Tir1^BALB/cOlaHsd
QTL Variant Detail

Summary

• QTL variant: Tir1^BALB/cOlaHsd
• Name: trypanosome infection response 1; BALB/cOlaHsd
• MGI ID: MGI:2445529
• QTL: Tir1 Location: unknown Genetic Position: Chr17, cM position of peak correlated region/allele: 17.98 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: BALB/cOlaHsd

Variant description

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

Notes

This allele exhibits additive inheritance in the (BALB/cOlaHsd x C57BL/6JOlaHsd)F2 cross and dominant inheritance in the (A/JOlaHsd x C57BL/6JOlaHsd)F2 cross from J:40771.

Candidate Genes

J:125686

Candidate gene search for Tir1 (18.2 cM, chr 17), a QTL associated with resistance to Trypanosome congolense infection, was employed using a whole genome expression approach. Mice from C57BL/6 (resistant) and A/J and BALB/c (susceptible) were infected with T. congolense. RNA samples were prepared from liver, spleen, and kidney at different time intervals post-infection. Genes exhibiting differential expression and involvement in infection pathways were given priority for analysis.

The Tir1 locus encompasses 344 genes. After gene expression and pathway analysis 32 candidate genes remained. Daxx at 17 cM was chosen as primary candidate because of its involvement in the apoptosis pathway. Sequence analysis revealed the presence of 3 SNPs exhibiting correlation with survival time after infection. Two of these polymorphisms are located in the Daxx 5' upstream region. The third polymorphism is a 3 nucleotide deletion resulting in the deletion of an aspartic acid residue in the susceptible A/J and BALB/c strains.

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

J:40771

A significant variation in the susceptibility of tryponosomiasis in inbred strains of mice enabled the quantitative analysis (QTL) of the trait in genetic crosses. The C57BL/6 strain is relatively resistant compared to the more susceptible strains BALB/cand A/J.

Linkage analysis was performed on F2 mice from both a (BALB/cOlaHsd x C57BL/6JOlaHsd)F2 cross and an (A/JOlaHsd x C57BL/6JOlaHsd)F2 cross. Genotyping was performed on mice with long and those with short survival times selecting for informative microsatellite markers providing coverage of all 19 autosomes and the X chromosome.

Analysis of the (BALB/cOlaHsd x C57BL/6JOlaHsd)F2 cross revealed 3 regions with significant LOD scores.

QTL Tir1 mapped to a region of Chromosome 17 between flanking markers D17Mit135 and D17Mit7 with a LOD score of 11.0 [Fig.1]. Tir1 had an additive effect on survival time and accounted for 14.6% of the variation. D17Mit36 mapped nearest the peak LOD score.

QTL Tir2 mapped to a region of Chromosome 5 between flankingmarkers D5Mit233 and D5Mit10 with a LOD score of 4.6 [Fig.1]. Tir2 also had a significant association with survival time with the resistance allele found to be fully dominant, accounting for 6.7% of the variation. D5Mit58 mapped nearest the peak LOD score.

QTL Tir3 mapped to a region of Chromosome 1 between flanking markers D1Nds2 and D1Mit17 with a LOD score of 5.7 [Fig.1]. This QTL had a additive effect and accounted for 8.9% of the variation. D1Mit425 mapped nearest the peak LOD score.

Analysis of the(A/JOlaHsd x C57BL/6JOlaHsd)F2 cross revealed 2 regions with significant LOD scores on both Chromosome 17 and Chromosome 5. The positions of both QTL appeared to be close to those mapped in (BALB/cOlaHsd x C57BL/6JOlaHsd)F2 cross.

5.27.2015 - Curators Note. Because the second cross here differs from the first we regard the second cross as a separate mapping experiment have have assigned the QTL identified on Chromosomes 17 and 5 with unique identifiers.

In the (A/JOlaHsd x C57BL/6JOlaHsd)F2 cross QTL Tir4 mapped to a region of Chromosome 17 flanked by markers D17Mit28 and D17Mit68 with a LOD score of 9.3 [Fig.1]. Tir4 accounted for 9% of the total variance. D17Mit52 mapped nearest the peak LOD score. The resistance allele was recessive.

In the same cross QTL Tir5 mapped to a region of Chromosme 5 between flanking markers D5Mit255 and D5Mit24 with a LOD score of 3.6 [Fig.1]. Tir5 accounted for 3.9% of the variance and the resistance allele was recessive.

A QTL on Chromosome 1 in the (A/JOlaHsd x C57BL/6JOlaHsd)F2 cross did not acheive significance.

J:63779

A further refined mapping for loci responsible for trypanosomiasis resistance in mice was achieved using advanced intercross lines. Advanced intercross lines were constructed by breeding the progeny from resistant C57BL/6JOlaHsd mice with susceptible mice from both the A/JOlaHsd and the BALBc/OlaHsd strains respectively. Phenotyping, genotyping, and linkage analysis was performed on the G6 progeny designated (B/B6)G6 and (A/B6)G6.

Table 1:

Chromosome 17

In the BALBc/OlaHsd x C57BL/6JOlaHsd G6, (B/B6)G6, population of 892 mice a previoulsy indentified QTL, Tir1 [J:40771], mapped to mouse Chromosome 17 at 18.2 cM nearest marker D17Mit16 (LOD 20.08). The 95% confidence interval was refined to 2.8 cM.

In the A/JOlaHsd x C57BL/6JOlaHsd G6, (A/B6)G6, population of 1986 mice a previoulsy identified QTL, Tir4 [J:40771] mapped to 17.9 cM nearest marker D17Mit175, (LOD 19.35). The 95% confidence interval was refined to 1.3 cM.

Analysis of the combined G6 populations provided an association nearest marker D17Mit16 (LOD 37.56). The 95% confidence interval in the combined data was refined further to 0.9 cM.

Chromosome 5

On mouse Chromosome 5 in the A/JOlaHsd x C57BL/6JOlaHsd G6 population a previously identified QTL, Tir5 [J:40771], mappped to 42.0 cM nearest marker D5Mit113 (LOD 4.63). The 95% confidence interval spanned 16 cM.

In the BALBc/OlaHsd x C57BL/6JOlaHsd G6 population, the previously identified Tir2 QTL identified on Chromosome 5 using the same strains [J:40771] did not acheive significance.

When the data from both Chromosome 5 G6 poulations was combined a peak was detected near D5Mit114 with a LOD score of 5.46 and a 95% confidence interval spanning 12 cM.

Chromosome 1

The Tir3 QTL previoulsy identified in J:98907 using an F2 cross, of the same strains used here, was resolved into 3 distinct QTL in the BALBc/OlaHsd x C57BL/6JOlaHsd G6 population.

Tir3a mapped to 60.0 cM nearest marker D1Mit87 with a LOD score of 4.15 and a 95% confidence interval spanning 9cM.

Tir3b mapped to 74.0 cM nearest markers D1Mit286 and D1Mit268 with a LOD score of 5.88 and a 95% confidence interval spanning 11 cM.

Tir3c mapped to 92.0 cM nearest marker D1Mit113 with a LOD score of 3.78 and a 95% confidence interval spanning 9.0 cM.

5.28.2015 Curators Note - The 3distinct QTL mapped on Chromosome 1 using the A/JOlaHsd x C57BL/6JOlaHsd G6 population represent 3 unique QTL not previously mapped using these strains. We consider this a separate mapping experiment and have named the larger QTL region Tir6 spanning a region for 62.5-96.0 cM encompassing Tir6a, Tir6b and Tir6c [Table 1.].

Tir6a mapped to 62.5 cM nearest marker D1Nds2 with a LOD score of 8.07 and a 95% confidence interval of 0.7 cM.

Tir6b mapped to 70.0 cM nearest markers D1Mit286 and D1Mit102 with a LODscore of 6.8 and a 95% confidence interval spanning 16 cM.

Tir6c mapped to 96.0cM nearest D1Mit16 with a LOD score of 5.49 and a 95% confidence interval spanning 18 cM.

Combining the data from the differing G6 populations for Tir3a and Tir6a resulted in a LOD score of 9.94 nearest D1Nds2 with a 95% confidence interval of 1.8 cM.

Combining the data from the differing G6 populations for Tir3b and Tir6b resulted in a LODscore of 11.3 nearest markers D1Mit286 and D1Mit102 with a 95% confidence interval spanning 10 cM.

Combining the data from the differing G6 populations for Tir3c and Tir6c resulted in a LOD score of 7.62 nearest D1Mit113 with a 95% confidence interval of 8 cM.

J:66474

Four backcross populations [(C57BL/6JOlaHsd x BALB/cOlaHsd)F1 x BALB/cOlaHsd, BALB/cOlaHsd x (C57BL/6JOlaHsd x BALB/cOlaHsd)F1, (BALB/cOlaHsd x C57BL/6JolaHsd)F1 x BALB/cOlaHsd, and BALB/cOlaHsd x (C57BL/6JOlaHsd x BALB/cOlaHsd)F1] were used to assess the effect of imprinting at loci involved in trypanosomiasis survival (Tir1, Tir2, and Tir3).

Tir1 showed significant linkage for trypanosomiasis survival time with parent of origin at D17Mit16 (LOD = 5.9). Animals from BALB/cOlaHsd fathers and (C57BL/6JOlaHsd x BALB/cOlaHsd)F1 or (C57BL/6JOlaHsd x BALB/cOlaHsd)F1 mothers exhibited higher survival rates than animals from (C57BL/6JOlaHsd x BALB/cOlaHsd)F1 or (C57BL/6JOlaHsd x BALB/cOlaHsd)F1 fathers and BALB/cOlaHsd mothers. Authors speculate that genomic imprinting may play a role in trypanosomiasis survival at Tir1.

Tir3 showed suggestive linkage for trypanosomiasis survival time and parent of origin at D1Mit102 (LOD = 2.2-2.8), and Tir2 was not detected for linkage to survival time and parent of origin.

J:98907

Linkage analysis was performed on 400 (BALB/cOlaHsd x C57BL/6JOlaHsd)F2 animals to identify QTL associated with resistance/susceptibility to trypanosomiasis. F2 animals were innoculated with T.congolense at 10-12 weeks of age. Parental strain BALB/cOlaHsdis susceptible to infection by T.congolense whereas parental strain C57BL/6JOlaHsd is resistant. 90 polymorphic markers were initially screened in a subset of F2 animals in the extreme 5% phenotype range. Subsequently the screen was expanded to F2 animals in the extreme 16% phenotype range using 120 polymorphic markers. The 3 loci that were identified together account for 32% of the variance.

Significant linkage to survival time mapped to a broad region of mouse Chromosome 17 (LOD=11). This locus is named Tir1 (trypanosome infection response 1). A two locus model yields a higher LOD score (LOD=15.1). Tir1 exhibits additive inheritance and explains 18% of the variance. The H2 locus maps to this region.

Significant linkage to survival time mapped to mouseChromosome 5 with LOD=4. This locus is named Tir2 (trypanosome infection response 2). Tir2 explains 6.1% of the variance. No known candidate genes have been identified for this QTL.

Significant linkage to survival time mapped to mouse Chromosome 1 withLOD=5. This locus is named Tir3 (trypanosome infection response 3). Resistanceto T.congolense shows dominant inheritance at Tir3. This QTL explains 10% of the variance. No known candidate genes have been identified for this QTL.

References

• Original: J:40771 Kemp SJ, et al., Localization of genes controlling resistance to trypanosomiasis in mice. Nat Genet. 1997 Jun;16(2):194-6
• All: 4 reference(s)