Mapping Data

Experiment

• Experiment
  TEXT-QTL
• Chromosome
  X
• Reference
  J:265478 Graham JB, et al., Extensive Homeostatic T Cell Phenotypic Variation within the Collaborative Cross. Cell Rep. 2017 Nov 21;21(8):2313-2325
• ID
  MGI:6828795

Genes

Gene	Assay Type
Hiq1	visible phenotype
Hiq2	visible phenotype
Hiq3	visible phenotype
Hiq4	visible phenotype
Hiq5	visible phenotype

Notes

• Reference
  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.
• Experiment
  In seeking to understand the complex interactions and pathways of the human immune response, researchers have long turned to inbred mouse models. Here, the authors describe variations in cellular immune phenotypes across F1 crosses of Collaborative Cross (CC) strains and reveal quantitative trait loci (QTL) responsible for several immune phenotypes.
  
  The authors conducted a comprehensive screen of 113 CC-RIX lines (derived from CC#/Unc mice) for immune response phenotypes.
  
  CC#/Unc-RIX lines were bred to ensure that lines were heterozygous for the H-2b locus, having one copy of the H-2b^b haplotype and one copy of the other various haplotypes at the MHC locus. This design was selected so that the authors could examine antigen-specific T cell responses for parallel studies of immunogenetics of virus infection while concurrently maintaining genetic variation throughout the rest of the genome. Through the screen, three to six adult, 8- to 10-week-old male mice were examined for each CC-RIX line, and the authors measured and cataloged an extensive list of T cell phenotypes within the spleen at steady state with no experimental manipulations. The range of phenotypes included frequency of T cell subsets, proportion of cells expressing various activation markers, frequency of cells producing inflammatory cytokines, and quantity of cells expressing tissue migration markers.
  
  The authors performed principal-component analysis (PCA) using the flow cytometry measures listed in Table S4 (using strain average values) and then plotted the top two principal components (PCs) to show strain clustering within these composite immune phenotypes. The authors performed QTL mapping on select T cell phenotypes using flow cytometry data in combination with haplotype reconstructions of the CC strains generated from the mouse universal genotyping array (MegaMUGA) platform (Morgan et al., 2015).
  
  Five significant QTL were identified (genome coordinates relative to GRCm38/mm10):
  
  Hiq1 (host immunity QTL 1, frequency of CD73+ Tregs) maps to Chr X: 160 Mb - telomere. PWK/PhJ contributes the high allele at Hiq1.
  
  Hiq2 (host immunity QTL 2, frequency of CXCR3+ Tregs) maps to Chr X: 100 - 106 Mb. PWK/PhJ contributes the low allele at Hiq2. When there is a PWK/PhJ allele present at 105.5 Mb, there is also an NZO/HlLtJ haplotype increasing CXCR3+ Tregs at Hiq2.
  
  Hiq3 (host immunity QTL 3, frequency of CXCR3+ CD4+ T cells) maps to Chr X: 100 - 106 Mb. PWK/PhJ contributes the low allele at Hiq3.
  
  Hiq4 (host immunity QTL 4, frequency of CXCR3+ CD8+ T cells) maps to Chr X: 100 - 106 Mb. PWK/PhJ contributes the low allele at Hiq4. When there is a PWK/PhJ allele present at 105.5 Mb, there is also a WSB/EiJ haplotype associated with increased CXCR3+ CD8+ T cells.
  
  Hiq5 (host immunity QTL 5, frequency of ICOS+ Tregs) maps to Chr X: 140 - 145 Mb. PWK/PhJ contributes the high allele at Hiq5.
  
  Although Hiq5 does not meet the threshold for statistical significance in the analysis, the allele effects are clear: the PWK/PhJ haplotype was associated with an increased frequency of ICOS+ Tregs also appeared to be a second, NZO/HlLtJ allele that had an intermediate increase in ICOS+ Tregs relative to the other six haplotypes. We have designiated this QTL Hiq5:
  
  Candidate genes for Hiq1-5 are given in Table 1 (note that Hiq3 does not appear in the table).