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At least 19 recordsLinked to original sources

PubMed2026

Duplex-Indel: a Snakemake pipeline for somatic Indel calling in Tn5 transposase-based duplex sequencing data.

SUMMARY: Duplex-Indel is a novel Snakemake workflow for detecting somatic small insertions and deletions (Indels) from Tn5 transposase-based duplex sequencing data. Duplex-Indel enhances the accuracy of mutation calling at the single-molecule level by requiring consensus support from both DNA strands for each somatic Indel, minimizing confounding from technical artifacts. Duplex-Indel extends somatic mutation calling in Tn5 transposase-based duplex sequencing data to include Indels. We have demonstrated the accuracy and robustness of Duplex-Indel using cancer cell lines. AVAILABILITY AND IMPLEMENTATION: Source code and documentation are available under the MIT license on GitHub at https://github.com/ealee-lab/duplex-indel and archived on Zenodo at https://doi.org/10.5281/zenodo.19228799.

Transposases↗

PubMed1975

Chemical synthesis and sequence studies of deoxyribooligonucleotides which constitute the duplex sequence of the lactose operator of Escherichia coli.

We have synthesized the deoxyribooligonucleotide fragments, constituting the sequence of the lac operator of Escherichia coli. Two of these fragments, d(pApApTpTpGpTpTpApT) (nonamer) and d(pApApTpTpGpTpGpApG) (nonamer), corresponding to the 5' termini of lac operator have been synthesized by the phosphodiester method. The remaining four fragments, d(ApCpApApTpT) (hexamer), d(ApTpApApCpApApTpT) (nonamer), d(ApApTpTpGpTpGpApGpCpGpG) (dodecamer), and d(ApApTpTpGpTpTpApTpCpCpGpCpTpC) (pentadecamer), have been synthesized by an improved phosphotriester method. All of the compounds were first characterized by venom and spleen phosphodiesterase digestion to obtain their base composition. The sequence of these oligonucleotides was fully confirmed by the characteristic mobility shifts of their partial venom phosphodiesterase digestion products on two-dimensional homochromatography. A comparative study of the two methods for the synthesis of oligonucleotides has revealed that the phosphotriester method is more convenient than the phosphodiester method because of higher yields and ease of handling large scale preparations.

Base Sequence↗

PubMed2026

Protocol for Duplex Sequencing of Mitochondrial DNA in Single Human Oocytes.

Oocytes are densely packed with mitochondria, the energy-producing organelles that contain their own genome, mitochondrial DNA (mtDNA). Each cell contains multiple copies of mtDNA, with copy number varying among tissue types. Oocytes possess the highest mtDNA copy number, containing hundreds of thousands of mtDNA molecules per cell. Because mitochondria are inherited exclusively through the maternal lineage, accurate detection of mtDNA variants is essential for studies of inheritance, aging, and disease. The presence of multiple mtDNA copies allows wild-type and mutant molecules to coexist within the same cell, a condition known as heteroplasmy, in which low-frequency and de novo variants may occur at frequencies below 1%. Conventional next-generation sequencing (NGS) lacks sufficient accuracy to reliably distinguish these rare variants from errors introduced during library preparation and sequencing. Here, we present a protocol for enriching mtDNA from single human oocytes using Exonuclease V to remove linear DNA, followed by duplex sequencing library preparation for highly accurate mtDNA analysis. This workflow enables error-corrected sequencing of individual oocytes, facilitating reliable detection of low-frequency mtDNA variants and analysis of heteroplasmy and de novo mutagenesis. The protocol provides a reproducible approach for investigating mitochondrial genome variation in single oocytes using Illumina-compatible sequencing platforms.

Humans↗

PubMed2025

A Universal Duplex Sequencing Approach for Accurate Detection of Somatic Mutations.

Ultra-accurate detection of rare somatic mutations is critical for understanding mutational processes in human disease, aging, and environmental exposures, yet current methods are limited by error rates, restricted genome coverage, and high DNA input. We present UDSeq, a duplex sequencing protocol combining random fragmentation, efficient UMI ligation, and quantitative input control to achieve near-complete genome/exome representation from as little as 100 pg DNA. Benchmarking in human sperm estimates a UDSeq error rate of ~2.5×10-9 per base pair. UDSeq captures mutational signatures from heterogeneous populations without clonal expansion, reproduces exposure-specific patterns in cell lines and rodent models, and enables cross-species profiling. Compared with prior duplex methods, UDSeq yields up to fourfold more usable duplex molecules, improves library conversion, and remains cost-effective. We include a step-by-step protocol with quality-control checkpoints for fragment size, ligation yield, library conversion, and duplication rate. UDSeq provides a scalable, low-input platform for accurate profiling of somatic mutagenesis.

Journal Article↗

PubMed1992

Studies of DNA dumbbells. I. Melting curves of 17 DNA dumbbells with different duplex stem sequences linked by T4 endloops: evaluation of the nearest-neighbor stacking interactions in DNA.

Seventeen DNA dumbbells were constructed that have duplex sequences ranging in length from 14 to 18 base pairs linked on the ends by T4 single-strand loops. Fifteen of the molecules have the core duplexes with the sequences 5'G-T-A-T-C-C-(W-X-Y-Z)-G-G-A-T-A-C3', where (W-X-Y-Z) represents a unique combination of A.T, T.A, G.C, and C.G base pairs. The remaining two molecules have the central sequence (W-X-Y-Z) = A-C and A-C-A-C-A-C. These duplex sequences were designed such that the central sequences include different combinations of the 10 possible nearest-neighbor (n-n) stacks in DNA. In this sense the set of molecules is complete and serves as a model system for evaluating sequence-dependent local stability of DNA. Optical melting curves of the samples were collected in 25, 55, 85, and 115 mM [Na+], and showed, regardless of solvent ionic strength, that the transition temperatures of the dumbbells vary by as much as 14 degrees for different molecules of the set. Results of melting experiments analyzed in terms of a n-n sequence-dependent model allowed evaluation of nine independent linear combinations of the n-n stacking interactions in DNA as a function of solvent ionic strength. Although there are in principle 10 possible different n-n interactions in DNA, these 10 are not linearly independent and therefore can not be uniquely determined. For molecules with ends, there are 9 linearly independent combinations, as opposed to circular or semiinfinite repeating copolymers where only 8 linear combinations of the 10 possible n-n interactions are linearly independent. The n-n interactions are presented as combinations of the deviations from average stacking for the 5'-3' base-pair doublets, delta Gi, and reveal several interesting features: (1) Titratable changes in the values of delta Gi with changing salt environment are observed. In all salts the most stable unique combination is delta G4 = (delta GGpC+delta GCpG)/2, and the least stable is the GpG/CpC stack, delta G2 = delta GGpG/CpC. (2) The chi 2 values of the fits of the evaluated delta Gi's to experimental data increased with decreasing [Na+], suggesting that significant interactions beyond nearest neighbors become more pronounced, particularly at 25 nM Na+.(ABSTRACT TRUNCATED AT 400 WORDS)

Base Sequence↗

PubMed2026

High-grade serous ovarian cancer is associated with increased TP53 mutation burden in uterine lavage.

High grade serous ovarian cancer (HGSC) has low survival partly due to the lack of methods for detection, diagnosis, and risk prediction. TP53 mutations, which drive HGSC, are found in gynecological tissues as the result of somatic evolution, but it is unknown whether an excess of mutations is linked to ovarian cancer. Here we investigate if TP53 mutation burden measured in uterine lavage, a minimally invasive gynecological liquid biopsy, can discriminate between patients with and without HGSC. We used ultradeep TP53 duplex sequencing (>15,000x duplex depth) to detect TP53 mutations in uterine lavage collected pre-operatively in 278 patients undergoing gynecological surgery for pelvic masses (average risk) or cancer risk-reduction (high risk). All lavages contained multiple TP53 mutant clones, which were used to quantify TP53 mutation burden frequency (MBF). Average risk patients with HGSC had significantly higher TP53 MBF independently of age and other risk factors (77% sensitivity, 89% specificity, AUC = 0.88). Excluding tumor TP53 clonal mutations from the lavage MBF calculation maintains this association, suggesting that it is the overall TP53 somatic mutation burden (rather than the discovery of the specific tumor driver mutation) that identifies HGSC. These results demonstrate that TP53 somatic mutations are common in uterine lavage but more abundant in patients with HGSC, highlighting a connection between TP53 somatic evolution and ovarian cancer. Uterine lavage offers a minimally invasive approach that could be valuable to identify patients with HGSC.

Journal Article↗

PubMed1992

Studies of DNA dumbbells. II. Construction and characterization of DNA dumbbells with a 16 base-pair duplex stem and Tn end loops (n = 2, 3, 4, 6, 8, 10, 14).

The preparation and characterization of DNA dumbbells that contain the 16 base-pair duplex sequences 5'G-C-A-T-A-G-A-T-G-A-G-A-A-T-G-C3' (set 1) and 5'G-C-A-T-C-A-T-C-G-A-T-G-A-T-G-C3' (set 2) are reported. The dumbbells of set 1 have the duplex stem nucleated on both ends by Tn (n = 2, 3, 4, 6, 8, 10, and 14) loops. The dumbbells of set 2 have Tn (n = 2, 4, 8, 10) end loops. For the molecules of set 1, effects of end loop size on the electrophoretic mobility, CD and UV absorbance spectra, and cleavage by restriction enzymes, were investigated. Effects of loop size on the CD spectra and restriction enzyme cleavage of the molecules of set 2 were also examined. Optical melting curves of the molecules of set 1 were collected as a function of sodium ion concentration from 30 to 120 mM. These investigations revealed that as loop size decreases, the electrophoretic mobilities, rates of enzyme cleavage, and optical melting temperatures increase. For end loops with at least three T's the observed increases are inversely proportional to loop size. The behavior of the dumbbell with T2 end loops departs from this linear dependence and is anomalous in every experimental context. For molecules with end loops comprised of at least four T's CD spectra were virtually indistinguishable. However, these spectra differed considerably from the CD spectrum of the T2-looped molecule. The CD spectrum of the dumbbell with T3 end loops displayed features common to the dumbbells with larger loops and T2 end loops. Thermodynamic evidence that the terminal G.C base pairs (bps) nucleating the T2 end loops were intact was obtained from a comparison of the melting temperature of this molecule with that of a DNA dumbbell containing the 14 central bps of the set 1 duplex sequence linked instead by end loops comprised of the four base sequence, C-T-T-C. The tm of this latter molecule was determined to be 9 degrees C less than that of the former dumbbell assumed to contain a 16-bp stem and T2 end loops.(ABSTRACT TRUNCATED AT 400 WORDS)

Base Composition↗

PubMed2026

Extensive and differential platinum chemotherapy mutagenesis in livers of children.

Childhood cancer survivors often experience late adverse effects that may be linked to chemotherapy mutagenesis. We studied chemotherapy mutagenesis in normal pediatric tissues using duplex sequencing (NanoSeq) to enable the detection of mutations from single DNA molecules. We found that platinum chemotherapeutics increased the mutation burdens of normal pediatric tissues to levels seen in adults. In the liver, platinum agents imparted a tissue-specific mutational signature that was absent from other tissues. Gene-focused duplex sequencing revealed that chemotherapy mutagenesis generates a great diversity of nonsynonymous variants, some of which may have functional potential, such as leukemogenic variants in blood. Our findings demonstrate extensive chemotherapy mutagenesis in normal tissues of children, which may provide a plausible link between chemotherapy exposure and adverse effects in later life.

Child↗

PubMed1992

Stabilities of double- and triple-strand helical nucleic acids.

In this selected literature survey, we have seen that the stabilities of duplexes and triplexes are governed by the vertical base stacking, the horizontal specific base-paired H-bonding and the environmental parameters. The entropic contribution in the solvation/desolvation process is important in driving the aggregation of NA strands and duplex formation, but base stacking and specific H-bonding maintain the helical order. Triplex formation shares most of the physical environmental prerequisites with those of duplex NAs. However, some additional environmental conditions are often needed. Only in low pH solution is the polycytidylic strand protonated and, thus, it is possible for the strand to bind to a G.C duplex sequence to give the C+(G.C) triplex. High ionic strength is often necessary for the screening of inter-phosphate repulsion due to the high linear charge density in triplexes. The presence of specific counterions is important for complexation. In the absence of negative supercoiling, existence of an intramolecular triplex is rare except under very acidic conditions for the formation of C+(G.C)-type intramolecular triplex. As expected, the stabilities of both inter- and intramolecular triplexes increase with sequence length. The thermodynamic principles of helix-coil transition of oligo-duplex may be described by the van't Hoff relationship, which assumes a two-state cooperative melting profile. Thus, the enthalpy, entropy and free energy of transition can be evaluated from the experimental melting curves (e.g. OD, DSC). For polynucleotides, because of the non-two-state nature of transition, the simple van't Hoff relationship is no longer valid, and direct calorimetry is needed to obtain reliable thermodynamic parameters. The pH and salt concentration dependence of duplex stability can be formulated and derived from a van't Hoff equation. Base-stacking patterns are simple in duplexes but not so in triplexes due to the diversity in triplet schemes. The sequence dependence of base stacking for duplexes has been characterized and employed to predict the stability of an arbitrary sequence. In conclusion, the stability of duplex is relatively well-characterized by thermodynamic data in terms of both base stacking and specific H-bonding. Thermodynamic studies of triplexes have been far fewer in number. Oligonucleotides have found application in the detection and localization of a mRNA or its gene, the detection of bacterial or viral sequences, and the inhibition of the translation of mRNA and the transcription and replication of DNA (Englisch and Gauss, 1991). In a different approach, oligonucleotides have been targeted directly to a DNA duplex motif of a gene in order to inhibit the expression at the beginning of the transcriptional process.(ABSTRACT TRUNCATED AT 400 WORDS)

Base Sequence↗

PubMed1992

Predicting antisense oligonucleotide inhibitory efficacy: a computational approach using histograms and thermodynamic indices.

Antisense oligonucleotides (ASOs) are designed to bind to a specific mRNA and selectively suppress its translation. To facilitate selection of optimal ASO targets, we have developed three thermodynamic indices to evaluate putative structural complexes important in ASO action. These indices are: a secondary structure score (Sscore), which estimates the strength of local mRNA secondary structures at the ASO target site; a duplex score (Dscore), which estimates the delta Gformation for the ASO:mRNA target sequence duplex; and a competition score (Cscore), which is the difference between the Dscore and the Sscore. We also present two histograms to graphically display these indices from different regions of the mRNA. The indices are compared to the inhibition reported in five studies of ASO-mediated suppression of gene expression. The Dscore is the most consistent predictor of ASO efficacy in four of the five studies (r2 from 0.44 to 0.99), while the results of the fifth study could not be predicted by any thermodynamic or physical index. Thus the Dscores and their histogram may prove useful in selection of ASO targets.

Algorithms↗

PubMed2026

Genomic characterization of the attenuated human cytomegalovirus strain TR-VAC developed for subviral particle vaccine production.

We report the complete genome sequence of the attenuated human cytomegalovirus strain TR-VAC, developed for subviral particle vaccine production. Oxford Nanopore duplex sequencing confirmed all engineered modifications, including UL130 repair, UL25 stop codons, ddFKBP insertion, GFP deletion, and retention of the bacterial artificial chromosome backbone, without large-scale structural rearrangements.

Human cytomegalovirus↗

PubMed1992

A potential gene target in HIV-1: rationale, selection of a conserved sequence, and determination of NMR distance and torsion angle constraints.

Recently, the capability for determining the high-resolution, sequence-dependent structure of oligonucleotides in solution via careful analysis of multidimensional NMR spectra and structure refinement procedures has been developed. Consequently, the rationale for selection of a genome sequence as a target for drug design based on the detailed three-dimensional structure of the target is presented. The concept is illustrated by the successful search for a highly conserved region of the HIV-1 genome's long terminal repeat which could serve as a molecular target. A compound which could selectively bind the target sequence could inhibit both RNA transcription from the integrated provirus and the reverse transcription process. Of 148 unique HIV-1 sequences examined, 147 exhibit a 21-base conserved sequence (nucleotides 70-90 in HIVHXB2R) in the R region of the long terminal repeat. The only exception, a minor constituent for one individual, has a change in the penultimate base. A 13 base pair duplex sequence, [d(AGCTTGCCTTGAG).d(CTCAAGGCAAGCT)], from this conserved region was selected and synthesized for NMR structure studies. Phase-sensitive proton two-dimensional nuclear Overhauser enhancement (2D NOE) and double-quantum-filtered correlation (2QF-COSY) spectra were obtained at 500 MHz for the DNA duplex. Exchangeable and nonexchangeable proton resonances were assigned. Quantitative assessments of the 2D NOE cross-peak intensities for different mixing times were carried out using conventional Fourier transform NMR and the maximum likelihood method (MLM). Distance constraints, along with upper and lower bounds, were obtained from the 2D NOE intensities using the iterative complete relaxation matrix algorithm MARDIGRAS. Distances entailing both exchangeable and nonexchangeable protons were determined: 7-11 experimental distance constraints per residue including interresidue and interstrand distances. Simulations of the scalar coupling effects manifest in 2QF-COSY cross-peaks by means of the program SPHINX/LINSHA were compared with experimental data to yield torsion angle constraints for the sugar rings. A single conformer was inadequate to describe any of the sugar puckers, but a rapid two-state equilibrium with one conformer strongly dominant (75-95%) provided a good fit of the 2QF-COSY cross-peaks. The sugar pucker of the major conformer exhibited significant variability for the various nucleotides but was roughly 2'-endo. Though derived independently and subject to different time-averaging effects, the 2QF-COSY and 2D NOE results are in accord.

Base Sequence↗

PubMed1979

Interactions of 4', 6-diamidine-2-phenylindole with synthetic polynucleotides.

4', 6-Diamidine-2-phenylindole forms fluorescent complexes with synthetic DNA duplexes containing AT, AU and IC base pairs; no fluorescent complexes were observed with duplexes containing GC base pairs or with duplexes containing a single AT base pair sandwiched between GC pairs. The binding site size is one molecule of dye per 3 base pairs. The intrinsic binding constants are higher for alternating sequence duplexes than for the corresponding homopolymer pairs. With the exception of the four-stranded helical poly rI which exhibits considerable fluorescence enhancement upon binding of the ligand, none of the single- or multi- stranded polyribonucleotides and ribo-deoxyribonucleotide hybrid structures form fluorescent complexes with the dye. Poly rI is the only RNA which forms a DNA B-like structure (Arnott et al. (1974) Biochem. J. 141, 537). The B conformation of the helix and the absence of guanine appear to be the major determinants of the specificity of the fluorescent binding mode of the dye. Nonfluorescent interactions of the dye with polynucleotides are nonspecific; UV absorption and circular dichroic spectra demonstrate binding to synthetic single- and double-stranded DNA and RNA analogs, including those containing GC base pairs.

Amidines↗

PubMed1976

Total synthesis of the structural gene for the precursor of a tyrosine suppressor transfer RNA from Escherichia coli. 7. Enzymatic joining of the chemically synthesized segments to form a DNA duplex corresponding to the nucleotide sequence 1-26.

Duplex [I], which represents the nucleotide sequence 1-26 of the double-stranded DNA corresponding to the precursor for a tyrosine suppressor tRNA, has been synthesized by the enzymatic joining of five chemically synthesized deoxyribooligonucleotide segments. The synthesis was accomplished in two different ways. In a one-step synthesis, all of the five segments were used together: segments 2, 3, and 5 carried 5'-33P-labeled phosphate groups while segment 4 carried a 32P-phosphate group. An alternative, two-step method involved the joining of 5'-32P-phosphorylated segment 2 to segment 4 (carrying 5'-OH group or 5'-32P- or 33P-labeled phosphate group) in the presence of segment 3 followed by the joining of [5-32P]segment 5 in a second step. The duplex [I]' (segments 2 to 5) thus obtained was phosphorlated at the 5'-ends with polynucleotide kinase and then joined to segment 1 to give duplex [I] quantitatively. The preparative methods described have the desired flexibility for performing the subsequent operations necessary for the total synthesis of the structural gene for the tyrosine suppressor tRNA precursor.

Base Sequence↗

PubMed1978

Clustered and interspersed repetitive DNA sequences in four amphibian species with different genome size.

We have compared the amount of clustered and interspersed repetitive sequences in the genome of four Amphibia with different DNA contents per haploid nucleus: two Anura (Xenopus laevis, 3 pg and Bufo bufo, 7 pg) and two Urodela (Triturus cristatus, 23 pg and Necturus maculosus, 52 pg). High molecular weight DNA of the four species was denatured and reassociated to the same Cot in order to obtain duplex sequences with a similar reiteration frequency. Single-stranded DNA was digested off with the Aspergillus S1 nuclease. DNA was then fractionated according to the molecular weight through an agarose A-50 column. We found that the amount of long repetitive sequences is roughly proportional to the genome size in the four species, while the number of short (about 300 base pairs) repetitive sequences is increased many-fold in the species with the larger DNA content, both in Anura and in Urodela.

Amphibians↗

PubMed1992

Kinetics and thermodynamics of triple-helix formation: effects of ionic strength and mismatches.

Thermodynamic and kinetic parameters for the triplex-forming reactions between a homopurine-homopyrimidine 22-base-pair duplex (sequence of the purine strand: 5'd[AAAGGAGGAGAAGAAGAAAAAA]3') and the four 22-dN third strands (22 dN: 5'd[TTTCCTCCTCTNCTTCTTTTTT]3', where N = A, C, T, or G) were determined from thermal denaturation and renaturation UV absorbance profiles. Cooling and heating curves were not superimposable and thus allowed us to determine the rate constants of association (k(on)) and dissociation (k(off)) as a function of temperature, assuming a two-state model analogous to that developed for duplex-forming reactions. Experiments were performed in 10 mM cacodylate buffer (pH 6.8) in the presence of NaCl concentrations ranging from 20 to 300 mM. Within experimental accuracy, the main results are the following: (i) The rate constants k(on) and k(off) result in linear Arrhenius plots, consistent with the prediction of two-state association and dissociation (ii) k(on) is independent of the nature of the base N located in the center of the third strand. (iii) k(on) strongly decreases when the NaCl concentration is decreased. (iv) The activation energy, E(on), is always negative and becomes more negative when the NaCl concentration is decreased. (v) k(off) is independent of NaCl concentration but depends on the base N, with its magnitude following the order C greater than G greater than A much greater than T. (vi) The activation energy, E(off), is independent of the base N. All these results are discussed in the light of a nucleation-zipping model similar to that developed for the duplex-coil transitions [Craig, M. E., Crothers, D. M., & Doty, P. (1971) J. Mol. Biol. 62, 383-401; Pörschke, D., Eigen, M. (1971) J. Mol. Biol. 62, 361-381].

Base Composition↗

PubMed2026

Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders.

Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) represent two major categories of neurodegenerative disorders-TAR DNA-binding protein 43 (TDP-43) and tau proteinopathies-for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 469 neurons from C9ORF72 ALS, C9ORF72 FTD, AD, and control brains revealed increased somatic single-nucleotide variants (sSNVs) and insertions/deletions (sIndels) in all three diseases. Mutational signature analysis identified a disease-associated sSNV signature consistent with oxidative damage and an sIndel process affecting 22% of ALS, 76% of FTD, and 61% of AD neurons-but only 2% of control neurons-resembling signature ID4, previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Rapid approach to DNA adduct recovery (RADAR) assays confirmed increased TOP1-DNA covalent complexes, and duplex sequencing confirmed the increased sIndels and identified single-strand events as likely precursor lesions. TOP1-associated sIndel mutagenesis and genome instability thus represent a mechanism shared by both TDP-43 and tau neurodegeneration.

Humans↗

PubMed2025

Recurrent patterns of widespread neuronal genomic damage shared by major neurodegenerative disorders.

Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) are common neurodegenerative disorders for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 429 neurons from three C9ORF72 ALS, six C9ORF72 FTD, seven AD, and twenty-three neurotypical control brains revealed significantly increased burdens in somatic single nucleotide variant (sSNV) and insertion/deletion (sIndel) in all three disease conditions. Mutational signature analysis identified a disease-associated sSNV signature suggestive of oxidative damage and an sIndel process, affecting 28% of ALS, 79% of FTD, and 65% of AD neurons but only 5% of control neurons (diseased vs. control: OR=31.20, p = 2.35×10-10). Disease-associated sIndels were primarily two-basepair deletions resembling signature ID4, which was previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Duplex sequencing confirmed the presence of sIndels and identified similar single-strand events as potential precursor lesions. TOP1-associated sIndel mutagenesis and resulting genome instability may thus represent a common mechanism of neurodegeneration.

Journal Article↗