Genomics and epigenomics using 2D nanopores

DNA methylation is an epigenetic modification caused by the addition of a methyl group to DNA and 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 MoS₂. We label each DNA methylated 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 blockage induced by the DNA strand, as well as by peaks in the transverse electronic sheet current across the 2D layer. The positions of the methylation sites can be clearly recognized by the relative positions of the dips in the recorded ionic current blockade and large deviations in the transverse sheet conductances. 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. Finally we propose techniques to improve the signal-to-noise (SNR) ratio in 2D solid state nanopores. In graphene, we demonstrate that the hydrophobic nature of the material can be utilized to introduce a ``step-wise'' translocation of a stretched ssDNA in a graphene nanopore, which can be used to detect bases via transverse sheet current. We also propose an information-theoretic approach to improve the SNR of the system by using matched filtering, which could possibly be used for real time base calling in solid state nanopores.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Electrical & Computer Engr

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2018

Author dc:creator

• Sarathy, Aditya

Contributors dc:contributor

• Leburton, Jean-Pierre
• Radenovic, Aleksandra
• Bhargava, Rohit
• Varshney, Lav R.

• DNA Sequencing, Epigenetics, Solid State Devices, Nanopores, Signal Processing

Statement dc:rights

• 2018 Aditya Sarathy

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/101688

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/101688