Single-Molecule Array Sequencing with Magnetic Sensors
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Solution Overview
Problem
Current DNA sequencing methods face limitations in achieving longer reads with low error rates, as cluster sequencers are limited by error propagation and single-molecule sequencers suffer from static and dynamic heterogeneity leading to high error rates unsuitable for high-precision diagnostics.
Innovation Solution
The development of single-molecule array sequencing (SMAS) devices equipped with magnetic sensors that detect labels attached to nucleotides incorporated into a single nucleic acid strand, coupled with error correction methods to mitigate errors in sequencing data, enabling longer reads and lower error rates.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cluster-based sequencing is used, then error rate is reduced through ensemble averaging, but read length is limited due to error propagation in molecular ensembles
Solution Approach 1:
The invention segments the sequencing process by binding individual DNA molecules to separate binding sites on the flow cell, with each sensor monitoring a single molecule independently. This segmentation prevents error propagation that occurs in cluster-based ensemble averaging, allowing longer reads while maintaining accuracy through individual molecule tracking rather than collective signal averaging.
2Length of moving object
If single-molecule sequencing is used, then read length is extended, but error rate increases due to static and dynamic heterogeneity
Solution Approach 1:
The system incorporates real-time feedback through continuous monitoring of each single DNA molecule by dedicated magnetic sensors during the sequencing process. This feedback mechanism allows for dynamic adjustment and verification of nucleotide incorporation events, mitigating errors caused by static and dynamic heterogeneity while maintaining long read lengths through persistent observation of individual molecules.
3Productivity
If single-molecule sensors are used, then throughput is increased through parallel sequencing of multiple molecules, but device complexity increases due to sensor array requirements
Solution Approach 1:
The invention replaces complex optical detection systems with magnetic sensor arrays that detect magnetic labels attached to nucleotides. This substitution simplifies the detection mechanism while enabling parallel monitoring of multiple single DNA molecules simultaneously, increasing throughput without proportionally increasing device complexity through straightforward magnetic field detection rather than complex optical pathways.
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
SMAS devices provide potentially higher throughput, lower error rates, and longer read lengths compared to cluster-based approaches, enhancing the accuracy and precision of nucleic acid sequencing.
Implementation Method 1
Each sensor of a plurality of sensors within an array of sensors of the SMAS device detects labels attached to nucleotides incorporated into a single nucleic acid strand bound to a respective binding site
Data Source
AI summary
Disclosed herein are embodiments of single-molecule array sequencing (SMAS) devices and systems. Each sensor of an array of sensors of the SMAS device is capable of detecting labels attached to nucleotides incorporated into a single nucleic acid strand bound to a respective binding site. Each sensor can detect a single label (e.g., fluorescent, magnetic, organometallic, charged molecule, etc.) attached to the incorporated nucleotide. Also disclosed are methods of using SMAS devices and systems for highly-scalable nucleic acid (e.g., DNA) sequencing based on sequencing by synthesis (SBS) of multiple instances of clonally amplified DNA immobilized on such SMAS devices. Also disclosed are error correction methods that mitigate errors (e.g., errant label detections or non-detections) made in sequencing individual nucleic acid strands.