Recombinants in the H‐2S/H‐2D interval of mouse chromosome 17 define the map position of a gene for cleft palate susceptibility

Abstract

The H-2 region of mouse chromosome 17 is known to include one or more genes that affect susceptibility to cortisone-induced cleft palate. We have now studied congenic strains that possess crossovers in the interval between H-2S and H-2D and have observed significant differences in susceptibility among recombinants that had been believed to possess the same H-2 haplotypes. Pregnant mice were injected on days 11 through 14 of gestation with 100 mg of cortisone per kg of body weight. The frequency of cleft palate in B10.A(2R) was significantly greater than in B10.A(1R), despite the fact that both have H-2a/H-2b crossovers in the interval between the S and D loci and have the same alleles at all loci that have been previously characterized. Both B10.BAR5 and B10.BAR12 were significantly more susceptible than B10.A(18R), although these strains also share the same alleles at all loci that have been previously characterized. All three of these strains have H-2b/H-2a recombinant chromosomes, with crossovers in the S/D interval. Genetic linkage between H-2 and the high-susceptibility gene of B10.BAR5 was confirmed by testing H-2 homozygotes derived by intercrossing backcross animals. These data therefore suggest that a gene coding for susceptibility, which we designate Cps-1, maps in the 350-kb interval between H-2S and H-2D, and the congenic strains that we have found to be different have different crossover points within this interval. Alleles at the Cps-1 locus have embryonic effects, but no demonstrable effects on the maternal environment.

P1 and cosmid clones define the organization of 280 kb of the mouse H-2 complex containing the Cps-1 and Hsp70 loci

“…The digests were subjected to field inversion gel electrophoresis as described Analysis of the segregation of Cps-1 with loci within this contig. Previous studies have demonstrated that a major gene affecting susceptibility to steroid-induced cleft palate is located in the interval between the H-2 class III complement genes and the class I locus H-2D (Gasser et al 1988). However, experiments using skin grafts have shown that many putative H-2 congenic strains contain demonstrable additional differences that are non-H-2-1inked.…”

“…The complete cloning of this interval should now provide the substrate for studies to identify uncloned H-2-1inked genes which have to date been localized only on the basis of their function. This may include the cleft palate susceptibility-1 (Cps-1) gene, which was mapped by testing congenic lines for their susceptibility to cortisone-induced cleft palate (Gasser et al 1988).…”

“…This region is of particular interest because the genes controlling several phenotypic traits appear to map within it. A gene that affects the antibody response to TNP-Ficoll (Shapiro et al 1985), the locus that controls the hematopoietic histocompatibility antigen, Hh-1 (Daley et al 1987), a gene that affects susceptibility to cortisone-induced cleft palate, Cps-1 (Gasser et al 1988), and a gene that affects susceptibility to experimental autoimmune orchitis, Orch-1 (Teuscher et al 1990;Snoek et al 1993), have all been localized to this interval. The isolation of this portion of the mouse H-2 complex in molecular clones will facilitate the identification of these functionally defined genes.…”

Fine mapping of the crossover-sites in theC4-H-2D region ofH-2 recombinant mouse strains

“…Several traits and genes involved in disease susceptibility have been mapped to the C4-H-2D segment, such as the response to TNP-Ficoll (Hillstrom Shapiro et al 1985), the gene for cleft palate susceptibility, Cps-1 (Demant 1985;Gasser et al 1988), Hh-1, the gene controlling the "hybrid resistance" to bone marrow and leukemia transplants (Rembecki et al 1988), and susceptibility to experimental allergic orchitis (Orch-1; Teuscher et al 1990). The phenotypes observed with these traits in recombinant haplotypes suggest that more than one recombination site exists between C4 and H-2D.…”

“…Several d/b and b/d recombinants were characterized for the Cps-1 (Gasser et al 1988) and Orch-1 (Teuscher et al 1990) genes. The analysis of these recombinants presented here maps both these genes to the Hsp70-Bat-5 segment.…”