Selection for somatic escape variants in SERPINA1 in the liver of patients with alpha-1 antitrypsin deficiency
Open accessAbstract
Somatic variants accumulate in non-malignant tissues with age. Functional variants, leading to clonal advantage of hepatocytes, accumulate in the liver of patients with acquired chronic liver disease (CLD). Whether somatic variants are common to CLD from differing etiologies is unknown. We analyzed liver somatic variants in patients with genetic CLD from alpha-1 antitrypsin (A1AT) deficiency or hemochromatosis. We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution. Acquired SERPINA1 variants are clustered at the carboxyl terminus of A1AT, leading to truncation. In vitro and in vivo, C-terminal truncation variants reduce disease-associated Z-A1AT polymer accumulation and disruption of the endoplasmic reticulum, supporting the C-terminal domain swap mechanism. Therefore, somatic escape variants from a deleterious germline variant are selected for in A1AT deficiency, suggesting that functional somatic variants are disease-specific in CLD and point to disease-associated mechanisms.
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Selected and more fit clones may share genomic events such as nonsynonymous mutations initially thought to be restricted to cancer.
“Interestingly, these selected and more fit clones may share genomic events such as nonsynonymous mutations initially thought to be restricted to cancer.17-24”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [18]
The Results (Somatic variants in the liver in genetic CLD; page not provided) report positive selection of somatic variants in SERPINA1 in diseased liver, and the Methods (Analysis of driver variants; page not provided) explain how excess nonsynonymous mutations were assessed. This supports selected clones carrying such mutations, but our copy does not say nonsynonymous mutations were initially thought to be restricted to cancer. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAcross most, if not all, tissues, after an initial expansion of the stem cell pool during early life, clonal heterogeneity tends to diminish over time.
“A consistent pattern has been observed across most, if not all, tissues: after an initial expansion of the stem cell pool during early life, clonal heterogeneity tends to diminish over time (Figure 1).17-24”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [18]
The Main and Results sections describe expansion of hepatocyte clones in chronic liver disease, but do not describe an early-life expansion of the stem-cell pool or a decline in clonal heterogeneity with age across tissues. Searches for those developmental and cross-tissue patterns found no passage addressing them (page numbers unavailable). (LLM, conf=0.74)
Experimental — accuracy not yet measured
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- Authors
- Brzozowska, N., Wu, L. Y. D., Khodzhaeva, V., Griffiths, W. J., Duckworth, A., Jung, H., Coorens, T. H. H., Hooks, Y., Chambers, J. E., Campbell, P. J., Marciniak, S. J., & Hoare, M.
- Affiliations
- Wellcome Sanger Institute (GB)
- University of Cambridge (GB)
- Addenbrooke's Hospital (GB)
- Broad Institute (US)
- Corresponding author
- Chambers, Joseph E.
- Campbell, Peter J.
- Marciniak, Stefan J.
- Hoare, Matthew
- ORCID
- Venue
- Nature Genetics
- Published
- 2025-03-10
- Volume
- 57
- Issue
- 4
- Pages
- 875-883
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC11985350
- OpenAlex
- W4408275891
- Cited by
- 11
- References
- 58
- Citations by year
- 2026: 6 · 2025: 5
- FWCI
- 6.47
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Funders
- Cancer Research UK (DRCPFA-Jun22\100001)
- RCUK | Medical Research Council (MR/X00970X/1, MR/V028669/1, MR/Y011813/1)
- Alpha1 Foundation
- Core grant from Wellcome Trust to the Wellcome Sanger Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- SERPINA1, alpha-1 antitrypsin deficiency, hemochromatosis, clonal selection, C-terminal truncation, endoplasmic reticulum stress, convergent evolution, liver
- MeSH terms
- alpha 1-Antitrypsin, Endoplasmic Reticulum, Humans, Liver, Liver Diseases, Selection, Genetic, Genetic Variation, alpha 1-Antitrypsin Deficiency
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Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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