Using the Collaborative Cross and Diversity Outbred Mice in Immunology

Abstract

The Collaborative Cross (CC) and the Diversity Outbred (DO) stock mouse panels are the most powerful murine genetics tools available to the genetics community. Together, they combine the strength of inbred animal models with the diversity of outbred populations. Using the 63 CC strains or a panel of DO mice, each derived from the same 8 parental mouse strains, researchers can map genetic contributions to exceptionally complex immunological and infectious disease traits that would require far greater powering if performed by genome‐wide association studies (GWAS) in human populations. These tools allow genes to be studied in heterozygous and homozygous states and provide a platform to study epistasis between interacting loci. Most importantly, once a quantitative phenotype is investigated and quantitative trait loci are identified, confirmatory genetic studies can be performed, which is often problematic using the GWAS approach. In addition, novel stable mouse models for immune phenotypes are often derived from studies utilizing the DO and CC mice that can serve as stronger model systems than existing ones in the field. The CC/DO systems have contributed to the fields of cancer immunology, autoimmunity, vaccinology, infectious disease, allergy, tissue rejection, and tolerance but have thus far been greatly underutilized. In this article, we present a recent review of the field and point out key areas of immunology that are ripe for further investigation and awaiting new CC/DO research projects. We also highlight some of the strong computational tools that have been developed for analyzing CC/DO genetic and phenotypic data. Additionally, we have formed a centralized community on the CyVerse infrastructure where immunogeneticists can utilize those software tools, collaborate with groups across the world, and expand the use of the CC and DO systems for investigating immunogenetic phenomena. © 2022 Wiley Periodicals LLC.

Mt10 Vaccine Protects Diversity Outbred Mice from CVB3 Infection by Producing Virus-Specific Neutralizing Antibodies and Diverse Antibody Isotypes

“…We previously reported the efficacy of the Mt10 vaccine virus in various inbred mouse models of myocarditis and T1D [ 15 , 16 , 17 ]. In this report, we evaluated the vaccine responses in DO mice, given their extensive genetic diversity comparable to an outbred human population [ 25 , 31 ]. Prior to testing the vaccine efficacy, it was necessary to titrate the viral dose to induce infection in the DO mice.…”

“…Of note, other outbred mouse strains such as CF-1, CD-1, NMRI, and Swiss outbred mice, are derived from a single branch of the mouse family tree and are not bred for maximum diversity. The DO mice on the other hand, were derived from all seven branches of the mouse family tree and are bred to maximize the genetic diversity comparable to the human population [ 24 , 25 , 49 , 50 ]. Thus, observations made in the DO mice may be translationally significant because they occur across a range of genetic backgrounds rather than in a single, inbred strain.…”

“…Furthermore, all eight founder strains capture single nucleotide polymorphisms (SNPs) and insertions/deletions at approximately four times the number of SNPs found in inbred mice [ 24 ]. Therefore, the DO mice carry a level of genetic diversity comparable with the human population, thus offering enormous genetic heterozygosity and allelic diversity to investigate vaccine responses that may have translational significance [ 25 ]. In this study, after establishing the CVB3 infection model, we evaluated the efficacy of Mt10, leading us to note that the vaccine provides complete protection in challenge studies with CVB3.…”

The knowns and unknowns of cardiac autoimmunity in viral myocarditis

“…To overcome this limitation, two genetically diverse mouse lines have been developed, namely, collaborative cross (CC) and diversity outbred (DO) mice. 230,231 Both CC and DO mice represent the genetic composition of eight different inbred mouse strains (five classic inbred and three wild-derived inbred). 230,231 We recently used the DO mice to investigate the development of myocarditis in response to CVB3 infection, and, as expected, only a small percentage of DO mice showed heart infiltrates despite developing pancreatitis (manuscript in preparation).…”

“…This limitation further complicates the relatability of the observations made in inbred mouse strains to the outbred human population, because testing in one inbred mouse strain is genetically akin to testing in a single person. To overcome this limitation, two genetically diverse mouse lines have been developed, namely, collaborative cross (CC) and diversity outbred (DO) mice 230,231 . Both CC and DO mice represent the genetic composition of eight different inbred mouse strains (five classic inbred and three wild‐derived inbred) 230,231 .…”