Entangled Mate Sequencing for Dual-Template Signal Disentanglement
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Solution Overview
Problem
Current DNA sequencing methods, such as capillary-based Sanger sequencing, are inefficient in simultaneously sequencing two template sequences, leading to a loss of information about which template region produced a specific signal, especially when sequencing two or more nucleotide bases simultaneously.
Innovation Solution
The method of entangled mate sequencing, which involves synchronously priming and sequencing two or more tethered nucleic acid sequences, allowing for the simultaneous determination of nucleotide sequences by generating mixed signals that can be disentangled using a reference collection of sequence signatures, thereby increasing the information gained per sequencing cycle.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If two template sequences are sequenced in the same reaction using a single primer or mixture of primers, then the information gathering efficiency is improved, but the ability to identify which template region produced which signal is lost
Solution Approach 1:
The patent segments the sequencing process into two distinct phases: (1) simultaneous sequencing of multiple templates using a single primer to generate entangled signals, and (2) computational disentanglement by comparing the mixed signal against a reference collection of all possible template pair signatures. This segmentation allows information from multiple templates to be captured efficiently while recovering template-specific information through systematic comparison.
Solution Approach 2:
The patent introduces a reference collection of sequence signatures as an intermediary element. This reference collection contains pre-calculated signatures for all possible template pairs, serving as a mediator that enables the disentanglement of mixed sequencing signals. By comparing the observed entangled signal against this reference library, the system can identify which specific template pair produced the signal, thereby recovering template-specific information without sacrificing sequencing efficiency.
2Measurement precision
If conventional sequencing methods are used for single template, then the sequence information is clear and unambiguous, but the information obtained per sequencing cycle is limited to 2 bits
Solution Approach 1:
The patent merges multiple template sequencing reactions into a single reaction cycle by using a single primer that can bind to multiple templates simultaneously. This combining approach captures information from multiple templates in parallel, increasing the information yield per cycle from 2 bits (single template) to potentially 4 bits or more (multiple templates), while the computational disentanglement process maintains sequence information clarity.
Solution Approach 2:
The patent adds a computational dimension to the sequencing process. Instead of relying solely on physical separation of templates (traditional approach), it introduces an information-theoretic dimension where the mixed signal is analyzed through mathematical comparison against a reference space of all possible template pairs. This dimensional transformation enables simultaneous sequencing of multiple templates while maintaining the ability to resolve individual sequence information.
Data Source
AI summary
Methods and compositions are provided for performing a set of N DNA sequencing reaction cycles whereby sequence information is obtained for approximately 2*N nucleotide bases.