Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis
Open accessAbstract
The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole-genome sequencing, we estimate that approximately 450 somatic mutations accumulated in the nonrepetitive genome within the healthy blood compartment of a 115-yr-old woman. The detected mutations appear to have been harmless passenger mutations: They were enriched in noncoding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes. The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.
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Aging hematopoietic stem cells progressively accumulate mutations and molecular alterations that can impair cellular function, give rise to preleukemic stem cells, and initiate age-associated myeloid malignancies.
“Aging hematopoietic stem cells progressively accumulate mutations and molecular alterations, which can impair cellular function, give rise to preleukemic stem cells, and initiate age-associated myeloid malignancies45, 46.”
From Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia (2015) · cites this paper as [45]
The introductory passage reports that mutations gradually accumulate in HSCs and describes a pathogenic mutation leading to acute myeloid leukemia. It does not establish that the accumulated alterations impair cellular function or give rise to preleukemic stem cells. The Abstract and Discussion instead describe the mutations observed in this healthy woman as largely harmless passengers. (LLM, conf=0.87)
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- Authors
- Holstege, H., Pfeiffer, W., Sie, D., Hulsman, M., Nicholas, T. J., Lee, C. C., Ross, T., Lin, J., Miller, M. A., Ylstra, B., Meijers-Heijboer, H., Brugman, M. H., Staal, F. J. T., Holstege, G., Reinders, M. J. T., Harkins, T. T., Levy, S., & Sistermans, E. A.
- Affiliations
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- San Diego Supercomputer Center (US)
- Delft University of Technology (NL)
- University of California, San Francisco (US)
- Leiden University Medical Center (NL)
- The University of Queensland (AU)
- Corresponding author
- Holstege, Henne
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2014-04-23
- Volume
- 24
- Issue
- 5
- Pages
- 733-742
- ISSN
- 1088-9051 (ISSN-L)
- PMC
- PMC4009603
- OpenAlex
- W2156407908
- Cited by
- 152
- References
- 10
- Citations by year
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- Type
- posted content
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc
- Locations
- Genome Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
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- Funders
- San Diego Supercomputer Center
- National Institutes of Health (8ul1tr000109-05)
- National Center for Advancing Translational Sciences (UL1-TR000109)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- somatic mutations, hematopoietic stem cells, aging, leukocytes, passenger mutations, non-coding regions, variant allele frequency, telomere length
- MeSH terms
- Aged, 80 and over, Female, Gene Frequency, Hematopoiesis, Hematopoietic Stem Cells, Humans, Leukocytes, Longevity, Mutation, Telomere, Genome, Conserved Sequence, Cell Lineage, AT Rich Sequence, Telomere Shortening, Clonal Evolution
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