The recombinant congenic strains—a novel genetic tool applied to the study of colon tumor development in the mouse

Abstract

The development of tumors in mice is under multigenic control, but, in spite of considerable efforts, the identification of the genes involved has so far been unsuccessful, because of the insufficient resolution power of the available genetic tools. Therefore, a novel genetic tool, the RC (Recombinant Congenic) strains system, was designed. In this system, a series of RC strains is produced from two inbred strains, a "background" strain and a "donor" strain. Each RC strain contains a different small subset of genes from the donor strain and the majority of genes from the background strain. As a consequence, the individual genes of the donor strain which are involved in the genetic control of a multigenic trait, become separated into different RC strains, where they can be identified and studied individually. One of the RC strains series which we produced is made from the parental strains BALB/cHeA (background strain) and STS/A (donor strain). We describe the genetic composition of this BALB/cHeA-C-STS/A (CcS/Dem) series and show, using 45 genetic autosomal markers, that it does not deviate from the theoretical expectation. We studied the usefulness of the CcS/Dem RC strains for analysis of the genetics of colon tumor development. The two parental strains, BALB/cHeA and STS/A, are relatively resistant and highly susceptible, respectively, to the induction of colon tumors by 1,2-dimethylhydrazine (DMH). The individual RC strains differ widely in colon tumor development after DMH treatment; some are highly susceptible, while others are very resistant. This indicates that a limited number of genes with a major effect are responsible for the high susceptibility of the STS strain. Consequently, these genes can be mapped by further analysis of the susceptible RC strains. The differences between the RC strains were not limited to the number of tumors, but the RC strains differed also in size of the tumors and the relative susceptibility of the two sexes. Our data indicate that the number of tumors and the size of tumors are not controlled by the same genes. The genetics of these different aspects of colon tumorigenesis can also be studied by the RC strains. The DMH-treated mice of the parental strains and the RC strains also developed anal tumors and haemangiomas in varying numbers. The strain distribution pattern (SDP) of susceptibility for each of the three types of tumors induced by DMH is different, indicating that development of these tumors is under control of different, largely non-overlapping, sets of genes.(ABSTRACT TRUNCATED AT 400 WORDS)

Five new mouse susceptibility to colon cancer loci, Scc11–Scc15

“…Pilot studies using AOM showed the same difference in colon tumor susceptibility between the two parental strains, BALB/c and STS, and the RC strain CcS-19 as reported previously for DMH-induced tumors (Moen et al, 1992;Van Wezel et al, 1996). The number and size of the AOM-induced colon tumors, however, was markedly higher.…”

“…Treatment of BALB/c and CcS-strain mice with repeated injections of the carcinogen 1,2-dimethylhydrazine (DMH) induces multiple colonic adenomas, that are benign, even if they are very large (Moen et al, 1991). Five loci affecting susceptibility to chemically induced colon cancer, Scc1-Scc5, were previously identified using 192 F 2 mice between susceptible RC strain CcS-19 and BALB/c.…”

“…In contrast to our previous studies using the carcinogen DMH alone or in combination with N-ethyl-Nnitrosourea (ENU) to induce colon tumors (Moen et al, 1992;Van Wezel et al, 1996), we used the direct metabolite of DMH, the carcinogen azoxymethan (AOM). Pilot studies using AOM showed the same difference in colon tumor susceptibility between the two parental strains, BALB/c and STS, and the RC strain CcS-19 as reported previously for DMH-induced tumors (Moen et al, 1992;Van Wezel et al, 1996).…”

Fine chromosomal localization of the mouse Par2 gene that confers resistance against urethane-induction of pulmonary adenomas

“…Thus, the Dcc remains as a candidate for Par2, although we previously demonstrated by loss of heterozygosity analysis that the Dcc locus may not be involved in mouse lung tumorigenesis as a tumor suppressor gene (Obata et al, 1996). There are two previous reports on restriction fragment length polymorphism of the mouse Dcc gene: alleles of C57BL and Mus spretus (Justice et al, 1992) and those of BALB/c and STS/A (Moen et al, 1992) can be distinguished. We are currently searching for such polymorphism between BALB and C57BL alleles of the Dcc gene, in order to determine whether it can be excluded as a candidate by genotyping R 7 B7 and R 7 B10 recombinants.…”

Mouse genetic model for antigen-induced airway manifestations of asthma

“…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. The RC system has been used most successfully to map genes in colon tumor susceptibility.…”