Copied to clipboard!

PTA_thyroid__RNA_

Exploring the somatic mutations in single cells derived from the thyroid

Type: Transcriptome Analysis
Archiver: European Genome-phenome Archive (EGA)

1 Dataset 1 Publication

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001016063	Our immune system contains multiple tolerance checkpoints to prevent the activation of self-reactive lymphocytes. How some lymphocytes escape these constraints to cause autoimmune disease remains poorly understood. A long-standing hypothesis in autoimmunity posits that somatic mutations in immune regulatory genes may enable self-reactive lymphocytes to bypass tolerance checkpoints. However, testing this hypothesis has proved challenging due to technical limitations in detecting somatic mutations in polyclonal cell populations. Here, we use deep whole-exome and targeted NanoSeq, a highly accurate single-molecule DNA sequencing protocol, to comprehensively search for driver mutations in autoimmune thyroid disease. This revealed a remarkably high number of B cell clones convergently acquiring loss-of-function somatic mutations in key immune checkpoint genes TNFRSF14 (also known as HVEM) and CD274 (encoding PD-L1), as well as less frequent driver mutations in a diversity of other immune genes. In highly inflamed biopsies, we detected tens to hundreds of independent immune-checkpoint mutant clones. Laser capture microdissection, methylation sequencing, spatial transcriptomics, immunohistochemistry and single-nucleus DNA sequencing localised these mutations to non-naive B cells and revealed frequent co-occurrence of drivers in single cells. We found widespread TNFRSF14 biallelic loss in mutant B cells, and several clones with as many as 4-6 driver mutations. Whilst each clone accounts for a small proportion of cells (typically <1%), the myriad mutant clones in each donor collectively amounted to a substantial fraction of B cells harbouring one or more driver mutations. Our results support the hypothesis that somatic mutations in autoimmune lymphocytes may allow them to escape tolerance constraints through a polyclonal cascade of somatic evolution. These findings provide new insights into the molecular basis of autoimmune disease and suggest novel diagnostic and therapeutic avenues.	Illumina NovaSeq 6000	1

Publications	Citations
Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity. Nicola PA, Lawson ARJ, Tidd A, Imbert J, Ishida Y, Wylie LA, Scott PA, Roberts K, Harvey LMR, Lensing SV, Cheng W, Abascal F, Leongamornlert D, Hooks Y, Mayho M, Müller-Sienerth N, Widaa S, Mincarelli L, Illing J, Peci F, Ng BL, Jarman GL, Russell AJC, Mahbubani KTA, Saeb-Parsy K, Paterson AL, Chatterjee K, Rahbari R, Bayraktar OA, Stratton MR, Campbell PJ, Tadross JA, Schoenmakers N, Martincorena I. Nature 654: 2026 131-141	2

Publications

Citations

Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity.
Nicola PA, Lawson ARJ, Tidd A, Imbert J, Ishida Y, Wylie LA, Scott PA, Roberts K, Harvey LMR, Lensing SV, Cheng W, Abascal F, Leongamornlert D, Hooks Y, Mayho M, Müller-Sienerth N, Widaa S, Mincarelli L, Illing J, Peci F, Ng BL, Jarman GL, Russell AJC, Mahbubani KTA, Saeb-Parsy K, Paterson AL, Chatterjee K, Rahbari R, Bayraktar OA, Stratton MR, Campbell PJ, Tadross JA, Schoenmakers N, Martincorena I. Nature 654: 2026 131-141