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Kai Wang - One of the best experts on this subject based on the ideXlab platform.
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Detection of DNA Base modifications by deep recurrent neural network on Oxford Nanopore sequencing data
Nature Communications, 2019Co-Authors: Qian Liu, Chuan-le Xiao, Guoliang Yu, Depeng Wang, Li Fang, Kai WangAbstract:DNA Base modifications, such as C5-methylcytosine (5mC) and N6-methyldeoxyadenosine (6mA), are important types of epigenetic regulations. Short-read bisulfite sequencing and long-read PacBio sequencing have inherent limitations to detect DNA modifications. Here, using raw electric signals of Oxford Nanopore long-read sequencing data, we design DeepMod, a bidirectional recurrent neural network (RNN) with long short-term memory (LSTM) to detect DNA modifications. We sequence a human genome HX1 and a Chlamydomonas reinhardtii genome using Nanopore sequencing, and then evaluate DeepMod on three types of genomes (Escherichia coli, Chlamydomonas reinhardtii and human genomes). For 5mC detection, DeepMod achieves average precision up to 0.99 for both synthetically introduced and naturally occurring modifications. For 6mA detection, DeepMod achieves ~0.9 average precision on Escherichia coli data, and have improved performance than existing methods on Chlamydomonas reinhardtii data. In conclusion, DeepMod performs well for genome-scale detection of DNA modifications and will facilitate epigenetic analysis on diverse species.DNA modification generates unique electric signals in Oxford Nanopore sequencing data but the signals can be complicated to decipher. Here, the authors develop a deep learning framework, DeepMod, to detect DNA Base modifications including 5mC and 6mA using Nanopore sequencing data
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detection of DNA Base modifications by deep recurrent neural network on oxford nanopore sequencing data
Nature Communications, 2019Co-Authors: Qian Liu, Chuan-le Xiao, Depeng Wang, Li Fang, Kai WangAbstract:DNA Base modifications, such as C5-methylcytosine (5mC) and N6-methyldeoxyadenosine (6mA), are important types of epigenetic regulations. Short-read bisulfite sequencing and long-read PacBio sequencing have inherent limitations to detect DNA modifications. Here, using raw electric signals of Oxford Nanopore long-read sequencing data, we design DeepMod, a bidirectional recurrent neural network (RNN) with long short-term memory (LSTM) to detect DNA modifications. We sequence a human genome HX1 and a Chlamydomonas reinhardtii genome using Nanopore sequencing, and then evaluate DeepMod on three types of genomes (Escherichia coli, Chlamydomonas reinhardtii and human genomes). For 5mC detection, DeepMod achieves average precision up to 0.99 for both synthetically introduced and naturally occurring modifications. For 6mA detection, DeepMod achieves ~0.9 average precision on Escherichia coli data, and have improved performance than existing methods on Chlamydomonas reinhardtii data. In conclusion, DeepMod performs well for genome-scale detection of DNA modifications and will facilitate epigenetic analysis on diverse species.
Haibo Zhou - One of the best experts on this subject based on the ideXlab platform.
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off target rna mutation induced by DNA Base editing and its elimination by mutagenesis
Nature, 2019Co-Authors: Changyang Zhou, Rong Zeng, Yidi Sun, Rui Yan, Yajing Liu, Erwei Zuo, Linxiao Han, Yu Wei, Haibo ZhouAbstract:Recently developed DNA Base editing methods enable the direct generation of desired point mutations in genomic DNA without generating any double-strand breaks1-3, but the issue of off-target edits has limited the application of these methods. Although several previous studies have evaluated off-target mutations in genomic DNA4-8, it is now clear that the deaminases that are integral to commonly used DNA Base editors often bind to RNA9-13. For example, the cytosine deaminase APOBEC1-which is used in cytosine Base editors (CBEs)-targets both DNA and RNA12, and the adenine deaminase TadA-which is used in adenine Base editors (ABEs)-induces site-specific inosine formation on RNA9,11. However, any potential RNA mutations caused by DNA Base editors have not been evaluated. Adeno-associated viruses are the most common delivery system for gene therapies that involve DNA editing; these viruses can sustain long-term gene expression in vivo, so the extent of potential RNA mutations induced by DNA Base editors is of great concern14-16. Here we quantitatively evaluated RNA single nucleotide variations (SNVs) that were induced by CBEs or ABEs. Both the cytosine Base editor BE3 and the adenine Base editor ABE7.10 generated tens of thousands of off-target RNA SNVs. Subsequently, by engineering deaminases, we found that three CBE variants and one ABE variant showed a reduction in off-target RNA SNVs to the Baseline while maintaining efficient DNA on-target activity. This study reveals a previously overlooked aspect of off-target effects in DNA editing and also demonstrates that such effects can be eliminated by engineering deaminases.
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off target rna mutation induced by DNA Base editing and its elimination by mutagenesis
Nature, 2019Co-Authors: Changyang Zhou, Chan Gu, Xinde Hu, Yixue Li, Rong Zeng, Haibo Zhou, Hui YangAbstract:Recently developed DNA Base editing methods enable the direct generation of desired point mutations in genomic DNA without generating any double-strand breaks1–3, but the issue of off-target edits has limited the application of these methods. Although several previous studies have evaluated off-target mutations in genomic DNA4–8, it is now clear that the deaminases that are integral to commonly used DNA Base editors often bind to RNA9–13. For example, the cytosine deaminase APOBEC1—which is used in cytosine Base editors (CBEs)—targets both DNA and RNA12, and the adenine deaminase TadA—which is used in adenine Base editors (ABEs)—induces site-specific inosine formation on RNA9,11. However, any potential RNA mutations caused by DNA Base editors have not been evaluated. Adeno-associated viruses are the most common delivery system for gene therapies that involve DNA editing; these viruses can sustain long-term gene expression in vivo, so the extent of potential RNA mutations induced by DNA Base editors is of great concern14–16. Here we quantitatively evaluated RNA single nucleotide variations (SNVs) that were induced by CBEs or ABEs. Both the cytosine Base editor BE3 and the adenine Base editor ABE7.10 generated tens of thousands of off-target RNA SNVs. Subsequently, by engineering deaminases, we found that three CBE variants and one ABE variant showed a reduction in off-target RNA SNVs to the Baseline while maintaining efficient DNA on-target activity. This study reveals a previously overlooked aspect of off-target effects in DNA editing and also demonstrates that such effects can be eliminated by engineering deaminases. Cytosine and adenine Base editors have undesired off-target effects on RNA, but this activity can be reduced in deaminase-engineered variants while preserving on-target DNA editing.
D M Hovorun - One of the best experts on this subject based on the ideXlab platform.
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is the dpt tautomerization of the long a g watson crick DNA Base mispair a source of the adenine and guanine mutagenic tautomers a qm and qtaim response to the biologically important question
Journal of Computational Chemistry, 2014Co-Authors: Olha O Brovarets, Roman O Zhurakivsky, D M HovorunAbstract:Herein, we first address the question posed in the title by establishing the tautomerization trajectory via the double proton transfer of the adenine·guanine (A·G) DNA Base mispair formed by the canonical tautomers of the A and G Bases into the A*·G* DNA Base mispair, involving mutagenic tautomers, with the use of the quantum-mechanical calculations and quantum theory of atoms in molecules (QTAIM). It was detected that the A·G ↔ A*·G* tautomerization proceeds through the asynchronous concerted mechanism. It was revealed that the A·G Base mispair is stabilized by the N6H···O6 (5.68) and N1H···N1 (6.51) hydrogen bonds (H-bonds) and the N2H···HC2 dihydrogen bond (DH-bond) (0.68 kcal·mol−1), whereas the A*·G* Base mispair—by the O6H···N6 (10.88), N1H···N1 (7.01) and C2H···N2 H-bonds (0.42 kcal·mol−1). The N2H···HC2 DH-bond smoothly and without bifurcation transforms into the C2H···N2 H-bond at the IRC = −10.07 Bohr in the course of the A·G ↔ A*·G* tautomerization. Using the sweeps of the energies of the intermolecular H-bonds, it was observed that the N6H···O6 H-bond is anticooperative to the two others—N1H···N1 and N2H···HC2 in the A·G Base mispair, while the latters are significantly cooperative, mutually strengthening each other. In opposite, all three O6H···N6, N1H···N1, and C2H···N2 H-bonds are cooperative in the A*·G* Base mispair. All in all, we established the dynamical instability of the А*·G* Base mispair with a short lifetime (4.83·10−14 s), enabling it not to be deemed feasible source of the A* and G* mutagenic tautomers of the DNA Bases. The small lifetime of the А*·G* Base mispair is predetermined by the negative value of the Gibbs free energy for the A*·G* → A·G transition. Moreover, all of the six low-frequency intermolecular vibrations cannot develop during this lifetime that additionally confirms the aforementioned results. Thus, the A*·G* Base mispair cannot be considered as a source of the mutagenic tautomers of the DNA Bases, as the A·G Base mispair dissociates during DNA replication exceptionally into the A and G monomers in the canonical tautomeric form. © 2013 Wiley Periodicals, Inc.
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atomistic nature of the dpt tautomerisation of the biologically important c c DNA Base mispair containing amino and imino tautomers of cytosine a qm and qtaim approach
Physical Chemistry Chemical Physics, 2013Co-Authors: Olha O Brovarets, D M HovorunAbstract:A theoretical study of tautomerisation of the biologically important cytosine·cytosine* (C·C*) DNA mismatch with a propeller-like structure (|C4N3N3C4| = 32.4°; C1 symmetry) and cis-oriented N1H glycosidic bonds, formed by the amino and imino tautomers of the C nucleoBase, via the asynchronous concerted double proton transfer (DPT) along two H-bonds through the transition state (TSC·C*↔C*·C) (|C4N3N3C4| = 48.5°; C1 symmetry) into the C*·C mispair was carried out for the first time. It was established that the C·C*/C*·C DNA Base mispair is associated by the antiparallel N4H⋯N4 (6.66 kcal mol−1), N3H⋯N3 (6.47 kcal mol−1) H-bonds and the O2⋯O2 van der Waals (vdW) contact (0.33 kcal mol−1), while the zwitterionic TSC·C*↔C*·C is stabilized by the parallel N4+H⋯N4− (13.55 kcal mol−1), N3+H⋯N3− (13.20 kcal mol−1) H-bonds and the O2+⋯O2− vdW contact (0.60 kcal mol−1). It was shown that the C·C* ↔ C*·C tautomerisation via the DPT is assisted by the O2⋯O2 vdW contact, that in contrast to the two others N4H⋯N4 and N3H⋯N3 H-bonds exists along the entire intrinsic reaction coordinate (IRC) range. The positive values of the Grunenberg's compliance constants (30.919 and 21.384 A mdyn−1 for C·C*/C*·C and TSC·C*↔C*·C, respectively) indicate that the O2⋯O2 vdW contact is a stabilizing closed-shell interaction. It was found that the middle N3H⋯N3 H-bond is anti-cooperative with the upper N4H⋯N4 H-bond and cooperative with the lower O2⋯O2 vdW contact. The 9 key points, which can be considered as electron-topological “fingerprints” of the asynchronous concerted C·C* ↔ C*·C tautomerisation process via the DPT were revealed along the IRC and examined in detail. It was shown that the C·C*/C*·C Base mispair is a thermodynamically and dynamically stable structure. Its lifetime is equal to 1.53 × 10−7 s at the MP2/cc-pVQZ//B3LYP/6-311++G(d,p) level of theory in vacuum. All 6 low-frequency intermolecular vibrations are able to develop during this time span.
Changyang Zhou - One of the best experts on this subject based on the ideXlab platform.
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off target rna mutation induced by DNA Base editing and its elimination by mutagenesis
Nature, 2019Co-Authors: Changyang Zhou, Rong Zeng, Yidi Sun, Rui Yan, Yajing Liu, Erwei Zuo, Linxiao Han, Yu Wei, Haibo ZhouAbstract:Recently developed DNA Base editing methods enable the direct generation of desired point mutations in genomic DNA without generating any double-strand breaks1-3, but the issue of off-target edits has limited the application of these methods. Although several previous studies have evaluated off-target mutations in genomic DNA4-8, it is now clear that the deaminases that are integral to commonly used DNA Base editors often bind to RNA9-13. For example, the cytosine deaminase APOBEC1-which is used in cytosine Base editors (CBEs)-targets both DNA and RNA12, and the adenine deaminase TadA-which is used in adenine Base editors (ABEs)-induces site-specific inosine formation on RNA9,11. However, any potential RNA mutations caused by DNA Base editors have not been evaluated. Adeno-associated viruses are the most common delivery system for gene therapies that involve DNA editing; these viruses can sustain long-term gene expression in vivo, so the extent of potential RNA mutations induced by DNA Base editors is of great concern14-16. Here we quantitatively evaluated RNA single nucleotide variations (SNVs) that were induced by CBEs or ABEs. Both the cytosine Base editor BE3 and the adenine Base editor ABE7.10 generated tens of thousands of off-target RNA SNVs. Subsequently, by engineering deaminases, we found that three CBE variants and one ABE variant showed a reduction in off-target RNA SNVs to the Baseline while maintaining efficient DNA on-target activity. This study reveals a previously overlooked aspect of off-target effects in DNA editing and also demonstrates that such effects can be eliminated by engineering deaminases.
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off target rna mutation induced by DNA Base editing and its elimination by mutagenesis
Nature, 2019Co-Authors: Changyang Zhou, Chan Gu, Xinde Hu, Yixue Li, Rong Zeng, Haibo Zhou, Hui YangAbstract:Recently developed DNA Base editing methods enable the direct generation of desired point mutations in genomic DNA without generating any double-strand breaks1–3, but the issue of off-target edits has limited the application of these methods. Although several previous studies have evaluated off-target mutations in genomic DNA4–8, it is now clear that the deaminases that are integral to commonly used DNA Base editors often bind to RNA9–13. For example, the cytosine deaminase APOBEC1—which is used in cytosine Base editors (CBEs)—targets both DNA and RNA12, and the adenine deaminase TadA—which is used in adenine Base editors (ABEs)—induces site-specific inosine formation on RNA9,11. However, any potential RNA mutations caused by DNA Base editors have not been evaluated. Adeno-associated viruses are the most common delivery system for gene therapies that involve DNA editing; these viruses can sustain long-term gene expression in vivo, so the extent of potential RNA mutations induced by DNA Base editors is of great concern14–16. Here we quantitatively evaluated RNA single nucleotide variations (SNVs) that were induced by CBEs or ABEs. Both the cytosine Base editor BE3 and the adenine Base editor ABE7.10 generated tens of thousands of off-target RNA SNVs. Subsequently, by engineering deaminases, we found that three CBE variants and one ABE variant showed a reduction in off-target RNA SNVs to the Baseline while maintaining efficient DNA on-target activity. This study reveals a previously overlooked aspect of off-target effects in DNA editing and also demonstrates that such effects can be eliminated by engineering deaminases. Cytosine and adenine Base editors have undesired off-target effects on RNA, but this activity can be reduced in deaminase-engineered variants while preserving on-target DNA editing.
Qian Liu - One of the best experts on this subject based on the ideXlab platform.
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Detection of DNA Base modifications by deep recurrent neural network on Oxford Nanopore sequencing data
Nature Communications, 2019Co-Authors: Qian Liu, Chuan-le Xiao, Guoliang Yu, Depeng Wang, Li Fang, Kai WangAbstract:DNA Base modifications, such as C5-methylcytosine (5mC) and N6-methyldeoxyadenosine (6mA), are important types of epigenetic regulations. Short-read bisulfite sequencing and long-read PacBio sequencing have inherent limitations to detect DNA modifications. Here, using raw electric signals of Oxford Nanopore long-read sequencing data, we design DeepMod, a bidirectional recurrent neural network (RNN) with long short-term memory (LSTM) to detect DNA modifications. We sequence a human genome HX1 and a Chlamydomonas reinhardtii genome using Nanopore sequencing, and then evaluate DeepMod on three types of genomes (Escherichia coli, Chlamydomonas reinhardtii and human genomes). For 5mC detection, DeepMod achieves average precision up to 0.99 for both synthetically introduced and naturally occurring modifications. For 6mA detection, DeepMod achieves ~0.9 average precision on Escherichia coli data, and have improved performance than existing methods on Chlamydomonas reinhardtii data. In conclusion, DeepMod performs well for genome-scale detection of DNA modifications and will facilitate epigenetic analysis on diverse species.DNA modification generates unique electric signals in Oxford Nanopore sequencing data but the signals can be complicated to decipher. Here, the authors develop a deep learning framework, DeepMod, to detect DNA Base modifications including 5mC and 6mA using Nanopore sequencing data
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detection of DNA Base modifications by deep recurrent neural network on oxford nanopore sequencing data
Nature Communications, 2019Co-Authors: Qian Liu, Chuan-le Xiao, Depeng Wang, Li Fang, Kai WangAbstract:DNA Base modifications, such as C5-methylcytosine (5mC) and N6-methyldeoxyadenosine (6mA), are important types of epigenetic regulations. Short-read bisulfite sequencing and long-read PacBio sequencing have inherent limitations to detect DNA modifications. Here, using raw electric signals of Oxford Nanopore long-read sequencing data, we design DeepMod, a bidirectional recurrent neural network (RNN) with long short-term memory (LSTM) to detect DNA modifications. We sequence a human genome HX1 and a Chlamydomonas reinhardtii genome using Nanopore sequencing, and then evaluate DeepMod on three types of genomes (Escherichia coli, Chlamydomonas reinhardtii and human genomes). For 5mC detection, DeepMod achieves average precision up to 0.99 for both synthetically introduced and naturally occurring modifications. For 6mA detection, DeepMod achieves ~0.9 average precision on Escherichia coli data, and have improved performance than existing methods on Chlamydomonas reinhardtii data. In conclusion, DeepMod performs well for genome-scale detection of DNA modifications and will facilitate epigenetic analysis on diverse species.