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The longitudinal dynamics and natural history of clonal haematopoiesis

View ORCID ProfileMargarete A. Fabre, View ORCID ProfileJosé Guilherme de Almeida, View ORCID ProfileEdoardo Fiorillo, View ORCID ProfileEmily Mitchell, Aristi Damaskou, View ORCID ProfileJustyna Rak, View ORCID ProfileValeria Orrù, View ORCID ProfileMichele Marongiu, View ORCID ProfileMS Vijayabaskar, View ORCID ProfileJoanna Baxter, Claire Hardy, View ORCID ProfileFederico Abascal, View ORCID ProfileMichael Spencer Chapman, Nicholas Williams, View ORCID ProfileJyoti Nangalia, View ORCID ProfileIñigo Martincorena, View ORCID ProfilePeter J. Campbell, View ORCID ProfileEoin F. McKinney, View ORCID ProfileFrancesco Cucca, View ORCID ProfileMoritz Gerstung, View ORCID ProfileGeorge S. Vassiliou.
doi: https://doi.org/10.1101/2021.08.12.455048
Margarete A. Fabre
1Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SD, UK
2Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0XY, UK
3Department of Haematology, University of Cambridge, Cambridge, CB2 0XY, UK.
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  • ORCID record for Margarete A. Fabre
José Guilherme de Almeida
4European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, CB10 1SD, UK
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  • ORCID record for José Guilherme de Almeida
Edoardo Fiorillo
5Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Lanusei, Italy
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Emily Mitchell
1Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SD, UK
2Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0XY, UK
3Department of Haematology, University of Cambridge, Cambridge, CB2 0XY, UK.
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Aristi Damaskou
2Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0XY, UK
3Department of Haematology, University of Cambridge, Cambridge, CB2 0XY, UK.
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Justyna Rak
2Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0XY, UK
3Department of Haematology, University of Cambridge, Cambridge, CB2 0XY, UK.
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Valeria Orrù
5Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Lanusei, Italy
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  • ORCID record for Valeria Orrù
Michele Marongiu
5Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Lanusei, Italy
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MS Vijayabaskar
2Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0XY, UK
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Joanna Baxter
6Cambridge Blood and Stem Cell Biobank, Department of Haematology, University of Cambridge, Cambridge, CB2 OAW, UK
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Claire Hardy
1Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SD, UK
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Federico Abascal
1Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SD, UK
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Michael Spencer Chapman
1Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SD, UK
2Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0XY, UK
3Department of Haematology, University of Cambridge, Cambridge, CB2 0XY, UK.
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Nicholas Williams
1Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SD, UK
2Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0XY, UK
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Jyoti Nangalia
1Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SD, UK
2Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0XY, UK
3Department of Haematology, University of Cambridge, Cambridge, CB2 0XY, UK.
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Iñigo Martincorena
1Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SD, UK
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Peter J. Campbell
1Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SD, UK
2Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0XY, UK
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Eoin F. McKinney
7Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, CB2 OAW, UK
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Francesco Cucca
5Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Lanusei, Italy
8Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy
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Moritz Gerstung
4European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, CB10 1SD, UK
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  • For correspondence: gsv20@cam.ac.uk moritz.gerstung@ebi.ac.uk
George S. Vassiliou.
1Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SD, UK
2Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0XY, UK
3Department of Haematology, University of Cambridge, Cambridge, CB2 0XY, UK.
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  • For correspondence: gsv20@cam.ac.uk moritz.gerstung@ebi.ac.uk
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Summary

Human cells acquire somatic mutations throughout life, some of which can drive clonal expansion. Such expansions are frequent in the haematopoietic system of healthy individuals and have been termed clonal haematopoiesis (CH). While CH predisposes to myeloid neoplasia and other diseases, we have limited understanding of how and when CH develops, what factors govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression. Here, we track 697 CH clones from 385 individuals aged 55 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, TP53) to over 50%/yr (SRSF2-P95H). Growth rates of clones with the same mutation differed by approximately +/−5%/yr, proportionately impacting “slow” drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole genome-sequenced haematopoietic colonies from 7 older individuals, 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 only drove expansion later in life, while growth of TET2-mutant clones showed minimal age-dependency. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterise the lifelong natural history of CH and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.

Competing Interest Statement

G.S.V. is a consultant for Astrazeneca and STRM.BIO. The other authors declare no competing interests.

Footnotes

  • https://github.com/josegcpa/clonal_dynamics

  • https://github.com/margaretefabre/Clonal_dynamics

  • https://doi.org/10.6084/m9.figshare.15029118

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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The longitudinal dynamics and natural history of clonal haematopoiesis
Margarete A. Fabre, José Guilherme de Almeida, Edoardo Fiorillo, Emily Mitchell, Aristi Damaskou, Justyna Rak, Valeria Orrù, Michele Marongiu, MS Vijayabaskar, Joanna Baxter, Claire Hardy, Federico Abascal, Michael Spencer Chapman, Nicholas Williams, Jyoti Nangalia, Iñigo Martincorena, Peter J. Campbell, Eoin F. McKinney, Francesco Cucca, Moritz Gerstung, George S. Vassiliou.
bioRxiv 2021.08.12.455048; doi: https://doi.org/10.1101/2021.08.12.455048
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The longitudinal dynamics and natural history of clonal haematopoiesis
Margarete A. Fabre, José Guilherme de Almeida, Edoardo Fiorillo, Emily Mitchell, Aristi Damaskou, Justyna Rak, Valeria Orrù, Michele Marongiu, MS Vijayabaskar, Joanna Baxter, Claire Hardy, Federico Abascal, Michael Spencer Chapman, Nicholas Williams, Jyoti Nangalia, Iñigo Martincorena, Peter J. Campbell, Eoin F. McKinney, Francesco Cucca, Moritz Gerstung, George S. Vassiliou.
bioRxiv 2021.08.12.455048; doi: https://doi.org/10.1101/2021.08.12.455048

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