Detection of ultra-rare mutations by next-generation sequencing
Open accessAbstract
Next-generation DNA sequencing promises to revolutionize clinical medicine and basic research. However, while this technology has the capacity to generate hundreds of billions of nucleotides of DNA sequence in a single experiment, the error rate of ∼1% results in hundreds of millions of sequencing mistakes. These scattered errors can be tolerated in some applications but become extremely problematic when “deep sequencing” genetically heterogeneous mixtures, such as tumors or mixed microbial populations. To overcome limitations in sequencing accuracy, we have developed a method termed Duplex Sequencing. This approach greatly reduces errors by independently tagging and sequencing each of the two strands of a DNA duplex. As the two strands are complementary, true mutations are found at the same position in both strands. In contrast, PCR or sequencing errors result in mutations in only one strand and can thus be discounted as technical error. We determine that Duplex Sequencing has a theoretical background error rate of less than one artifactual mutation per billion nucleotides sequenced. In addition, we establish that detection of mutations present in only one of the two strands of duplex DNA can be used to identify sites of DNA damage. We apply the method to directly assess the frequency and pattern of random mutations in mitochondrial DNA from human cells.
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Duplex sequencing enables the detection of mutations as low as 1 in 10^8 nucleotides sequenced.
“duplex sequencing enables the detection of mutations as low as 1 in 10 8 nucleotides sequenced (17, 18).”
From Why Cockayne syndrome patients do not get cancer despite their DNA repair deficiency (2016) · cites this paper as [17]
The Abstract reports a theoretical background error rate of less than one artifactual mutation per 10^9 nucleotides, consistent with the potential to detect very rare mutations. But the Results (Mutant Recovery; page not provided) demonstrate recovery only down to one mutant molecule per 10,000 wild-type molecules, not detection at one in 10^8. (LLM, conf=0.85)
Experimental — accuracy not yet measuredDNA degradation with time (guanosine oxidation, cytosine deamination) interferes with rare allele detection.
“DNA degradation with time (i.e. guanosine oxidation, cytosine deamination) is known to interfere with rare allele detection34”
From Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia (2015) · cites this paper as [34]
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- Authors
- Schmitt, M. W., Kennedy, S. R., Salk, J. J., Fox, E. J., Hiatt, J. B., & Loeb, L. A.
- Affiliations
- Departments of aPathology,
- Genome Sciences, and
- University of Washington (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-08
- Volume
- 109
- Issue
- 36
- Pages
- 14508-14513
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3437896
- OpenAlex
- W2143197030
- Cited by
- 1,047
- References
- 53
- Citations by year
- 2026: 58 · 2025: 81 · 2024: 85 · 2023: 68 · 2022: 88 · 2021: 88 · 2020: 88 · 2019: 79 · 2018: 77 · 2017: 77 · 2016: 81 · 2015: 60 · 2014: 75 · 2013: 39 · 2012: 3
- FWCI
- 22.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (T32AG000057, P01 AG0751, P01AG001751, F30AG039173, F30AG033485, Z01AG000751)
- National Cancer Institute (R01CA102029, R01CA115802)
- National Institute of General Medical Sciences (T32GM007266)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- duplex sequencing, sequencing error rate, strand-specific sequencing, DNA damage detection, mitochondrial DNA mutations, tumor heterogeneity, mixed culture
- MeSH terms
- DNA Damage, Humans, Mutation, Neoplasms, Oligonucleotides, Research Design, Metagenome, High-Throughput Nucleotide Sequencing
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