Nucleic Acid Sequence Reconstruction in Repeat Regions

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Solution Overview

Problem

Conventional nucleotide sequence analysis techniques fail to accurately determine the sequence of a nucleic acid template, particularly in repeat regions, often producing an 'average sequence' instead of a specific copy due to errors introduced during sequencing and sample preparation.

Innovation Solution

A method involving aligning unmutated sequence reads to mutated sequence reads, applying an optimization process to estimate the probability that unmutated sequence reads derive from the same copy of a repeat region, and determining a per-base accuracy score to identify the most probable sequence of the nucleic acid template.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional error correction techniques are used to correct sequencing errors, then sequencing errors are reduced, but accuracy in repeat regions deteriorates and average sequences are produced instead of specific copies

Engineering Contradiction:

Improvesequencing error correctionVSAvoidrepeat region sequence accuracy

Core Design Contradiction:

ReliabilityVSMeasurement precision

Solution Approach 1:

The patent segments the sequencing data by creating a graph structure where different paths represent different copies of repeat regions. Instead of treating all reads uniformly, the method divides them into haplotype-specific groups based on linkage information from flanking regions, allowing accurate reconstruction of individual repeat copies rather than producing an average sequence.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent introduces flanking regions as intermediaries to resolve ambiguity in repeat regions. By using the unique sequences adjacent to repeats as anchoring points, the method can correctly assign reads to specific repeat copies, thereby maintaining measurement precision in repeat regions while still correcting sequencing errors.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Measurement precision

If mutations are removed from sequence reads to determine the template sequence, then sequence accuracy is improved, but difficulty in handling repeat regions with multiple copies increases

Engineering Contradiction:

Improvesequence accuracyVSAvoidrepeat region handling complexity

Core Design Contradiction:

Measurement precisionVSDevice complexity

Solution Approach 1:

The patent employs dynamic programming and probabilistic models that adapt to the specific structure of repeat regions. The algorithm dynamically adjusts its approach based on local sequence characteristics, allowing it to handle varying degrees of repeat complexity without requiring a fixed complex structure for all cases.

Inventive Principle:

Principle #15Dynamics

Solution Approach 2:

The method changes parameters such as mutation rates and linkage probabilities based on local sequence context. By adjusting these parameters dynamically according to the specific repeat region being analyzed, the system can accurately determine template sequences while managing the complexity of different repeat structures.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20260018247A1Systems and methods of determining a nucleic acid sequence based on mutated sequence reads

Publication Date: 2026.01.15 ILLUMINA INC

AI summary

Described herein are methods and systems for determining a sequence of a nucleic acid template by removing mutations found in a mutated sequence read. In some embodiments, methods and systems include steps of aligning unmutated sequence reads of a nucleic acid template to mutated sequence reads, and determining a most probable sequence of the nucleic acid template and a per-base accuracy score correlated with the probability that the base matches with the nucleic acid template, thereby determining the sequence of the nucleic acid template.