Detection of base modifications by enhancing electrical contrast in nanopores

A method of detecting a presence or absence of a single naturally-or synthetically-modified nucleobase in a polynucleotide molecule, the method comprising:

• (a) contacting said polynucleotide molecule with one or more reagents capable of selectively attaching a detectable moiety to at least one said naturally-or synthetically-modified nucleobase in said polynucleotide molecule or to at least one nucleobase adjacent to at least one naturally-or synthetically-modified nucleobase in said polynucleotide molecule, to form a labeled nucleobase in said polynucleotide molecule, wherein said presence or said absence of said modified nucleobase is determined by said attaching;
• and
• (b) assaying said polynucleotide molecule using a nanopore device,
• thereby detecting a presence or absence of said labeled nucleobase of said polynucleotide molecule,
• wherein a presence of said labeled nucleobase is indicative of an initial absence of said modified nucleobase at or near the position of the labeled nucleobase.