MHC Congenic Mouse Strains Are Identical at All Loci Except the MHC

Detailed analysis of the H-2 complex in mice was made possible by the development of congenic mouse strains. Inbred mouse strains are syngeneic or identical at all genetic loci. Two strains are congenic if they are genetically identical

TABLE 7-ll H-2 Haplotypes of some mouse strains

H-2 ALLELES

TABLE 7-ll H-2 Haplotypes of some mouse strains

H-2 ALLELES

Prototype strain

Other strains with the same haplotype

Haplotype

K

IA

IE

S

D

CBA

AKR, C3H, B10.BR, C57BR

k

k

k

k

k

k

DBA/2

BALB/c, NZB, SEA, YBR

d

d

d

d

d

d

C57BL/10 (B10)

C57BL/6, C57L, C3H.SW, LP, 129

b

b

b

b

b

b

A

A/He, A/Sn, A/Wy, B10.A

a

k

k

k

d

d

A.SW

B10.S, SJL

s

s

s

s

s

s

A.TL

t1

s

k

k

k

d

DBA/1

STOLI, B10.Q, BDP

q

q

q

q

q

q

(a) Mating of inbred mouse strains with different MHC haplotypes Homologous chromosomes with MHC loci b/b

H-2b parent b/b

H-2b parent

H-2k parent

(b) Skin transplantation between inbred mouse strains with same or different MHC haplotypes

Parental recipient

Skin graft donor

Progeny recipient

Parental recipient

k/k

Parent b/k k/k

Parent

(a) Illustration of inheritance of MHC haplotypes in inbred mouse strains. The letters b/b designate a mouse homozy-gous for the H-2b MHC haplotype, k/k homozygous for the H-2k haplotype, and b/k a heterozygote. Because the MHC loci are closely linked and inherited as a set, the MHC haplotype of F1 progeny from the mating of two different inbred strains can be predicted easily. (b) Acceptance or rejection of skin grafts is controlled by the MHC type of the inbred mice. The progeny of the cross between two inbred strains with different MHC

haplotypes (H-2fc and H-2k) will express both haplotypes (H-2fc/k) and will accept grafts from either parent and from one another. Neither parent strain will accept grafts from the offspring. (c) Inheritance of HLA haplotypes in a hypothetical human family. In humans, the paternal HLA haplotypes are arbitrarily designated A and B, maternal C and D. Because humans are an outbred species and there are many alleles at each HLA locus, the alleles comprising the haplo-types must be determined by typing parents and progeny. (d) The genes that make up each parental haplotype in the hypothetical family in (c) are shown along with a new haplotype that arose from recombination (R) of maternal haplotypes.

Progeny b/k

(c) Inheritance of HLA haplotypes in a typical human family c?--?

Parents

Progeny

(d) A new haplotype (R) arises from recombination of maternal haplotypes

HLA Alleles

Haplotypes

A B C D R

A

B

C

DR

DQ

DP

1

7

w3

2

1

1

2

8

w2

3

2

2

3

44

w4

4

1

3

ยป

7

3

4

3

44

w4

7

3

Cross

Interbreeding

Cross

Interbreeding

Strain-A skin grafts

Skin Graft Acceptance Congenic Mice

Backcross

Select for b/b at H-2 complex a/b a/b

Backcross

Select for b/b at H-2 complex

FIGURE 7-3

Production of congenic mouse strain A.B, which has the genetic background of parental strain A but the H-2 complex of strain B. Crossing inbred strain A (H-20) with strain B (H-2b) generates F, progeny that are heterozygous (o/b) at all H-2 loci. The F, progeny are interbred to produce an F2 generation, which includes o/o, o/b, and b/b individuals. The F2 progeny homozygous for the B-strain H-2 complex are selected by their ability to reject a skin graft from strain A; any progeny that accept an A-strain graft are eliminated from future breeding. The selected b/b homozy-gous mice are then backcrossed to strain A; the resulting progeny are again interbred and their offspring are again selected for b/b homozygosity at the H-2 complex. This process of backcrossing to strain A, intercrossing, and selection for ability to reject an A-strain graft is repeated for at least 12 generations. In this way A-strain homozygosity is restored at all loci except the H-2 locus, which is homozygous for the B strain.

I Interbreed, select, and vjz backcross for > 10 cycles

Strain A^B

Strain A^B

except at a single genetic locus or region. Any pheno-typic differences that can be detected between congenic strains are related to the genetic region that distinguishes the strains. Congenic strains that are identical with each other except at the MHC can be produced by a series of crosses, backcrosses, and selections. Figure 7-3 outlines the steps by which the H-2 complex of homozygous strain B can be introduced into the background genes of homozy-gous strain A to generate a congenic strain, denoted A.B. The first letter in a congenic strain designation refers to the strain providing the genetic background and the second letter to the strain providing the genetically different MHC region. Thus, strain A.B will be genetically identical to strain A except for the MHC locus or loci contributed by strain B.

During production of congenic mouse strains, a crossover event sometimes occurs within the H-2 complex, yielding a recombinant strain that differs from the parental strains or the congenic strain at one or a few loci within the H-2 complex. Figure 7-4 depicts haplotypes present in several recombinant congenic strains that were obtained during pro-

Parental

Congenic

Recombinant congenic

FIGURE 7-4

Parental

Congenic

Recombinant congenic

Strain haplotype

A

a

B10

b

B10.A

a

B10.A (2R)

h2

B10.A (3R)

i3

B10.A (4R)

h4

B10.A (18R)

i18

Examples of recombinant congenic mouse strains generated during production of the B10.A strain from parental strain B10 (H-2b) and parental strain A (H-20). Crossover events within the H-2 complex produce recombinant strains, which have o-haplotype alleles (blue) at some H-2 loci and b-haplotype alleles (orange) at other loci.

duction of a B10.A congenic strain. Such recombinant strains have been extremely useful in analyzing the MHC because they permit comparisons of functional differences between strains that differ in only a few genes within the MHC. Furthermore, the generation of new H-2 haplotypes under the experimental conditions of congenic strain development provides an excellent illustration of the means by which the MHC continues to maintain heterogeneity even in populations with limited diversity.

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