Enzymatic synthesis and nanopore sequencing of 12-letter supernumerary DNA

Hinako Kawabe, Christopher A. Thomas, Shuichi Hoshika, Myong-Jung Kim, Myong-Sang Kim, Logan Miessner, Nicholas Kaplan, Jonathan M. Craig, Jens H. Gundlach, Andrew H. Laszlo, Steven A. Benner and Jorge A. Marchand ()
Additional contact information
Hinako Kawabe: University of Washington
Christopher A. Thomas: University of Washington
Shuichi Hoshika: Foundation for Applied Molecular Evolution
Myong-Jung Kim: Foundation for Applied Molecular Evolution
Myong-Sang Kim: Firebird Biomolecular Sciences LLC
Logan Miessner: University of Washington
Nicholas Kaplan: University of Washington
Jonathan M. Craig: University of Washington
Jens H. Gundlach: University of Washington
Andrew H. Laszlo: University of Washington
Steven A. Benner: Foundation for Applied Molecular Evolution
Jorge A. Marchand: University of Washington

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract The 4-letter DNA alphabet (A, T, G, C) as found in Nature is an elegant, yet non-exhaustive solution to the problem of storage, transfer, and evolution of biological information. Here, we report on strategies for both writing and reading DNA with expanded alphabets composed of up to 12 letters (A, T, G, C, B, S, P, Z, X, K, J, V). For writing, we devise an enzymatic strategy for inserting a singular, orthogonal xenonucleic acid (XNA) base pair into standard DNA sequences using 2′-deoxy-xenonucleoside triphosphates as substrates. Integrating this strategy with combinatorial oligos generated on a chip, we construct libraries containing single XNA bases for parameterizing kmer basecalling models for commercially available nanopore sequencing. These elementary steps are combined to synthesize and sequence DNA containing 12 letters – the upper limit of what is accessible within the electroneutral, canonical base pairing framework. By introducing low-barrier synthesis and sequencing strategies, this work overcomes previous obstacles paving the way for making expanded alphabets widely accessible.

Date: 2023
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DOI: 10.1038/s41467-023-42406-z

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