Interval mapping and congenic strains for a blood pressure QTL on rat Chromosome 13

The renin locus (Ren) on rat Chromosome (Chr) 13 had previously been shown to cosegregate with blood pressure in crosses involving Dahl salt-sensitive (S) and Dahl salt-resistant (R) rats. In the present work, interval mapping of blood pressure on Chr 13 with a large F₂ (S × R), n = 233, population yielded a maximum LOD = 4.2 for linkage to blood pressure, but the quantitative trait locus (QTL) was only poorly localized to a large 35-centiMorgan (cM) segment of Chr 13. In the linkage analysis, the S-rat QTL allele (S) was associated with higher, and the R-rat QTL allele (R) with lower blood pressure, the difference between homozygotes being about 20 mm Hg. A congenic strain was made by introgressing the R-rat Ren allele into the recipient S strain. This congenic strain showed a 24 mm Hg reduction (P = 0.004) in blood pressure compared with S rats for rats fed 2% NaCl diet for 24 days; this difference was confirmed by two other independent tests. Two congenic substrains were derived from the first congenic strain with shorter R Chr 13 segments on the S background. Comparisons among these congenic strains showed that a blood pressure QTL was in the 24-cM chromosomal segment between Syt2 and D13M1Mit108. This segment does not include the renin locus, which is thus excluded from being the gene on rat Chr 13 responsible for genetic differences in blood pressure detected by linkage analysis. Received: 20 December 1996 / Accepted: 7 April 1997     

Mapping genetic loci that regulate lipid levels in a NZB/B1NJxRF/J intercross and a combined intercross involving NZB/B1NJ, RF/J, MRL/MpJ, and SJL/J mouse strains

The NZB/B1NJ (NZB) mouse strain exhibits high cholesterol and HDL levels in blood compared with several other strains of mice. To study the genetic regulation of blood lipid levels, we performed a genome-wide linkage analysis in 542 chow-fed F2 female mice from an NZBxRF/J (RF) intercross and in a combined data set that included NZBxRF and MRL/MpJxSJL/J intercrosses. In the NZBxRF F2 mice, the cholesterol and HDL concentrations were influenced by quantitative trait loci (QTL) on chromosome (Chr) 5 [logarithm of odds (LOD) 17-19; D5Mit10] that was in the region identified earlier in crosses involving NZB mice, but two QTLs on Chr 12 (LOD 4.7; D12Mit182) and Chr 19 (LOD 5.7; D19Mit1) were specific to the NZBxRF intercross. Triglyceride levels were affected by two novel QTLs at D12Mit182 (LOD 8.7) and D15Mit13 (LOD 3.5). The combined-cross linkage analysis (1,054 mice, 231 markers) 1) identified four shared QTLs (Chrs 5, 7, 14, and 17) that were not detected in one of the parental crosses and 2) improved the resolution of two shared QTLs. In summary, we report additional loci regulating lipid levels in NZB mice that had not been identified earlier in crosses involving the NZB strain of mice. The identification of shared loci from multiple crosses increases confidence toward finding the QTL gene.     

Identification of a new quantitative trait locus on Chromosome 7 controlling disease severity of collagen-induced arthritis in rats

 Autoimmune diseases, such as rheumatoid arthritis, Crohn's disease, and multiple sclerosis, are regulated by multiple genes. Major histocompatibility complex (MHC) genes have the strongest effects, but non-MHC genes also contribute to disease susceptibility/severity. In this paper, we describe a new non-MHC quantitative trait locus, Cia8, on rat Chromosome (Chr) 7 that controls collagen-induced arthritis severity in F2 progeny of DA and F344 inbred rats, and present an updated localization of Cia4 on the same chromosome. We also describe the location of mouse and human genes, orthologous to the genes in the genomic intervals containing Cia4 and Cia8, and provide evidence that the segment of rat Chr 7 containing Cia4 and Cia8 is homologous to segments of mouse Chr 10 and 15 and human Chr 8, 12, and 19. Received: 1 November 1998 / Revised: 24 January 1999     

Assignment of a locus for mouse lung tumor susceptibility to proximal Chromosome 19

Previous studies have hypothesized that at least three genetic loci contribute to differences in pulmonary adenoma susceptibility between mouse strains A/J and C57BL/6J. One gene that may confer susceptibility to lung tumorigenesis is the Kras protooncogene. To identify other relevant loci involved in this polygenic trait, we determined tumor multiplicity in 56 randomly chosen N-ethyl-N-nitrosourea-treated (A/J×C57BL/6J) N1×C57BL/6 backcross (AB6N2) progeny and correlated it with genotypes at 77 microsatellite markers spanning the genome. A correlation of lung tumor multiplicity phenotypes with genotypes of microsatellite markers on distal Chromosome (Chr) 6 in the Kras region (Pas1) was confirmed, and a new region on Chr 19 (designated Pas3) was identified that also contributes to susceptibility. Linkage analysis on Chr 19 with 270 AB6N2 mice localized the region flanked by D19Mit42 and D19Mit19 that is most closely associated with lung tumor susceptibility. The Pas3 locus may be an enhancer of the susceptibility locus on Chr 6.     

Genetic Modifiers ofLeprAssociated with Variability in Insulin Production and Susceptibility to NIDDM

In an attempt to identify the genetic basis for susceptibility to non-insulin-dependent diabetes mellitus within the context of obesity, we generated 401 genetically obeseLepr^fa/Lepr^faF2 WKY13M intercross rats that demonstrated wide variation in multiple phenotypic measures related to diabetes, including plasma glucose concentration, percentage of glycosylated hemoglobin, plasma insulin concentration, and pancreatic islet morphology. Using selective genotyping genome scanning approaches, we have identified three quantitative trait loci (QTLs) on Chr. 1 (LOD 7.1 for pancreatic morpholology), Chr. 12 (LOD 5.1 for body mass index and LOD 3.4 for plasma glucose concentration), and Chr. 16 (P< 0.001 for genotype effect on plasma glucose concentration). The obese F2 progeny demonstrated sexual dimorphism for these traits, with increased diabetes susceptibility in the males appearing at approximately 6 weeks of age, as sexual maturation occurred. For each of the QTLs, the linked phenotypes demonstrated sexual dimorphism (more severe affection in males). The QTL on Chr. 1 maps to a region vicinal to that previously linked to adiposity in studies of diabetes susceptibility in the nonobese Goto–Kakizaki rat, which is genetically closely related to the Wistar counterstrain we employed. Several candidate genes, including tubby (tub), multigenic obesity 1 (Mob1), adult obesity and diabetes (Ad), and insulin-like growth factor-2 (Igf2), map to murine regions homologous to the QTL region identified on rat Chr. 1.     

Mapping murine loci for seizure response to kainic acid

Mature DBA/2J (D2) mice are very sensitive to seizures induced by various chemical and physical stimuli, whereas C57BL/6J (B6) mice are relatively seizure resistant. We have conducted a genome-wide search for quantitative trait loci (QTLs) influencing the differential sensitivity of these strains to kainic acid (KA)-induced seizures by studying an F₂ intercross population. Parental, F₁, and F₂ mice (8–10 weeks of age) were injected subcutaneously with 25 mg/kg of KA and observed for 3 h. Latencies to focal and generalized seizures and status epilepticus were recorded and used to calculate an overall seizure score. Results of seizure testing indicated that the difference in susceptibility to KA-induced seizures between D2 and B6 mice is a polygenic phenomenon with at least 65% of the variance due to genetic factors. First-pass genome screening (10-cM marker intervals) in F₂ progeny (n = 257) documented a QTL of moderate effect on Chromosome (Chr) 1 with a peak LOD score of 5.5 (17% of genetic variance explained) localized between D1Mit30 and D1Mit16. Provisional QTLs of small effect were detected on Chr 11 (D11Mit224–D11Mit14), 15 (D15Mit6–D15Mit46) and 18 (D18Mit9–D18Mit144). Multiple locus models generally confirmed the Mapmaker/QTL results and also provided evidence for another QTL on Chr 4 (D4Mit9). Multilocus analysis of seizure severity suggested that additional loci on Chrs 5 (D5Mit11), 7 (D7Mit66), and 15 (D15Nds2) might also contribute to KA-induced seizure response. Overall, our results document a complex genetic determinism for KA-induced seizures in these mouse strains with contributions from as many as eight QTLs. Received: 16 April 1996 / Accepted: 21 October 1996     

Genetic contributions of nonautoimmune SWR mice toward lupus nephritis.

(SWR x New Zealand Black (NZB))F(1) (or SNF(1)) mice succumb to lupus nephritis. Although several NZB lupus susceptibility loci have been identified in other crosses, the potential genetic contributions of SWR to lupus remain unknown. To ascertain this, a panel of 86 NZB x F(1) backcross mice was immunophenotyped and genome scanned. Linkage analysis revealed four dominant SWR susceptibility loci (H2, Swrl-1, Swrl-2, and Swrl-3) and a recessive NZB locus, Nba1. Early mortality was most strongly linked to the H2 locus on chromosome (Chr) 17 (log likelihood of the odds (LOD) = 4.59 - 5.38). Susceptibility to glomerulonephritis was linked to H2 (Chr 17, LOD = 2.37 - 2.70), Swrl-2 (Chr 14, 36 cM, LOD = 2.48 - 2.71), and Nba1 (Chr 4, 75 cM, LOD = 2.15 - 2.23). IgG antinuclear autoantibody development was linked to H2 (Chr 17, LOD = 4.92 - 5.48), Swrl-1 (Chr 1, 86 cM, colocalizing with Sle1 and Nba2, LOD = 2.89 - 2.91), and Swrl-3 (Chr 18, 14 cM, LOD = 2.07 - 2.13). For each phenotype, epistatic interaction of two to three susceptibility loci was required to attain the high penetrance levels seen in the SNF(1) strain. Although the SWR contributions H2, Swrl-1, and Swrl-2 map to loci previously mapped in other strains, often linked to very similar phenotypes, Swrl-3 appears to be a novel locus. In conclusion, lupus in the SNF(1) strain is truly polygenic, with at least four dominant contributions from the SWR strain. The immunological functions and molecular identities of these loci await elucidation.     

Congenic mapping and candidate gene analysis for streptozotocin-induced diabetes susceptibility locus on mouse chromosome 11

Streptozotocin (STZ) has been widely used to induce diabetes in rodents. Strain-dependent variation in susceptibility to STZ has been reported; however, the gene(s) responsible for STZ susceptibility has not been identified. Here, we utilized the A/J-11^SM consomic strain and a set of chromosome 11 (Chr. 11) congenic strains developed from A/J-11^SM to identify a candidate STZ-induced diabetes susceptibility gene. The A/J strain exhibited significantly higher susceptibility to STZ-induced diabetes than the A/J-11^SM strain, confirming the existence of a susceptibility locus on Chr. 11. We named this locus Stzds1 (STZ-induced diabetes susceptibility 1). Congenic mapping using the Chr. 11 congenic strains indicated that the Stzds1 locus was located between D11Mit163 (27.72 Mb) and D11Mit51 (36.39 Mb). The Mpg gene, which encodes N-methylpurine DNA glycosylase (MPG), a ubiquitous DNA repair enzyme responsible for the removal of alkylated base lesions in DNA, is located within the Stzds1 region. There is a close relationship between DNA alkylation at an early stage of STZ action and the function of MPG. A Sanger sequence analysis of the Mpg gene revealed five polymorphic sites in the A/J genome. One variant, p.Ala132Ser, was located in a highly conserved region among rodent species and in the minimal region for retained enzyme activity of MPG. It is likely that structural alteration of MPG caused by the p.Ala132Ser mutation elicits increased recognition and excision of alkylated base lesions in DNA by STZ.

     

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.     

QTL on mouse chromosomes 1 and 4 causing sperm-head morphological abnormality and male subfertility

The B10.M mouse strain represents a model for male subfertility as it produces a significantly low number of offspring. The only known male reproductive phenotype of this strain is its high frequency of sperm-head morphological abnormalities (44.7 ± 2.4 %). We previously reported that this phenotype was the product of two recessive loci. In this study we mapped the loci causing the high frequency of sperm-head morphological abnormalities in this strain using F2 animals produced by crossing B10.M and C3H mice. Quantitative trait loci (QTL) analysis (n = 178) identified two recessive genes, one on Chromosome (Chr) 1 (LOD score = 30.585) and one on Chr 4 (LOD score = 4.532). Further analysis (n = 854) mapped the locus on Chr 1 between Ercc5 (23.55 cM) and D1Mit528 (25.95 cM) and the locus on Chr 4 between D4Mit148 (69.48 cM) and D4Mit170 (70.47 cM). It was also found that the effects of these two loci were not independent. The major locus on Chr 1 determines the expression of sperm-head abnormalities, while the locus on Chr 4 enhances the frequency of abnormalities only when the genotype of the Chr 1 locus is homozygous for the B10.M allele. The major locus on Chr 1 was named sperm-head morphology 1 (Shm1), while the modifier locus on Chr 4 was named sperm-head morphology 2 (Shm2).     

Rbt (rabo torcido), a new mouse skeletal mutation involved in anteroposterior patterning of the axial skeleton,maps close to the ts (tail-short) locus and distal to the sox9 locus on chromosome 11

Rbt (Rabo torcido) is a new semidominant mouse mutant with a variety of skeletal abnormalities. Heterozygous Rbt mutants display homeotic anteroposterior patterning problems along the axial skeleton that resemble Polycomb group and trithorax gene mutations. In addition, the Rbt mutant displays strong similarities to the phenotype observed in Ts (Tail-short), indicating also a homeotically transformed phenotype in these mice. We have mapped the Rbt locus to an interval of approximately 6 cM on mouse Chromosome (Chr) 11 between microsatellite markers D11Mit128 and D11Mit103. The Ts locus was mapped within a shorter interval of approximately 3 cM between D11Mit128 and D11Mit203. This indicates that Rbt and Ts may be allelic mutations. Sox9, the human homolog of which is responsible for the skeletal malformation syndrome campomelic dysplasia, was mapped proximal to D11Mit128. It is, therefore, unlikely that Ts and Rbt are mouse models for this human skeletal disorder. Received: 14 April 1996 / Accepted: 22 July 1996     

Haplotype analysis of intra-specific backcross curly-tail mice confirms the localization of ct to Chromosome 4

We have determined the order of a number of SSR and SSC polymorphic markers that map to distal mouse Chromosome (Chr) 4 and have used analysis of these markers in backcrosses designed to test the localization of the curly-tail (ct) mutation. We have confirmed that ct maps to this region, close to the locus D4Mit69. Our results also support the hypothesis that ct is a semidominant, rather than a recessive, mutation, since we have identified abnormal-tailed mice that are likely to be heterozygous at the ct locus. Finally, we examined Pax7 as a candidate gene for the ct mutation and found no evidence of protein sequence differences in ct compared with wild-type mice.     

Genetic dissection of testicular weight in the mouse with the BXD recombinant inbred strains

Testicular weights were studied in the mouse BXD recombinant inbred (RI) strains. These strains were derived from DBA/2J and C57BL/6J progenitors that differ significantly in their testicular weights (0.224 g ± 0.015 vs. 0.161 g ± 0.03, P < 0.0001). The heritability of testicular weights was calculated to be 0.53, and the minimum number of responsible effective factors was estimated to be 5.7. The total genome scanning of the BXD RI strains with over 1000 markers revealed a quantitative trait locus (QTL) on mouse Chromosome (Chr) 13 near the D13Mit3 marker (LOD score 6.9). This QTL region was designated Twq1 and associated with over 75% of genetic variability. Received: 23 January 1998 / Accepted: 16 March 1998     

Quantitative trait loci for baseline erythroid traits

A substantial genetic contribution underlies variation in baseline peripheral blood counts. We performed quantitative trait locus/loci (QTL) analyses to identify chromosome (Chr) regions harboring genes influencing the baseline erythroid parameters in F₂ intercrosses between NZW/LacJ, SM/J, and C57BLKS/J inbred mice. We identified multiple significant QTL for red blood cell (RBC) count, hemoglobin (Hgb) and hematocrit (Hct) levels, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean cell hemoglobin concentration (CHCM). We identified four RBC count QTL: Rbcq1 (Chr 1, peak LOD score at 62 cM,), Rbcq2 (Chr 4, 60 cM), Rbcq3 (Chr 11, 34 cM), and Rbcq4 (Chr 10, 60 cM). Three MCV QTL were identified: Mcvq1 (Chr 7, 30 cM), Mvcq2 (Chr 11, 6 cM), and Mcvq3 (Chr 10, 60 cM). Single significant loci for Hgb (Hgbq1, Chr 16, 32 cM), Hct (Hctq1, Chr 3, 42 cM), and MCH (Mchq1, Chr 10, 60 cM) were identified. The data support the existence of a common RBC/MCH/MCV locus on Chr 10. Two QTL for CHCM (Chcmq1, Chr 2, 48 cM; Chcmq2, Chr 9, 44 cM) and an interaction between Chcmq2 with a locus on Chr 19 were identified. These analyses emphasize the genetic complexity underlying the regulation of erythroid peripheral blood traits in normal populations and suggest that genes not previously recognized as significantly impacting normal erythropoiesis exist.     

An autoimmune diabetes locus (Idd21) on mouse Chromosome 18

Twenty-four named Idd loci that contribute to the development of autoimmune diabetes in the nonobese diabetic (NOD) mouse have been mapped by linkage and congenic analysis. Previously, meta-analysis of genome-wide linkage scans supported the existence of a locus for susceptibility to autoimmune phenotypes on rodent Chromosome (Chr) 18, in a position orthologous to the human type 1 diabetes susceptibility locus IDDM6 (human Chr 18q12-q23). However, an autoimmune diabetes susceptibility locus has not previously been reported on mouse Chr 18. In this study, we demonstrate linkage of the majority of mouse Chr 18 to diabetes in a (ABH × NOD)F₁ × NOD backcross. Congenic analysis, introgressing at least 92% of Biozzi ABH Chr 18 onto the NOD background, confirmed the presence of a diabetes locus. The chromosome substitution strain (NOD.ABH-Chr18) had reduced diabetes incidence compared with NOD mice (P < 0.0001). We have named the Chr 18 diabetes locus Idd21.     

Association of a lithogenic Abcg5/Abcg8 allele on Chromosome 17 (Lith9) with cholesterol gallstone formation in PERA/EiJ mice

To examine further the genetic determinants of cholesterol gallstone susceptibility in inbred mice, we performed quantitative trait locus (QTL) analysis of an intercross of gallstone-susceptible PERA/EiJ and gallstone-resistant DBA/2J inbred mice. Three hundred twenty-four F₂ offspring were phenotyped for cholelithiasis during consumption of a lithogenic diet and genotyped using microsatellite markers. Linkage analysis was performed by interval mapping. In addition, we analyzed the combined datasets from this cross and from an independent cross of strain PERA and gallstone-resistant I/Ln mice. QTL mapping detected one significant new gallstone susceptibility (Lith) locus on Chromosome 13 (Lith15). A second significant QTL on Chr 6 (Lith16) confirmed a previous QTL. Furthermore, suggestive QTLs confirmed Lith loci from previous crosses on Chromosomes 1, 2, 5, 16 and X. QTL analysis of the dataset derived from the combined crosses increased the detection power and narrowed confidence intervals of Lith loci on Chromosomes 2, 6, 13, and 16. Moreover, the analysis of combined datasets revealed a shared QTL between both crosses on Chromosome 17 (Lith9). Significantly higher mRNA expression of Abcg5 and Abcg8 in strain PERA compared with strains I/Ln and DBA/2 further substantiated that the PERA allele of Abcg5/Abcg8 was responsible for lithogenicity underlying Lith9.     

A rat homolog of the mouse deafness mutant jerker (je)

An autosomal recessive deafness mutant was discovered in our colony of Zucker (ZUC) rats. These mutants behave like shaker-waltzer deafness mutants, and their inner ear pathology classifies them among neuroepithelial degeneration type of deafness mutants. To determine whether this rat deafness mutation (−) defines a unique locus or one that has been previously described, we mapped its chromosomal location. F₂ progeny of (Pbrc:ZUC × BN/Crl) A/a B/b H/h+/− F₁ rats were scored for coat color and behavioral phenotypes. Segregation analysis indicated that the deafness locus might be loosely linked with B on rat Chromosome (Chr) 5 (RNO5). Therefore, 40 −/− rats were scored for BN and ZUC alleles at four additional loci, D5Mit11, D5Mit13, Oprd1, and Gnb1, known to map to RNO5 or its homolog, mouse Chr 4 (MMU4). Linkage analysis established the gene order (cM distance) as D5Mit11–(19.3)–B–(17.9)–D5Mit13–(19.2)–Oprd1–(21.5) − (1.2) Gnb1, placing the deafness locus on distal RNO5. The position of the deafness locus on RNO5 is similar to that ofjerker (je) on MMU4; the phenotypes and patterns of inheritance of the deafness mutation and je are also similar. It seems likely that the mutation affects the rat homolog of je. The rat deafness locus should, therefore, be named jerker and assigned the gene symbol Je. Received: 13 June 1995 / Accepted: 4 January 1996     

Use of intercross outbred mice and single nucleotide polymorphisms to map skin cancer modifier loci

Car-R and Car-S outbred mouse lines, phenotypically selected for resistance and susceptibility to skin carcinogenesis respectively, show significant linkage disequilibrium (LD) at genetic markers mapping on chromosomal regions where skin cancer modifier loci (Skts3, Skts1, and Psl1 on Chrs 5, 7, and 9 respectively) have been mapped in standard crosses. Analysis of these regions for genetic linkage with skin cancer phenotypes in 245 (Car-R × Car-S)F₂ intercross mice, by using single nucleotide polymorphisms (SNPs), revealed significant linkage at a possible allelic form of the Skts1 locus, whose mapping region was shortened to a <5.5-cM interval near the Tyr locus. The Car-derived Skts1 locus was linked with papilloma multiplicity and latency by a recessive inheritance of the susceptibility allele. Putative loci on Chr 5 (Skts3) and 9 (Psl1) showed no significant linkage. These results point to the important role of the Stks1 locus in mouse skin tumorigenesis in independent crosses. The shortened Skts1 mapping region should facilitate the identification of candidate genes. Received: 23 June 2000 / Accepted: 22 November 2000     

BB rat diabetes susceptibility and body weight regulation genes colocalize on Chromosome 2

The genetic etiology of Type 1 (insulin-dependent) diabetes mellitus is complicated by the apparent presence of several diabetes susceptibility genetic regions. Type 1 diabetes in the inbred BioBreeding (BB) rat closely resembles the human disorder and was previously shown to involve two genes: the lymphopenia (lyp) region on Chromosome (Chr) 4 and RT1 ^u in the major histocompatibility complex (MHC) on Chr 20. In addition, a segregation analysis of an F₂ intercross between the diabetes-prone congenic BB DR ^lyp/lyp,u/u and F344^{+/+, lv/lv} rats indicated that at least one more genetic factor was responsible for Type 1 diabetes. In this study, we generated F₂N₂ progeny in a cross between non-diabetic F₂(DR ^lyp/lyp,u/u × F344) ^lyp/lyp,u/u and diabetic DR ^lyp/lyp,u/u rats. In a subsequent total genome scan, a third factor was mapped to the 21.3-cM region on Chr 2 between D2Mit14 and D2Mit15 (peak LOD score 4.7 with 67% penetrance). Interestingly, the homozygosity of the BB allele (b/b) for the Chr 2 region was significantly associated with a greater weight reduction after fasting than the homozygosity of the F344 allele (f/f, p < 0.008). In conclusion, the development of Type 1 diabetes in the congenic DR ^lyp/lyp rat is controlled by at least three genes: lymphopenia, MHC, and a third factor that may play a role in metabolism and body weight regulation. Received: December 1998 / Accepted: 10 May 1999     

The positions of 12 simple sequence repeat markers relative to reference loci on mouse Chromosome 16

The genetic map positions of 12 simple sequence repeat (SSR) markers spanning mouse Chromosome (Chr) 16 were determined relative to reference markers on that chromosome. Interval mapping data were obtained with a panel of DNAs from two intersubspecific backcrosses. All but one of the markers were typed by use of nonradioactive polymerase chain reaction (PCR) products analyzed on agarose gels. The marker order was determined to be Prm-1, D16Mit9, Igl-1, D16Mit29, D16Mit1/D16Mit2, Smst, D16Mit4, D16Mit11, Gap43, D16Mit14, D16Mit30, D16Mit5, Pit-1, D16Mit27, D16H21S16 (formerly D21S16h), D16Mit19, App, D16Mit7, Sod-1. Two of these markers mapped to the known human Chr 21 (HSA21)/Chr 16 conserved linkage group. Nine additional SSR markers could not be typed because they were not polymorophic (four markers), did not amplify MOLD/Rk DNA (three markers), or failed to give PCR products under a range of conditions (two markers). A subset of the most robust SSRs provide a useful marker set for the analysis of previously unmapped crosses.