Nucleic Acid Constriction Device for Genomic Structural Analysis

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Solution Overview

Problem

Current technologies face challenges in directly visualizing and mapping the intricate dynamic interactions of nucleic acid structures in their native genomic, subcellular, and subnuclear context, which is crucial for understanding gene regulation and its biological and pathophysiological functions, especially for structural variants and rare disorders.

Innovation Solution

The use of constriction devices to generate feature density profiles of nucleic acid molecules by translocating them through a constriction region, measuring signals, and determining binned denaturing profiles, allowing for analysis of primary, secondary, tertiary, and quaternary structures, and their associations, which provides insight into genomic variations and structural changes.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If sequencing technologies are used to analyze nucleic acid structures, then single-nucleotide variants can be identified, but structural variants spanning large genomic ranges cannot be effectively resolved

Engineering Contradiction:

Improvesingle-nucleotide variant detectionVSAvoidgenomic range coverage

Core Design Contradiction:

Measurement precisionVSLength of stationary object

Solution Approach 1:

The patent segments the nucleic acid molecule into manageable units by translocating it through a nanopore constriction, where short segments are analyzed sequentially. This allows the entire long molecule to be examined piece by piece, enabling both single-nucleotide resolution and coverage of large genomic ranges that would be impossible to analyze as a single continuous unit.

Inventive Principle:

Principle #1Segmentation

2Measurement precision

If a bottom-up approach is used to analyze nucleic acid structures, then discrete segments can be interrogated, but the native contextual information is lost

Engineering Contradiction:

Improvesegment analysisVSAvoidnative structural context

Core Design Contradiction:

Measurement precisionVSLoss of information

Solution Approach 1:

The nanopore translocation process maintains continuous analysis of the nucleic acid molecule as it passes through the constriction. The sequential detection of segments preserves their original order and spatial relationships, maintaining the native contextual information while enabling detailed segment-by-segment analysis. This continuous process prevents the loss of structural context that occurs with discrete isolation methods.

Inventive Principle:

Principle #20Continuity of useful action

3Length of stationary object

If conventional optical genome mapping is used, then large genomic features can be visualized, but intricate dynamic interactions of nucleic acid structures cannot be directly observed

Engineering Contradiction:

Improvegenomic feature spanVSAvoiddynamic structural interactions

Core Design Contradiction:

Length of stationary objectVSDifficulty of detecting and measuring

Solution Approach 1:

The patent replaces optical detection methods with electrical detection through nanopore current measurements. This substitution enables direct observation of dynamic structural interactions as they occur during translocation, providing real-time detection of conformational changes, protein binding events, and other dynamic processes that cannot be captured by static optical imaging methods.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

4Measurement precision

If labeling bodies are bound to nucleic acid molecules for analysis, then structural features can be identified, but the analysis process becomes more complex

Engineering Contradiction:

Improvestructural feature identificationVSAvoidlabeling and analysis process

Core Design Contradiction:

Measurement precisionVSDevice complexity

Solution Approach 1:

The nucleic acid molecule itself serves as the detection probe through its intrinsic electrical properties and physical characteristics during translocation. The molecule's sequence, structure, and conformational state directly modulate the nanopore current without requiring external labels or tags. This self-service approach simplifies the overall process by eliminating labeling steps while maintaining high structural feature identification capability.

Inventive Principle:

Principle #25Self-service

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

This method enables the generation of linear physical maps that can identify genomic rearrangements and structural variations, offering a more efficient and detailed understanding of nucleic acid structures and their functions, contributing to better disease diagnosis and understanding of genetic disorders.

Implementation Method 1

measuring an electrical signal that is modulated as the macromolecules or polymers translocate

Methodology Applied

Scientific EffectElectrical signal modulation: Conduction (electrical)

Implementation Method 2

partially de-naturing at least a portion of the long nucleic acid molecule by exposing at least a portion of the molecule to at least one denaturing condition

Methodology Applied

Scientific EffectDenaturation: Melting

Data Source

PatentUS20230235387A1Devices and methods for genomic structural analysis

Publication Date: 2023.07.27 DIMENSIONGEN

AI summary

Disclosed are methods for generating physical maps from feature density profiles of a nucleic acid using a constriction device, and associated methods of analyzing said genomic profiles. In addition, disclosed are devices and methods for analyzing secondary, tertiary and quaternary structures on nucleic acids in spatial and temporal context of the 3-D organization of the genome in a constriction or sensor device.