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Supplemental material, MSJ963937_supplemental_material for PRF1 mutation alters immune system activation, inflammation, and risk of autoimmunity by Carlo Sidore, Valeria Orrù, Eleonora Cocco, Maristella Steri, Jamie RJ Inshaw, Maristella Pitzalis, Antonella Mulas, Stuart McGurnaghan, Jessica Frau, Eleonora Porcu, Fabio Busonero, Mariano Dei, Sandra Lai, Gabriella Sole, Francesca Virdis, Valentina Serra, Fausto Poddie, Alessandro Delitala, Michele Marongiu, Francesca Deidda, Mauro Pala, Matteo Floris, Marco Masala, Suna Onengut-Gumuscu, Catherine C Robertson, Lidia Leoni, Annapaola Frongia, Maria Rossella Ricciardi, Margherita Chessa, Nazario Olla, Mario Lovicu, Annalisa Loizedda, Andrea Maschio, Luisa Mereu, Paola Ferrigno, Nicolo Curreli, Lenuta Balaci, Francesco Loi, Liana AP Ferreli, Maria Grazia Pilia, Antonello Pani, Maria Giovanna Marrosu, Goncalo R Abecasis, Stephen S Rich, Helen Colhoun, John A Todd, David Schlessinger, Edoardo Fiorillo, Francesco Cucca and Magdalena Zoledziewska in Multiple Sclerosis Journal

Supplemental material, MSJ963937_supplemental_material for PRF1 mutation alters immune system activation, inflammation, and risk of autoimmunity by Carlo Sidore, Valeria Orrù, Eleonora Cocco, Maristella Steri, Jamie RJ Inshaw, Maristella Pitzalis, Antonella Mulas, Stuart McGurnaghan, Jessica Frau, Eleonora Porcu, Fabio Busonero, Mariano Dei, Sandra Lai, Gabriella Sole, Francesca Virdis, Valentina Serra, Fausto Poddie, Alessandro Delitala, Michele Marongiu, Francesca Deidda, Mauro Pala, Matteo Floris, Marco Masala, Suna Onengut-Gumuscu, Catherine C Robertson, Lidia Leoni, Annapaola Frongia, Maria Rossella Ricciardi, Margherita Chessa, Nazario Olla, Mario Lovicu, Annalisa Loizedda, Andrea Maschio, Luisa Mereu, Paola Ferrigno, Nicolo Curreli, Lenuta Balaci, Francesco Loi, Liana AP Ferreli, Maria Grazia Pilia, Antonello Pani, Maria Giovanna Marrosu, Goncalo R Abecasis, Stephen S Rich, Helen Colhoun, John A Todd, David Schlessinger, Edoardo Fiorillo, Francesco Cucca and Magdalena Zoledziewska in Multiple Sclerosis Journal

Funder: European Research Council, Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis1-4. The understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression remains limited5,6. Here we track 697 clonal haematopoiesis clones from 385 individuals 55 years of age or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A and TP53) to more than 50% per year (SRSF2P95H). Growth rates of clones with the same mutation differed by approximately ±5% per year, proportionately affecting slow drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole-genome sequences of haematopoietic colonies from 7 individuals from an older age group, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations drove expansion only later in life, whereas TET2-mutant clones emerged across all ages. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterize the lifelong natural history of clonal haematopoiesis and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.