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

52 Pages Posted: 2 May 2019 Publication Status: Review Complete

See all articles by Manish Kumar

Manish Kumar

European Molecular Biology Laboratory (EMBL) - Rome - Epigenetics and Neurobiology Unit

Andreas Buness

European Molecular Biology Laboratory (EMBL) - Rome - Epigenetics and Neurobiology Unit

Andreas Hierhholzer

European Molecular Biology Laboratory (EMBL) - Rome - Epigenetics and Neurobiology Unit

Andrea Cerase

European Molecular Biology Laboratory (EMBL) - Rome - Epigenetics and Neurobiology Unit

Anton Enright

European Bioinformatics Institute

Phil Avner

European Molecular Biology Laboratory (EMBL) - Rome - Epigenetics and Neurobiology Unit

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Abstract

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.

Keywords: Transgressive Phenotypes, Consomic Mice, Chromosomal Substitution Strains, IgM, Immunoglobulin-M, B-cells, CCR7

Suggested Citation

Kumar, Manish and Buness, Andreas and Hierhholzer, Andreas and Cerase, Andrea and Enright, Anton and Avner, Phil, Insights from Transgressive Trait Analysis in Consomic Mice: CCR7 Links B-Cell Maturation with Hyper-IgM Phenotype (April 30, 2019). Available at SSRN: https://ssrn.com/abstract=3379973 or http://dx.doi.org/10.2139/ssrn.3379973
This version of the paper has not been formally peer reviewed.

Manish Kumar (Contact Author)

European Molecular Biology Laboratory (EMBL) - Rome - Epigenetics and Neurobiology Unit

Italy

Andreas Buness

European Molecular Biology Laboratory (EMBL) - Rome - Epigenetics and Neurobiology Unit ( email )

Italy

Andreas Hierhholzer

European Molecular Biology Laboratory (EMBL) - Rome - Epigenetics and Neurobiology Unit ( email )

Italy

Andrea Cerase

European Molecular Biology Laboratory (EMBL) - Rome - Epigenetics and Neurobiology Unit ( email )

Italy

Anton Enright

European Bioinformatics Institute ( email )

Cambridge
United Kingdom

Phil Avner

European Molecular Biology Laboratory (EMBL) - Rome - Epigenetics and Neurobiology Unit ( email )

Italy