Modified Reference Genome for Accurate Genetic Variation Mapping
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Solution Overview
Problem
Current nucleic acid analysis methods, particularly in high-throughput sequencing, fail to accurately identify genetic variations in genes with highly similar counterparts due to incorrect mapping and assembly of sequencing reads, leading to difficulties in detecting rare disease-associated polymorphisms.
Innovation Solution
A modified reference genome is created by altering counterpart genes, forcing sequence reads from highly similar genes to map to the gene of interest, allowing for accurate determination of genetic variations using microprocessor-dependent methods and systems.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If standard mapping and assembly methods are used, then processing speed is maintained, but mapping accuracy deteriorates when highly similar genes are present
Solution Approach 1:
The patent applies local quality by differentiating the reference genome at specific loci corresponding to highly similar genes. Instead of making the entire reference genome complex, only the problematic regions are differentiated with unique identifiers or markers that enable accurate mapping of reads to the correct gene copy, thereby improving mapping accuracy without proportionally increasing overall complexity.
Solution Approach 2:
The reference genome is segmented into standard regions and specially marked regions corresponding to highly similar genes. This segmentation allows the mapping algorithm to handle different regions with different strategies - standard mapping for most regions and targeted differentiation for gene-rich or paralogous regions, resolving the contradiction between speed and accuracy.
2Reliability
If reads are mapped to reference genome, then sequencing throughput is maintained, but detection reliability deteriorates for genetic variations in highly similar genes
Solution Approach 1:
The patent incorporates feedback mechanisms where the mapping algorithm continuously evaluates read alignment quality and gene copy assignments. When ambiguity is detected in reads mapping to highly similar genes, the system uses feedback information from surrounding genomic context, read depth, and alignment scores to iteratively refine the assignment, ensuring reliable detection while maintaining throughput.
Solution Approach 2:
The reference genome is pre-modified with differentiated markers at locations of highly similar genes before sequencing. This preliminary action provides built-in guidance for the mapping algorithm, enabling reliable discrimination between gene copies without requiring complex real-time analysis, thus maintaining high throughput while improving detection reliability.
3Measurement precision
If existing software is used for mapping, then computational resources are minimized, but measurement precision deteriorates due to incorrect read mapping
Solution Approach 1:
The patent changes key parameters of the mapping process by introducing differentiated markers and modified reference sequences at critical loci. This parameter change enables standard mapping algorithms to achieve high precision without requiring excessive computational resources, as the modifications guide the algorithm rather than requiring complete reanalysis of every read.
Data Source
AI summary
Provided herein are novel methods, systems and processes for mapping sequence reads to a modified reference genome and determining the presence or absence of a genetic variation, or the likelihood thereof, in a gene of interest in a subject.