Cdcs6^C3H/HeJBir
QTL Variant Detail

Summary

• QTL variant: Cdcs6^C3H/HeJBir
• Name: cytokine deficiency colitis susceptibility 6; C3H/HeJBir
• MGI ID: MGI:2159178
• QTL: Cdcs6 Location: unknown Genetic Position: Chr18, Syntenic

Variant origin

• Strain of Specimen: C3H/HeJBir

Variant description

• Allele Type: QTL
• Inheritance: Other (see notes)

Notes

Cdc6 interacts epistatically with Cdcs1 and a locus 8 cM proximal to Cdcs4.

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.

J:154082

The mouse Cd14 gene is within the interval of Cdcs6. Cd14 was considered a good candidate gene because of expression differences between C57BL/6J mice (low Cd14 expression, conferring susceptibility) and C3/J-Il10 mice (high Cd14 expression, presumably conferring resistance).

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

J:72978

Genome scan at a resolution of ^{20 cM was performed on 408 animals from a (C3Bir.129P2(B6)-Il10/Lt x B6.129P2-Il10tm1Cgn/Lt)F2 intercross to identify QTLs associated with colitis susceptibility. Il10-deficient parental strain C3Bir.129P2(B6)-Il10tm1Cgn/Lt is susceptible to colitis and develops severe lesions whereas the resistant B6.129P2-Il10tm1Cgn/Lt develops mild lesions. A major colitis susceptibility locus, Cdcs1 (cytokine deficiency colitis susceptibility 1), maps from 67 cM - 75 cM on mouse Chromosome 3 with a maximum LOD score of 26.5 at D3Mit348 for all colitis phenotypes. C3H/HeJBir-derived alleles confer additively inherited colitis susceptibility at Cdcs1. Fabp2, Egf, and Nfkb1 are candidate genes for Cdcs1. Cdcs2 maps to 32.8 cM mouse Chromosome1 with a LOD score of 4.3 at D1Mit156 in linkage to colon score, severity, and hyperplasia in the distal colon. Cdcs2 exhibits additive interactions with Cdcs1. C3H/HeJBir-derived alleles confer colitis susceptibility at Cdcs2. Casp8, Cd28, Cd152, and Icos are candidate genes for Cdcs2. Cdcs3 maps to 65 cM near D2Mit62 on mouse Chromosome 2 with C3H/HeJBir-derived alleles conferring recessively inherited susceptibility to colitis. Cdcs3 affects hyperplasia and ulceration in the distal colon. Candidate genes for Cdcs3 are Thbs1, B2m, Il1, and Pcna. Cdcs4 maps to 21 cM on mouse Chromosome 8 and is linked to cecum total score at D8Mit191. C57BL/6J-derived alleles confer colitis susceptibility at Cdcs4. Defcr, Scc8 and the Defb locus are candidate genes for Cdcs4. Cdcs5 maps to 19 cM on mouse Chromosome 17 with C57BL/6J-derived alleles conferring recessive colitis susceptibility. Cdcs5 interacts epistatically with Cdcs4 and affects spleen/body weight ratio. Candidate genes for Cdcs5 are H2-Ea, C4, Slp, and Tnf. Cdcs6 maps from 32 cM - 50 cM on mouse Chromosome 18 with C57BL/6J-derived alleles conferring colitis susceptibility. Cdcs6 interacts with Cdcs1 and a locus at D8Mit94 (8 cM proximal to Cdcs4) to affect cecum hyperplasia. Candidate genes for Cdcs6 are Dcc and Apc.* Authors also list Mad2l1 and Mad4 as candidate genes for Cdcs6: the position of these genes as given in MGD are on mouse Chromosome 6 and mouse Chromosome 5, respectively. *}

References

• Original: J:72978 Farmer MA, et al., A major quantitative trait locus on chromosome 3 controls colitis severity in IL-10-deficient mice. Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13820-5
• All: 2 reference(s)