IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v584y2020i7819d10.1038_s41586-020-2430-6.html
   My bibliography  Save this article

Monogenic and polygenic inheritance become instruments for clonal selection

Author

Listed:
  • Po-Ru Loh

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

  • Giulio Genovese

    (Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Steven A. McCarroll

    (Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard
    Harvard Medical School)

Abstract

Clonally expanded blood cells that contain somatic mutations (clonal haematopoiesis) are commonly acquired with age and increase the risk of blood cancer1–9. The blood clones identified so far contain diverse large-scale mosaic chromosomal alterations (deletions, duplications and copy-neutral loss of heterozygosity (CN-LOH)) on all chromosomes1,2,5,6,9, but the sources of selective advantage that drive the expansion of most clones remain unknown. Here, to identify genes, mutations and biological processes that give selective advantage to mutant clones, we analysed genotyping data from the blood-derived DNA of 482,789 participants from the UK Biobank10. We identified 19,632 autosomal mosaic chromosomal alterations and analysed these for relationships to inherited genetic variation. We found 52 inherited, rare, large-effect coding or splice variants in 7 genes that were associated with greatly increased vulnerability to clonal haematopoiesis with specific acquired CN-LOH mutations. Acquired mutations systematically replaced the inherited risk alleles (at MPL) or duplicated them to the homologous chromosome (at FH, NBN, MRE11, ATM, SH2B3 and TM2D3). Three of the genes (MRE11, NBN and ATM) encode components of the MRN–ATM pathway, which limits cell division after DNA damage and telomere attrition11–13; another two (MPL and SH2B3) encode proteins that regulate the self-renewal of stem cells14–16. In addition, we found that CN-LOH mutations across the genome tended to cause chromosomal segments with alleles that promote the expansion of haematopoietic cells to replace their homologous (allelic) counterparts, increasing polygenic drive for blood-cell proliferation traits. Readily acquired mutations that replace chromosomal segments with their homologous counterparts seem to interact with pervasive inherited variation to create a challenge for lifelong cytopoiesis.

Suggested Citation

  • Po-Ru Loh & Giulio Genovese & Steven A. McCarroll, 2020. "Monogenic and polygenic inheritance become instruments for clonal selection," Nature, Nature, vol. 584(7819), pages 136-141, August.
  • Handle: RePEc:nat:nature:v:584:y:2020:i:7819:d:10.1038_s41586-020-2430-6
    DOI: 10.1038/s41586-020-2430-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-020-2430-6
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-020-2430-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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. 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.
    3. 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.
    4. Yash Pershad & Taralynn Mack & Hannah Poisner & Yasminka A. Jakubek & Adrienne M. Stilp & Braxton D. Mitchell & Joshua P. Lewis & Eric Boerwinkle & Ruth J. F. Loos & Nathalie Chami & Zhe Wang & Kathle, 2024. "Determinants of mosaic chromosomal alteration fitness," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:584:y:2020:i:7819:d:10.1038_s41586-020-2430-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.