DNA mismatch and damage patterns revealed by single-molecule sequencing

Mei Hong Liu, Benjamin M. Costa, Emilia C. Bianchini, Una Choi, Rachel C. Bandler, Emilie Lassen, Marta Grońska-Pęski, Adam Schwing, Zachary R. Murphy, Daniel Rosenkjær, Shany Picciotto, Vanessa Bianchi, Lucie Stengs, Melissa Edwards, Nuno Miguel Nunes, Caitlin A. Loh, Tina K. Truong, Randall E. Brand, Tomi Pastinen, J. Richard Wagner, Anne-Bine Skytte, Uri Tabori, Jonathan E. Shoag and Gilad D. Evrony ()
Additional contact information
Mei Hong Liu: New York University Grossman School of Medicine
Benjamin M. Costa: New York University Grossman School of Medicine
Emilia C. Bianchini: New York University Grossman School of Medicine
Una Choi: New York University Grossman School of Medicine
Rachel C. Bandler: New York University Grossman School of Medicine
Emilie Lassen: Cryos International Sperm and Egg Bank
Marta Grońska-Pęski: New York University Grossman School of Medicine
Adam Schwing: New York University Grossman School of Medicine
Zachary R. Murphy: New York University Grossman School of Medicine
Daniel Rosenkjær: Cryos International Sperm and Egg Bank
Shany Picciotto: Case Western Reserve University School of Medicine
Vanessa Bianchi: The Hospital for Sick Children
Lucie Stengs: The Hospital for Sick Children
Melissa Edwards: The Hospital for Sick Children
Nuno Miguel Nunes: The Hospital for Sick Children
Caitlin A. Loh: New York University Grossman School of Medicine
Tina K. Truong: New York University Grossman School of Medicine
Randall E. Brand: University of Pittsburgh School of Medicine
Tomi Pastinen: Children’s Mercy Kansas City
J. Richard Wagner: Université de Sherbrooke
Anne-Bine Skytte: Cryos International Sperm and Egg Bank
Uri Tabori: The Hospital for Sick Children
Jonathan E. Shoag: Case Western Reserve University School of Medicine
Gilad D. Evrony: New York University Grossman School of Medicine

Nature, 2024, vol. 630, issue 8017, 752-761

Abstract: Abstract Mutations accumulate in the genome of every cell of the body throughout life, causing cancer and other diseases1,2. Most mutations begin as nucleotide mismatches or damage in one of the two strands of the DNA before becoming double-strand mutations if unrepaired or misrepaired3,4. However, current DNA-sequencing technologies cannot accurately resolve these initial single-strand events. Here we develop a single-molecule, long-read sequencing method (Hairpin Duplex Enhanced Fidelity sequencing (HiDEF-seq)) that achieves single-molecule fidelity for base substitutions when present in either one or both DNA strands. HiDEF-seq also detects cytosine deamination—a common type of DNA damage—with single-molecule fidelity. We profiled 134 samples from diverse tissues, including from individuals with cancer predisposition syndromes, and derive from them single-strand mismatch and damage signatures. We find correspondences between these single-strand signatures and known double-strand mutational signatures, which resolves the identity of the initiating lesions. Tumours deficient in both mismatch repair and replicative polymerase proofreading show distinct single-strand mismatch patterns compared to samples that are deficient in only polymerase proofreading. We also define a single-strand damage signature for APOBEC3A. In the mitochondrial genome, our findings support a mutagenic mechanism occurring primarily during replication. As double-strand DNA mutations are only the end point of the mutation process, our approach to detect the initiating single-strand events at single-molecule resolution will enable studies of how mutations arise in a variety of contexts, especially in cancer and ageing.

Date: 2024
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DOI: 10.1038/s41586-024-07532-8

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