Cell-Free Nucleic Acid Analysis Using Nucleosome-Targeted Bait Sets
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Solution Overview
Problem
Current cancer diagnostic assays for cell-free nucleic acids focus primarily on tumor-related somatic variants, neglecting nucleosome-associated regions that can provide insights into disease states and tissue types, limiting the detection of structural variations and instabilities.
Innovation Solution
A bait set panel is developed to selectively enrich for nucleosome-associated regions of the genome, utilizing bait sets configured to capture genomic regions with differential nucleosomal occupancy, which are characteristic of disease states or tissue types, and employing a method to sequence these regions for enhanced analysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If current methods focus on tumor-related somatic variants, then detection of SNVs, CNVs, fusions, and indels is improved, but detection of structural variations and instabilities in nucleosome-associated regions is neglected
Solution Approach 1:
The patent segments the genome into nucleosome-associated regions and non-nucleosome regions, creating separate enrichment strategies for each. This allows targeted capture of nucleosome-associated regions with differential occupancy patterns while maintaining detection of traditional somatic variants, thus resolving the contradiction between focused detection and comprehensive information capture
Solution Approach 2:
The patent adds a new dimension of analysis by incorporating nucleosome occupancy patterns alongside traditional genetic variant detection. This multi-dimensional approach enables simultaneous detection of both somatic variants and structural variations in nucleosome-associated regions, transforming a single-track detection method into a comprehensive multi-parameter assay
2Reliability
If bait sets are designed to capture nucleosome-associated regions with differential occupancy, then detection sensitivity for disease states and tissue types is improved, but assay complexity increases
Solution Approach 1:
The patent performs preliminary identification and characterization of nucleosome-associated regions with differential occupancy patterns before designing the bait sets. By pre-mapping these regions and establishing their disease-state specificity, the assay reduces complexity during execution while maintaining high detection reliability, as the enrichment targets are predetermined and well-characterized
Solution Approach 2:
The patent changes the enrichment parameter from traditional genetic variant targeting to nucleosome occupancy pattern-based targeting. This parameter shift allows capture of regions with differential nucleosomal occupancy that are characteristic of specific disease states and tissue types, improving diagnostic reliability without requiring complete redesign of the assay framework
3Measurement precision
If enrichment focuses on nucleosome-associated regions, then detection of insertions and deletions is improved, but sequencing load requirements increase
Solution Approach 1:
The patent extracts and enriches specifically for nucleosome-associated regions containing insertions and deletions, separating these targets from the whole genome. This extraction approach concentrates sequencing resources on regions most likely to contain the variants of interest, improving detection precision while reducing the total sequencing load required compared to whole-genome sequencing
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The enrichment method improves the detection of genetic variants, particularly insertions and deletions, by focusing on nucleosome-associated regions, enhancing the accuracy and sensitivity of cancer detection and monitoring.
Implementation Method 1
A bait set panel is developed to selectively enrich for nucleosome-associated regions of the genome, utilizing bait sets configured to capture genomic regions with differential nucleosomal occupancy
Data Source
AI summary
The present disclosure provides a method for enriching for multiple genomic regions using a first bait set that selectively hybridizes to a first set of genomic regions of a nucleic acid sample and a second bait set that selectively hybridizes to a second set of genomic regions of the nucleic acid sample. These bait set panels can selectively enrich for one or more nucleosome-associated regions of a genome, said nucleosome-associated regions comprising genomic regions having one or more genomic base positions with differential nucleosomal occupancy, wherein the differential nucleosomal occupancy is characteristic of a cell or tissue type of origin or disease state.