Single-Molecule Sequencing with Single-Photon Accuracy

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Solution Overview

Problem

Existing single-molecule sequencing technologies struggle to accurately detect minor sequence variants due to consensus determination methods that treat them as 'noise', leading to low primary accuracy and inability to analyze individual strand mutations in DNA samples with mixtures of different sequences.

Innovation Solution

A process involving a support with aligned sample spots and optical projections, coupled with a multipixel detector for single photon detection, allows precise alignment and individual analysis of single molecules with high accuracy, eliminating the need for complex algorithms by achieving primary accuracy of at least 99.9% in a single measurement.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If consensus determination methods are used to analyze DNA sequences, then the sequencing process can be automated and high-throughput, but the primary accuracy decreases to 85-90% and minor sequence variants are obscured as noise

Engineering Contradiction:

Improvesequencing throughputVSAvoidprimary accuracy

Core Design Contradiction:

ProductivityVSMeasurement precision

Solution Approach 1:

The invention segments the DNA sequencing process into individual single-molecule analysis units. Each DNA molecule is analyzed separately on the support surface, with laser beams focused on individual spots containing single molecules. This segmentation eliminates the consensus-based approach that requires multiple measurements, achieving primary accuracy of at least 99.9% in a single measurement while maintaining high throughput through parallel processing of multiple molecules.

Inventive Principle:

Principle #1Segmentation

2Reliability

If complex statistical algorithms are used to estimate the correct DNA sequence, then consensus sequences can be determined, but the detection of individual strand mutations and minor sequence variants is lost

Engineering Contradiction:

Improveconsensus sequence determinationVSAvoidminor sequence variants

Core Design Contradiction:

ReliabilityVSLoss of information

Solution Approach 1:

The invention extracts and analyzes each DNA molecule individually rather than processing them as a population. By isolating single molecules on the support surface and analyzing them separately with single-photon detection, the method preserves information about minor sequence variants and individual strand mutations that would otherwise be lost in consensus-based approaches requiring complex statistical algorithms.

Inventive Principle:

Principle #2Taking out (Extraction)

3Measurement precision

If repeated measurements are performed to achieve high accuracy, then the sequencing reliability improves, but the time consumption and productivity decrease

Engineering Contradiction:

Improvesequencing accuracyVSAvoidmeasurement time

Core Design Contradiction:

Measurement precisionVSLoss of time

Solution Approach 1:

The invention replaces the mechanical approach of repeated measurements with an optical detection system using single-photon detection. The support surface with aligned sample spots and optical projections enables direct, high-precision detection of individual DNA molecules in a single measurement, achieving at least 99.9% primary accuracy without requiring multiple sequencing rounds, thereby eliminating time loss while maintaining high accuracy.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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

The method achieves nearly 100% accuracy in sequencing DNA strands without requiring repeated measurements, enabling the detection of individual DNA molecule sequences and their distributions with high precision.

Implementation Method 1

a light source, particularly a multipoint laser providing at least one illuminated volume element

Methodology Applied

Scientific EffectLaser: Laser

Implementation Method 2

detection of the sequentially released monomeric molecules... on the basis of the time-dependent change, caused when nucleotide building blocks are cleaved off, in the fluorescence of said nucleic acid molecules

Methodology Applied

Scientific EffectFluorescence: Fluorescence