Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis
- Henne Holstege1,10,
- Wayne Pfeiffer2,
- Daoud Sie3,
- Marc Hulsman4,
- Thomas J. Nicholas5,
- Clarence C. Lee6,
- Tristen Ross6,
- Jue Lin7,
- Mark A. Miller2,
- Bauke Ylstra3,
- Hanne Meijers-Heijboer1,
- Martijn H. Brugman8,
- Frank J.T. Staal8,
- Gert Holstege9,
- Marcel J.T. Reinders4,
- Timothy T. Harkins6,
- Samuel Levy5 and
- Erik A. Sistermans1
- 1Department of Clinical Genetics, VU University Medical Center, 1007 MB Amsterdam, The Netherlands;
- 2San Diego Supercomputer Center, UCSD, La Jolla, California 92093, USA;
- 3Department of Pathology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands;
- 4Delft Bioinformatics Laboratory, Delft University of Technology, 2628 CD Delft, The Netherlands;
- 5Department of Molecular and Experimental Medicine, Scripps Translational Science Institute, San Diego, California 92037, USA;
- 6Advanced Applications Group, Life Technologies, Beverly, Massachusetts 01915, USA;
- 7Department of Biochemistry and Biophysics UCSF, San Francisco, California 94143, USA;
- 8Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
- 9Centre for Clinical Research, University of Queensland, Herston, QLD 4006, Australia
Abstract
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.
Footnotes
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↵10 Corresponding author
E-mail h.holstege{at}vumc.nl
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.162131.113.
Freely available online through the Genome Research Open Access option.
- Received June 22, 2013.
- Accepted March 3, 2014.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
