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Non-B DNA structure discovery and function assessment using nanopore translocation times

Award Number: R01HG014255
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Non-B DNA structure discovery and function assessment using nanopore translocation times - Abstract The canonical double helical structure of DNA (B-DNA) allows for stability and high-fidelity replication, but emerging evidence suggests an increasingly important role for non-canonical (or non-B) DNA structures in the cell. Non-B DNA structures have been (a) implicated in genetic disorders and carcinogenesis due to their increased mutability, (b) associated with variability in promotor activity, and (c) established as a substrate and site of localization for human telomerase and a putative mechanism for specifying centromere identity. Experimental discovery of non-B DNA structures requires specialized, low-throughput protocols that can be prohibitively expensive and typically target a subset of non-B DNA types. Computational methods offer a lower-cost and higher throughput alternative, but rely on DNA base motifs resulting in two fundamental limitations: (1) few regions having non-B DNA motifs are occupied by non-B DNA structures at any point in time, and thus non-B DNA structure predictions have high false-positive rates that typically limit analyses to aggregate statistics; and (2) non-B DNA structures without well-characterized DNA base motifs are missed entirely. The inability to reliably and efficiently predict non-B DNA structures is a major scientific gap that delays the characterization non-B DNA’s role in medically relevant biological processes and disease. Recently, we discovered that non-B DNA motifs are associated with significant variability in the DNA translocation speeds of nanopore sequencing. We developed predictive models to infer where non- B structure is likely to form among locations occupied by non-B DNA motifs using translocation times as features and performed extensive in silico validation of the predicted structures. While these preliminary analyses demonstrated the feasibility of non-B DNA structure prediction from nanopore sequencing, several significant technical limitations and scientific knowledge gaps limit the tool’s generalizability and performance; we propose to resolve these issues by pursuing two aims: (1) predict and validate non-B DNA structures using nanopore translocation times and other molecular sequencing dynamics; and (2) assess the functional relevance of non-B DNA structures for clinically relevant phenotypes. Successful completion of this project will provide software tools that enable efficient and precise characterization of non-B DNA structures at the single sample level from third-generation sequencing platforms. The proposed research will also generate novel associations between non-B DNA structures and clinically relevant phenotypes. Well- documented and open-source tools will be made easily accessible for usage in new study designs or to reanalyze existing third-generation sequencing data.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $805,000 )
2025	2025	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Human Genome Research	000	1	9/22/2025	NEW	$805,000
														Subtotal = $805,000

Grand Total All Awards = $805,000

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Non-B DNA structure discovery and function assessment using nanopore translocation times

Award Number: R01HG014255

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/20/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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