Genomic DNA Fragment Mapping to Preserve Connectivity and Phasing
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Solution Overview
Problem
Traditional nucleic acid sequencing methods, including shotgun approaches, lose connectivity and proximity information of genomic fragments, making it difficult to reconstruct phasing information for diploid and polyploid genomes, and identify the origin of fragments in mixed samples.
Innovation Solution
Introduce insert elements into target nucleic acids to subdivide them into linked sections, capturing fragments on a solid support surface in proximity to their original locations, allowing for sequencing and analysis based on relative distances.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Loss of information
If traditional shotgun sequencing methods are used, then sequencing coverage is achieved, but connectivity and proximity information of genomic fragments is lost
Solution Approach 1:
The patent uses insert elements as intermediary components that are introduced into target nucleic acids to serve as physical markers. These insert elements remain associated with the fragmented genomic DNA during sequencing, acting as mediators that preserve and transmit connectivity information from the original genomic context to the sequencing reads, thereby resolving the information loss problem while maintaining process feasibility
Solution Approach 2:
The patent applies preliminary action by introducing insert elements into target nucleic acids before fragmentation and sequencing occurs. This pre-positioning of markers ensures that connectivity information is preserved throughout the sequencing process, allowing downstream analysis to reconstruct phasing and haplotype information without requiring complex post-processing
2Measurement precision
If genomic DNA is fragmented for sequencing, then sequencing depth is improved, but phasing information for diploid and polyploid genomes is lost
Solution Approach 1:
Insert elements serve as intermediary markers that are introduced into target nucleic acids prior to fragmentation. These markers remain physically associated with the fragmented DNA segments, enabling the reconstruction of phasing information by tracking which fragments originated from the same parental chromosome, thus preserving diploid and polyploid genetic information through the sequencing process
Solution Approach 2:
The patent adds an additional dimension of information by incorporating insert elements that provide spatial and contextual markers beyond the primary sequence data. This extra dimension of information encoding allows the system to recover phasing and haplotype information that would otherwise be lost in conventional one-dimensional sequencing approaches
3Productivity
If fragments are captured randomly on solid support surface, then sequencing throughput is increased, but origin identification of fragments in mixed samples is difficult
Solution Approach 1:
The insert elements act as intermediary identifiers that are introduced into target nucleic acids before random capture on the solid support surface. These markers enable the tracking and identification of fragment origins even after random distribution, allowing computational methods to associate fragments with their source samples or genomic regions while maintaining high sequencing throughput
Solution Approach 2:
The system employs feedback mechanisms where the presence and position of insert elements provide information that feeds into the data analysis pipeline. This feedback allows the system to correct for random capture effects and reconstruct the original sample composition and fragment origins through iterative computational analysis of the marked fragments
Data Source
AI summary
A method of sequencing a target nucleic acid polymer by (a) modifying a target nucleic acid polymer to produce a modified nucleic acid polymer; (b) producing fragments of the modified nucleic acid polymer, wherein the fragments are attached to locations on a solid support surface (c) determining nucleotide sequences from the fragments at the locations; and (d) producing a representation of the nucleotide sequence for the target nucleic acid polymer based on the nucleotide sequences from the fragments and the relative distances between the locations on the solid support surface.