Mapping of multiple mouse loci related to the farnesyl pyrophosphate synthetase gene

The prenyltransferases are a class of enzymes involved in the synthesis of sterol and nonsterol isoprene compounds. We report here the chromosomal mapping of nine loci in the mouse that hybridize to the cDNA for the enzyme farnesyl pyrophosphate synthetase (FPS), a prenyltransferase that catalyzes the synthesis of an intermediate common to both the sterol and nonsterol branches of the isoprene biosynthetic pathway. Mapping was performed with genomic DNA from a mouse-hamster somatic cell hybrid panel, and by linkage analysis with recombinant inbred strains and the progeny of an interspecific backcross. The mapped loci have been designated farnesyl pyrophosphate synthetase-like-1 (Fpsl-1) on mouse Chromosome (Chr) 3; Fpsl-2 on Chr 4; Fpsl-3, Fpsl-4, and Fpsl-5, dispersed on Chr 10; Fpsl-6 on Chr 12; Fpsl-7 on Chr 13; Fpsl-8 on Chr 17; and Fpsl-9 on Chr X. It is presently unclear which of these loci encode active prenyltransferases and which may correspond to pseudogenes. The strongly hybridizing loci provide convenient genetic markers for seven mouse chromosomes.     

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.     

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.     

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.     

Synteny conservation of the Huntington's disease gene and surrounding loci on mouse Chromosome 5

The mouse homologs of the Huntington's disease (HD) gene and 17 other human Chromosome (Chr) 4 loci (including six previously unmapped) were localized by use of an interspecific cross. All loci mapped in a continuous linkage group on mouse Chr 5, distal to En2 and Il6, whose human counterparts are located on Chr y. The relative order of the loci on human Chr 4 and mouse Chr 5 was maintained, except for a break between D5H4S115E and Idua/rd, with relocation of the latter to the opposite end of the map. The mouse HD homolog (Hdh) mapped within a cluster of seven genes that were completely linked in our data set. In human these loci span a1.8 Mb stretch of human 4p 16.3 that has been entirely cloned. To date, there is no phenotypic correspondence between human and mouse mutations mapping to this region of synteny conservation.     

A genetic linkage map of rat Chromosome 5 reveals extensive linkage conservation with mouse Chromosome 4

Linkages among three biochemical loci (Acol, Ahd2, and Mup1) and four microsatellite loci (A8, Glut1, Jun, and Pnd) were determined to construct a linkage map of rat Chromosome (Chr) 5. Consequently, an extensive linkage map on rat Chr 5 was constructed with the following gene order: A8-Aco1-Mup1-Jun-Glut1-Ahd2-Pnd. In this linkage map, the Jun and A8 loci are newly placed, and two previously reported linkage groups on rat Chr 5 are connected by the Jun locus. The linkage map indicates an extensive linkage conservation between the loci on rat Chr 5 and those on mouse Chr 4.     

Mapping of the mouse ornithine decarboxylase-related sequence family

A family of DNA sequences homologous to the mRNA encoding ornithine decarboxylase (ODC) and comprising 12 members in the mouse genome has been analyzed genetically. The inheritance of variant DNA restriction fragments detected by ODC cDNA probes on Southern blots of DNA from inbred strain mice was determined in six sets of recombinant inbred (RI) mouse strains. The distributions of these variations among the RI strains were then compared with the RI strain distribution patterns (SDPs) of previously mapped loci. This allowed the identification of nine independent ODC-related loci, of which eight could be localized to specific regions of the mouse genome: Odc-rs1 near Lamb2 on Chromosome (Chr) 1; Odc-rs2 near Psp on Chr 2; Odc-rs5, a complex locus comprising at least 5–7 copies of the ODC sequence, associated with Igk on Chr 6; Odc-rs6 between Abpa and Tam-1 on proximal Chr 7; Odc-rs7 near Hbb on distal Chr 7; Odc-rs12 near Agt and Emv-2 on distal Chr 8; Odc-rs8 associated with the Igh complex on Chr 12; and Odc-rs9 near Otf-3f on Chr 14. The ODC-related sequence family thus comprises a set of genomically dispersed marker loci, and alleles for several of these loci can be analyzed simultaneously in DNA from mice or cell lines. DNA from mice of 70 inbred strains has been characterized for alleles at all nine Odc-rs loci.     

Loci on Chromosomes 2, 4, 9, and 16 for body weight,body length,and adiposity identified in a genome scan of an F<Subscript>2</Subscript> intercross between the 129P3/J and C57BL/6ByJ mouse strains

Mice have proved to be a powerful model organism for understanding obesity in humans. Single gene mutants and genetically modified mice have been used to identify obesity genes, and the discovery of loci for polygenic forms of obesity in the mouse is an important next step. To pursue this goal, the inbred mouse strains 129P3/J (129) and C57BL/6ByJ (B6), which differ in body weight, body length, and adiposity, were used in an F₂ cross to identify loci affecting these phenotypes. Linkages were determined in a two-phase process. In the first phase, 169 randomly selected F₂ mice were genotyped for 134 markers that covered all autosomes and the X Chromosome (Chr). Significant linkages were found for body weight and body length on Chr 2. In addition, we detected several suggestive linkages on Chr 2 (adiposity), 9 (body weight, body length, and adiposity), and 16 (adiposity), as well as two suggestive sex-dependent linkages for body length on Chrs 4 and 9. In the second phase, 288 additional F₂ mice were genotyped for markers near these regions of linkage. In the combined set of 457 F₂ mice, six significant linkages were found: Chr 2 (Bwq5, body weight and Bdln3, body length), Chr 4 (Bdln6, body length, males only), Chr 9 (Bwq6, body weight and Adip5, adiposity), and Chr 16 (Adip9, adiposity), as well as several suggestive linkages (Adip2, adiposity on Chr 2; Bdln4 and Bdln5, body length on Chr 9). In addition, there was a suggestive linkage to body length in males on Chr 9 (Bdln4). For adiposity, there was evidence for epistatic interactions between loci on Chr 9 (Adip5) and 16 (Adip9). These results reinforce the concept that obesity is a complex trait. Genetic loci and their interactions, in conjunction with sex, age, and diet, determine body size and adiposity in mice.     

Polygenetic susceptibility and resistance to 4-nitroquinoline 1-oxide-induced tongue carcinomas in the rat

Oral administration of 4-nitroquinoline 1-oxide (4NQO) to rats induced a high incidence of tongue carcinomas (TCs). The inbred Dark-Agouti (DA) strain of rats showed much higher susceptibility to 4NQO-induced TCs than the Wistar-Furth (WF) strain. Our previous study on crosses between the two strains postulated a semidominant susceptibility gene in DA and a semidominant resistance gene in WF rats. This hypothesis was confirmed by the genetic analysis of the back-crosses to either parent with PCR-based microsatellite assay. Using the number of TCS with >5 mm diameter as a quantitative parameter, we mapped a quantitative trait locus Stc1 (Susceptibility to TC) favouring TC development near the locus D19Mit9 on Chr. 19 with a peak LOD score of 6.08. Two other regions in Chr. 3 and Chr. 14 showed weak linkage for susceptibility, but were not statistically significant. On the other hand, another quantitative trait locus Rtc1 (Resistance to TC) providing resistance to TCs was mapped on Chr. 1 between the loci of D1Mit1 and D1Mit3 with a peak LOD score of 3.30. Quantitative parameters such as the number of tumours in the tongue or upper alimentary tract, the frequency of larger tumours and their maximum size were closely correlated and principally determined by Stc1 and Rtc1. Therefore the susceptibility to 4NQO-induced TCs in crosses between DA and WF is explained by the combinations of genotypes at these two loci. Possible candidate genes for Stc1 and Rtc1 are discussed.     

The linkage map of sheep Chromosome 6 compared with orthologous regions in other species

The genetic linkage map of sheep Chromosome (Chr) 6 has been extended to include 35 loci with the addition of 11 RFLP and 12 microsatellite loci. The sex-averaged linkage map now spans 154 cM from phosphodiesterase cyclic GMP beta polypeptide (PDE6B) to OarCP125, an anonymous sheep microsatellite. The male and female map lengths, at 180 cM and 132 cM respectively, did not differ significantly. The physical assignment of PDE6B to Chr 6q33-qter orientates the linkage map on sheep Chr 6 with PDE6B near the telomere and OarCP125 towards the centromere. The order and genetic distances between loci are similar for the sheep Chr 6 and cattle Chr 6 maps, except for the position of the casein genes. The sheep Chr 6 linkage map is also comparable to portions of human Chr 4, mouse Chrs 5 and 3, and pig Chr 8. The synteny between sheep Chr 6 and human Chr 4 has been extended from PDE6B (4p16.3) to epidermal growth factor (EGF, 4q25-q27). However, a region from platelet-derived growth factor receptor α polypeptide (PDGFRA) to bone morphogenetic protein 3 (BMP3), which spans 19 cM on sheep Chr 6, appears to be inverted with respect to the human and mouse loci. Other differences in the gene order between sheep, pig, and mouse suggest more complex rearrangements. Received: 16 August 1995 / Accepted: 12 December 1995     

Multiple obesity QTLs identified in an intercross between the NZO (New Zealand obese) and the SM (small) mouse strains

The inheritance of adiposity levels has been investigated in an intercross of the obese, diabetes-prone NZO and the small, lean SM mouse strains. Adiposity index (AI) was defined as the sum of four fat pad weights divided by body weight. DNA pools from fat and lean mice were analyzed with microsatellite variants to screen the genome for quantitative trait loci (QTLs) affecting AI. Ten significant QTLs affecting AI were identified on Chromosome (Chr) 1 (three loci), Chr 2, Chr 5 (two loci), Chr 6 (two loci), Chr 7, and Chr 17. Most of the QTLs appear to be novel. Several QTLs differentially affect specific fat depots. Thus, Chr 2 and Chr 7 QTLs affect gonadal more than inguinal fat, while the converse is true for the Chr 17 QTL. Gender influences the expression of several of the QTLs. For example, effects of the proximal Chr 1 QTL (Obq7) on AI appears to be primarily in males. The proximal AI QTL on Chr 6 (Obq13) maps near the neuropeptide Y (Npy) locus. Sequence analysis of the Npy gene revealed a 1-nucleotide deletion within a highly conserved portion of the 3′ untranslated region in strain NZO. However, the deletion is polymorphic among mouse strains. Furthermore, lack of association between this same variant and AI in previously analyzed crosses raises doubt that it is the basis of Obq13. The present cross is the fourth in a series of intercrosses among 10 inbred strains arranged such that each strain is crossed with each adjacent strain within a circle. This design affords multiple opportunities to analyze each segregating QTL. Received: 17 July 2000 / Accepted: 9 October 2000     

Chromosomal Mapping of Mouse Genes Expressed Selectively within the Central Nervous System

We have used RFLP analysis on DNA from a panel of interspecific (C57BL/6J × Mus spretus) F₁ × M. spretus backcross offspring to assign the genes encoding 10 neuron-specific mRNAs and 2 loci corresponding to cyclophilin 2-related sequences to the mouse chromosomal map. The Pss1 locus encoding the forebrain-enriched protein kinase C substrate RC3, a component of dendritic spines, mapped to proximal Chr 9. The Camkl locus encoding the calmodulin-binding protein kinase-like vesicle protein 1G5 mapped to distal Chr 9. The Gng7 locus encoding the γ7 G-protein subunit, highly enriched in the striatum and presumptively coupled to dopamine receptors, mapped to mid-Chr 10. The Htr1f, Htr5a, Htr5b, and Htr7 loci, encoding four serotonin receptors, mapped to Chr 16.5, 1, and 19, respectively. The Peplb locus, encoding a CD26 ectopeptidase-like neuronal membrane protein activated by kainate and long-term potentiation, mapped to Chr 5. The D2Sut1e and Cpu3 loci, encoding neural proteins of unknown functions, mapped to Chrs 2 and 9, respectively. Two cyclophilin 2-related loci, Cphn2-r1 and Cphn2-r2, mapped to different regions of Chr 9. Comparison of these 12 newly mapped loci with the existing mouse map and known regions of syntenic homology with the human map, along with the known features and expression profiles of the products of these genes, suggests a few candidates for mouse mutations and human neurological and immunological deficits, including the Tourette syndrome and Bloom syndrome genes.     

Imprinted methylation profiles for proximal mouse Chromosomes 11 and 7 as revealed by methylation-sensitive representational difference analysis

Proximal mouse Chromosome (Chr) 11 shares regions of orthology with the candidate gene region for the imprinting growth disorder Silver-Russell syndrome (SRS) on human Chr 7p. It has previously been shown that mice with two maternal or two paternal copies (duplications, Dp) of proximal Chr 11 exhibit reciprocal growth phenotypes. Those with two paternal copies show fetal and placental overgrowth, while those with two maternal copies are growth retarded. The growth retardation observed in the latter is reminiscent of the intrauterine growth restriction (IUGR) observed in SRS patients with maternal uniparental disomy for Chr 7 (mUPD7). We have carried out a methylation-sensitive representational difference analysis (Me-RDA) screen to look for regions of differential methylation (DMRs) associated with imprinted genes. For these experiments, we have used mouse embryos with uniparental duplications of Chrs 11 and 7 proximal to the breakpoint of the reciprocal translocation T(7;11)40Ad. Two previously known imprinted loci associated with paternal allele hypomethylation were recovered on proximal mouse Chr 11, U2af1-rs1 and Meg1/Grb10. These two genes map 15 cM apart, so it seems likely that they are within separate imprinted domains that do not contain additional DMRs. The known imprinted gene Peg3, located on mouse proximal Chr 7, was also detected in our screen. The finding that Peg3 was differentially methylated in embryos with uniparental inheritance of proximal Chr 7 confirms that Peg3 is located proximal to the breakpoint of T40Ad in G-band 7A2. Because GRB10 has previously been reported to be a candidate gene for SRS, we analysed 22 patients for epimutations of the GRB10 differentially methylated region that could lead to the altered expression of this gene. No such mutations were found.     

Mapping of ornithine aminotransferase gene sequences to mouse Chromosomes 7, X,and 3

Ornithine aminotransferase (OAT), a mitochondrial matrix enzyme, is deficient in patients with gyrate atrophy of the choroid and retina. In human, the OAT structural gene maps to Chromosome (Chr) 10q26 and several OAT-related sequences, some of which are known to be processed pseudogenes, which map to Xp11.3–11.21. Here, we report chromosomal localization in the mouse of the OAT gene and related sequences. Genomic DNA blot analysis of a well-characterized panel of Chinese hamster x mouse somatic cell hybrids using a human OAT probe revealed two murine loci, one on mouse Chr 7 and the other on Chr X. In addition, segregation of restriction fragment length polymorphisms (RFLPs) detected by the OAT probe in recombinant inbred (RI) strains detected a third locus on Chr 3 and positioned the X locus near Cf-8 and Rsvp. Progeny of an intersubspecific backcross were used to map the Chr 7 locus between Tyr and Int-2, near Cyp2e-1.     

Mapping of the MouseLy-6, Xp-14, andGdc-1 loci to chromosome 15

TheLy-6 locus is now regarded as a gene complex consisting of at least five closely linked loci (Ly-6A-Ly-6E) whose polymorphic products are identified by monoclonal antibodies and distinguished by different tissue distributions.Ly-6 has been assigned by other investigators to chromosome (Chr) 9 (linked toThy-1 or to Chr 2. We report that theLy-6 gene complex, together with theXp-14 andGdc -1 loci, is situated on Chr 15 linked toGpt1. These new linkage data are derived from four sources: (1) three separate crosses that failed to demonstrate linkage ofLy-6 to eitherThy-4 on Chr 9 or to any of five genes present on Chr 2; (2) the NXSM recombinant inbred strains, which suggested the linkage ofLy-6 andXp-14 toGpt-1 on Chr 15; (3) severalGpt-1 andGdc-1 congenic strains that confirmed the assignment ofLy-6 andXp-14 to Chr 15; and (4) backcrosses that further confirmed the linkage ofLy-6, Gpt-1, Gdc-4, andXp-14, the probable gene order beingGpt-11/Ly-6 Xp-14-Gdc-1.     

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.     

Contrasting epistatic interactions between rat quantitative trait loci controlling mammary cancer development

We previously defined quantitative trait loci (QTLs) that control susceptibility to 7,12-dimethylbenz(α)anthracene-induced mammary carcinoma in SPRD-Cu3 (susceptible) and WKY (resistant) rats. Two of these QTLs, assigned to chromosomes (Chr) 10 and 18, control tumor growth rate and invasiveness. In this study we characterized a congenic strain in which a large segment of WKY Chr 10 was introduced in the SPRD-Cu3 genetic background and demonstrated that this chromosome segment controls this tumor trait. The WKY allele at this QTL (Mcsta1) reduces the growth rate of the fastest growing tumors by 26%. We also previously showed that two SPRD-Cu3-WKY congenic strains containing a WKY chromosome segment derived either from Chr 5 or from Chr 18 exhibit a reduction in tumor multiplicity (QTLs Msctm1 and Mcstm2, respectively) (with no reduction in tumor growth rate in the Chr 18 congenic). In this study we generated a double congenic strain, which contains the two WKY differential segments from Chr 5 and 18, to determine how these two segments interact with one another. Interestingly, two types of epistatic interactions were found: no additive effect was seen with respect to tumor multiplicity, while a reduction in tumor growth rate was observed. It thus appears that WKY alleles located on Chr 5 and Chr 8 interact epistatically in a contrasting manner to modulate tumor multiplicity (in a nonadditive manner) and growth rate (in a synergic manner). Tumor growth rate is thus influenced by two QTLs, on Chr 10 (Mcsta1) and on Chr 18 (Mcsta2), the action of the latter being dependent on the presence of the Chr5 QTL (Mcstm1). The expression level of positional and functional candidate genes was also analyzed. On Chr 5, Pla2g2a is subject to a syntenic control while expression of the Tp53 (Chr 10) and Pmai1/Noxa (Chr 18) genes appears to be controlled by several mammary cancer resistance QTLs.     

Localization of two mouse genes encoding the protein tyrosine kinase receptor-related protein RYK

We have mapped the gene encoding the murine RYK growth factor receptor protein tyrosine kinase by genetic linkage analysis with recombinant inbred strains of mouse. Two distinct Ryk loci (Ryk-1 and Ryk-2) were identified. Ryk-1 mapped to Chromosome (Chr) 9, whereas Ryk-2 mapped to Chr 12. A similar arrangement of RYK-related loci was previously determined in the human. Synteny has already been established between murine Chr 9 in the region of Ryk-1, and human chromosome 3q11–12, the location of the human RYK-1 gene. However, the Ryk-2/RYK-2 loci on murine Chr 12 and human chr 17p13.3 define a new region of synteny.     

Genetic and physical mapping of the natural resistance-associated macrophage protein 1 (NRAMP1) in chicken

The chicken natural resistance-associated macrophage protein 1 (NRAMP1) gene has been mapped by linkage analysis by use of a reference panel to develop the chicken molecular genetic linkage map and by fluorescence in situ hybridization. The chicken homolog of the murine Nramp1 gene was mapped to a linkage group located on Chromosome (Chr) 7q13, which includes three genes (CD28, NDUSF1, and EF1B) that have previously been mapped either to mouse Chr 1 or to human Chr 2q. Physical mapping by pulsed-field gel electrophoresis revealed that NRAMP1 is tightly linked to the villin gene and that the genomic organization (gene order and presence of CpG islands) of the chromosomal region carrying NRAMP1 is well conserved between the chicken and mammalian genomes. The regions on mouse Chr 1, human Chr 2q, and chicken Chr 7q that encompass NRAMP1 represent large conserved chromosomal segments between the mammalian and avian genomes. The chromosome mapping of the chicken NRAMP1 gene is a first step in determining its possible role in differential susceptibility to salmonellosis in this species.     

Genetic Analysis of Susceptibility to Dextran Sulfate Sodium-Induced Colitis in Mice

The genetic basis for differential sensitivity of inbred mice to inflammatory bowel disease induced by dextran sulfate sodium (DSS) is unknown. Susceptible C3H/HeJ were outcrossed to partially resistant C57BL/6J mice. F2 and N2 progeny were phenotyped by evaluating histopathologic lesions in large intestine detected 16 days after a 5-day period of feeding 3.5% DSS. Screening for DSS colitis (Dssc) loci revealed quantitative trait loci (QTL) on Chr 5 (Dssc1) and Chr 2 (Dssc2). These traits contributed additively, explaining 17.5% of the variation in total colonic lesions. Additional QTL on Chr 18 and 1 that collectively explained 11% of the variation in total colon lesions were indicated. In the cecum, only a putative QTL on Chr 11 was associated with pathology (lesion severity) in the cecum. Reduced DSS susceptibility was observed in congenic stocks in which the highly susceptible NOD/Lt strain carried putative resistance alleles from either B6 on Chr 2 or from the highly resistant NON/Lt strain on Chr 9. We conclude that multiple genes control susceptibility to DSS colitis in mice. PossibleDssccandidate genes are discussed in terms of current knowledge of inflammatory bowel disease susceptibility loci in humans.