Spatial Haplotype Distribution Analysis via Barcoded Capture Probes
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Solution Overview
Problem
Current methods for analyzing spatial heterogeneity in biological tissues fail to provide comprehensive data on the position of single cells within a tissue sample, limiting the characterization of biological conditions and the understanding of disease mechanisms.
Innovation Solution
A method involving a two-dimensional array of capture probes with spatial barcodes is used to determine the spatial distribution of haplotypes in a biological sample by obtaining sequence reads from a substrate, allowing for the identification and alignment of sequence reads to determine haplotype identities and their spatial distribution, which characterizes the biological condition.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If single cell techniques for variant detection are used, then variant detection capability is improved, but spatial position information of cells in tissue samples is lost
Solution Approach 1:
The method segments the tissue sample into individual cell analysis units while preserving spatial coordinates. Each cell's variant detection is performed independently through single-cell sequencing, yet the spatial position is recorded as metadata associated with each cell's sequence data, enabling both precise variant detection and spatial mapping.
Solution Approach 2:
The patent implements a nested structure where spatial position information is embedded within the sequence data framework. The spatial coordinates are integrated as part of the data structure for each detected variant, allowing hierarchical analysis from tissue-level spatial distribution down to cell-level variant detection without information loss.
2Loss of information
If techniques providing data for a small handful of analytes in intact tissue are used, then spatial information is preserved, but the number of analytes that can be analyzed is limited
Solution Approach 1:
The method employs a universal single-cell sequencing platform that can analyze multiple analyte types (various genetic variants, mutations, and genomic features) within the same tissue sample. The spatial barcoding system serves multiple functions by simultaneously preserving spatial information while enabling comprehensive multi-analyte detection through flexible library preparation and sequencing approaches.
Solution Approach 2:
The patent utilizes parameter changes in the sequencing process to expand analyte detection capacity. By adjusting sequencing depth, read length, and library preparation parameters, the system can detect different types of genetic variants (SNVs, indels, structural variants) while maintaining spatial resolution through the barcoded capture probes.
Data Source
AI summary
A method determining a biological condition of a subject using a spatial distribution of haplotypes is provided in which sequence reads are obtained from a two-dimensional array of positions on a substrate upon contacting a biological sample of the subject with the two-dimensional array of positions on the substrate. Each capture probe plurality in a set of capture probe pluralities is at a different position in the two-dimensional array, associates with one or more analytes from the biological sample, and has a corresponding spatial barcode from a plurality of spatial barcodes. Each sequence read includes a spatial barcode of the corresponding capture probe plurality. The barcoded sequence reads are used to quantify each haplotype for each of a plurality of loci thereby determining the spatial distribution of the one or more haplotypes in the biological sample which, in turn, is used to characterize the biological condition of the subject.