Haplotype Block Detection via Matched Filtering
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Solution Overview
Problem
Current genotyping technologies face challenges in efficiently and non-destructively determining the genetic sequence of single cells, such as gametes or embryonic cells, where genetic material is sparse, and often require expensive and inconvenient multiple cell evaluations.
Innovation Solution
The method involves creating matched filters based on nucleotide-derived signals from reference DNA samples with known haplotype blocks, which are compared to signals from the cell of interest to determine the presence of specific haplotype blocks, allowing for accurate genotyping without destructive sequencing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If standard sequencing methodologies are used on single cells, then genetic sequence information can be obtained, but the method is destructive and cannot preserve cell viability
Solution Approach 1:
The patent replaces destructive mechanical/chemical sequencing processes with non-destructive optical imaging and computational matched filtering. Instead of physically breaking down DNA for sequencing, the system uses optical signals and pattern recognition to determine haplotype blocks, preserving cell integrity.
Solution Approach 2:
The patent introduces matched filters as an intermediary computational tool that compares imaged DNA patterns against reference haplotype blocks. This intermediary process enables genetic analysis without direct contact or destruction of the target DNA, acting as a non-invasive mediator between the cell and analysis.
2Reliability
If multiple cells of identical genome are evaluated to improve genotyping accuracy, then more genetic material is available for analysis, but the process becomes more expensive and inconvenient
Solution Approach 1:
The patent performs preliminary action by creating matched filters from reference haplotype blocks before analyzing the target cell. These pre-computed filters enable accurate genotyping of a single cell by comparing its imaged DNA pattern against the reference patterns, eliminating the need to evaluate multiple cells.
Solution Approach 2:
The patent uses copies of reference haplotype blocks to create matched filters that can be applied to the target cell. Instead of requiring multiple physical cell samples, the system creates computational copies of reference patterns that serve as templates for identifying haplotype blocks in the single target cell.
3Measurement precision
If the resolution of nucleotide-derived signal is increased to directly resolve individual nucleotides, then sequencing accuracy improves, but the complexity and cost of the imaging system increases significantly
Solution Approach 1:
The patent transitions from attempting to resolve individual nucleotides in one dimension (direct spatial resolution) to analyzing haplotype blocks as patterns across multiple dimensions. By comparing overall signal patterns and using matched filtering in the computational domain, the system achieves accurate genotyping without requiring ultra-high spatial resolution imaging capabilities.
Solution Approach 2:
The patent performs preliminary computational processing by creating matched filters that encode the expected patterns of haplotype blocks. This pre-computation allows the system to interpret lower-resolution images accurately by matching them against known patterns, rather than requiring the imaging system to resolve every nucleotide individually.
Data Source
AI summary
Disclosed herein are systems and methods for evaluating segments of DNA within a single strand or chromosome using matched filtering. DNA within a cell of interest, such as a gamete or embryonic cell, may be imaged at high resolution to provide an input signal. Matched filters may be created for reference signals from reference samples of cells having homologous chromosomes that share the same haplotypes as the DNA within the cell of interest. By applying a matched filter for a given haplotype to the input signal it can be determined whether the DNA within the cell of interest shares the same haplotype as the reference sample. The nucleotide sequence of one or more segments of DNA from the cell of interest may be reconstructed by identifying the haplotypes present in the DNA.