Sequencing a DNA analog composed of artificial bases

Sequencing a DNA analog composed of artificial bases

Abstract “ALternative Isoinformational ENgineered” (ALIEN) DNA is a biomimetic polymer composed of four entirely anthropogenic nucleotides. These alternative nucleosides form base pairs orthogonal to canonical bases and fold into the familiar B-form DNA double-helix, endowing ALIEN DNA with valuable...

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Main Authors: Christopher A. Thomas, Henry Brinkerhoff, Jonathan M. Craig, Shuichi Hoshika, Desislava Mihaylova, Akira M. Pfeffer, Michaela C. Franzi, Sarah J. Abell, Jessica D. Carrasco, Jens H. Gundlach, Steven A. Benner, Andrew H. Laszlo
Format: Article
Language:English
Published: Nature Portfolio 2025-08-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-61991-9
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Summary:Abstract “ALternative Isoinformational ENgineered” (ALIEN) DNA is a biomimetic polymer composed of four entirely anthropogenic nucleotides. These alternative nucleosides form base pairs orthogonal to canonical bases and fold into the familiar B-form DNA double-helix, endowing ALIEN DNA with valuable biotechnological applications. The ability to sequence ALIEN DNA is essential for its continued development. However traditional sequencing approaches rely on chemical recognition of ACGT-DNA and cannot be easily adapted to ALIEN DNA. Here we demonstrate de novo nanopore sequencing of DNA comprised entirely of the four anthropogenic DNA bases. We show direct, label-free, single-molecule sequencing of such nucleic acids without the requirements of fluorescent labels, transliteration, amplification, or enzymatic synthesis. This paves the way for routine, accessible, and high-accuracy sequencing of DNA beyond A, C, G, and T.
ISSN:2041-1723

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