Allele Calling Using Parental Genetic Data
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Solution Overview
Problem
Current pre-implantation genetic diagnosis (PGD) techniques for IVF are unreliable, expensive, and inefficient in accurately determining genetic data from a single cell, particularly for aneuploidy and disease-linked loci, leading to high error rates and limited ability to screen for chromosomal abnormalities and complex disease phenotypes.
Innovation Solution
A method that uses secondary genetic data from related individuals to reconstruct and improve the fidelity of genetic data from a single cell, including determining ploidy states, allelic states, and identifying insertions, deletions, and repeats, by combining statistical probabilities from multiple expert techniques and utilizing parental and related genetic information to infer accurate genetic states.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If direct measurements of DNA are performed on a single cell, then genetic data can be obtained, but the measurements are highly error-prone and noisy
Solution Approach 1:
The patent performs whole genome amplification before genetic analysis to create multiple copies of the single cell's DNA. This preliminary amplification step ensures sufficient DNA material is available for multiple measurements and statistical analysis, thereby improving measurement precision and reliability without requiring multiple cells
Solution Approach 2:
The patent uses statistical models that incorporate prior genetic information from parents and related individuals as feedback to correct and refine measurements from the single cell. This feedback mechanism allows the system to identify and correct noisy or erroneous measurements by comparing against expected genetic patterns
2Measurement precision
If multiple expert techniques are used to determine genetic states, then accuracy improves, but computational complexity increases
Solution Approach 1:
The patent combines multiple expert techniques (allele calling, ploidy calling, relatedness estimation) into a unified statistical framework that simultaneously determines all genetic states. This merging approach improves accuracy by considering all evidence together while managing computational complexity through integrated probability calculations rather than separate sequential analyses
3Reliability
If genetic data from related individuals is used to reconstruct single cell data, then fidelity improves, but data processing requirements increase
Solution Approach 1:
The patent uses statistical probability models as intermediaries to connect genetic data from related individuals with the single cell measurements. These models efficiently integrate information from multiple sources by calculating likelihoods and posterior probabilities, thereby improving data fidelity without requiring exhaustive processing of all possible data combinations
Data Source
AI summary
Disclosed herein is a system and method for making allele calls, and for determining the ploidy state, in one or a small set of cells, or where a limited quantity of genetic data is available. Poorly or incorrectly measured base pairs, missing alleles and missing regions are reconstructed and the haplotypes are determined using expected similarities between the target genome and the knowledge of the genomes of genetically related individuals. In one embodiment, incomplete genetic data from an embryonic cell are reconstructed at a plurality of loci using the genetic data from both parents, and possibly one or more sperm and/or sibling embryos. In another embodiment, the chromosome copy number can be determined using the same input data. In another embodiment, these determinations are made for embryo selection during IVF, for non-invasive prenatal diagnosis, or for making phenotypic predictions.