Phase-Protecting Reagent Flow Orderings for Sequencing Accuracy
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Solution Overview
Problem
Current nucleic acid sequencing methods using sequencing-by-synthesis face errors due to phase loss effects such as incomplete extension and carry forward events, leading to loss of phasic synchrony among template strands, which degrades sequencing accuracy and efficiency.
Innovation Solution
Implementing phase-protecting reagent flow orderings that are not cyclical or tailored to specific templates, but rather designed to resynchronize out-of-sync templates with the in-sync population, using permutations of nucleotide species like 'TACG TACG TACT CAGT ATGC AGAC TGCG' or de Bruijn sequences to maintain phasic synchrony and reduce sequencing errors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If cyclical reagent flow orderings are used in sequencing-by-synthesis, then sequencing throughput is improved, but phase loss effects occur leading to degraded sequencing accuracy
Solution Approach 1:
The patent applies dynamics by transitioning from static cyclical flow orderings to dynamic adaptive flow orderings that change based on real-time detection of phase synchronization status. The system monitors template synchrony and adjusts the reagent flow ordering accordingly, allowing the sequencing process to adapt its behavior to maintain both high throughput and accuracy.
Solution Approach 2:
The patent implements feedback mechanisms that continuously monitor the phase synchronization of template strands during sequencing. Based on this feedback, the system dynamically adjusts the reagent flow ordering to correct phase loss effects, thereby maintaining sequencing accuracy while preserving throughput benefits.
2Productivity
If standard reagent flow orderings are used, then sequencing efficiency is maintained, but phase-related errors accumulate reducing read length
Solution Approach 1:
The patent applies preliminary action by proactively detecting phase loss effects before they significantly degrade sequencing quality. The system monitors template synchrony in real-time and implements corrective flow ordering changes before phase-related errors accumulate to problematic levels, thereby extending effective read length while maintaining efficiency.
3Reliability
If phase-protecting reagent flow orderings are implemented to reduce phase loss effects, then sequencing accuracy is improved, but system complexity increases
Solution Approach 1:
The patent applies self-service by enabling the sequencing system to automatically monitor its own phase synchronization status and autonomously adjust flow orderings without external intervention. The system self-diagnoses phase loss conditions and self-corrects by implementing appropriate flow ordering changes, managing the increased complexity through automation rather than manual control.
4Productivity
If out-of-sync templates are allowed to continue sequencing without intervention, then throughput is maintained, but sequencing errors increase
Solution Approach 1:
The patent applies dynamics by implementing conditional flow orderings that adapt based on the synchronization status of template populations. When out-of-sync templates are detected, the system dynamically switches to protective flow orderings for affected cycles, then returns to high-throughput orderings when synchrony is restored, thereby managing the trade-off between throughput and accuracy.
Data Source
AI summary
A system for nucleic acid sequencing includes a machine-readable memory and a processor configured to execute machine-readable instructions. The instructions, when executed by the processor, cause the system to expose template polynucleotide strands in a plurality of defined spaces of a sensor array to a series of flows of nucleotide species, the series comprising a sequence of random flows; and obtain, for each of the series of flows of nucleotide species, a signal indicative of how many nucleotide incorporations occurred for that particular flow to determine a predicted sequence of nucleotides corresponding to the template polynucleotide strands.