Targeted enrichment and high‐resolution digital profiling of mitochondrial DNA deletions in human brain
Open accessAbstract
Due largely to the inability to accurately quantify and characterize de novo deletion events, the mechanisms underpinning the pathogenic expansion of mtDNA deletions in aging and neuromuscular disorders remain poorly understood. Here, we outline and validate a new tool termed 'Digital Deletion Detection' (3D) that allows for high-resolution analysis of rare deletions occurring at frequencies as low as 1 × 10(-8) . 3D is a three-step process that includes targeted enrichment for deletion-bearing molecules, single-molecule partitioning of genomes into thousands of droplets for direct quantification via droplet digital PCR, and breakpoint characterization using massively parallel sequencing. Using 3D, we interrogated over 8 billion mitochondrial genomes to analyze the age-related dynamics of mtDNA deletions in human brain tissue. We demonstrate that the total deletion load increases with age, while the total number and diversity of unique deletions remain constant. Our data provide support for the hypothesis that expansion of pre-existing mutations is the primary factor contributing to age-related accumulation of mtDNA deletions.
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mtDNA mutations associated with premature aging occur from early, pre-existing deletions and not de novo deletions.
“Therefore, the authors agree that mtDNA mutations associated with premature aging occur from early, pre-existing deletions and not de novo deletions (Taylor et al., 2014).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Taylor et al., 2014
Using Digital Deletion Detection (3D), Taylor et al. report that although the total deletion load increases in human brain with aging, the number and diversity of deletions remains constant.
“Using Digital Deletion Detection (3D), a newer technology that allows for the study of rare, low occurring mtDNA deletions, Taylor et al. (2014) report that although the total deletion load increases in human brain with aging, the number and diversity of deletions remains constant.”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Taylor et al., 2014
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- Authors
- Taylor, S. D., Ericson, N. G., Burton, J. N., Prolla, T. A., Silber, J. R., Shendure, J., & Bielas, J. H.
- Affiliations
- Fred Hutch Cancer Center (US)
- University of Washington (US)
- University of Wisconsin–Madison (US)
- University of Washington Medical Center (US)
- Corresponding author
- Bielas, Jason H.
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2013-09-11
- Volume
- 13
- Issue
- 1
- Pages
- 29-38
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC4068027
- OpenAlex
- W2076704428
- Cited by
- 67
- References
- 41
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 2 · 2023: 3 · 2022: 6 · 2021: 3 · 2020: 8 · 2019: 2 · 2018: 5 · 2017: 8 · 2016: 12 · 2015: 6 · 2014: 6
- FWCI
- 3.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Aging Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute of Environmental Health Sciences (F32ES021703, R01ES019319)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- mitochondrial DNA deletions, target enrichment, droplet digital PCR, human brain, aging, de novo deletion, mitochondrial genome, neuromuscular disorders
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Aging, Brain, DNA Mutational Analysis, DNA, Mitochondrial, Humans, Middle Aged, Mitosis, Sequence Deletion, Genetic Heterogeneity, Young Adult
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