The recombinant congenic strains for analysis of multigenic traits: genetic composition

Abstract

The genetic control of susceptibility to many common diseases, including cancer, is multigenic both in humans and in animals. This genetic complexity has presented a major obstacle in mapping the relevant genes. As a consequence, most geneticists and molecular biologists presently focus on "single gene" diseases. To make the multigenic diseases accessible to genetic and molecular analysis, we developed a novel genetic tool, the recombinant congenic strains (RCS) in the mouse (4). The RC strains are produced by inbreeding of mice of the second backcross generation between two inbred strains, one of which serves as the "donor" and the other as the "background" strain. A series of RCS consists of approximately 20 strains, each carrying a different set of genes: approximately 12.5% genes from the common donor inbred strain, the remaining 87.5% from the common background inbred strain. As the set of donor strain genes in each RC strain is different, the nonlinked genes of the donor strain involved in the control of a multigenic trait, e.g., cancer susceptibility, become distributed into different RC strains where they can be analyzed one by one. Hence, the RCS system transforms a multigenic trait into a series of single gene traits, where each gene contributing to the multigenic control can be mapped and studied separately. Recently we demonstrated that the RCS system is indeed capable of resolving multigenic traits, which are hardly analyzable otherwise, by mapping four new colon tumor susceptibility loci (8; P. C. Groot, C. J. A. Moen, W. Dietrich, L. F. M. van Zutphen, E. S. Lander, and P. Demant, unpublished results). For successful application of the RCS system, extensive genetic characterization of the individual recombinant congenic strains is essential. In this paper we present detailed information about the genetic composition of three series of RC strains on the basis of typing of 120-180 markers distributed along all autosomes. The data indicate that the relative representation of the donor strain genes in the RC strains does not deviate from the theoretical expectation, and that the RC strains achieved a very high degree of genetic homogeneity and for all practical purposes can be considered inbred strains. The density and distribution of markers reported here permits an effective mapping of unknown genes of donor strain origin at almost all autosomal locations. Much of this information has been obtained using the new class of genetic markers, the simple sequence repeat polymorphisms.(ABSTRACT TRUNCATED AT 400 WORDS)

Interspecific Recombinant Congenic Strains Between C57BL/6 and Mice of the Mus spretus Species: A Powerful Tool to Dissect Genetic Control of Complex Traits

“…Theoretical considerations predict that $95% of the genome of the donor strain can be transferred and distributed within a series of 20 RCSs (Demant and Hart 1986;Moen et al 1997). Five sets of such RCSs have been produced between pairs of laboratory inbred strains (Groot et al 1992;Martin et al 1992b;Fortin et al 2001b) and the results have fulfilled the theoretical expectations . Since each RCS carries only a small fraction of the donor genome, multiple genes controlling a trait are likely to be isolated in different strains (Demant and Hart 1986;Moen et al 1991).…”

“…We observed that in 87% of cases, strains segregating for the two alleles at a particular locus in the first series of genotyping (average F ¼ 8.7) had fixed the B6 allele in the second series (average F ¼ 24.6). No such genomewide selection has been observed in recombinant inbred or recombinant congenic strains established from laboratory strains, which showed the expected proportion from the two parental strains (Groot et al 1992;Stassen et al 1996). The final genetic makeup of IRCSs and ICSs suggests that it is hardly feasible to introduce .4-5% of the M. spretus genome in a B6 background, because of the large number of interchromosomal epistatic interactions.…”

Thioredoxin-Interacting Protein

“…To this end, we studied TXNIP-deficient HcB-19 mice. HcB-19 mice are an inbred congenic C3H mouse strain (33,34) that harbors a spontaneous inactivating nonsense mutation in exon 2 at codon 97, resulting in dramatically reduced TXNIP mRNA and protein levels (29). Glucose induces TXNIP expression and apoptosis in primary islets.…”

Mouse genetic model for antigen-induced airway manifestations of asthma

“…18 In several diseases, the recombinant congenic (RC) strains of mice have proven to be a powerful tool to provide the mapping of genes controlling complex traits. 17,[19][20][21][22][23][24][25][26][27] A series of RC strains comprises approximately 20 homozygous strains, each of which contains on average 87.5% genes of a common background strain and 12.5% of a common donor strain. 26,28 In this way, the RC system transforms a multigenic difference into a set of mono-or oligogenic differences and hence offers higher resolution power in mapping the quantitative trait loci and detecting their mutual interactions than the standard genetic methods.…”