The evolutionary dynamics and fitness landscape of clonal hematopoiesis
Abstract
Somatic mutations acquired in healthy tissues as we age are major determinants of cancer risk. Whether variants confer a fitness advantage or rise to detectable frequencies by chance remains largely unknown. Blood sequencing data from ~50,000 individuals reveal how mutation, genetic drift, and fitness shape the genetic diversity of healthy blood (clonal hematopoiesis). We show that positive selection, not drift, is the major force shaping clonal hematopoiesis, provide bounds on the number of hematopoietic stem cells, and quantify the fitness advantages of key pathogenic variants, at single-nucleotide resolution, as well as the distribution of fitness effects (fitness landscape) within commonly mutated driver genes. These data are consistent with clonal hematopoiesis being driven by a continuing risk of mutations and clonal expansions that become increasingly detectable with age.
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Some somatic variants provide a fitness advantage to hematopoietic stem cell clones, allowing them to become disproportionally represented in the blood.
“The vast majority of these mutations are inconsequential, but some variants provide a fitness advantage to HSC clones, allowing them to become disproportionally represented in the blood (2).”
From <i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i> (2022) · cites this paper as [2]
Dnmt3a heterozygous variants provide very minor fitness advantages to hematopoietic stem cells that require the extended lifespan of humans to manifest measurable phenotypes.
“However, we and others have shown that Dnmt3a HET HSCs produce only modest phenotypes in mice (25,26), likely because these variants provide very minor fitness advantages to HSCs (2) that require the extended lifespan of humans to manifest measureable phenotypes.”
From <i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i> (2022) · cites this paper as [2]
The vast majority of somatic mutations acquired by hematopoietic stem cells are inconsequential.
“The vast majority of these mutations are inconsequential, but some variants provide a fitness advantage to HSC clones, allowing them to become disproportionally represented in the blood (2).”
From <i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i> (2022) · cites this paper as [2]
In CHIP, TET2 mutations show highest clonal expansion rates over time, with an estimated 10% annual growth rate compared with 5% for DNMT3A mutations.
“In the context of CHIP, TET2 mutations show highest clonal expansion rates over time (with an estimated 10% annual growth rate compared with 5% of DNMT3A mutations7,8,10).”
From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [10]
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- Authors
- Watson, C. J., Papula, A. L., Poon, G. Y. P., Wong, W. H., Young, A. L., Druley, T. E., Fisher, D. S., & Blundell, J. R.
- Affiliations
- University of Cambridge (GB)
- Stanford University (US)
- Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, St. Louis, MO, USA.
- Washington University in St. Louis (US)
- Corresponding author
- Watson, Caroline J.
- Blundell, Jamie R.
- ORCID
- Venue
- Science
- Published
- 2020-03-27
- Volume
- 367
- Issue
- 6485
- Pages
- 1449-1454
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W3013784317
- Cited by
- 444
- References
- 14
- Citations by year
- 2026: 35 · 2025: 51 · 2024: 62 · 2023: 80 · 2022: 95 · 2021: 76 · 2020: 43 · 2019: 2
- FWCI
- 46.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- National Science Foundation
- National Cancer Institute
- Stand Up To Cancer
- UK Research and Innovation
- Cancer Research UK Cambridge Centre
- Bei Shan Tang Foundation
- Cancer Research UK
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- clonal hematopoiesis, somatic mutations, fitness landscape, positive selection, genetic drift, hematopoietic stem cells, distribution of fitness effects, driver genes, aging, cancer risk, clonal expansion
- MeSH terms
- Aging, Biological Evolution, Gene Frequency, Genetics, Population, Hematopoiesis, Hematopoietic Stem Cells, Humans, Models, Genetic, Mutation, Selection, Genetic, Genetic Drift, Genetic Fitness, Mutation Rate
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