e e ences he ein). I should be no ed, howe e , ha he e may be
some bi ds ha ha e asci es bu hei hea a io esembles ha o
a mo e heal hy bi d (and ice e sa). This could be, o ins ance,
because hei hea is ole an agains asci es-induced hypoxia. Thus,
528 | A. Kause, S. an Dalen, and H. Bo enhuis
i is possible ha hea a io, a measu e o esis ance, may in ac
in ol e a componen o ole ance in i . I is expec ed ha body weigh
is educed only in a ec ed animals wi h hea a io g ea e han 27%
o 30%, whe eas in heal hy animals no ela ionship be ween hea
a io and body weigh should exis . To make such a pla eau-linea
model (Ra agnolo and Misz al 2000a,b), hea a io equal o o below
29% was coded as ze o, and hea a io g ea e han 29% was coded as:
RATIO-29%. This co ec ed hea a io ( ai : RATIOPla ) was hen used
as an x-axis in he ole ance analysis. The pla eau-linea ole ance e-
g ession model wi h RATIOPla (Akaike In o ma ion C i e ia [AIC] ¼
3654; Bayesian In o ma ion C i e ia [BIC] =3674) fi ed he da a be e
han he linea model in which RATIO was used as he x-axis (AIC ¼
3842; BIC =3866). The gene ic model 3 p o ided in he nex sec ion
was used in his compa ison o bo h models. Mo eo e , AIC and BIC
we e used o find he bes -fi ing h eshold o 29% wi hin he po en ial
hea a ios o 27% o 30%. I should be no ed ha RATIO is used
he e as he con inuous-scale measu e o asci es esis ance, whe eas
RATIOPla is used only as he x-axis in he ole ance analysis (ye
hei gene ic analysis p oduced simila esul s). Sample size was 7710,
7039, and 6991 bi ds o BW2, BW7, and RATIO, espec i ely. The
ai means a e gi en in Table 1 and File S1.
Gene ic analysis
All analyses we e pe o med wi h mul i ai animal models using
ASReml (Gilmou e al. 2006). The animal model akes in o accoun
all he ela ionships be ween indi iduals in he pedig ee. Body weigh s
BW2 and BW7 we e analyzed wi h he animal “ ai mean”model:
yij ¼ miþanimjþdamkþGENDERlþBATCHm
·STABLEnþAGEpþe o ijklmnp ð1Þ;
and RATIO wi h he animal “ ai mean”model:
yij ¼miþanimjþdamkþGENDERlþBATCHm ·STABLEn
þAGEpþPERSONqþe o ijklmnpq
ð2Þ;
whe e y
ij
is an obse a ion o a ai i(i¼1-3) o he j h indi idual
(j¼1-numbe o indi iduals); m
i
is he mean o ai i; anim
j
is he
andom animal gene ic e ec wi h a pedig ee; dam
k
is he andom
dam e ec wi hou a pedig ee (k¼1-788); GENDER
l
is he fixed
e ec o gende (l¼1-2); BATCH
m
·STABLE
n
is he fixed in e ac-
ion o ea ing ba ch (m¼1-5) and s able (n¼1-2); AGE
p
is he
fixed e ec o animal age when a ai iwas eco ded ( o BW2 p¼
12-13 days, o BW7 p¼45-46, o RATIO p¼46-48); and
PERSON
q
is he fixed e ec o a cu e o a hea (q¼1-11), and
e o is he andom e o .
Asci es ole ance was analyzed wi h he andom eg ession animal
model:
yj¼b0jþb1jþb0kþb1kþGENDERl þBATCHm·STABLEn
þAGEpþPERSONqþb0þb1þ b1BATCHm·STABLEn
þb1PERSONqþe o ijklmnpq ð3Þ;
whe e y
j
is BW7 o an animal j;b
0j
is he andom in e cep o an
animal j;b
1j
is he andom ole ance slope o BW7 on RATIOPla o
an animal j;b
0k
is he andom in e cep o dam k;b
1k
is he andom
ole ance slope o BW7 on RATIOPla o dam k;b
0
is he fixed
popula ion mean in e cep ; b
1
is he fixed popula ion mean ole ance
slope; b
1
BATCH
m
·STABLE
n
is he fixed ole ance slope o each
mba ch and ns able; and b
1
PERSON
q
is he fixed ole ance slope
o each cu e . To a oid he e ogeneous e o a iance infla ing
gene ic a iance in slope (Lillehamme e al. 2009), esidual a iance
was es ima ed wi hin fi e RATIOPla classes along he x-axis. The
classes we e defined as: RATIOPla ¼0, 0–5, 5–10, 10–15, and .15.
Animal and si e solu ions om hese mixed models a e es ima ed
b eeding alues (EBVs) quan i ying he gene ic le el o indi iduals o
a ai .
An addi ional model was un in which BW2 was included in o he
model 3 as a fixed co a ia e (i.e., a eg ession e m). This accoun s o
a possibili y ha asci es migh ha e been mo e common among ini-
ially as o slow g owing indi iduals. In ac , BW2 had e y weak
gene ic and pheno ypic co ela ions wi h RATIO (
G
¼0.12 60.12,
P
¼0.04 60.02; Table 2), and hence in ou da a asci es incidence
was independen o ini ial g ow h. When ini ial hos pe o mance and
esis ance a e co ela ed, o example, pa hogens a e non andomly
dis ibu ed ac oss indi iduals, and his is no accoun ed o in he
s a is ical model, biased ole ance gene ic a iance is es ima ed (Kause
2011).
Va iances and a iance a ios we e conside ed significan when
0.98 imes hei s anda d e o did no include ze o (one- ailed es ).
Co ela ions we e conside ed significan when 1.96 imes hei
s anda d e o did no include ze o ( wo- ailed es ).
Fo ole ance analysis o be e ec i e, each si e amily should ha e
bo h heal h and a ec ed indi iduals. The si es had an a e age o 36%
o hei o sp ing a ec ed ( ange, 9.4-89.7%, n¼83 si es), and 90% o
he si es had 14.8% o 60.3% o hei o sp ing a ec ed. I is also good
o no e ha si es and dams ha e b o he s, sis e s, and cousins in he
da a, and he animal model accoun s o all hese ela ionships in he
gene ic analysis, con ibu ing u he o a solid analysis.
Co a iance unc ions
Gene ic and ma e nal (dam) a iance o BW7 as a unc ion
o RATIOPla ajec o y was calcula ed: as x’
Ra ioPla
Gx
Ra ioPla
,whe e
nTable 1 T ai means (uni s in b acke s), gene ic a iances (V
G
), ma e nal a iances (V
M
), he i abili ies (h
2
), ma e nal
e ec a ios (m
2
), and hei s anda d e o s (6SE)
BW2 (g) BW7 (g) RATIO (%) INTERCEPT (g) SLOPE
a
(g/%)
Mean 248 2075 28.2% 2080 -14.6
V
G
6SE 309 657.01 12952 62865 15.1 62.559 10640 62540 57.8 637.47
V
M
6SE 59.3 612.66 2913 6778 1.17 60.518 2771 6769 23.0 623.11
h
2
6SE 0.33 60.05 0.18 60.04 0.34 60.05 22
m
2
6SE 0.06 60.01 0.04 60.01 0.03 60.01 22
V
P
946 73479 46.72 22
a
V
G
and V
M
om he model including he fixed BW2 co a ia e we e 59.34 633.0 and 6.50 618.9, espec i ely.
Volume 2 May 2012 | Tole ance Gene ics | 529
G¼s2
b0sb0b1
sb0b1s2
b1,ands2
b0and s2
b1a e ei he gene ic o ma e nal
a iances o in e cep and slope, and sb0b1is he espec i e co a i-
ance be ween hese wo e ms (Kolmodin and Bijma 2004). The e m
x
Ra ioPla
is a ec o [1 Ra ioPla ]9in which Ra ioPla e e s o
a RATIOPla alue on he x-axis. The fi e sepa a e en i onmen al
a iances (V
E
) o BW7 combined wi h gene ic (V
G
) and ma e nal
a iances (V
M
) es ima ed along RATIOPla ajec o y allowed he
calcula ion o BW7 pheno ypic a iance (V
P
¼V
E
+V
G
+V
M
),
he i abili y (h
2
¼V
G
/V
P
), and ma e nal e ec a io (m
2
¼V
M
/
V
P
) as a unc ion o hea a io ajec o y. Finally, ollowing Calus e al.
(2004), a gene ic co ela ion be ween heal hy bi ds (RATIOPla ¼0)
anda ec edbi ds(RATIOPla .0) a a ce ain RATIOPla alue was
calcula ed as: G¼x0
’GxRa ioPla
ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
x0
’Gx0xRa ioPla
’GxRa ioPla
p,whe eGis he ge-
ne ic (co) a iance ma ix o slope and in e cep , x
0
is a ec o o [1 0]’
o heal hy animals wi h RATIOPla o ze o, and x
Ra ioPla
is as desc ibed
ea lie . To ease he in e p e a ion o figu es, RATIOPla alues we e
back- ans o med o he o iginal hea a io alues.
RESULTS
Gene ic and ma e nal a ia ion
The esul s e ealed significan gene ic a ia ion o g ow h and hea
a io, an indica o o asci es esis ance (Table 1). Body weigh s a 2
and 7 weeks had mode a e he i abili ies o 0.33 and 0.18, espec i ely.
Hea a io he i abili y was 0.34. These he i abili ies had low s anda d
e o s, and all h
2
es ima es we e g ea e han hei s anda d e o s.
Ma e nal e ec a ios o BW2, BW7, and RATIO we e small bu
exis en wi h es ima es below o equal o 0.06 (Table 1). These esul s
a e simila o he p e ious es ima es (De G ee e al. 2001; Moghadam
e al. 2001; Pakdel e al. 2005), confi ming ha he da a beha ed in
a solid expec ed way.
The esul s e ealed significan gene ic a iance o asci es
ole ance. Gene ic a iance o ole ance slope was 57.8 and 59.3 o
models ei he excluding o including BW2 as a fixed co a ia e e m,
espec i ely (Table 1). The a iance es ima es we e 1.5 and 1.8 imes
g ea e han hei s anda d e o s, implying hey we e s a is ically
significan . Tha he wo models p oduced simila es ima es implies
a solid da a s uc u e o ole ance analysis, e en wi hou s a is ical
co ec ion o he ini ial g ow h pe o mance (Kause 2011). Figu e 1
in oduces he a e age ole ance slope o he popula ion, showing
dec easing body weigh wi h inc easing hea a io in a ec ed bi ds.
EBVs o ole ance slope o animals in he o sp ing gene a ion
anged om 224.2 o 27.07 and o si es o he o sp ing gene a ion
om 224.9 o 26.97 (Figu e 2). Some geno ypes we e hence less
sensi i e (weake nega i e slope) while o he s we e e y sensi i e
(s ong nega i e slope). Ma e nal e ec ole ance slope solu ions o
he dams o he o sp ing gene a ion anged om 218.9 o 210.8.
This e eals smalle a ia ion o he ma e nal e ec compa ed o he
gene ic e ec s (Figu e 2) as expec ed based on he a iance compo-
nen s (Table 1).
The s anda d e o o ma e nal slope a iance was o equal size o
he a iance es ima e (Table 1). Howe e , he dam slope e ec was
kep in he model because i is needed o co a iance unc ions o
calcula e he significan ma e nal e ec in BW7 (Table 1) along he
hea a io ajec o y.
Fo he model excluding he BW2 co a ia e, gene ic a iance o
INTERCEPT was 10640, ha is, compa able wi h gene ic a iance o
12952 o BW7. Simila pa e n was obse ed o ma e nal a iances
o INTERCEPT and BW7 (Table 1).
Gene ic co ela ions be ween body weigh s
Body weigh a week 2 and 7 displayed mode a e posi i e co ela ions
(Table 2). Simila ly, ma e nal and gene ic co ela ions be ween BW2
and INTERCEPT we e mode a ely posi i e (Table 3) and compa able
wi h he co ela ions o BW2 and BW7 (Table 2). These a e ypical
esul s o successi e body weigh measu emen s.
T ade-o be ween ole ance and esis ance
Resis ance and ole ance we e gene ically independen , implying a lack
o gene ic ade-o (Table 3). This was indica ed by he nonsignifican
weak gene ic co ela ion be ween RATIO and ole ance slope (Table
3). The ma e nal co ela ion was s ongly nega i e bu wi h a e y
high s anda d e o .
nTable 2 Gene ic (uppe panel, abo e diagonal), ma e nal (uppe panel, below diagonal), and pheno ypic
co ela ions (lowe panel) and hei s anda d e o s (6SE)
BW2 BW7 RATIO
Gene ic and ma e nal co ela ions
BW2 0.60 60.09 0.12 60.12
BW7 0.78 60.10 20.33 60.12
RATIO 20.14 60.22 20.35 60.22
Pheno ypic co ela ions
BW2 0.47 60.01 0.04 60.02
BW7 20.23 60.02
Figu e 1 Pheno ypic ela ionship be ween 7-week body weigh and
hea a io. The pla eau-linea eg ession o he popula ion ob ained
om he s a is ical model 3 is d awn hough he da a.
530 | A. Kause, S. an Dalen, and H. Bo enhuis
T ade-o be ween ole ance and g ow h
Gene ic and ma e nal co ela ions be ween ole ance slope and
INTERCEPT we e weakly nega i e bu nonsignifican , implying ha
body weigh o heal hy bi ds was no ela ed o he le el o ole ance
(Table 3). Likewise, ma e nal and gene ic co ela ions o ole ance
slope wi h BW2 we e low.
T ade-o be ween esis ance and g ow h
No gene ic ade-o was obse ed be ween esis ance and body weigh
a 2 weeks o age (Table 2). The co ela ions o RATIO wi h BW2
we e low, and 1.96 imes hei SE always included ze o. Simila ly,
ma e nal and gene ic co ela ions be ween RATIO and INTERCEPT
(i.e., BW7 in asci es- ee bi ds) we e weak and nonsignifican (Table
3). These esul s oge he indica e ha asci es incidence was pheno-
ypically and gene ically independen o g ow h in asci es- ee bi ds.
A 7 weeks o age, he co ela ions o RATIO wi h BW7, which
includes he weigh s o bo h heal hy and asci ic bi ds, we e all
mode a ely nega i e ( om 20.23 o 20.33; Table 2). This shows ha
when he body weigh o bo h heal hy and a ec ed bi ds a e analyzed
oge he , o e all igo is obse ed and bi ds gene ically mo e p one o
asci es ha e lowe body weigh s. Pheno ypic and gene ic co ela ions
o RATIOPla wi h BW7 (
P
¼20.30;
G
¼20.42) we e highe han
he espec i e co ela ions o RATIO (
P
¼20.22;
G
¼20.33). This
is expec ed when he e is a nonlinea ela ionship be ween hea a io
and BW7 (Figu e 1).
Asci es-induced geno ype-by-en i onmen in e ac ions
Va iance componen es ima es o 7-week body weigh changed wi h
inc easing hea a io (Figu e 3). Pheno ypic a iance calcula ed om
he aw da a sepa a ely o he fi e x-axis classes along he RATIOPla
ajec o y was ele a ed wi h inc easing hea a io. The pheno ypic
a iance om he andom eg ession ole ance model was lowe com-
pa ed wi h he pheno ypic a iance om he aw da a because he
fixed e ec s elimina ed pa o he a iance. Howe e , he e was a en-
dency ha he pheno ypic a iances we e mo e simila a he high
hea a io end. This occu ed because he ma e nal and gene ic a -
iances we e ele a ed a he igh -hand side o he ajec o y, whe eas
he en i onmen al a iance was pa allel wi h he pheno ypic a iance
o he aw da a (Figu e 3).
Coe ficien s o pheno ypic a ia ion om he andom eg ession
model we e 11.5%, 11.7%, 13.8%, 15.2%, and 19.1% a he fi e x-axis
classes, showing ha he inc ease in a iance was no a consequence
o a change in he BW7 mean.
In con as o he a iance componen s, he e we e only mino
changes in he i abili ies and ma e nal e ec a ios o BW7 along he
hea a io ajec o y (Figu e 4). Mo eo e , he h
2
and m
2
es ima es
om he andom eg ession model displayed a U-shaped end along
he hea a io ajec o y (Figu e 4). The andom eg ession es ima es
o h
2
we e equal o sligh ly lowe , and he m
2
es ima es equal o
sligh ly g ea e han he espec i e mean model es ima es.
Gene ic co ela ion be ween heal hy and a ec ed bi ds was e-
duced om uni y o 0.45 a hea a io o 46.5% (Figu e 5), indica ing
ex ensi e geno ype e- anking be ween heal hy and se e ely a ec ed
bi ds.
DISCUSSION
Random eg ession analysis o ole ance
The andom eg ession me hodology sugges ed by Kause (2011) was
applied he e o ole ance analysis. The p esen s udy demons a ed he
me i o andom eg essions and co a iance unc ions o es ima e
gene ic a iance o ole ance slope, i s gene ic co ela ions wi h o he
ai s, and in ec ion-induced geno ype e- anking and changes in ge-
ne ic a ia ion. By using an animal model, we we e able o es ima e
EBVs o indi iduals e en hough ole ance i sel canno be eco ded
om an indi idual. The EBVs can be used o selec ing gene ically
supe io indi iduals bu also in gene mapping s udies. We applied he
pla eau-linea model o Ra agnolo and Misz al (2000a,b), ye an al-
e na i e would ha e been a mix u e model analysis (Ze ehda an e al.
2006), which would assume hea a io has wo unde lying dis ibu-
ions, one o heal hy and one o a ec ed bi ds whose g ow h is
di e en a ec ed. So a , he challenge in animal science has been ha
esis ance and ole ance a e di ficul o uncouple, and he ai s may be
con ounded in ai eco ding. Fo ins ance, whe he an animal su -
i es h ough a challenge es is in ac de e mined oge he by ani-
mal’s esis ance and ole ance. Recen ly Ødegå d e al. (2011a,b)
de eloped a cu e model o sepa a e “suscep ibili y”and “endu ance”
om a challenge es da a wi h ime-un il-dea h obse a ions. These
Figu e 2 F equency dis ibu ions o ole ance slope solu ions o he
ma e nal e ec (dam slope es ima e, n= 788 dams o he o sp ing
gene a ion), o EBVs o he animals in he o sp ing gene a ion (animal
slope EBV, n= 7722 o sp ing), and o EBVs o si es o he o sp ing
gene a ion (si e slope EBV, n= 83 si es).
nTable 3 Gene ic (abo e diagonal) and ma e nal (below diagonal) co ela ions and hei s anda d e o s (6SE)
BW2 RATIO INTERCEPT SLOPE
BW2 0.09 60.11 0.71 60.07 20.27 60.24
RATIO 20.31 60.22 0.15 60.14 20.36 60.27
INTERCEPT 0.76 60.09 0.003 60.26 20.30 60.27
SLOPE 20.005 60.31 20.80 60.49 20.26 60.36
Volume 2 May 2012 | Tole ance Gene ics | 531

wo concep s a e compa able wi h he defini ions o esis ance and
ole ance. Along he same lines, Á nason (1999) and U ios e e al.
(2007) ha e p oposed a bi a ia e linea - h eshold model ha can be
used o analyze whe he an animal su i ed (a h eshold ai ) and
how long i ook un il dea h (a linea ai ). These new s a is ical
de elopmen s p o ide no el ools o inc ease ou unde s anding o
gene ics o al e na i e s a egies o figh agains pa asi es, pa hogen,
and p oduc ion diseases.
Gene ic a ia ion o ole ance and esis ance
The fi s majo finding o ou s udy was ha bo h ole ance and
esis ance exhibi ed gene ic a ia ion. Tole ance o asci es displayed
significan gene ic a iance, wi h he ole ance slope EBVs anging
om weakly nega i e (less sensi i e geno ype) o s ongly nega i e
(mo e sensi i e), bu no comple ely ole an geno ypes we e obse ed.
Resis ance, measu ed as he hea a io, had mode a e he i abili y o
0.34. These esul s show ha bo h esis ance and ole ance a e
expec ed o espond o selec ion. Imp o ed esis ance and ole ance
can be bo h used o educe he ha m ul e ec s o asci es on bi ds.
In sheep, nema ode ole ance is ypically analyzed as he di e ence
be ween body weigh be o e and a e a gas oin es inal nema ode
a ack. This app oach does no only analyze ole ance because i
con ounds bo h na u al empo al a ia ion in g ow h (e.g.,g ow h
cu es) and he impac o pa asi es on g ow h (Bisse and Mo is
1996). Ne e heless, hese s udies a e o g ea in e es because o he
lack o p e ious s udies on gene ics o ole ance o in ec ions o p o-
duc ion disease in animals. In sheep, esis ance measu ed as ecal egg
coun o in es inal nema odes has highe he i abili y (h
2
¼0.26-0.34)
han wo ole ance indica o s, li e weigh gain dep ession (h
2
¼0.09)
and wool g ow h dep ession (h
2
¼0.08), du ing an expe imen al
challenge wi h nema ode la ae (Albe s e al. 1987). He i abili ies
o ole ance measu ed as age a fi s d ench and d ench sco e we e
0.13 and 0.14 in he s udy by Bisse e al. (1994) and 0.06 and 0.03 in
he s udy by Bisse e al. (1996), eflec ing again ha ole ance may
ha e only modes gene ic a ia ion in sheep. D enching eflec s ol-
e ance because i was applied only o he animals whose li e weigh
change was below an accep able h eshold. In dai y cows, indi idual
a ia ion exis s o loss in milk yield in esponse o expe imen ally
induced Esche ichia coli mas i is (Vandepu e-Van Messom e al.
1993). Di e en inb ed mice s ains display di e ences in ole ance
agains mala ia Plasmodium chabaudi (Råbe g e al. 2007).
Compa ed wi h animals, s udies on gene ic a ia ion in ole ance
o in ec ions a e plen i ul in plan s (Fineblum and Raushe 1995;
Ti fin and Raushe 1999; Koskela e al. 2002; Ko e and Schaal
2002; Ca e al. 2006; and e e ences he ein). Fo ins ance, A abi-
dopsis haliana accessions show gene ic di e gence in ole ance o
bac e ia Pseudomonas sy ingae (Ko e and Schaal 2002). Common
monkey-flowe Mimulus gu a us displays close- o-ze o he i abili y
(h
2
,0.03) o bo h esis ance and ole ance o Cucumbe mosaic
i us, ole ance measu ed as he di e ence be ween a pai o con ol
and in ec ed indi iduals (Ca e al. 2006). S inging ne le U ica
dioica displays amily di e ences in ole ance o holopa asi ic Dodde
Cuscu a eu opaea (Koskela e al. 2002).
In ou s udy, ole ance he i abili y could no be es ima ed because
he da a included only one eco d pe indi idual. He i abili ies o
ole ance eg ession pa ame e s can be es ima ed when each indi-
idual has se e al pe o mance obse a ions. By using eg ession
slopes o indi iduals as aw obse a ions in he gene ic analysis, bo h
en i onmen al and gene ic componen s o slope a iance, and hence
also he i abili y, can be es ima ed (Schae e 2004).
T ade-o be ween ole ance and esis ance
The second majo finding was ha esis ance was gene ically inde-
penden o ole ance, and hus he ai s did no display a gene ic
ade-o . Simul aneous gene ic imp o emen o asci es esis ance and
ole ance is hence possible.
In line wi h ou s udy, he me a-analysis o 31 s udies on 17 plan
species demons a es ha in gene al ole ance and esis ance o
he bi o es a e weakly gene ically co ela ed (Leimu and Ko iche a
2006). Albe s e al. (1987) ound in sheep a o able posi i e gene ic
co ela ions ( ¼0.31-1.00) be ween esis ance ( ecal nema ode egg
coun ) and ole ance (weigh gain and wool g ow h dep essions)
agains nema odes, bu h ee o ou co ela ions we e nonsignifican
wi h la ge SEs. Pipe and Ba ge (1988) showed in sheep ha o sp ing
o si es su e ing he g ea es nema ode bu dens also ended o su e
he g ea es p oduc ion losses unde a nema ode a ack. In con as ,
Bisse e al. (1994; 1996) ound no gene ic ela ion be ween esis ance
Figu e 3 Pheno ypic (V
P
), en i onmen al (V
E
), gene ic (V
G
), and ma e nal
a iance (V
M
) o 7-week body weigh es ima ed using andom eg essions
and co a iance unc ions and pheno ypic a iance calcula ed di ec ly om
he aw da a (V
P
aw da a) as a unc ion o hea a io.
Figu e 4 Va iance a ios o 7-week body weigh as a unc ion o hea
a io. He i abili y (h
2
) and ma e nal e ec a io (m
2
) we e es ima ed
using andom eg essions and co a iance unc ions. He i abili y
(h
2
MM) and ma e nal e ec a io (m
2
MM) we e es ima ed using mean
model 1 ( om Table 1).
532 | A. Kause, S. an Dalen, and H. Bo enhuis
( ecal egg coun ) and ole ance (d enching sco e) o nema ode pa a-
si es in Romney sheep ( ¼20.18 o 0.21). These esul s oge he
imply no gene ic ade-o be ween esis ance and ole ance.
The analysis o fi e inb ed mice s ains showed a s ong gene ic
ade-o be ween esis ance and ole ance o mala ia (Råbe g e al.
2007). Co ela ions ac oss dis inc inb ed s ains do no need o be
consis en wi h wi hin-popula ion gene ic co ela ions.
T ade-o be ween ole ance and g ow h
The hi d majo finding he e was he nonsignifican gene ic co ela ions
o ole ance slope wi h body weigh s in asci es- ee bi ds. In o he
wo ds, heal hy bi ds wi h high body weigh we e no gene ically mo e
p one o a s ong educ ion in body weigh as he esul o asci es
compa ed wi h he heal hy bi ds wi h a lowe body weigh . Bo h he
heo y (Kolmodin e al. 2003; an de Waaij 2004) and some obse a-
ions (e.g., Ra agnolo and Misz al 2000a) imply ha well-pe o ming
indi iduals a e gene ically mo e sensi i e o changes in an en i onmen .
No e idence o such a gene ic ade-o was ound he e o ole ance
and body weigh . These esul s imply ha simul aneous b eeding o
bo h inc eased g ow h and asci es ole ance is possible.
In he e iew by Núñez-Fa án e al. (2007), 8 o he o al 9 s udies
on plan s showed a gene ic cos o ole ance, ypically in e ms o
educed seed o ui p oduc ion. None heless, he cos s ha e been
obse ed o be en i onmen dependen (Núñez-Fa án e al. 2007). In
b oile s, s udies wi h addi ional ai s o in mo e dep i ed en i on-
men al condi ions migh e eal gene ic ade-o s o asci es ole ance.
T ade-o be ween esis ance and g ow h
The ou h majo finding was ha he co ela ion s uc u e be ween
asci es esis ance and body weigh was labile. E en he sign o he
co ela ion was swi ched implying ha he p esence o absence o
a disease c ea es a labile co ela ion s uc u e. The exp ession o
pheno ypic o gene ic cos s o esis ance a ied depending on he age
o he bi ds and asci es incidence in a popula ion. A cos o esis ance
is undamen al o he heo ies o main enance o gene ic poly-
mo phism (Boo s and Bowe s 1999; Bes e al. 2008), bu he exp es-
sion o cos s may be mo e labile han assumed by he models.
The likely explana ion o he labile co ela ion is ha he
incidence o in ec ed indi iduals and he se e i y o pe o mance
educ ion due o asci es can influence he sign o he co ela ion. The
simula ion by Ze ehda an e al. (2006) showed ha g ow h unde
condi ions o no asci es (o ea ly g ow h) can be weakly o no co -
ela ed wi h asci es incidence. This is because g ow h e a da ion has
no ye influenced g ow h pe o mance o indi iduals. In con as , he
sign o he co ela ion is swi ched o nega i e when asci es incidence is
inc eased (o in olde animals wi h mo e se e e symp oms) because
he a ec ed indi iduals su e om educed g ow h (Ze ehda an e al.
2006).
The model by Ze ehda an e al. (2006) is suppo ed wi h he eal
da a. Gene ic co ela ion be ween asci es and 35-d body weigh in
nona ec ed b oile s is posi i e ( ¼0.29), whe eas he co ela ion
in he whole popula ion wi h bo h a ec ed and nona ec ed indi id-
uals included is nega i e ( ¼20.26) (de G ee e al. 2001). Such
a change is in line wi h ou obse a ions ha pheno ypic and gene ic
co ela ions o asci es esis ance wi h ini ial 2-week body weigh we e
0.04 and 0.12 bu wi h 7-week body weigh 20.23 and 20.33, e-
spec i ely. Likewise, he gene ic co ela ion o hea a io wi h body
weigh o asci es- ee bi ds ( ai INTERCEPT) was 0.15. A simila
change in co ela ion s uc u e du ing g ow h occu s o skele al
de o ma ions (Kause e al. 2005) and ca a ac induced by a pa asi e
in ainbow ou (Kuukka-An ila e al. 2010).
Consequen ly, es ing o a ela ionship be ween hos pe o mance
and asci es, o any disease educing hos pe o mance, is challenging
because he incidence o in ec ed animals and he se e i y o hos
pe o mance educ ion can influence he sign o he co ela ion. This
c ea es a iabili y ac oss s udies in he co ela ions. Thus, he ques ion
is whe he he e a e ce ain egula i ies in he manne in which he
gene ic ade-o s a y and e ol e (Kause e al. 2001; Kause and Mo in
2001) and which ac o s c ea e such a ia ion (Núñez-Fa án e al.
2007). The p esen s udy s esses he ac ha diseases can induce
changes in co ela ions, leading o en i onmen -dependen co ela ed
gene ic esponses o selec ion.
Disease-induced geno ype-by-en i onmen in e ac ions
The final majo finding was ha asci es induced geno ype-by-
en i onmen in e ac ions in body weigh . Pheno ypic and gene ic
a iance o body weigh was inc eased wi h inc easing hea a io.
Simila ly, Pakdel e al. (2005) and Ze ehda an e al. (2006) obse ed
highe pheno ypic coe ficien s o a ia ion in body weigh o b oile s
held in cold compa ed o b oile s held in wa m empe a u e. In he
p esen s udy, he change in body weigh he i abili y was e y modes ,
he he i abili y es ima e anging om 0.13 o 0.18. Pakdel e al. (2005)
ound he i abili ies o 0.50 and 0.42 wi h o e lapping confidence lim-
i s in 5-week body weigh o b oile s held unde wa m and cold
condi ions, espec i ely.
Two nonmu ually exclusi e explana ions exis o he obse ed
change in body weigh a ia ion. Fi s , di e ging ole ance slopes
inc ease gene ic and nongene ic a iance o body weigh wi h in-
c easing asci es se e i y. Body weigh a ia ion is ele a ed because
g ow h o bi ds is di e en ly influenced by asci es. Second, andom
eg essions can a ificially c ea e an inc easing o u-shaped a iance
pa e n ac oss an x-axis (Ra agnolo and Mis zal 2002b; Kause 2011).
Because e en he aw pheno ypic a iance displayed an inc easing
end, he la e explana ion does no ully explain he obse ed end
he e.
In ec ions can change he i abili ies o pe o mance ai s. Fo
ins ance, Lewis e al. (2009) showed in pigs ele a ed he i abili ies o
ep oduc ion ai s in esponse o po cine ep oduc i e and espi a-
o y synd ome ou b eaks. Cha man ie e al. (2004) showed educed
Figu e 5 Gene ic co ela ion be ween heal hy and a ec ed bi ds wi h
di e en hea a ios (on x-axis), calcula ed using andom eg essions
and co a iance unc ions.
Volume 2 May 2012 | Tole ance Gene ics | 533
he i abili y o a sus leng h in Blue i (Pa us cae uleus)unde blowfly
la ae a ack. Kause e al. (2007) showed inc eased liabili y-scale he -
i abili y o skele al de ec s as a unc ion o inc easing de ec incidence.
Asci es did no jus induce a scaling e ec (a change in a iance),
bu also geno ype e- anking ac oss heal hy and a ec ed bi ds. The
mos ex eme gene ic co ela ion be ween heal hy and a ec ed bi ds
was 0.45. Pakdel e al. (2005) ound e en s onge geno ype-by-en i-
onmen in e ac ion o body weigh o b oile s held unde cold and
wa m empe a u e (
G
be ween en i onmen s ¼0.28). The wo o ms
o geno ype-by-en i onmen in e ac ion, scaling e ec and e- anking,
acili a e en i onmen -dependen gene ic changes. Mo eo e , when
gene ic co ela ions be ween hos pe o mance and esis ance o ol-
e ance a e changed in esponse o in ec ion, as shown he e, he gene ic
ou come o selec ion in en i onmen s wi h di e en ial pa hogen bu -
den becomes e en mo e mul i ace ed.
Asci es is a clea example in which selec ion in disease- ee and
diseased popula ion would esul in di e en gene ic esponses in hos
pe o mance and asci es esis ance/ ole ance. The modifica ion o
gene ic a chi ec u e o g ow h and li e-his o y ai s by pa hogens,
pa asi es, and p oduc ion diseases, media ed by ole ance gene ics,
may play a mo e undamen al ole in mic oe olu ion han was
p e iously hough.
ACKNOWLEDGMENTS
We hank he s a a Cob Hend ix Gene ics/Cobb Eu ope BV
Boxmee o he da a collec ion and Gosse Veninga o his suppo .
The wo k was financially suppo ed Cobb Eu ope BV and Wagenin-
gen Uni e si y, The Ne he lands.
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Communica ing edi o : D.-J. de Koning
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