Genomic Variation Tags for Fine Structural Variation Mapping

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Solution Overview

Problem

Current methods for high-throughput analysis of fine structural variations in nucleic acids, such as array comparative genomic hybridization and fosmid paired-end mapping, are inefficient and costly, particularly for identifying inversions, translocations, and other nucleic acid rearrangements, limiting their application in broad population surveys and cohort studies.

Innovation Solution

A method involving the creation of genomic variation tags (GVTs) by fragmenting DNA, ligating adaptors with restriction endonuclease recognition sites, and producing oligomerized GVT pairs for efficient sequencing, allowing for high-resolution genomic mapping and identification of fine structural variations.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If array comparative genomic hybridization is used for copy number determination, then reliable detection of DNA copy-number differences is achieved, but the method is not suited to address inversions, translocations and other types of nucleic acid rearrangements

Engineering Contradiction:

Improveability to detect different types of genomic variationsVSAvoiddetection capability for specific variation types

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent creates a universal mapping system using paired-end tags that can detect multiple types of genomic variations (copy number changes, inversions, translocations, and other rearrangements) through a single method, making the system adaptable to various variation types while maintaining reliable detection capability for each

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Measurement precision

If fosmid paired-end mapping is used to identify structural variations, then nearly 300 sites of structural variations can be identified, but the immense cost and logistical efforts preclude its use in broad population surveys

Engineering Contradiction:

Improveidentification accuracy of structural variationsVSAvoidthroughput for population surveys

Core Design Contradiction:

Measurement precisionVSProductivity

Solution Approach 1:

The patent replaces expensive fosmid vectors with inexpensive plasmid vectors for cloning and propagation, dramatically reducing the cost per sample and enabling high-throughput population surveys while maintaining the paired-end mapping approach's ability to accurately identify structural variations

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The patent changes the vector system parameter from fosmid to plasmid, which has different propagation characteristics and cost structures, thereby improving productivity for population surveys while preserving measurement precision through the same tag-based mapping methodology

Inventive Principle:

Principle #35Parameter changes

3Manufacturing precision

If fosmid vectors are used for propagation, then genomic DNA libraries with uniform size inserts can be produced, but very low copy-numbers make reliable automated DNA production and sequencing difficult to maintain

Engineering Contradiction:

Improveuniformity of genomic insert sizeVSAvoidautomated DNA production efficiency

Core Design Contradiction:

Manufacturing precisionVSProductivity

Solution Approach 1:

The patent substitutes plasmid vectors for fosmid vectors, replacing a system with low copy-number and production difficulties with one that supports high copy-number propagation and efficient automated DNA production, thereby improving productivity while maintaining insert uniformity through controlled cloning procedures

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Data Source

PatentEP1969146B1Methods for nucleic acid mapping and identification of fine-structural-variations in nucleic acids and utilities

Publication Date: 2010.10.06 LOK SI

AI summary

The present invention relates generally to methods for high-throughput analysis of fine structural variations in nucleic acids. In particular, the present invention relates to novel strategies, vector and vector components to produce pairs of linked-nucleic acid tags, wherein constituent members of a linked nucleic acid tag-pair are of a user defined separation distance, and/or are markers of nucleic acid positions that demarcate adjacent cleavage sites for one or more different restriction endonucleases along the length of a target nucleic acid molecule.