Direct detection of 8-oxo-dG using nanopore sequencing

Marc Pagès-Gallego, Daan M. K. van Soest, Nicolle J. M. Besselink, Roy Straver, Janneke P. Keijer, Carlo Vermeulen, Alessio Marcozzi, Markus J. van Roosmalen, Ruben van Boxtel, Boudewijn M. T. Burgering (), Tobias B. Dansen () and Jeroen Ridder ()
Additional contact information
Marc Pagès-Gallego: Utrecht University
Daan M. K. van Soest: Utrecht University
Nicolle J. M. Besselink: Utrecht University
Roy Straver: Utrecht University
Janneke P. Keijer: Utrecht University
Carlo Vermeulen: Utrecht University
Alessio Marcozzi: Cyclomics
Markus J. van Roosmalen: Oncode Institute
Ruben van Boxtel: Oncode Institute
Boudewijn M. T. Burgering: Utrecht University
Tobias B. Dansen: Utrecht University
Jeroen Ridder: Utrecht University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Genomic DNA is under constant oxidative damage, with 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxo-dG) being the prominent lesion linked to mutagenesis, epigenetics, and gene regulation. Existing methods to detect 8-oxo-dG rely on indirect approaches, while nanopore sequencing enables direct detection of base modifications. A model for 8-oxo-dG detection is currently missing due to the lack of training data. Here, we develop a strategy using synthetic oligos to generate long, 8-oxo-dG context-variable DNA molecules for deep learning and nanopore sequencing. Our training approach addresses the rarity of 8-oxo-dG relative to guanine, enabling specific detection. Applied to a tissue culture model of oxidative damage, our method reveals uneven genomic 8-oxo-dG distribution, dissimilar context pattern to C>A mutations, and local 5-mC depletion. This dual measurement of 5-mC and 8-oxo-dG at single-molecule resolution uncovers new insights into their interplay. Our approach also provides a general framework for detecting other rare DNA modifications using synthetic DNA and nanopore sequencing.

Date: 2025
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DOI: 10.1038/s41467-025-60391-3

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