Send to

Choose Destination
Genome Res. 2019 Nov 6. pii: gr.247882.118. doi: 10.1101/gr.247882.118. [Epub ahead of print]

Clonal copy-number mosaicism in autoreactive T lymphocytes in diabetic NOD mice.

Author information

McGill University Health Centre Research Institute, Sultan Qaboos University.
McGill University Health Centre Research Institute.
University of Toronto, Princess Margaret Cancer Centre.
McGill University Health Centre Research Institute;


Concordance for type 1 diabetes is far from 100% in monozygotic twins and in the inbred NOD mice, despite genetic identity and shared environment during incidence peak years. This points to stochastic determinants such as post-zygotic mutations (PZMs) in the expanding antigen-specific autoreactive T cell lineages, by analogy to their role in the expanding tumor lineage in cancer. Using comparative genomic hybridization of DNA from pancreatic lymph-nodes memory CD4+ T cells of 25 diabetic NOD mice, we found lymphocyte-exclusive mosaic somatic copy-number aberrations (CNAs) with highly nonrandom independent involvement of the same gene(s) across different mice, some with an autoimmunity association (ex: Ilf3 and Dgka). We confirmed genes of interest using the gold standard approach for CNA quantification, Multiplex ligation-dependent probe amplification (MLPA), as an independent method. As controls, we examined lymphocytes expanded during normal host defense (17 NOD and BALB/c mice infected with Leishmania major parasite). Here, CNAs found were fewer and significantly smaller compared to those in autoreactive cells (P= 0.0019). We determined a low T cell clonality for our samples suggesting a pre-thymic formation of these CNAs. In this study, we are describing a novel, unexplored phenomenon of a potential causal contribution of PZMs in autoreactive T cells in T1D pathogenesis. We expect that further exploration of point mutations and studies in human T cells will enable the further delineation of driver genes to target for functional studies. Our findings challenge the classical notions of autoimmunity and open conceptual avenues toward individualized prevention and therapeutics.

Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center