Embryo Genotype Reconstruction for Noisy Single-Cell DNA
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Solution Overview
Problem
Current methods for pre-implantation genetic diagnosis (PGD) and prenatal diagnosis suffer from high error rates, low accuracy, and high costs, particularly in detecting aneuploidy and disease-linked loci due to noisy genetic data from single cells, and there is a need for a more reliable and cost-effective method to analyze multiple genetic markers in embryos and fetuses.
Innovation Solution
A system that uses secondary genetic data from related individuals, such as parents and siblings, to reconstruct and clean noisy genetic data from embryos or fetuses, improving the accuracy of aneuploidy and disease-linked gene detection by leveraging known genetic relationships and mechanisms of meiosis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If genetic data from single cells is used for pre-implantation genetic diagnosis, then the ability to screen embryos for aneuploidy and disease-linked loci is enabled, but the error rate increases and accuracy decreases due to noisy genetic data
Solution Approach 1:
The patent introduces parental genetic data as an intermediary to mediate the noisy single-cell genetic data. By using known parental genotypes and applying Bayesian inference, the system reconstructs the embryonic genotype with higher accuracy. The parental data acts as a reference framework that helps resolve ambiguities and errors in the single-cell measurements, effectively filtering noise while preserving true genetic signals.
Solution Approach 2:
The patent implements a feedback mechanism where the measured single-cell genetic data is continuously refined by comparing it against expected inheritance patterns from parental data. The Bayesian inference process provides feedback loops that adjust probability estimates of embryonic genotypes based on accumulated evidence from multiple loci and parental information, progressively improving measurement accuracy through iterative refinement.
2Reliability
If traditional PGD methods are used to detect aneuploidy and disease-linked loci, then genetic screening is performed, but the cost increases and reliability decreases
Solution Approach 1:
The patent creates a virtual copy of the embryonic genome through computational reconstruction using parental genetic data and Bayesian inference. Instead of relying solely on expensive and error-prone physical single-cell sequencing, the system generates a computationally derived genotype that serves as a reliable proxy, reducing the need for repeated expensive testing while maintaining high detection reliability.
Solution Approach 2:
The patent makes the parental genetic data serve multiple functions: it provides a reference for accurate embryonic genotype reconstruction, enables detection of both aneuploidy and disease-linked loci simultaneously, and allows for quality control validation. This multi-functionality reduces the need for separate specialized tests, thereby lowering overall costs while maintaining comprehensive screening reliability.
3Adaptability or versatility
If single cell genetic analysis is performed, then embryo screening for multiple genetic markers is enabled, but the data quality deteriorates due to noise and errors
Solution Approach 1:
The patent performs preliminary action by obtaining and analyzing parental genetic data before the actual embryonic genotype reconstruction. This advance preparation creates a robust reference framework that enables accurate interpretation of the subsequent single-cell embryonic data. The parental data analysis is done beforehand to establish inheritance patterns and expected allele transmissions, which then guide the reconstruction process and help identify and correct errors in the embryonic measurements.
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.