Ity3^MOLF/EiJ
QTL Variant Detail

Summary

• QTL variant: Ity3^MOLF/EiJ
• Name: immunity to S. typhimurium 3; MOLF/EiJ
• MGI ID: MGI:2154171
• Synonyms: Ity3^MOLF/Ei
• QTL: Ity3 Location: Chr1:131156308-165139464 bp Genetic Position: Chr1, cM position of peak correlated region/allele: 56.92 cM
• QTL Note: genome coordinates based on the boundaries of the QTL region

Variant origin

• Strain of Specimen: MOLF/EiJ

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers susceptibility to infection by Salmonella typhimurium compared to C57BL/6J. (J:45962)
• Inheritance: Recessive

Notes

Candidate Genes

J:108692

Congenic animals derived from resistant C57BL/6J and susceptible MOLF/Ei parentals were used to test the candidacy of Tlr5 for the Salmonella susceptibility QTL Ity3 (71.5 cM on chromosome 1). Introgression of MOLF/Ei-derived Ity3 onto a C57BL/6J geneticbackround included the Tlr5 locus. The following parentals and congeic lines were tested by injection with flagellin:

C57BL/6J

MOLF/Ei

B6.MOLF-Slc11a1 Ity3 (homozygous for MOLF/Ei alleles at Tlr5)

B6.MOLF-Slc11a1 Ity3^B6/MOLF (heterozygous for C57BL/6J and MOLF/Ei alleles at Tlr5)

B6.MOLF-Slc11a1 (homozygous for C57BL/6J alleles at Tlr5)

Serum IL-6 and CXCL-1 were measured at different time points (0, 60, and 90 minutes) after flagellin administration. Congenic animals homozygous for MOLF/Ei alleles at Tlr5 (B6.MOLF-Slc11a1 Ity3)exhibited the strongest response to flagellen stimulation out of all lines tested as indicated by significantly higher levels of serum IL-6 and CXCL-1. Parental strain MOLF/Ei exhibits the lowest serum IL-6 and CXCL-1 levels compared to parental C57BL/6Jand all 3 congenic lines. The results indicate the effect of Tlr5 is dependent on strain background. Therefore, it is unlikely Tlr5 is responsible for the Ity3 susceptible phenotype.

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

J:45962

191 animals from a (C57BL/6J x MOLF/Ei)F2 cross were typed for 115 markers to identify QTLs involved in resistance to Salmonella typhimurium infection. While parental C57BL/6J and MOLF/Ei strains are susceptible to infection by S.typhimurium, segregationof resistance alleles at Nramp1 and Lps in the MOLF/Ei strain confers a resistant phenotype to F2 progeny. Three significant QTLs were mapped in this study: Ity1 (LOD=18.8 at D1Mcg4 spanning 21.6cM-54.4cM) and Ity3 (LOD=4.8 at D1Mit100 spanning 59.7cM-87.7cM) on chromosome 1, and Ity2 (LOD=7.0 at D11Mit5 spanning 27cM-49cM) on chromosome 11. Ity1 confers dominantly inherited resistance to infection by S.typhimurium and is in linkage (within 6kb) to Nramp1, while Ity3 confers recessively inherited susceptibility. The Ity1 QTL most likely represents mouse Slc11a1. The Ity2 locus has an additive effect and confers a resistant phenotype. Ity2 was analyzed for interaction with Nramp1 and no interaction was detected. Three suggestive QTLs were also identifiedon chromosomes 6, 10, and 13. The resistance locus on chromosome 6 (LOD=3.6 at D6Mit9) appears to have an additive effect, while the susceptibility loci on chromosomes 10 (LOD=3.1 at D10Mit91) and 13 (LOD=2.4 at D13Mit117) are recessively inherited.

J:126552

Previously identified Salmonella susceptibility QTLs Ity2 and Ity3 were confirmed and refined by linkage analysis of 232 (C57BL/6J x MOLF/EiJ)F2 animals. Parental strain MOLF/EiJ is susceptible to Salmonella typhimurium infection compared to parental strain C57BL/6J. Ity2 and Ity3 were further analyzed using subcongenic lines and candidate genes were identified using gene expression profiling after infection with S. typhimurium.

Ity2 was refined to an interval on mouse Chromosome 11 between D11Mit112 (32 cM) and Mpo (49 cM). Peak linkage occurred at Nos2 (45.6 cM) with LOD=7.8. Ity/Ity2 congenic animals were constructed by selecting for MOLF/EiJ-derived donor DNA at D1Mcg4 (Ity) and D11Mit84 - Mpo (Ity2) on a C57BL/6J genetic background. This line was then bred into two different subcongenic lines, RecD and RecI. At least two different loci were found to contribute to S. typhimurium resistance and were named Ity2a and Ity2b. Ity2a maps to a 23 Mb interval from D11Mit109 (19 cM) to D11Mit26 (33.3 cM) while Ity2b maps to a 13 Mb interval from D11Mit5 (37 cM) to D11Mit8 (46 cM). Gene expression analysis identified Havcr2 as a promising candidate gene for Ity2a. No candidate genes were identified for Ity2b.

Ity3 was refined to an interval on mouseChromosome 1 between D1Mit135 (59.7 cM) and D1Mit201 (79 cM) with peak linkage of LOD=4.1 occurring between D1Mit218 (67 cM) and D1Mit100 (71.5 cM). Ity/Ity3 congenic animals were constructed by selecting for MOLF/EiJ-derived donor DNA at D1Mcg4 (Ity) and D1Mit135 - D1Mit17 (Ity3) on a C57BL/6J genetic background. This line displayed significantly reduced survival time after S. typhimurium infection. Subcongenic lines RecA, RecB, RecC, and RecE were constructed and localized the Ity3 critical region to a34 Mb interval between D1Mit193 (68 cM) and D1Mit63 (87.8 cM). Gene expression analysis identified Lax1 and Chi3l1 as potential candidate genes for Ity3.

References

• Original: J:45962 Sebastiani G, et al., Mapping of genetic modulators of natural resistance to infection with Salmonella typhimurium in wild-derived mice. Genomics. 1998 Jan 15;47(2):180-6
• All: 3 reference(s)