Linkage Disequilibrium Analysis for Low-Coverage Genomic Identity
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Solution Overview
Problem
Current methods for determining whether two DNA samples originate from the same individual are challenging when DNA coverage is low, as they rely on identifying alleles at polymorphic sites, which is difficult due to limited sequence information and fragmented DNA, especially in ancient or degraded samples.
Innovation Solution
A method using linkage disequilibrium (LD) scores calculated from independent DNA sequences to determine the likelihood that sequences are from a single individual, employing publicly available SNP databases and next-generation sequencing to analyze polymorphic sites, even with low sequence coverage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If low-coverage shotgun sequencing is used to analyze ancient or degraded DNA samples, then the ability to sequence highly fragmented DNA is improved, but the ability to identify alleles at polymorphic sites deteriorates
Solution Approach 1:
The invention transitions from analyzing individual SNP alleles in isolation to examining pairs of SNPs in linkage disequilibrium. By adding the dimension of pairwise relationships between polymorphic sites, the method extracts more information from low-coverage data. The LD score aggregation across many SNP pairs compensates for the low coverage at individual sites, enabling reliable individual identification even when most positions have no observations in a single library.
2Reliability
If direct comparison of alleles at polymorphic sites is performed between two low-coverage libraries, then individual identification can be attempted, but the number of informative sites for comparison deteriorates to a very small number
Solution Approach 1:
The invention merges information from many SNP pairs by aggregating LD scores across the genome. Instead of relying on a small number of directly observed informative sites, the method combines weak signals from numerous SNP pairs in linkage disequilibrium. This aggregation approach accumulates sufficient statistical power to reliably distinguish between samples from the same individual versus different individuals, even when each individual SNP has very low coverage.
3Measurement precision
If SNP-based forensic analysis using a small set of curated SNPs is used, then individual identification can be performed, but the markers are not observed in low-coverage shotgun sequencing of the genome
Solution Approach 1:
The invention creates a universal method that works with both targeted SNP panels and low-coverage whole-genome sequencing data. By using linkage disequilibrium patterns across many polymorphic sites rather than relying on a specific small set of curated SNPs, the approach is adaptable to different sequencing strategies. The method can utilize any polymorphic sites present in the low-coverage data, making it universally applicable regardless of which specific markers are observed.
Data Source
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AI summary
Disclosed are methods for testing biological samples containing genomic nucleic acids obtained from an organism having a genome, such as a human genome. It is often desirable to analyze a DNA sample or more than one, different DNA samples, to determine whether the sample comes from one individual or two individuals. The present method requires very low amounts of DNA and can use partial sequences of DNA fragments. Partial sequences are analyzed for the presence of polymorphisms (e.g. SNP's) that can be mapped to a reference SNP map. The distance between similar SNPS, which are genetically linked, can be used to statistically determine a likelihood of identity of individuality in a sample.