Insights from Transgressive Trait Analysis in Consomic Mice: CCR7 Links B-Cell Maturation with Hyper-IgM Phenotype

Mice carrying single chromosome substitutions (consomic mice) provide a unique platform for investigating complex phenotypes. A proportion of such phenotypes fall into the category of transgressive phenotypes, i.e. heritable extreme phenotypes lying outside the range of either parent. We hypothesized that analysis of transgressive phenotype in consomic mice potentially reveals unique cellular and molecular signatures associated with extreme phenotypic variations. We used a system-biology approach to build a reference set of 571 transgressive phenotypes in consomic mice using phenome metadata and additional 13 B-cell specific transgressive phenotypes using experimental data. As a proof of concept, we investigated clinically-relevant hyper-IgM phenotype. A combination of flow-cytometry, RNA-Sequencing and in-vitro validation confirmed that the hyper-IgM is associated with defective B-cell lymphopoiesis at the cellular and the down-regulation of the CCR7 gene at the molecular level. Our approach provides a complete pipeline to discover and validate transgressive phenotypes relevant to health and disease conditions.