Parental Genotype Reconstruction for Noisy Single-Cell DNA
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Solution Overview
Problem
Current genetic testing methods for pre-implantation genetic diagnosis (PGD) and prenatal diagnosis are unreliable, costly, and suffer from high error rates due to noisy genetic data, particularly in the analysis of single cells or small quantities of DNA, leading to issues like allele drop-out and low accuracy in detecting aneuploidy and disease-linked loci.
Innovation Solution
A system that utilizes secondary genetic data from genetically related individuals, such as parents and siblings, to reconstruct and clean noisy genetic data from embryos or fetuses, improving the accuracy of chromosome copy number determination and disease-linked gene identification.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Loss of time
If genetic data from a single cell or small quantity of DNA is analyzed directly, then the cost and time for genetic testing is reduced, but the measurement precision and reliability deteriorate due to noisy data and allele drop-out
Solution Approach 1:
The system performs preliminary actions by obtaining and storing parental genetic data before the actual embryonic genetic analysis. This preparatory step creates a reference framework that will be used to clean and validate the noisy single-cell genetic data, thereby improving measurement precision without increasing the actual testing time for the embryo itself
Solution Approach 2:
Parental genetic data serves as an intermediary element that mediates between the noisy single-cell embryonic data and the final accurate genetic diagnosis. By comparing embryonic alleles against parental genotypes, the system can identify and correct measurement errors, filling in missing alleles and filtering out false positives
2Quantity of substance
If genetic data from a single cell is analyzed, then the cost of testing is reduced, but the reliability of detecting aneuploidy and disease-linked loci deteriorates due to high error rates
Solution Approach 1:
The system implements feedback by continuously comparing the measured embryonic alleles against the expected inheritance patterns from parental genotypes. When discrepancies are detected (such as allele drop-out or false positives), the system uses the parental reference data to correct these errors, thereby maintaining high reliability even when analyzing limited DNA quantities
Solution Approach 2:
Parental genetic data is obtained and processed in advance to establish a reliable reference framework. This preliminary action creates a validation mechanism that significantly improves the reliability of detecting aneuploidy and disease-linked loci in the embryonic sample, even when only small amounts of DNA are available
3Device complexity
If noisy genetic measurements are used directly, then the complexity of the testing system is reduced, but the accuracy of chromosome copy number determination deteriorates
Solution Approach 1:
Parental genetic data acts as an intermediary that enables accurate copy number determination without requiring complex additional instrumentation. By using the parental genotypes as a reference, the system can distinguish between true copy number variations and measurement noise through simple allele comparison and inheritance pattern analysis
Solution Approach 2:
The system creates a virtual copy of the expected genetic data by inferring embryonic alleles from parental genotypes based on Mendelian inheritance patterns. This copied reference data can then be compared against the actual measurements to identify and correct errors, improving copy number accuracy without adding physical complexity to the system
Data Source
AI summary
Disclosed herein is a system and method for increasing the fidelity of measured genetic data, for making allele calls, and for determining the state of aneuploidy, in one or a small set of cells, or from fragmentary DNA, where a limited quantity of genetic data is available. Poorly or incorrectly measured base pairs, missing alleles and missing regions are reconstructed using expected similarities between the target genome and the genome of genetically related individuals. In accordance with one embodiment, incomplete genetic data from an embryonic cell are reconstructed at a plurality of loci using the more complete genetic data from a larger sample of diploid cells from one or both parents, with or without haploid genetic data from one or both parents. In another embodiment, the chromosome copy number can be determined from the measured genetic data, with or without genetic information from one or both parents.