Stsl7^{CC042/GeniUnc}
QTL Variant Detail

Summary

• QTL variant: Stsl7^{CC042/GeniUnc}
• Name: Salmonella typhimurium susceptibility locus 7; CC042/GeniUnc
• MGI ID: MGI:6446911
• QTL: Stsl7 Location: Chr7:115699235-128501724 bp Genetic Position: Chr7, Syntenic

Variant origin

• Strain of Specimen: CC042/GeniUnc

Variant description

• Allele Type: QTL
• Inheritance: Not Specified

Notes

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

J:291046

QTL Reference Notes

The Collaborative Cross (CC) is a large (~1,000 line) panel of recombinant inbred (RI) mouse strains being developed through a community effort (Churchill et al. 2004). The CC combines the genomes of eight genetically diverse founder strains - A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ - to capture nearly 90% of the known variation present in laboratory mice. CC strains are derived using a unique funnel breeding scheme. Once inbred, the RI CC lines can be used to generate thousands of potential 'outbred' but completely reproducible genomes through the generation of recombinant inbred crosses (RIX). The designation 'PreCC' is used to describe a mapping population of CC mice that is still at incipient stages of inbreeding. CTC (2004), Churchill, G. A., et al.. The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nat Genet. 36, 1133-7.

Salmonella is an intracellular bacterium found in the gastrointestinal tract of mammalian, avian, and reptilian hosts. The authors have investigated the susceptibility of Collaborative Cross (CC) strains to intravenous infection with Salmonella enterica serovar Typhimurium as a model of human systemic invasive infection.

In this model, strain CC042/GeniUnc (CC042) mice displayed extreme susceptibility with very high bacterial loads and mortality. CC042 mice showed lower spleen weights and decreased splenocyte numbers before and after infection, affecting mostly CD8 T cells, B cells, and all myeloid cell populations, compared with control C57BL/6J mice. CC042 mice also had lower thymus weights with a reduced total number of thymocytes and double-negative and double-positive (CD4, CD8) thymocytes compared to C57BL/6J mice. Analysis of bone marrow-resident hematopoietic progenitors showed a strong bias against lymphoid-primed multipotent progenitors.

An F2 cross between CC042 and C57BL/6NCrl mice identified two loci associated with differences in bacterial loads:

Stsl6 (Salmonella typhimurium susceptibility locus 6) maps to Chr 7: 34.5 - 51.5 Mb with a peak LOD score of 4.50 at 46.23 Mb (29.66 cM; BackupUNC070497127). Stsl6 showed a semidominant mode of inheritance, with heterozygotes having a bacterial load intermediate between those of the two types of homozygotes. Stsl6 accounts for 19.8% of trait variance.

Stsl7 (Salmonella typhimurium susceptibility locus 7) maps to Chr 7: 116.1 - 128.9 Mb with a peak LOD score of 4.06 at 123.78 Mb (67.42 cM; BackupJAX00654337). Homozygotes at Stsl7 had 10 times higher liver bacterial loads, with alleles inherited in a recessive manner. Stsl7 accounts for 18% of trait variance.

CC042 mice inherited the Stsl6 and Stsl7 QTL regions from the WSB/EiJ founder. Other CC strains also inherited WSB/EiJ alleles in either or both QTL regions but had much lower bacterial loads than CC042 mice. In particular, CC035 mice also carried WSB/EiJ-derived alleles at Stsl6 and Stsl7. This result suggests that the susceptibility alleles present at these two loci in CC042 mice could result from de novo mutations which occurred during the development of the CC042 strain. These private variants have been previously identified by the sequencing of CC strains and are publicly available (Srivastava, 2017).

Three private variants were identified in the Stsl6 confidence interval in genes Ush1c, Ccdc123, and 4930435C17Rik.

In the Stsl7 region, CC042 carried a loss-of-function variant, unique to this strain, in the integrin alpha L (Itgal) gene, the causative role of which was confirmed by a quantitative complementation test. Notably, Itgal loss of function increased the susceptibility to S. Typhimurium in a (C57BL/6J x CC042)F1 mouse background but not in a C57BL/6J mouse inbred background.

References

• Original: J:291046 Zhang J, et al., A Loss-of-Function Mutation in the Integrin Alpha L (Itgal) Gene Contributes to Susceptibility to Salmonella enterica Serovar Typhimurium Infection in Collaborative Cross Strain CC042. Infect Immun. 2019 Dec 17;88(1)
• All: 1 reference(s)