On nanopore DNA sequencing by signal and noise analysis of ionic current

Wen, Chenyu; Zeng, Shuangshuang; Zhang, Zhen; Hjort, Klas; Zhang, Shi-Li

doi:10.1088/0957-4484/27/21/215502

Cited by 20 publications

(15 citation statements)

References 92 publications

(218 reference statements)

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“…This observation agrees well with a previous theoretical study suggesting that increase in pore size or thickness could significantly reduce the signal, making it difficult to distinguish from the noise. 55 In addition to the pore size, the ionic current through nanopores may be affected by the electroosmotic flow (EOF) through the pore. The electro-osmotic flow (EOF) is the consequence of the electrostatic interaction between an applied electric field and a charged nanopore.…”

Section: Resultsmentioning

confidence: 99%

Detection and mapping of DNA methylation with 2D material nanopores

et al. 2017

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DNA methylation is an epigenetic modification involving the addition of a methyl group to DNA, which is heavily involved in gene expression and regulation, thereby critical to the progression of diseases such as cancer. In this work we show that detection and localization of DNA methylation can be achieved with nanopore sensors made of two-dimensional (2D) materials such as graphene and molybdenum di-sulphide (MoS2). We label each DNA methylation site with a methyl-CpG binding domain protein (MBD1), and combine molecular dynamics simulations with electronic transport calculations to investigate the translocation of the methylated DNA-MBD1 complex through 2D material nanopores under external voltage biases. The passage of the MBD1-labeled methylation site through the pore is identified by dips in the current blockade induced by the DNA strand, as well as by peaks in the transverse electronic sheet current across the 2D layer. The position of the methylation sites can be clearly recognized by the relative positions of the dips in the recorded ionic current blockade with an estimated error ranging from 0% to 16%. Finally, we define the spatial resolution of the 2D material nanopore device as the minimal distance between two methylation sites identified within a single measurement, which is 15 base pairs by ionic current recognition, but as low as 10 base pairs by transverse electronic conductance detection, indicating better resolution with this latter technique. The present approach opens a new route for precise and efficient profiling of DNA methylation.

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Section: Resultsmentioning

confidence: 99%

Detection and mapping of DNA methylation with 2D material nanopores

et al. 2017

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“…This contribution in Figure 6 is measured in percentages of the total flicker noise including both surface and bulk components. Note that the membrane thickness has no influence on the flicker noise as the access region 17 close to the nanopore is not considered in the model. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 13 noise level when using small-diameter pores in thin membranes to boost signal and improve base resolution in DNA sequencing.…”

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confidence: 99%

Generalized Noise Study of Solid-State Nanopores at Low Frequencies

et al. 2017

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Nanopore technology has been extensively investigated for analysis of biomolecules, and a success story in this field concerns DNA sequencing using a nanopore chip featuring an array of hundreds of biological nanopores (BioNs). Solid-state nanopores (SSNs) have been explored to attain longer lifetime and higher integration density than what BioNs can offer, but SSNs are generally considered to generate higher noise whose origin remains to be confirmed. Here, we systematically study low-frequency (including thermal and flicker) noise characteristics of SSNs measuring 7 to 200 nm in diameter drilled through a 20-nm-thick SiN x membrane by focused ion milling. Both bulk and surface ionic currents in the nanopore are found to contribute to the flicker noise, with their respective contributions determined by salt concentration and pH in electrolytes as well as bias conditions. Increasing salt concentration at constant pH and voltage bias leads to increase in the bulk ionic current and noise therefrom. Changing pH at constant salt concentration and current bias results in variation of surface charge density, and hence alteration of surface ionic current and noise. In addition, the noise from Ag/AgCl electrodes can become predominant when the pore size is large and/or the salt concentration is high. Analysis of our comprehensive experimental results leads to the establishment of a generalized nanopore noise model. The model not only gives an excellent account of the experimental observations, but can also be used for evaluation of various noise components in much smaller nanopores currently not experimentally available.

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“…Оскільки сигнал іонного струму крізь біологічну чи твердотільну нанопору є дуже малим за амплітудою, шум представляє значну проблему, яка суттєво обмежує чутливість нанопори. В роботах [23][24][25] наведено порівняння рівнів шуму для різних матеріалів нанопор, їх діаметрів та довжин. У [24] показано, що біологічні нанопори мають кращі показники шуму порівняно з твердодільними нанопорами.…”

Section: моделювання та аналіз сигналівunclassified

Simulation and Analysis of Bionanopore Dna Sequencing Signals for Genetic Mutations Detection

Ievdoshchenko¹,

Ivanko²,

Ivanushkina³

et al. 2021

Microsyst., Electron. & Acoust.

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The application of genomic signal processing methods to the problem of modeling and analysis of nanoporous DNA sequencing signals is considered in the paper. Based on the nucleotide sequences in the norm and in the case of mutations, 1200 signals are simulated, which represent 4 classes: norm, missense mutation, insertion mutation and deletion mutation. Correlation analysis was used to determine the similarity of nanoporous DNA sequencing signals using a cross-correlation function between two current signals in the protein nanopore, specifically signal in norm and in the presence of mutation. The location of the correlation peak determines the type of mutation (insertion or deletion), as well as the alignment of the same nucleotide sequences using a defined signal shift. The results of applying machine learning methods to the problem of classification of nanoporous DNA sequencing signals significantly depend on the noise level of the registered current signals through the protein nanopore and the type of mutation. Given a relatively low noise level, when the values of the ion current through a protein nanopore for different nucleotides do not intersect, the classification accuracy reaches 100%. In the case of increasing the standard deviation of the law of distribution of noise components, there is an overlap of the levels of current values in the nanopore in the case of its blocking by nucleotides of the close size. As a result, errors in the definition of normal and single nucleotide mutations (missense or nonsense) often occur, especially if the levels of current steps in the nanopore for two nucleotides are similar (for example, guanine and thymine, thymine and adenine, adenine and cytosine) and noise masks their contribution to reduction current in the nanopore. Mutations of insertion and deletion of a certain nucleotide sequence are often classified without errors, because these mutations are characterized by a shift of several nucleotides between normal signals and pathology, which increases the distance between these signals. Among the machine learning methods that have demonstrated the high accuracy of classification of the signals of nanopore-based DNA sequencing, the methods of linear discriminant, k-nearest neighbors classifier (with Euclidean distance and the sufficient number of nearest neighbors), as well as the method of reference vectors should be mentioned. The best results were obtained for the classification method of support vector machines. The use of linear, quadratic and cubic kernel functions shows the high accuracy of correctly classified signals - from 93 to 100%.

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On nanopore DNA sequencing by signal and noise analysis of ionic current

Cited by 20 publications

References 92 publications

Detection and mapping of DNA methylation with 2D material nanopores

Detection and mapping of DNA methylation with 2D material nanopores

Generalized Noise Study of Solid-State Nanopores at Low Frequencies

Simulation and Analysis of Bionanopore Dna Sequencing Signals for Genetic Mutations Detection

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