Divergent selection for humoral immune responsiveness in chickens: distribution and effects of major histocompatibility complex types

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Divergent selection for humoral immune responsiveness

in chickens: distribution and effects of major

histocompatibility complex types

M-H Pinard, Jam van Arendonk, Mgb Nieuwland, Aj van der Zijpp

To cite this version:

Original

article

Divergent

selection for humoral

immune

_{responsiveness}

in

chickens:

distribution and effects of

_major

histocompatibility complex

types

M-H Pinard

1

JAM Van Arendonk

MGB

Nieuwland

AJ Van der

_Zijpp

1

Department of Animal Husbandry,

Wageningen Agricultural

University, Wageningen;

2

Department of Animal Breeding, - Wageningen Agricultural University, Wageningen;

3

DLO-Research Institute for Animal Production Schoonoord, Zeist, The Netherlands

(Received

13 _{April 1992; accepted} 20 November

₁₉₉₂₎

Summary - Chickens were selected for 10 _generations for _high and low _antibody response

to sheep red blood cells; in _addition, a randombred control line was maintained. All birds

(n

=

_{1 602)}

_{from the 9th and 10th}

generations were _typed for _{major histocompatibility}

complex B-types. All identified types were _present in the control line but the selected lines showed

_divergent

distributions. The 121

_B-haplotype

was predominant in the

high

line in the form of 121-121 _B-genotype, whereas the 114 _B-haplotype was most _frequent in the form of 114-114 and 114-124 _B-genotypes in the low line. To _explain these _frequency

changes,

effects of _B-genotypes on the selected trait were _{estimated, using} a mixed animal

model. The _B-genotypes were

responsible

for a _{significant part} of variation of the trait within _lines, but their effects differed between lines. These effects could be related _partly

to the changes in _B-genotype distribution.

chicken _/ immune response / selection / animal model / major histocompatibility

complex

Résumé - Sélection divergente sur la réponse immunitaire chez la poule: distribution et effets des types du _{complexe majeur} d’histocompatibilité. Des _poulets ont été sélectionnés _pendant 10 _{générations} sur la réponse immunitaire haute et basse à des glo-bules rouges de mouton; une _lignée témoin était _{également maintenue par} accouplements

*

Correspondence and _reprints: MH _Pinard, Laboratoire de _{Génétique Factorielle, INRA,} 78352 _{Jouy-en-Josas Cedex,} France

**

au hasard. Tous les animau!

_(n

=

₁₆₀₂₎

des _{générations 9 et 10 ont} été _analysés

pour leurs types B du _{complexe majeur d’histocompatibilité.} Tous les _{types identifiés} étaient présents dans la lignée témoin, alors que les lignées sélectionnées _{présentaient} des distributions _divergentes pour ces _types B. L’haplotype B 121 était prédominant dans la _lignée haute sous la forme du génotype B 121-121, alors que l’haplotype B 114 était le

plus fréquent dans la lignée basse sous _{la forme des génotypes} B _114-114 et _{114-124. Afin}

d’expliqaer ces _changements de fréquence des types B, les _effets des _génotypes B sur la

réponse immunitaire aux _{globules rouges} de mouton ont été estimés à l’aide d’un modèle animal m.i.xte. Les _génotypes B étaient _responsables d’une part significative de la variation du caractère _{intralignée,} mais leurs _effets étaient variables suivant la _lignée. Ces effets pouvaient en _{partie expliquer} les _changements de _fréquence des _types B.

poule / réponse immunitaire _/ sélection _/ modèle _{animal / complexe majeur}

d’histocompatibilité

INTRODUCTION

In recent _years, there has been a

_growing

interest in

_improving

the

_genetic

resistance of domestic

_species

to infectious diseases. This

_improvement

may be

accomplished

indirectly by

selective

_breeding

for immune

_{responsiveiiess}

_and/or

for _genes or

marker _genes for immune

_{responsiveness}

and disease resistance

_(Warner

et

_al,

_1987).

Moreover,

advances in molecular

_technique

have

_opened

_promising

ways for

directly

introducing advantageous

genes into animals

by

genetic

engineering

(Lamont, 1989).

Successful selection

_experiments

for

_high

and low

_antibody

_response to

_sheep

red

blood cells

_(SRBC)

have been

_reported

in mice

_(Biozzi

et

_al,

₁₉₇₉₎

and in chickens

(eg

Van der

_Zijpp

et

_al,

_1988; Martin et

_al,

_1990).

In the former

_experiment,

Pinard

et al

₍₁₉₉₂₎

have estimated

_heritability

for the selected trait as 0.31.

_However,

even if

the humoral response to SRBC is under

_polygenic

control,

some specific

genes

might

play

a major role,

and the _genes of the

_major

_{histocompatibility}

_complex

_(MHC)

are

prime

candidates. The MHC genes encode

highly polymorphic

cell surface

proteins

that have been shown to

_play

an _important role in immune

_{responsiveness}

and disease _{resistance in many}

_species

_including

chickens

_(Bacon,

_1987;

_Gavora,

_1990; Lamont and

_Dietert,

_1990).

Estimation of

_MHC-type

effects remains a delicate

task, especially

in the framework of selected outbred lines.

_Ignoring

the

_{relationships}

between individuals

may, for

example,

often lead to overestimation of the MHC effect

(Mallard

et

al,

1991).

The choice of the method to estimate

_single

_gene effects

_separately

from the

background

genes is therefore crucial

(Kennedy

et

al,

1992).

MATERIALS AND METHODS

Selection lines

The selection

_experiment

has been described in detail elsewhere

_(Van

der

_Zijpp

et

al,

1988; Pinard et

_al,

_1992).

_Briefly,

chickens were

_{bidirectionally}

selected from an ISA Warren cross base

population

for 10

_generations.

The selection criterion was the total

_antibody

_(Ab)

_titer, 5 d

_postprimary

immunization with 1 ml 25%

sheep

red blood cells

_(SRBC)

diluted in

_{phosphate-buffered}

saline.

_Antibody

titers

measured

_against

SRBC were

_expressed

as the

_log

₂

of the

_reciprocal

of the

_highest

blood

_plasma

_giving

_{complete agglutination.}

In addition to the

_high

_(H)

and low

(L)

lines,

a random-bred control

_(C)

line was maintained.

_{Every generation,}

there were ! 300 chicks each in the H and L lines and 250 chicks in the C

_line,

from which x

r 25 males and 50 females in the H and L lines and ;zz 40 males and 70 females in the C line were used to

_produce

the next

_generation.

In the 9th

_generation,

the

inbreeding

level was _7.3, 3.6 and 9.4% in the

H,

C and L

lines,

respectively.

The numbers of birds in the

H,

C and L lines of the ninth and tenth

_generations

are

given

in table I.

Typing

for MHC

_haplotype

Major histocompatibility complex haplotypes

were determined

_by

direct

haemag-glutination,

using

alloantisera obtained from the lines. Four _serotypes,

_{provisionally}

called

_B1l

₄

_,

_B1

_l9

_,

_,

_izi

_B

and

B

lz4

were identified in the tested birds. As

compared

to

for both B-F and B-G.

_Only

B

114

and

W

19

showed similarities for B-G with

B

14

and

B

19

,

respectively,

whereas

B

12i

showed similarities for B-F with

B

21

_(Pinard

et

al,

1991;

Pinard and

_Hepkema,

_1992).

A MHC genotype was defined as the combi-nation of 2

_{haplotypes. Serological}

_typing

was

_performed

on the _parents of the 8th

generation,

on all the females and the selected males of the 8th _generation, and on all the birds of the 9th and 10th

_generations.

_Only

the results of MHC

_typing

in the 9th and 10th _generations were used in the

_analysis.

_Segregation

of the

_haplotypes

was checked for

_consistency

within families over _generations, and inconsistent data were removed from the

_analysis.

Statistical

_analysis

Comparison

of MHC _type

_frequencies

between the lines was

_performed

by x2

tests.

Effects of MHC genotype on the Ab _response were estimated within lines

_using

the

_following

mixed model:

Where:

Abj

k

i

m

= the Ab titer of the mth

chick,

p = _{a constant,}

generation

i

= the fixed effect of the ith

generation

(9, 10),

sex

j = the fixed effect of the

jth

_sex of the

chick,

line

k

= the fixed effect of the kth line

(H,

C,

L),

MHC!1

= the fixed effect of the lth MHC _genotype within the kth

line,

Uijklm =

the random additive

_genetic

effect on the Ab titer in the mth chick

and

eijklm = a random error.

The fixed effect of

_generation

accounted for environmental differences between

generations

9 and 10. The sex effect corrected for a

higher

Ab _response to SRBC in

females than in males.

_{Relationships}

between individuals from the 10

_generations

and Ab data of the 9th and 10th

_generations

were used in this

study.

The mixed

model was

_applied

_assuming

a

_heritability

of _0.31, as estimated

_previously

_(Pinard

et

_al,

_1992).

Solutions for the model were obtained

_using

the PEST program

(Groeneveld,

1990; Groeneveld and

_Kovak,

_1990),

which is a

_{generalized procedure}

to set up and solve systems of mixed model

_{equations containing genetic}

covariances

between observations.

Differences between _genotypes within lines were tested as

_orthogonal

contrasts

using

the F test values as estimated

_by

PEST. The overall effect of _genotypes in a line was estimated

_{by testing,}

jointly

_against

the error variance term

_Q

_{e, n -}

1

independent

differences between _genotypes, with n

_being

the number of _genotypes

Heterozygote

superiority

was estimated within-line for each available combina-tion of

_{haplotypes by}

_testing

the difference between the

_heterozygote

_genotypes and the _average of their

_homozygous

_{counterparts.} The overall

_heterozygote

supe-riority

in a line was estimated

_by

_testing

the difference between these

_heterozygote

genotypes and the average of their

homozygous

counterparts.

The effect of

_haplotype

i was estimated within-line

by

_testing

the difference

between _genotype combinations

_comprised

of the

_haplotype

i and their _counterparts

. , ., , . ! rn -

Sj(Geno!-Geno!)

.)

..

comprised

of a reference

haplotype

_r, as

_following:

E! (Geno2! - Geno,.! ) !

with

p

Geno

ij

,

and

_Geno

_rj

_being

the estimated effects of MHC _genotypes

_comprised

of

haplotypes

i and

_j,

and r and

_j,

_{respectively,}

and _p

_being

the number of

_pairwise

combinations.

RESULTS

MHC distribution in the different lines

Frequencies

of MHC _genotypes and

_haplotypes

in the 9th and 10th

_generations

for the

_H,

C and L lines are

_given

in tables I and

_II,

_{respectively.}

_Frequencies

of _genotypes and

_haplotypes

were

significantly (P

<

_0.01)

different between lines in the 9th and in the 10th

_generation.

In the C

_line,

all 10

_possible

_genotypes were _{present, with,a}

_predominance

of the 119-124

_B-genotype,

and the 119 and 124

_B-haplotypes

were

_prevalent.

The distribution of MHC _genotype and of MHC

haplotype

in the H line was

_opposite

to those in the L line..The 121-121

_B-genotype

predominated

in the H

_line,

whereas the 114-114 and 114-124

_B-genotypes

were most

_frequent

in the L line. In the H

line,

the 121

_{B-haplotype frequency}

reached 79% at the _expense of the 114

_B-haplotype,

which tended to

_disappear.

On the contrary, the 121

_{B-haplotype disappeared}

between the 8th and the 9th

generation

in the L line

_(data

not

_shown).

In the L

line,

the 114

_B-haplotype

was found most

compared

to the

_124,

and

_especially

the 119

_{B-haplotypes.}

Heterozygous

birds were in the

_majority

in the C

line,

whereas

homozygous

birds were most

_frequent

in the H line and to a lesser extent in the L line. This

_tendency

was more

pronounced

in the 10th

_generation.

Estimation of MHC

_genotype

effects on the Ab _response

Estimates of MHC

_genotype

effects on the Ab _response to SRBC are

_given

in table

III. The overall effect of MHC _genotypes was _greater in the selected lines than in the C

line,

and the total

_genetic

variance

_{explained by}

MHC _genotypes was _greater in the H and C lines than in the L line. This

_high

_genetic variance in the H line arose

from extreme estimate values of the

114-124,

119-119 and 124-124

_B-genotypes

despite

their low

_frequency

value. The

_ranking

of _genotypes

_according

to their

Estimation

_{of heterozygote superiority}

Estimates of

_heterozygote

_superiority

for each available combination and overall

lines are

_given

in table IV. In the C

line,

a

moderately

_positive

general

effect of

heterozygous

genotypes was demonstrated. This

_positive

effect

appeared

in the 119-124

_B-genotype,

and was marked in the 121-124

_B-genotype.

In the L

_line,

a

general

heterozygous disadvantage

was

_{non-significant.}

This

_negative

_{effect, however,}

was

significant only

for the 114-124

_B-genotype.

In the H

line,

not all the

_heterozygous

combinations could be evaluated because of

_missing

genotypes. In the H

_line,

there

was a

_{significant negative}

effect of

_heterozygous

_genotypes

_overall,

and of the 121-124 and the 119-124

_B-genotypes.

’

Estimation of MHC

_haplotype

effects on the Ab _response

In the C and L

_lines,

all

_possible

combinations of

_haplotypes

were _present.

Therefore,

in these

_lines,

the choice of a reference

_haplotype

did not affect either the

_ranking,

or the value of the differences between

_haplotype

estimates. Results are

_presented

in table V

_taking

the 119

_B-haplotype

as the reference. In the H

line,

haplotype

effects were not estimated because it was not

_possible

to write a linear combination of _genotypes, which would estimate the difference between 2

haplotypes.

The estimated Ab titer of the 114

_B-haplotype

was

significantly

lower

than the estimate of the 119

_B-haplotype

in the L line

_{(table V).}

In the C

_line,

the

estimated Ab titer of the 114

_B-haplotype

was

significantly

lower than the estimates

of the 121 and 124

_B-haplotypes

in the C line.

Relationship

between the effects of MHC

_types

on

_antibody

response and their

_frequency

on the selected

_trait,

_frequencies

of MHC _types and their estimated effects on the

Ab titer were

compared.

When not

_considering

the extreme values of rare _genotypes in the H

_{line, remaining}

_genotype estimated effects were not

_{significantly}

different from each

_{other; therefore,}

results

from

the estimation of MHC

_genotype

effect on

the Ab _response from the H line will not be considered.

The

_ranking

of estimates of

_haplotype

effects on the Ab _response in the L line

(table V),

was in total _agreement with the distribution of these

haplotypes

in the selected lines

_{(table II).}

_Likewise,

the

_ranking

of the _114, 119 and

121

_B-haplotype

effects estimated in the C line could

_explain

the

_haplotype

distribution in the

selected lines.

Genotypes

which were most

_frequent

in the L line had

also,

on the

whole,

lower

effects on the Ab response than genotypes which were rare in the L

_line,

as estimated in the L line

_{(fig 1)}

and in the C line

_{(fig 2).}

_Genotypes

which were most

_frequent

in

the L line had

_globally

lower effects on the Ab _{response in} the C line than _genotypes

which were most common in the H line

_{(fig 2).}

The

_{major exception}

was the 121-121

B-genotype

which was most

_frequent

in the H

_line,

but had a low effect on the Ab response in the C line

(fig 2).

In

_conclusion,

estimation on MHC genotype and

_haplotype

effects on the Ab response in the C and L line could

explain

the observed distribution of MHC types in the L line and

_{only partly}

those observed in the H line.

DISCUSSION

Changes

of _gene

_frequency

_may be due to

_genetic

drift,

difference in fitness of

certain _{genotypes, or,} in case of

_selection,

to direct effect or

_linkage

with _genes

affecting

the selected trait

_{(Falconer, 1989).}

Even after 10

_generations,

_genetic

drift is not

_likely

to

_explain

such dramatic

changes

of MHC _type

_frequency

in

opposite

directions.

_{Moreover, previous genetic}

_analysis

of 9

_generations

did not

show _{any apparent}

_{genetic drift,}

and

_inbreeding,

which affects

_{genetic drift,}

was low

species

(Melnick

et

_al,

_1981;

_f!stergard

et

_al,

_1989;

Gautschi and

_Gaillard,

_1990).

Therefore,

a

_possible

effect of natural selection cannot be excluded.

_{This, however,}

cannot

_explain

the

_opposite

_changes

in MHC _type distributions in the H and L

lines,

as

_compared

to the C line. The

_significant

differences in effect of the MHC genotype on the selected trait are evidence for a direct or

_closely

linked effect of MHC _genes on the Ab _{response to} SRBC.

The MHC _type

_frequencies

were not measured in the initial base

_population

or in the first

_generations

of selection.

_However,

the control line was

_produced

from the base

_{population by}

random

_mating

and

_displayed

in the 10th

_generation

all

haplotype

combinations,

whereas the selected lines

_{presented divergent}

distributions .

of MHC _types. Given the

_relatively

low level of

_inbreeding

in the C

_line,

it thus seems

reasonable that the

_frequencies

in the C line represent the distribution of MHC _types

in the base

_population,

and that the MHC _type

_frequencies

have

_changed

in the

selected lines.

Changes

in MHC _gene

_frequency,

or at

_least,

differences in MHC _type distribu-tions between lines selected for immune

_{responsiveness}

or disease resistance have

been

_reported

_(Gavora

et

al, 1986;

Heller et

al,

1991).

In a similar

_experiments

to ours with chickens selected for

_high

and low _{immune response} to

_SRBC,

differences

was also

_predominant

in our H line

_(Pinard

and

_Hepkema,

_1992).

_Typing

for MHC

antigens

in lines of mice

_divergently

selected for Ab _{response to} SRBC

_(Biozzi

et

al,

1979)

also revealed 2 distinct

_haplotypes

in the 2 lines

_(Colombani

et

_al,

_1979).

Estimation of MHC _genotype effect and of

_{heterozygote advantage produced}

different results between the lines. Immune _{responsiveness} to various

_antigens

like SRBC has been demonstrated to be influenced

_by

non-MHC as well as

_by

MHC genes

(Palladino

et

al, 1977;

Gyles

et

al,

1986; Kim et

al,

1987; Lamont and

Dietert,

1990).

Significant

interactions between MHC and the selected

_background

genome were also

reported

in a similar selection

_experiment

to ours

_(Dunnington

et

al,

1989).

In

addition,

specific

heterozygote

advantage

may result from

genetic

complementation

between both MHC and non-MHC _genes.

In

segregating

populations,

the estimation

_{of single}

gene effects can lead to biased

results because of the

_{likely confounding}

effects between _{the marker gene and the}

polygenes

(Bentsen

and

_Klemetsdal,

_1991).

Selection is an extra source of bias because the birds

being

selected are

_{likely sharing}

_advantageous

alleles for both the marker gene and the

polygenes.

Kennedy

et al

₍₁₉₉₂₎

showed that unbiased

estimates of a

_single

_gene effects can be obtained

_by

mixed model

_analysis

from a

of

_using

data from all

_generations

with an unknown _genotype.

Indeed,

Carnier and Arendonk

₍₁₉₉₂₎

demonstrated

_by

simulation that

_including

observations in

previous generations

of which _genotype information was

_missing

resulted in

larger

biases. In our

_estimation,

bias due to selection could not be eliminated

_by

the use of the

_{complete relationship}

matrix

_only.

This bias

_might

have contributed to the differences in

_genotypic

effects observed between the lines.

The present and

_previous

results

_(Pinard

et

_al,

₁₉₉₂₎

are in _agreement with a

_polygenic

control of

_antibody

_{response to} SRBC.

Moreover,

one of the loci

involved

_might

be part

of,

or linked _to, the

B-complex.

However,

the

linkage

and the nature of the interactions between MHC or MHC-linked genes and other immune response genes are not known.

Besides,

during

10

_generations

of

_multiple

_matings,

recombinations between MHC-linked and other immune response genes

might

have

occurred, causing

altered

_linkage

_(Pevzner

et

_al,

_1978;

_Lamont;

_1989).

In

_conclusion,

results of the estimation of MHC effect from selected

_populations

should be considered with _caution,

_especially

when the _genotypes are not known in all the

_generations.

In our

_experiment,

estimation of MHC effect _may be obtained from the control

_line,

_providing

a

_larger

number of birds.

Alternatively,

one could

study

a

F

2

population

that

will

be

produced

from the

high

and low lines.

REFERENCES

Bacon LD

₍₁₉₈₇₎

Influence of the

_major

_{histocompatibility}

_complex

on disease

resistance and

_{productivity. Poultry}

Sci _66, 802-811

Bentsen

HB,

Klemetsdal G

₍₁₉₉₁₎

The use of fixed effects models and mixed models to estimate

_single

_gene associated effects on

_polygenic

traits. Genet Sel Evol _23,

407-419

Biozzi

_G,

Mouton

_D,

Heumann

_AM,

Bouthillier

_Y,

Stiffel

_C,

Mevel JC

₍₁₉₇₉₎

Genetic

_analysis

of

_antibody

responsiveness

to

_sheep

_erythrocytes

in crosses between lines of mice selected for

_high

or low

antibody

synthesis. Immunology

36,

427-438

Carnier

P,

Arendonk JAM

₍₁₉₉₂₎

Estimation of effects of

single

genes on

quantita-tive traits in

_populations

under selection. A simulation

_study.

In: Proc

_43rd

Annu

Meet EAAP.

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