Haplotype Phasing via Synthetic Polymorphism Markers
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Solution Overview
Problem
Next-generation sequencing technologies produce short sequence reads, making it difficult to determine haplotypes when genetic variants are far apart on a chromosome, as current methods struggle to phase alleles located on different sequenced fragments.
Innovation Solution
Incorporating synthetic polymorphisms into nucleic acid fragments, such as 8-oxoguanine, isocytosine, and isoguanine, allows for the alignment of sequenced fragments to determine haplotypes by creating a unique pattern of artificial polymorphisms that can bridge the distance between naturally occurring SNPs, enabling haplotype phasing and characterization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If next-generation sequencing technologies are used, then sequencing capacity and accuracy are improved, but sequence read length becomes short making it difficult to determine haplotypes of variants far apart on a chromosome
Solution Approach 1:
The patent introduces synthetic polymorphisms (artificial markers) as intermediaries to bridge the gap between naturally occurring SNPs that are far apart on a chromosome. These synthetic markers are incorporated into nucleic acid fragments during library preparation, and their patterns serve as mediators to link and phase distant variants across multiple sequencing reads, effectively extending the functional read length beyond the physical sequence read length limitation.
2Adaptability or versatility
If synthetic polymorphisms are incorporated into nucleic acid fragments, then haplotype determination for distant variants is enabled, but manufacturing complexity increases
Solution Approach 1:
The synthetic polymorphisms are incorporated into the nucleic acid fragments during the library preparation step, which is performed before sequencing. This preliminary action ensures that the artificial markers are already in place when the library is constructed, eliminating the need for complex post-sequencing synthesis or modification steps and simplifying the overall manufacturing process while maintaining the enhanced haplotype determination capability.
Data Source
AI summary
The present disclosure provides methods and systems for determining and/or characterizing one or more haplotypes and/or phasing of haplotypes in a nucleic acid sample. In particular, the disclosure provides methods for determining a haplotype and/or phasing of haplotypes in a nucleic acid sample by incorporating synthetic polymorphisms into fragments of a nucleic acid sample and utilizing the synthetic polymorphisms in determining one or more haplotypes and/or phasing of haplotypes.