Abstract
The Collaborative Cross (CC) is an emerging panel of recombinant inbred mouse strains. Each strain is genetically distinct but all descended from the same eight inbred founders. In 66 strains from incipient lines of the CC (pre-CC), as well as the 8 CC founders and some of their F1 offspring, we examined subsets of lymphocytes and antigen-presenting cells. We found significant variation among the founders, with even greater diversity in the pre-CC. Genome-wide association using inferred haplotypes detected highly significant loci controlling B-to-T cell ratio, CD8 T-cell numbers, CD11c and CD23 expression. Comparison of overall strain effects in the CC founders with strain effects at QTL in the pre-CC revealed sharp contrasts in the genetic architecture of two traits with significant loci: variation in CD23 can be explained largely by additive genetics at one locus, whereas variation in B-to-T ratio has a more complex etiology. For CD23, we found a strong QTL whose confidence interval contained the CD23 structural gene Fcer2a. Our data on the pre-CC demonstrate the utility of the CC for studying immunophenotypes and the value of integrating founder, CC, and F1 data. The extreme immunophenotypes observed could have pleiotropic effects in other CC experiments.
Highlights
Understanding the genetics of the immune system has been critical in unraveling the mechanisms of the major questions in immunology of the past 50 years, including those regarding antibody diversity, T-cell recognition and the function of the major histocompatibility complex
Production of the Collaborative Cross (CC) population was initiated in 2005.10–12 Three different cohorts of CC mice are in existence,[5] and our analysis focuses only on strains initiated at The Oak Ridge National Laboratory (ORNL)
In agreement with the additive effects observed in the incomplete diallel, we found that F1 hybrids from crosses of the low-CD23 strains with B6 have a CD23 Mean Fluorescence Intensity (MFI) which is significantly higher than the low-CD23 strains
Summary
Understanding the genetics of the immune system has been critical in unraveling the mechanisms of the major questions in immunology of the past 50 years, including those regarding antibody diversity, T-cell recognition and the function of the major histocompatibility complex. The resulting CC lines, each bred from a structured and randomized combination of these eight founders, surpass any available RI panel in genetic diversity, number of recombination events (and potential QTL mapping resolution) and eventually in number of available strains.[6,7,8,9] From an experimental design perspective, the CC offers greater reproducibility and balance than outbred populations of similar genetic diversity. Analysis of incipient CC strains (pre-CC) from ORNL demonstrated balanced allele frequencies and well-distributed recombination events.[13]
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