Double Minute Chromosome Reconstruction via Breakpoint Graphs

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Solution Overview

Problem

Current methods for analyzing genomic rearrangements in cancer diagnostics are limited by the difficulty in discovering all true structural variants and filtering out false positives, particularly in initial tumor diagnosis and monitoring using blood samples, where double-stranded DNA structures like double minutes (DMs) are not comprehensively sequenced, hindering the identification of amplified oncogenes and tumor suppressors.

Innovation Solution

A method using whole-genome paired-end sequence analysis to identify high-confidence breakpoints and associated high copy numbers, enabling the reconstruction of intact DMs by determining relative copy numbers, refining breakpoints, and generating a breakpoint graph to determine genomic arrangements indicative of double minutes, which can be done using computational systems and algorithms like BAMBAM and bridget.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If current methods for analyzing genomic rearrangements are used, then some structural variants can be identified, but the ability to discover all true structural variants and filter false positives is limited

Engineering Contradiction:

Improvestructural variant detection accuracyVSAvoidfalse positive rate

Core Design Contradiction:

Measurement precisionVSReliability

Solution Approach 1:

The patent segments the complex task of structural variant detection into multiple analytical components: paired-end mapping to identify potential breakpoints, copy number analysis to detect amplifications and deletions, and circular genome reconstruction to identify double minutes. This segmentation allows each component to be optimized independently, improving overall detection accuracy while reducing false positives through multiple layers of validation.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent introduces computational intermediaries including breakpoint graphs and circular genome assembly algorithms that serve as mediators between raw sequencing data and final structural variant calls. These intermediaries process and validate structural variant candidates, filtering out false positives while preserving true variants through systematic computational validation steps.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Quantity of substance

If whole-genome sequencing is used to identify all structural variants, then comprehensive genomic analysis is achieved, but the complexity of analyzing and reconstructing large regions of the tumor genome increases

Engineering Contradiction:

Improvecomprehensive structural variant detectionVSAvoidgenome reassembly complexity

Core Design Contradiction:

Quantity of substanceVSDevice complexity

Solution Approach 1:

The patent divides the tumor genome into manageable segments using paired-end sequencing reads, where each read pair defines a specific genomic interval. Structural variants are identified by analyzing discordant read pairs within these segments, and breakpoint graphs are constructed by connecting segments at identified breakpoints. This segmentation transforms the overwhelming task of whole-genome reassembly into a series of localized, tractable problems.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent introduces graphical representations (breakpoint graphs and circular genome assemblies) as an additional dimension for analyzing genomic data. Instead of working solely with linear genome coordinates, the patent maps structural variants onto graphs where nodes represent genomic segments and edges represent connectivity, enabling intuitive visualization and computational processing of complex rearrangements including circular double minutes.

Inventive Principle:

Principle #17Another dimension (Dimensionality change)

3Ease of operation

If blood-based diagnostic assays are developed using somatic rearrangements, then non-invasive monitoring is enabled, but technical challenges make them unsuitable for initial tumor diagnosis

Engineering Contradiction:

Improvenon-invasive monitoring capabilityVSAvoiddiagnostic sensitivity for initial diagnosis

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The patent develops a universal genomic analysis platform that can process and interpret structural variant data from multiple sample types including both tissue biopsies and liquid biopsies (blood samples). The same computational pipeline for identifying structural variants, constructing breakpoint graphs, and assembling circular genomes applies regardless of sample source, enabling the method to serve both initial diagnosis (using tissue) and non-invasive monitoring (using blood) with consistent analytical rigor.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS10961586B2MDM2-containing double minute chromosomes and methods therefore

Publication Date: 2021.03.30 FIVE3 GENOMICS LLC

AI summary

Contemplated systems and methods allow for computational genomic analysis using paired-end sequence analysis and split read refinement to thereby identify high-confidence breakpoints associated with high copy numbers and orientation of rearrangements, which is then the basis for full reconstruction of double minutes (DM). In especially preferred aspects, the DM will also include an oncogene or tumor suppressor gene, and/or may be found in blood or blood derived fluids.