Localization of two insulin-dependent diabetes (Idd) genes to the Idd10 region on mouse Chromosome 3

Multiple genes control the development of autoimmune diabetes both in humans and in the nonobese diabetic (NOD) strain of mouse. Previously, three insulin-dependent diabetes (Idd) genes, Idd3, Idd10, and Idd17, were localized to mouse Chromosome (Chr) 3. The B10- or B6-derived resistance alleles at Idd10 and Idd3 together provide the NOD mouse with nearly complete protection from diabetes. In the present study, the 10.2-cM region encoding Idd10 was defined further with newly developed congenic strains. A locus, located in the centromeric 2.1 cM of the 10.2 cM region, contributed to the Idd10 trait. However, this locus did not account for the full effect of Idd10, suggesting the presence of a second gene in the distal portion of the 10.2-cM region. This second gene is designated as Idd18 and is localized to a 5.1-cM region. The resolution of the originally defined Idd3 locus into at least four separate loci, Idd3, Idd10, Idd17, and Idd18, illustrates the complex polygenic nature of diabetes. Received: 27 August 1997 / Accepted: 22 December 1997     

The diabetes susceptibility locus Idd5.1 on mouse chromosome 1 regulates ICOS expression and modulates murine experimental autoimmune encephalomyelitis

Linkage analysis and congenic mapping in NOD mice have identified a susceptibility locus for type 1 diabetes, Idd5.1 on mouse chromosome 1, which includes the Ctla4 and Icos genes. Besides type 1 diabetes, numerous autoimmune diseases have been mapped to a syntenic region on human chromosome 2q33. In this study we determined how the costimulatory molecules encoded by these genes contribute to the immunopathogenesis of experimental autoimmune encephalomyelitis (EAE). When we compared levels of expression of costimulatory molecules on T cells, we found higher ICOS and lower full-length CTLA-4 expression on activated NOD T cells compared with C57BL/6 (B6) and C57BL/10 (B10) T cells. Using NOD.B10 Idd5 congenic strains, we determined that a 2.1-Mb region controls the observed expression differences of ICOS. Although Idd5.1 congenic mice are resistant to diabetes, we found them more susceptible to myelin oligodendrocyte glycoprotein 35-55-induced EAE compared with NOD mice. Our data demonstrate that higher ICOS expression correlates with more IL-10 production by NOD-derived T cells, and this may be responsible for the less severe EAE in NOD mice compared with Idd5.1 congenic mice. Paradoxically, alleles at the Idd5.1 locus have opposite effects on two autoimmune diseases, diabetes and EAE. This may reflect differential roles for costimulatory pathways in inducing autoimmune responses depending upon the origin (tissue) of the target Ag.     

Mapping the diabetes polygene Idd3 on mouse Chromosome 3 by use of novel congenic strains

Development of novel congenic mouse strains has allowed us to better define the location of the diabetogenic locus, Idd3, on Chromosome (Chr) 3. Congenic strains were identified by use of published and newly developed microsatellite markers, their genomes fingerprinted by a rapid, fluorescence-based approach, and their susceptibility to type 1 diabetes evaluated. The maximum interval containing Idd3 is now approximately 4 cM.     

The autoimmune diabetes locus Idd9 regulates development of type 1 diabetes by affecting the homing of islet-specific T cells

Several genetic insulin-dependent diabetes (Idd) intervals that confer resistance to autoimmune diabetes have been identified in mice and humans, but the mechanisms by which they protect against development of diabetes have not been elucidated. To determine the effect of Idd9 on the function of islet-specific T cells, we established novel BDC-Idd9 mice that harbor BDC2.5 TCR transgenic T cells containing the Idd9 of diabetes-resistant B10 mice. We show that the development and functional responses of islet-specific T cells from BDC-Idd9 mice are not defective compared with those from BDC mice, which contain the Idd9 of diabetes-susceptible NOD mice. Upon transfer, BDC T cells rapidly induced severe insulitis and diabetes in NOD.scid mice, whereas those from BDC-Idd9 mice mediated a milder insulitis and induced diabetes with a significantly delayed onset. BDC and BDC-Idd9 T cells expanded comparably in recipient mice. However, BDC-Idd9 T cells accumulated in splenic periarteriolar lymphatic sheaths, whereas BDC T cells were mainly found in pancreatic lymph nodes and pancreata of recipients, indicating that the transferred T cells differed in their homing. We provide evidence that the migration pattern of transferred BDC and BDC-Idd9 T cells at least partly depends on their differential chemotaxis toward the CCR7 ligand CCL19. Taken together, our data show that the Idd9 locus regulates development of type 1 diabetes by affecting the homing of islet-specific T cells.     

The deafness locus (dn) maps to mouse Chromosome 19

The deafness mouse has profound sensorineural hearing loss with degeneration of hair cells soon after birth. The mode of inheritance is recessive, and there are no associated phenotypic anomalies. Thus, this mouse provides a model for recessive, nonsyndromic, prelingual deafness. We have mapped the gene causing deafness in the mouse to Chromosome (Chr) 19 by analysis of 230 intersubspecific backcross progeny. No recombinants were found with the microsatellite marker D19Mit14. The loci for two guanine nucleotide-binding proteins are tightly linked to this marker, and they are being investigated as possible candidate genes. The identification of the defective gene in the mouse will help to explain the mechanism that causes hair cell degeneration and is likely to identify a homologous gene for deafness in humans.     

The genetic map around the tail kinks (tk) locus on mouse Chromosome 9

Tail kinks (tk) is a classical mouse skeletal mutation, located on Chromosome (Chr) 9. As the first step for the positional cloning of the tk gene, we have established a genetic map of a region surrounding the tk locus by generating a backcross segregating for tk. From this backcross, 1004 progeny were analyzed for the coat-color phenotype of the proximally located dilute (d) gene and for the distally flanking microsatellite marker, D9Mit12. Fifty-six recombinants between d and tk and 75 recombinants between tk and D9Mit12 were identified, completing a panel of 130 recombinants including one double recombinant. This panel allowed us to map five microsatellite loci as well as d and Mod-1 with respect to tk. We show that one of the microsatellite markers mapped, D9Mit9, does not recombine at all with tk in our backcross. This indicates that the D9Mit9 locus will serve as a good starting point for a chromosomal walk to the tk gene.     

Low resolution mapping around the flavivirus resistance locus (Flv) on mouse Chromosome 5

Although the phenomenon of innate resistance to flaviviruses in mice was recognized many years ago, it was only recently that the genetic locus (Flv) controlling this resistance was mapped to mouse Chromosome (Chr) 5. Here we report the fine mapping of the Flv locus, using 12 microsatellite markers which have recently been developed for mouse Chr 5. The new markers were genotyped in 325 backcross mice of both (C3H/HeJxC3H/ RV)F₁xC3H/HeJ and (BALB/cxC3H/RV)F₁xBALB/c backgrounds, relative to Flv. The composite genetic map that has been constructed identifies three novel microsatellite loci, D5Mit68, D5Mit159, and D5Mit242, tightly linked to the Flv locus. One of those loci, D5Mit159, showed no recombinations with Flv in any of the backcross mice analyzed, indicating tight linkage (<0.3 cM). The other two, D5Mit68 and D5Mit242, exhibited two and one recombinations with Flv (0.6 and 0.3 cM) respectively, defining the proximal and distal boundaries of a 0.9-cM segment around this locus. The proximal flanking marker, D5Mit68, maps to a segment on mouse Chr 5 homologous to human Chr 4. This, together with the previous data produced by our group, locates Flv to a region on mouse Chr 5 carrying segments that are conserved on either human Chr 4, 12, or 7, but present knowledge does not allow precise identification of the syntenic element.     

Mapping of the murine type 1 diabetes locus Idd20 by genetic interaction

In the nonobese diabetes mouse, the murine type 1 diabetes susceptibility locus Idd20 interacts genetically with the diabetes resistance locus Idd19. Both Idds are located on distal mouse Chromosome 6, and previous studies on NOD.C3H congenic strains have shown that C3H alleles at Idd20 can suppress the disease-promoting effects of C3H alleles at Idd19 in both spontaneous and cyclophosphamide-induced diabetes. In this article we present the construction of novel congenic strains which, while maintaining the C3H alleles at Idd19, have allowed the candidate interval of Idd20 to be reduced from 4 to 1.8 cM. The analysis of these strains shows that Idd20 controls the progression of insulitis. Idd20 also increases the suppressive but not the pathogenic activity of splenocytes in diabetes transfer experiments. Our results suggest that the two Chromosome 6 susceptibility loci, Idd6 and Idd20, interact with the resistance locus Idd19 by regulating the activity of suppressor cells in the peripheral immune system.     

Mapping around the Fused locus on mouse Chromosome 17

We have established a high-resolution genetic map of the region surrounding the Fused locus as a first step towards the molecular identification and analysis of this gene. The candidate region has been covered to a large extent by YAC and P1 contigs, and has been partly characterized by pulsed-field gel analysis.     

A locus for radiation-induced gastroschisis on mouse Chromosome 7

Gastroschisis (abdominal wall defects) occurs with a high frequency in the mouse inbred strain HLG compared with C57BL/6J mice. The risk of gastroschisis increases significantly after exposure to irradiation with X-rays during preimplantation development and follows a recessive mode of inheritance for the HLG susceptibility alleles. We have used a backcross strategy and genome-wide microsatellite typing to chromosomally map this trait. A suggestive linkage for a locus responsible for radiation-induced gastroschisis (Rigs1) was found in a region of mouse Chromosome 7. Received: 13 May 1998 / Accepted: 6 August 1998     

High-resolution genetic mapping of the sucrose octaacetate taste aversion (Soa) locus on mouse Chromosome 6

An acetylated sugar, sucrose octaacetate (SOA), tastes bitter to humans and has an aversive taste to at least some mice and other animals. In mice, taste aversion to SOA depends on allelic variation of a single locus, Soa. Three Soa alleles determine `taster' (Soa <sup>a</sup> ), `nontaster' (Soa ^b ), and `demitaster' (Soa ^c ) phenotypes of taste sensitivity to SOA. Although Soa has been mapped to distal Chromosome (Chr) 6, the limits of the Soa region have not been defined. In this study, mice from congenic strains SW.B6-Soa ^b , B6.SW-Soa ^a , and C3.SW-Soa ^a/c and from an outbred CFW strain were genotyped with polymorphic markers on Chr 6. In the congenic strains, the limits of introgressed donor fragments were determined. In the outbred mice, linkage disequilibrium and haplotype analyses were conducted. Positions of the markers were further resolved by using radiation hybrid mapping. The results show that the Soa locus is contained in a ∼1-cM (3.3–4.9 Mb) region including the Prp locus. Received: 5 February, 2001 / Accepted: 1 May, 2001     

Genetic mapping near the myd locus on mouse Chromosome 8

Myodystrophy (myd), an autosomal recessive mutation of the mouse characterized by progressive weakness and dystrophic muscle histology, maps to the central portion of Chromosome (Chr) 8 (Lane et al. J. Hered 67, 135, 1976). This portion of Chr 8 contains the genes for a mitochondrial uncoupling protein (Ucp) and kallikrein (Kal3), which map to distal 4q in the human, providing evidence for a segment of homology. Characteristics of the myd phenotype coupled with this homology suggest that myd may be a mouse homolog of facioscapulohumeral muscular dystrophy (FSHD), which maps to human 4q35. We have confirmed and expanded the region of mouse 8-human 4 homology by generating a map of Chr 8 in an interspecific backcross of C57BL/6J and a partially inbred strain derived from M. spretus. The map is comprised of the genes for Ucp, coagulation factor XI (Cf11), and chloride channel 5 (Clc5), all of which have homologs on distal human 4q, 15 microsatellite loci, and the membrane cofactor protein pseudogene (Mcp-ps). To place myd in the genetic map, 75 affected progeny from an intersubspecific backcross of animals heterozygous for myd with Mus musculus castaneus were genotyped with Chr 8 microsatellite loci. The mutation maps between D8Mit30 and D8Mit75, an interval that is flanked by genes with human homologs at distal 4q. These results are consistent with the possibility that myd is the mouse homolog of FSHD.     

Mapping of the Mod-1 locus on mouse Chromosome 9

A new method for typing the Mod-1 locus on mouse Chromosome (Chr) 9 was developed, based on restriction fragment length polymorphism (RFLP) within a polymerase chain reaction (PCR)-amplified fragment. The new method led us to revise the strain distribution pattern (SDP) of Mod-1 in the BXD (C57BL/6JxDBA/2J) and AKXD (AKR/J x DBA/2J) recombinant inbred (RI) strains. The new SDP eliminates several previously reported examples of double recombination events between Mod-1 and the closest flanking loci in the BXD and AKXD strains. In the BXD strains, the revised SDP of Mod-1 was identical to that of the Mod-1-related D9Rtil locus. Thus, the identity of D9Rtil as a Mod-1-related locus rather than Mod-1 itself is in question. The method was also applied to an interspecific backcross panel between an inbred strain of Mus musculus molossinus (MSM/Ms) and C57BL/6J to map Mod-1 with respect to surrounding microsatellite loci, defining the proximal localization of Mod-1 with respect to D9Mit10 with a genetic distance of 0.6±0.6 cM.