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Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations

Author

Listed:
  • Po-Ru Loh

    (Brigham and Women’s Hospital and Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Giulio Genovese

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Robert E. Handsaker

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Hilary K. Finucane

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard)

  • Yakir A. Reshef

    (Harvard University)

  • Pier Francesco Palamara

    (University of Oxford)

  • Brenda M. Birmann

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Michael E. Talkowski

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Center for Genomic Medicine, Massachusetts General Hospital
    Massachusetts General Hospital and Harvard Medical School)

  • Samuel F. Bakhoum

    (Memorial Sloan Kettering Cancer Center
    Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine)

  • Steven A. McCarroll

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Alkes L. Price

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Harvard T.H. Chan School of Public Health)

Abstract

The selective pressures that shape clonal evolution in healthy individuals are largely unknown. Here we investigate 8,342 mosaic chromosomal alterations, from 50 kb to 249 Mb long, that we uncovered in blood-derived DNA from 151,202 UK Biobank participants using phase-based computational techniques (estimated false discovery rate, 6–9%). We found six loci at which inherited variants associated strongly with the acquisition of deletions or loss of heterozygosity in cis. At three such loci (MPL, TM2D3–TARSL2, and FRA10B), we identified a likely causal variant that acted with high penetrance (5–50%). Inherited alleles at one locus appeared to affect the probability of somatic mutation, and at three other loci to be objects of positive or negative clonal selection. Several specific mosaic chromosomal alterations were strongly associated with future haematological malignancies. Our results reveal a multitude of paths towards clonal expansions with a wide range of effects on human health.

Suggested Citation

  • Po-Ru Loh & Giulio Genovese & Robert E. Handsaker & Hilary K. Finucane & Yakir A. Reshef & Pier Francesco Palamara & Brenda M. Birmann & Michael E. Talkowski & Samuel F. Bakhoum & Steven A. McCarroll , 2018. "Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations," Nature, Nature, vol. 559(7714), pages 350-355, July.
    • Handle: RePEc:nat:nature:v:559:y:2018:i:7714:d:10.1038_s41586-018-0321-x
    DOI: 10.1038/s41586-018-0321-x
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    Cited by:

    1. Andrew K. Ressler & Daniel A. Snellings & Romuald Girard & Carol J. Gallione & Rhonda Lightle & Andrew S. Allen & Issam A. Awad & Douglas A. Marchuk, 2023. "Single-nucleus DNA sequencing reveals hidden somatic loss-of-heterozygosity in Cerebral Cavernous Malformations," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    2. Kelly L. Bolton & Youngil Koh & Michael B. Foote & Hogune Im & Justin Jee & Choong Hyun Sun & Anton Safonov & Ryan Ptashkin & Joon Ho Moon & Ji Yeon Lee & Jongtak Jung & Chang Kyung Kang & Kyoung-Ho S, 2021. "Clonal hematopoiesis is associated with risk of severe Covid-19," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
    3. Derek W. Brown & Liam D. Cato & Yajie Zhao & Satish K. Nandakumar & Erik L. Bao & Eugene J. Gardner & Aubrey K. Hubbard & Alexander DePaulis & Thomas Rehling & Lei Song & Kai Yu & Stephen J. Chanock &, 2023. "Shared and distinct genetic etiologies for different types of clonal hematopoiesis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Weiyin Zhou & Anja Fischer & Martin D. Ogwang & Wen Luo & Patrick Kerchan & Steven J. Reynolds & Constance N. Tenge & Pamela A. Were & Robert T. Kuremu & Walter N. Wekesa & Nestory Masalu & Esther Kaw, 2023. "Mosaic chromosomal alterations in peripheral blood leukocytes of children in sub-Saharan Africa," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Derek W. Brown & Weiyin Zhou & Youjin Wang & Kristine Jones & Wen Luo & Casey Dagnall & Kedest Teshome & Alyssa Klein & Tongwu Zhang & Shu-Hong Lin & Olivia W. Lee & Sairah Khan & Jacqueline B. Vo & A, 2022. "Germline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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