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0.0005 (0.05%) of the B6 genome remains. After the 12th backcross generation, heterozygous (rs) sibling pairs are interbred, and homozygous rapid (rr) acet-ylator progeny are selected and used to found the A.B6 congenic line. A mirror image procedure can be used to produce the reciprocal slow acetylator congenic line, B6.A-Nats, or B6.A for short.

The average length of the chromosomal segment that is donated to the background can be calculated. An approximation of the length in centiMorgans is given by 200/n where n is the number of backcross generations, and for a congenic strain created by 12 backcross generations, the inbred partner and its congenic differ by 15-20 cM.

Other methods can be used to create a congenic line; the method chosen depends on the characteristics of the differential allele and whether it affects survival and fertility. The backcross method schematized in Figure 9.2 is applicable when the allele contributed by the donor strain is transmitted as an autosomal dominant or codominant character. The cross-intercross system, which involves a somewhat more complicated mating system, is used when the differential allele is recessive and undetectable in the heterozygous state. Details of this system are given by Flaherty.12

Recently, with the advent of complete genetic linkage maps, Lander and Schork proposed a strategy to construct "speed congenics'' in only 3-4 generations instead of 12 or more generations according to the standard protocol described above by using marker breeding.13 Yui et al.14 and Monel et al.15 have applied this strategy to the construction of mouse congenic strains while Jeffs et al. have applied a similar strategy to the construction of rat congenic strains.16

The vocabulary and symbols customarily applied to congenic strains are set forth by Snell.11 Individual congenic strains are named by an abbreviation of the background strain (also called the ''inbred partner'') followed by a period followed by an abbreviation of the donor strain. The rapid acetylator congenic strain diagrammed in Figure 9.2 would be called A.B6-Natr where Nat r is the name of the differential allele contributed by the donor strain. The reciprocal congenic slow acetylator strain, in which B6 is the background strain and A is the donor strain, would be designated B6.A-Nats where Nats represents the differential slow N-acetyltransferase allele.

The availability of ''quartets'' provides a tool well suited to the search for the effects of background genes on the expression of a differential allele. The quartet consists of the two parental strains and the reciprocal congenic partner strains derived from them. In the specific illustration referred to earlier, A and B6 are the parental strains while A.B6 and B6.A are the reciprocal congenic strains (Figure

9.2). Differences among various quartet members reveal the background effects that influence the expression of either allele at the differential locus. In this example, comparison of strains A and B6 reveals the effects of the background genes plus the effects of the differential allele (upper and lower panels of Figure

9.3), whereas the comparison of the strains in the column on the left (A and A.B6) or of the column on the right (B6 and B6.A) reveals the effects of allelic differences expressed on different backgrounds. Cross comparisons, as for A vs. B6.A or B6 vs. A.B6, reveals the influence of background differences on the differential alleles.

Other crosses between different quartet members can yield additional information of interest. For instance, comparison of parental (say strain A) mice with the hybrid animals resulting from the cross A x B6.A reveals the influence of the F1 background relative to that of the inbred background on the expression of the differential allele. And finally, since the chromosomal segments introduced in reciprocal congenic strains are almost inevitably of different lengths, comparison of the F1 offspring of the parental strains (A x B6) with the F1s from the reciprocal congenic strains (A.B6 x B6.A) affords a way of assessing the influence of the nonidentical regions that immediately surround the differential allele on its expression.

It is intuitively evident that congenic strains provide a versatile and very powerful method for the analysis of genetic variation.

Double Congenic Mouse Strains

A double congenic strain differs from its inbred background partner at two loci. The two loci are usually unlinked and they may be derived from the same second (donor) strain or different second strains. A double congenic line is created from crosses between two congenic inbred strains. The F1 progeny are then interbred and the F2 offspring are typed for both loci. With two unlinked loci, 16 combinations of gametes are possible among F2 progeny (Figure 9.4). One in 16 offspring

Strain A

Strain B6

Chr 8

Strain A.B6

Natr vs Nats difference plus background difference^

A.B6 vs B6

background differences

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