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Evidence of genetic epistasis in autoimmune diabetes susceptibility revealed by mouse congenic sublines

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Abstract

Susceptibility to autoimmune diabetes is a complex genetic trait. Linkage analyses exploiting the NOD mouse, which spontaneously develops autoimmune diabetes, have proved to be a useful tool for the characterization of some of these traits. In a linkage analysis using 3A9 TCR transgenic mice on both B10.BR and NOD.H2k backgrounds, we previously determined that both the Idd2 and Idd13 loci were linked to the proportion of immunoregulatory CD4-CD8- double negative (DN) T cells. In addition to Idd2 and Idd13, five other loci showed weak linkage to the proportion of DN T cells. Of interest, in an interim analysis, a locus on chromosome 12 is linked to DN T cell proportion in both the spleen and the lymph nodes. To determine the impact of this locus on DN T cells, we generated two congenic sublines, which we named Chr12P and Chr12D for proximal and distal, respectively. While 3A9 TCR:insHEL NOD.H2k-Chr12D mice were protected from diabetes, 3A9 TCR:insHEL NOD.H2k-Chr12P showed an increase in diabetes incidence. Yet, the proportion of DN T cells was similar to the parental 3A9 TCR NOD.H2k strain for both of these congenic sublines. A genome-wide two dimensional LOD score analysis reveals genetic epistasis between chromosome 12 and the Idd13 locus. Altogether, this study identified further complex genetic interactions in defining the proportion of DN T cells, along with evidence of genetic epistasis within a locus on chromosome 12 influencing autoimmune susceptibility.

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Acknowledgements

We thank all of the animal house staff for aid in maintaining the mouse colonies used in this study.

Funding

This work was supported by the Canadian Diabetes Association (Grant OG-3-13-4018) and the Canadian Institutes of Health Research (Grant PJT 159603) to SL. RC and ANP received scholarships from Diabète Québec and l’Université de Montréal. RC and VD received scholarships from the Fonds de recherche Québec-Santé. SL is a Research Scholars Emeritus from the Fonds de recherche Québec -Santé.

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Author notes

  1. Roxanne Collin

    Present address: CellCarta, 201 President Kennedy Avenue, Suite 3900, Montreal, Quebec, H2X 3Y7, Canada

Authors and Affiliations

  1. Cellular Immunogenetics laboratory, Division of Immunology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, H1T 2M4, Canada

    Roxanne Collin, Véronique Dugas, Geneviève Chabot-Roy & Sylvie Lesage

  2. Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montreal, Quebec, H3C 3J7, Canada

    Roxanne Collin, Véronique Dugas & Sylvie Lesage

  3. RPM Bioinfo Solutions inc, 97 Montcalm, Blainville, J7C 2R7, Canada

    Adam-Nicolas Pelletier

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  1. Roxanne Collin
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Contributions

RC acquired data, analyzed data, participated in the elaboration of the experimental plan, prepared the figures, and corrected and approved the manuscript. VD acquired data, generated the congenic mice, participated in the elaboration of the experimental plan, and corrected and approved the manuscript. ANP acquired data, analyzed data, participated in the elaboration of the experimental plan, and corrected and approved the manuscript. GCR acquired data and corrected and approved the manuscript. SL participated in the elaboration of the experimental plan, supervised the study, and wrote the manuscript.

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Correspondence to Sylvie Lesage.

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The Maisonneuve-Rosemont Hospital ethics committee, overseen by the Canadian Council for Animal Protection, approved the experimental procedures.

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Collin, R., Dugas, V., Pelletier, AN. et al. Evidence of genetic epistasis in autoimmune diabetes susceptibility revealed by mouse congenic sublines. Immunogenetics 73, 307–319 (2021). https://doi.org/10.1007/s00251-021-01214-9

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