Thank you very much, Alex!!

Hidden mutations in immune cells linked to autoimmune disease Mutations in immune cells may be the missing piece in the autoimmune disease puzzle.

Here is the press release too, with some lovely words from Goodnow. [end] www.sanger.ac.uk/news_item/hi...

This project has been a remarkable collective effort by many people, in my group and beyond (huge thanks to all!), and particularly by Pan Nicola and Andrew Lawson. Special thanks to the patients for donating their samples. [24/]

Please read the paper if you are interested. We have tried to present the data as clearly as we could, while trying to cautiously acknowledge the many unknowns and limitations. We hope you enjoy it as much as we did. [23/] rdcu.be/fdqbr

... success of deep B cell depletion therapies, etc. More importantly, if these mutations play an important role in the pathogenesis of autoimmune diseases (which will need to be confirmed by more studies!), autoimmune diseases could be open to oncology-like precision medicine. [22/]

If true, a polyclonal cascade model could explain several clinical observations, such as (1) the increased risk of MALT lymphoma in Hashimoto (same drivers!), (2) the long subclinical evolution of some autoimmune diseases, (3) epitope spreading, (4) the unexpected... [21/]

Whereas additional studies are needed, our results support Burnet's/Goodnow's hypotheses. Somatic mutations in autoimmune lymphocytes may allow them to escape tolerance constraints through a polyclonal cascade of somatic evolution. [20/]

The paper packs many other goodies, like mutational signature analyses (suggesting much more frequent germinal centre reactions in mutant clones) and antibody synthesis (showing multiple mutant clones to be self-reactive against TPO/TG). Even a supplementary note with Burnet's old ideas. [19/]

Whilst each clone accounts for a small fraction of cells (typically <1%), the myriad mutant clones in each donor amounted to a substantial fraction of B cells harbouring driver mutations, although variably across patients. [18/]

Using this single-nucleus whole-genome data, we reconstructed a phylogeny showing that some clones had accrued 5-6 driver mutations (including quadruple loss of TNFRSF14 and CD274/PDL1) over many years (even decades) of silent evolution before diagnosis. [17/]

Many of these biallelic losses were due to truncating point mutations followed by copy number loss of the other allele, revealing very frequent copy number changes in autoimmune B cells. [16/]

We then applied new single-nucleus whole-genome sequencing (PTA) to cells from 3 donors and found a staggering landscape of multihit acquisition in B cells, with widespread TNFRSF14 biallelic loss, and clones with 4-6 driver mutations (highly unexpected outside of cancer). [15/]

Using laser microdissection as well as spatial transcriptomics, we mapped these mutations to clonal germinal centres (TLS) and to plasma cells. Remarkably, many germinal centres were taken over by a single mutant clone. [14/]

These genes are causally linked to thyroid autoimmunity, as shown by GWAS, mouse models, and by the common occurrence of thyroiditis in cancer patients treated with PDL1 inhibitors. We now see these mutations occurring in great numbers in autoimmune thyroid patients. [13/]

These two immune checkpoint genes are very special as they ensure that self-reactive B cells are kept silenced. By losing these genes through somatic mutations, these B cells hijack T cell help and are stimulated to expand. [12/]

We then extended this to 14 patients, including early disease cases, finding convergent selection on many immune regulatory genes across donors. Specifically, we found highly convergent loss of TNFRSF14 (aka HVEM) and CD274 (PD-L1) genes in B cells. [11/]

We applied NanoSeq to 3 tissue biopsies from Hashimoto disease, the most common autoimmune disease, affecting ~5% of people. This revealed an incredible landscape of convergent selection, with hundreds of inactivating immune checkpoint mutations in just 3 patients. [10/]

Somatic mutation landscapes at single-molecule resolution Nature - NanoSeq is used to detect mutations in single DNA molecules and analyses show that mutational processes that are independent of cell division are important contributors to somatic...

In the last few years, we developed whole-exome NanoSeq, an ultra-accurate form of duplex sequencing that can detect somatic mutations down to single molecules of DNA in any gene and cell type. [9/] rdcu.be/fdBu9 (2021) and rdcu.be/fdBuO (2025)

Goodnow and others have started to provide beautiful pioneering evidence of unusually large clones carrying driver mutations in some patients. But testing these ideas in classical polyclonal autoimmune disease remained challenging. [8/] pubmed.ncbi.nlm.nih.gov/32059783/

Testing these ideas has been very difficult. Unlike cancers, which are clonal diseases and easy to sequence, autoimmune diseases are highly polyclonal with many clones of B and T cells attacking our tissues. This makes the detection of mutations in single clones very difficult. [7/]

In the 1950-1970s, Burnet proposed that somatic mutations could allow lymphocytes to escape those constraints and cause autoimmunity. In 2007, Goodnow proposed a modern version of this idea in a fascinating hypothesis paper. [6/] www.sciencedirect.com/science/arti...

Every day, our bodies are estimated to produce several billion naive B cells of which ~20% are estimated to be able to recognise antigens in our own tissues. Critically, they are kept silenced (anergic) by multiple tolerance checkpoints, preventing autoimmune attack. [5/]

Autoimmunity is believed to result from a combination of germline predisposition, environmental triggers, and a failure of regulation, though exactly what molecular changes lead to the failure of regulation is debated (limiting our ability to treat them effectively). [4/]

Autoimmune diseases affect ~10% of the population and, remarkably, we still do not know the exactly molecular changes that initiate the breakdown in tolerance to lead to autoimmune disease. [3/]

Since our initial discoveries in 2015-2018 showing that ageing tissues are colonised by large numbers of microscopic clones carrying cancer driver mutations, a major question for us has been whether this phenomenon could contribute to ageing and major diseases, beyond cancer [2/]

Excited to share our latest work in Nature. Applying single-molecule and single-cell DNA sequencing methods, we uncover an extraordinary landscape of somatic mutations in immune checkpoint genes in autoimmune B cells, suggesting that somatic mutations may be key to autoimmunity [1/n] rdcu.be/fdqbr

🚨 New paper from our lab just published in Nature🚨

www.nature.com/articles/s41...

Discover how 🌱 tumour formation is shaped by tissue context from the very beginning. Cancer is not driven by genetics alone

✨Fantastic team led by Greta Skrupskelyte, Eduardo Rojo, @hariajith.bsky.social

Somatic genomics as a discovery engine for biomedicine Somatic mutations, or genetic changes occurring in cells after conception, are widespread in healthy tissues but are conventionally viewed as signs of…

Somatic genomics as a discovery engine for biomedicine - a Perspective in Cell
www.sciencedirect.com/science/arti...

$125m awarded to five visionary teams $125m awarded to five visionary teams

📰 News announcement! www.cancergrandchallenges.org/new-teams-an...

We’re thrilled to welcome five world-leading scientific teams, each awarded up to £20 million, to take on some of the toughest unanswered questions in #CancerResearch.

Find out more about the teams and their challenges.

Ancestry and somatic profile indicate acral melanoma origin and prognosis - Nature Analysis of the somatic and transcriptomic profile of 123 acral melanoma samples from Mexican patients helps understand tumour origins and prognosis, and highlights the importance of including samples...

We are very happy to see our study finally appear online @nature.com! This has been work of nearly 10 years in collaboration with the National Institute of Genome Medicine 🇲🇽, the National Cancer Institute 🇲🇽, the @sangerinstitute.bsky.social and others ⬇️

www.nature.com/articles/s41...