cfDNA Polymorphism Detection in Mixed Genomes Without Enrichment
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Solution Overview
Problem
Current methods for identifying genetic polymorphisms in mixed genomic samples, such as fetal and maternal DNA in maternal blood or cancer patient cells, are invasive and lack efficient non-invasive techniques for distinguishing between multiple genomes.
Innovation Solution
A method involving whole genome sequencing of clonally amplified or single cfDNA molecules, using massively parallel sequencing-by-synthesis or sequencing-by-ligation, to identify polymorphisms in a mixture of genomes without enrichment, allowing for the differentiation and association of polymorphisms with specific genomes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If invasive testing methods (amniocentesis or CVS) are used for prenatal diagnosis, then diagnostic accuracy is improved, but patient safety deteriorates due to 1% miscarriage risk
Solution Approach 1:
The patent extracts and analyzes fetal genetic material (cell-free DNA) from maternal blood plasma, obtaining the required diagnostic information without performing invasive procedures on the fetus. This extraction approach enables noninvasive prenatal diagnosis while maintaining diagnostic accuracy for chromosomal aneuploidies.
Solution Approach 2:
The patent uses maternal blood plasma as an intermediary medium that contains fetal cell-free DNA. By analyzing this intermediary substance, the method obtains fetal genetic information indirectly, avoiding direct invasive contact with the fetus while still achieving accurate diagnostic results.
2Ease of operation
If whole genome sequencing is performed on unenriched mixtures of cfDNA, then noninvasive diagnosis is achieved, but measurement precision deteriorates due to difficulty in distinguishing fetal from maternal polymorphisms
Solution Approach 1:
The patent performs preliminary identification of polymorphic positions in the fetal genome before analyzing the mixed cfDNA sample. By having advance knowledge of fetal-specific polymorphic positions, the method can accurately distinguish fetal DNA sequences from maternal sequences in the unenriched mixture, resolving the precision problem while maintaining noninvasive operation.
Solution Approach 2:
The method uses feedback from identified polymorphic patterns to improve differentiation between fetal and maternal genomes. By analyzing sequence tags at polymorphic positions and comparing allele frequencies, the system refines its ability to distinguish fetal from maternal origin, enhancing measurement precision in the mixed sample.
Data Source
AI summary
The present invention relates to methods comprising identifying polymorphisms in samples comprising mixtures of genomes, and for determining and/or monitoring the presence or absence of disorders associated with the identified polymorphisms.