Cdcs9^C3H/HeJBir
QTL Variant Detail

Summary

• QTL variant: Cdcs9^C3H/HeJBir
• Name: cytokine deficiency colitis susceptibility 9; C3H/HeJBir
• MGI ID: MGI:2388741
• QTL: Cdcs9 Location: Chr4:142230872-142230960 bp Genetic Position: Chr4, cM position of peak correlated region/allele: 75.67 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: C3H/HeJBir

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers colitis susceptibility compared to C57BL/6J. (J:78917)
• Inheritance: Dominant

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

This allele is consistent with a dominant or additive mode of inheritance.

Candidate Genes

J:109420

Microarray analysis was used to identify candidate genes for colitis susceptibility QTLs. Messenger RNA was analyzed for expression differences between colitis susceptible inbred strain C3H/HeJBir-Il10^tm1Cgn and colitis resistant inbred strain C57BL/6J-Il10^tm1Cgn.

Capn3 (67.2 cM) on mouse Chromosome 2 is upregulated 1.5- to 2-fold in C3H/HeJBir-Il10^tm1Cgn animals. This candidate gene maps to the Cdcs3 (cytokine deficiency colitis susceptibility 3) interval centered near 65 cM.

Gbp1 (67.4 cM) on mouse Chromosome 3 is upregulated over 15-fold in C3H/HeJBir-Il10^tm1Cgn animals. This candidate gene is known to be polymorphic between C3H/HeJBir and C57BL/6J and exhibits expression differences in these parental wild type strains. Gbp1 maps to the Cdcs1 (cytokine deficiency colitis susceptibility 1) interval centered near 62 cM. Adh1 at 71.2 cM and Bglap2 at 42.6 cM also map to the same QTL interval. Adh1 is upregulated 1.5- to 2-fold, and Blgap2 is upregulated 2- to 5-fold, in C3H/HeJBir-Il10^tm1Cgnanimals.

Pla2g2a (68 cM) on mouse Chromosome 4 is upregulated over 15-fold in C3H/HeJBir-Il10^tm1Cgn animals. This candidate gene is known to be polymorphic between C3H/HeJBir and C57BL/6J and exhibits expression differences in these parental wild typestrains. Pla2g2a maps to the Cdcs9 (cytokine deficiency colitis susceptibility 9) interval centered near 71 cM. Moreover, C57BL/6J animals are known to carry the frameshift mutation Pla2g2a^Min1-s resulting in multiple intestinal neoplasia. The human ortholog PLA2G2A maps near a irritable bowel disorder (IBD) susceptibility locus named IBD7. Gnb1 (79.4 cM) also maps to the Cdcs9 QTL interval and is upregulated 2- to 5-fold in C57BL/6J-Il10^tm1Cgn animals. Errfi1 (formerly 1300002F13Rik) and Tceb3 also map to the Cdcs9 interval and are upregulated 1.5- to 2-fold in C57BL/6J-Il10^tm1Cgn animals.

Areg (51 cM) on mouse Chromosome 5 maps near the Cdcs10 QTL interval centered around 45 cM. This candidate gene is upregulated 1.5- to 2-fold in C57BL/6J-Il10^tm1Cgn animals.

Mtmr7 maps to mouse Chromosome 8 near the Cdcs4 interval centered around 21 cM. This candidate gene is upregulated over 15-fold in C57BL/6J-Il10^tm1Cgn animals.

Cd14 (31 cM) on mouse Chromosome 18 is upregulated 5- to 15-fold in C3H/HeJBir-Il10^tm1Cgn animals. CD14 also exhibits expression differences in parental wild type strains C3H/HeJBir and C57BL/6J. This candidate gene maps to the Cdcs6 (cytokine deficiency colitis susceptibility 6) interval centered near 41 cM. The human ortholog CD14 maps near a human irritable bowel disorder (IBD) susceptibility locus named IBD5.

Glo1 (16 cM) and Ly6g6c on mouse Chromosome 17 are upregulated 2- to 5-fold in C57BL/6J-Il10^tm1Cgn animals. This candidate gene maps to the Cdcs5 (cytokine deficiency colitis susceptibility 5) interval centered near 19 cM. Hspa1a (18.9 cM) and Hspa1b (18.9 cM) also map to Cdcs5 and are upregulated 1.5- to 2-fold in C57BL/6J-Il10^tm1Cgn animals.

Mapping and Phenotype information for this QTL, its variants and associated markers

J:78917

A genome scan using 69 microsatellite markers at an average resolution of 20.4 cM was performed on 2 backcross populations to identify QTLs associated with colitis susceptibility. The backcross populations used are (C3H/HeJBir-Il10^tm1Cgn x C57BL/6J-Il10^tm1Cgn)F1 x C3H/HeJBir-Il10^tm1Cgn and (C57BL/6J-Il10^tm1Cgn x C3H/HeJBir-^Il10tm1Cgn)F1 x C57BL/6J-Il10^tm1Cgn. They are referred to by the authors as N2(C3H)-Il10^-/- and N2(B6)-Il10^-/-, respectively. Parental strain C3H/HeJBir-Il10^tm1Cgn exhibits severe lesions of the cecum and colon as early as 4 weeks of age whereas parental strain C57BL/6J-Il10^tm1Cgn exhibits mild lesions. Colitis susceptibility loci mapped to mouse Chromosome 12 (Cdcs7 and Cdcs8) in the N2(C3H)-Il10^-/- backcross, and to mouse Chromosomes 4 (Cdcs9) and 5 (Cdcs10) in the N2(B6)-Il10^-/- backcross. Cdcs7 is an epistatic locus with peak colitis linkage at 38 cM on chromosome 12 at D12Mit214. The QTL range spans 10 cM - 50 cM. Homozygosity for C3H/HeJBir-derived allelesat Cdcs7 in conjunction with C3H/HeJBir-derived alleles at D3Mit257 contribute to colitis susceptibility. Cdcs8 maps to the same location as Cdcs7 (38 cM on chromosome 12) with a LOD score of 3.2 but exhibits a different mode of inheritance than Cdcs7.C57BL/6J-derived alleles confer colitis susceptibility in a recessive or additive fashion at Cdcs8. On mouse Chromosome 4, Cdcs9 maps to 71 cM at D4Mit13 with a QTL range of 60 cM - 80 cM. C3H/HejBir-derived alleles confer colitis susceptibility in a dominant or additive fashion at Cdcs9. On mouse Chromosome 5, Cdcs10 maps to 45 cM at D5Mit205 with a QTL range of 36 cM - 60 cM. C3H/HejBir-derived alleles confer colitis susceptibility in a dominant or additive fashion at Cdcs10. The following suggestive loci were also identified: Chromosome 3 at D3Mit257 (C3H/HeJBir-derived allele conferring recessive or additive susceptibility), Chromosome 8 at D8Mit200 (C57BL/6J-derived allele conferring dominant or additive susceptibility), and Chromosome 13 at D13Mit179 (C57BL/6J-derived allele conferring susceptibility).

References

• Original: J:78917 Mahler M, et al., Genetics of Colitis Susceptibility in IL-10-Deficient Mice: Backcross versus F2 Results Contrasted by Principal Component Analysis. Genomics. 2002 Sep;80(3):274
• All: 1 reference(s)