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Peer-reviewedCC BY-NC-NDNature Genetics

Patterns and drivers of 43,617 mosaic chromosomal alterations in blood

  • David Shin-Hsiung Tang1,2,3,4,5,6
  • Nolan Kamitaki7,8,5,6
  • Ronen E. Mukamel7,5,6
  • Simone Rubinacci7,5,9,6
  • Po‐Ru Loh10,11,12,7,6
12 affiliations
  1. 1Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. [email protected]
  2. 2Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. [email protected]
  3. 3Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. [email protected]
  4. 4Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]
  5. 5Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
  6. 6Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
  7. 7Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
  8. 8Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
  9. 9Institute for Molecular Medicine Finland, Helsinki, Finland
  10. 10Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. [email protected]
  11. 11Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. [email protected]
  12. 12Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]
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Abstract

Clonal expansions of hematopoietic cells carrying mosaic chromosomal alterations (mCAs) are commonly detectable in elderly individuals. Here, we studied 43,617 autosomal mCAs that we ascertained in 484,081 UK Biobank participants using new, high-resolution computational methods to analyze blood-derived whole-genome sequencing data. Shorter mCAs (≤1 Mb) clustered at 53 genomic hotspots (34 previously undetected), several of which implicated chromosomal fragile sites as a recurrent source of somatic deletions. Chronic lymphocytic leukemia (CLL)-associated deletions at 13q14 were detectable in 1% of 65- to 70-year-old individuals—a five-fold higher rate than previously observed—suggesting opportunities for incorporating this mosaic mutation in clinical screening and in genetic association studies. Rare protein-coding variants in 38 genes associated ( p <1.2×10 - 5 ; FDR<0.01) with clonal expansions of copy-neutral loss of heterozygosity (CN-LOH) mutations that modified the allelic dosages of these variants, implicating genes in DNA damage response, cell cycle, cytokine signaling, and protein ubiquitination pathways as targets of clonal selection via CN-LOH-induced allelic substitution. For several genes with proliferation-increasing functions, CN-LOH mutations produced revertant mosaicism, removing deleterious inherited variants. Polygenic effects of common inherited variants within CN-LOH mutations also contributed modestly to clonal selection. These results show that our blood genomes are constantly evolving as we age and often accrue mCAs in predictable ways.

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Cite

BibTeXRIS
BibTeX
@article{tang2026patterns,
  title = {{Patterns and drivers of 43,617 mosaic chromosomal alterations in blood}},
  author = {David Shin-Hsiung Tang and Nolan Kamitaki and Ronen E. Mukamel and Simone Rubinacci and Po‐Ru Loh},
  journal = {Nature Genetics},
  year = {2026},
  month = may,
  doi = {10.1038/s41588-026-02592-0},
  url = {https://doi.org/10.1038/s41588-026-02592-0},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Patterns and drivers of 43,617 mosaic chromosomal alterations in blood
AU  - David Shin-Hsiung Tang
AU  - Nolan Kamitaki
AU  - Ronen E. Mukamel
AU  - Simone Rubinacci
AU  - Po‐Ru Loh
PY  - 2026
DA  - 2026/05/19
JO  - Nature Genetics
DO  - 10.1038/s41588-026-02592-0
UR  - https://doi.org/10.1038/s41588-026-02592-0
AB  - Clonal expansions of hematopoietic cells carrying mosaic chromosomal alterations (mCAs) are commonly detectable in elderly individuals. Here, we studied 43,617 autosomal mCAs that we ascertained in 484,081 UK Biobank participants using new, high-resolution computational methods to analyze blood-derived whole-genome sequencing data. Shorter mCAs (≤1 Mb) clustered at 53 genomic hotspots (34 previously undetected), several of which implicated chromosomal fragile sites as a recurrent source of somatic deletions. Chronic lymphocytic leukemia (CLL)-associated deletions at 13q14 were detectable in 1% of 65- to 70-year-old individuals—a five-fold higher rate than previously observed—suggesting opportunities for incorporating this mosaic mutation in clinical screening and in genetic association studies. Rare protein-coding variants in 38 genes associated ( p <1.2×10 - 5 ; FDR<0.01) with clonal expansions of copy-neutral loss of heterozygosity (CN-LOH) mutations that modified the allelic dosages of these variants, implicating genes in DNA damage response, cell cycle, cytokine signaling, and protein ubiquitination pathways as targets of clonal selection via CN-LOH-induced allelic substitution. For several genes with proliferation-increasing functions, CN-LOH mutations produced revertant mosaicism, removing deleterious inherited variants. Polygenic effects of common inherited variants within CN-LOH mutations also contributed modestly to clonal selection. These results show that our blood genomes are constantly evolving as we age and often accrue mCAs in predictable ways.
SN  - 1061-4036
SN  - 1546-1718
ER  -