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Cited by 116Cancer Genomics and DiagnosticsDNA Repair MechanismsT-cell and B-cell Immunology

Diverse mutational landscapes in human lymphocytes

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Machado, Heather E., Mitchell, Emily, Øbro, Nina F., Kübler, Kirsten, Davies, Megan, Leongamornlert, Daniel, Cull, Alyssa, Maura, Francesco +17 more·2022·Nature
DOI 10.1038/s41586-022-05072-7PMC PMC9402440
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Abstract

The lymphocyte genome is prone to many threats, including programmed mutation during differentiation 1 , antigen-driven proliferation and residency in diverse microenvironments. Here, after developing protocols for expansion of single-cell lymphocyte cultures, we sequenced whole genomes from 717 normal naive and memory B and T cells and haematopoietic stem cells. All lymphocyte subsets carried more point mutations and structural variants than haematopoietic stem cells, with higher burdens in memory cells than in naive cells, and with T cells accumulating mutations at a higher rate throughout life. Off-target effects of immunological diversification accounted for approximately half of the additional differentiation-associated mutations in lymphocytes. Memory B cells acquired, on average, 18 off-target mutations genome-wide for every on-target IGHV mutation during the germinal centre reaction. Structural variation was 16-fold higher in lymphocytes than in stem cells, with around 15% of deletions being attributable to off-target recombinase-activating gene activity. DNA damage from ultraviolet light exposure and other sporadic mutational processes generated hundreds to thousands of mutations in some memory cells. The mutation burden and signatures of normal B cells were broadly similar to those seen in many B-cell cancers, suggesting that malignant transformation of lymphocytes arises from the same mutational processes that are active across normal ontogeny. The mutational landscape of normal lymphocytes chronicles the off-target effects of programmed genome engineering during immunological diversification and the consequences of differentiation, proliferation and residency in diverse microenvironments.

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  • Somatic events, such as deletions, exist in normal B-cells.

    “Interestingly, the existence of somatic event, such as deletions, in normal B-cells have been recently reported using B-cell single cell expansion WGS.”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [74]

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Cited by

Sorted by citations

Authors
Machado, H. E., Mitchell, E., Øbro, N. F., Kübler, K., Davies, M., Leongamornlert, D., Cull, A., Maura, F., Sanders, M. A., Cagan, A. T. J., McDonald, C., Belmonte, M., Shepherd, M. S., Vieira Braga, F. A., Osborne, R. J., Mahbubani, K., Martincorena, I., Laurenti, E., Green, A. R., Getz, G., Polak, P., Saeb-Parsy, K., Hodson, D. J., Kent, D. G., & Campbell, P. J.
Affiliations
  • Wellcome Sanger Institute (GB)
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
  • Broad Institute (US)
  • University of York (GB)
  • Sylvester Comprehensive Cancer Center (US)
  • University of Cambridge (GB)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
  • Kent, David G.
  • Campbell, Peter J.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2022-08-10
Volume
608
Issue
7924
Pages
724-732
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-022-05072-7
PMC
PMC9402440
OpenAlex
W4290989173
Cited by
116
References
6
Citations by year
2026: 24 · 2025: 36 · 2024: 32 · 2023: 19 · 2022: 5
FWCI
9.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo
  • Apollo (cc-by)
Funders
  • AstraZeneca
  • Massachusetts General Hospital
  • European Hematology Association (TRTH182)
  • Japan Agency for Medical Research and Development
  • Wellcome Trust (203151/A/16/Z, 107630/Z/15/Z, /Z/15/Z, 203151/Z/16/Z, 203151)
  • Cancer Research UK (DCRPGF∖100008, RCCFEL∖100072, 21762, 15008, 21777)
  • National Institute for Health and Care Research
  • Blood Cancer UK (15008)
  • Directorate for Biological Sciences
  • Medical Research Council (MR/V005502/1, MC_PC_17230, 203151/Z/16/Z)
  • Biotechnology and Biological Sciences Research Council (BB/P002293/1)
  • NIHR Cambridge Biomedical Research Centre
  • National Cancer Institute (U24CA210999)
  • H2020 European Research Council (715371)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
mutational landscape, lymphocytes, naive B cells, memory B cells, T cells, hematopoietic stem cells, point mutations, structural variants, off-target mutations, IGHV mutation, germinal center, malignant transformation, whole genome sequencing
MeSH terms
B-Lymphocytes, Cell Differentiation, DNA Damage, Humans, Immunologic Memory, Lymphocytes, Mutation, Neoplasms, Germinal Center, Cell Proliferation, Cellular Microenvironment

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