Phased Fetal Genomic Sequence Calculation from Maternal Samples
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Solution Overview
Problem
Current methods for deep whole-genome sequencing of fetal DNA from maternal samples are economically infeasible for widespread clinical or commercial use due to the low percentage of fetal DNA present, making it challenging to identify inherited alleles in a fetus non-invasively.
Innovation Solution
The development of processes and systems that utilize novel technological and computational approaches to detect and phase fetal genomic sequences from maternal samples, incorporating chromosome-specific genomic information from both parents, and employing methods like whole-genome sequencing, array hybridization, and massively parallel sequencing to determine the phased composition of fetal heritable genomic regions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If deep whole-genome sequencing of fetal DNA from maternal samples is performed, then fetal genomic sequences can be identified, but the cost becomes economically infeasible for widespread clinical use
Solution Approach 1:
The patent segments the whole-genome sequencing approach by focusing sequencing efforts on specific chromosomal regions and informative loci rather than sequencing the entire fetal genome. This is achieved through targeted sequencing of regions with informative variants that can distinguish paternal and maternal alleles, reducing the total sequencing cost while maintaining sufficient precision for disease risk assessment.
Solution Approach 2:
The patent extracts and analyzes only the necessary genomic information from maternal samples by identifying and sequencing specific informative loci that enable fetal phasing. This extraction approach removes the need for expensive whole-genome sequencing by focusing computational and sequencing resources only on regions that provide diagnostic utility for identifying inherited alleles.
2Measurement precision
If conventional sequencing technologies are used for fetal DNA analysis, then sequencing can be performed, but the low percentage of fetal DNA (3-40%) makes accurate identification difficult
Solution Approach 1:
The patent performs preliminary identification of informative loci and parental allele assignment before sequencing. By pre-identifying which genomic regions contain informative variants that can distinguish paternal and maternal alleles, the subsequent sequencing process can be optimized to target only these regions, improving detection accuracy despite the low fetal DNA percentage in maternal samples.
Solution Approach 2:
The patent uses maternal genomic information as an intermediary to facilitate fetal allele identification. By comparing sequencing data from informative loci against known maternal alleles, the system can indirectly identify fetal-inherited alleles through phasing algorithms, overcoming the challenge of detecting low-abundance fetal DNA signals in the presence of abundant maternal DNA.
3Reliability
If phased genomic information is determined using parental sequence data, then disease risk prediction improves, but the complexity of computational analysis increases
Solution Approach 1:
The patent segments the computational analysis into distinct modular steps: (1) identification of informative loci, (2) determination of parental alleles at these loci, (3) sequencing of maternal sample regions, (4) phasing of fetal alleles based on informative loci, and (5) disease risk assessment. This segmentation reduces overall computational complexity by processing data in manageable stages rather than requiring complex integrated analysis of entire genomes.
Solution Approach 2:
The patent applies local quality analysis by focusing computational resources only on informative loci and their surrounding regions rather than analyzing the entire genome. This localized approach maintains high reliability for disease risk prediction at clinically relevant regions while significantly reducing computational complexity through targeted rather than comprehensive analysis.
Data Source
AI summary
The present invention provides processes for calculating phased genomic sequences of the fetal genome using fetal DNA obtained from a maternal sample. The processes and systems of the present invention utilize novel technological and computational approaches to detect fetal genomic sequences and determine the phased heritable genomic sequences. The invention could be used, e.g., to identify in utero deleterious mutations carried by the parents and inherited by a fetus within a particular heritable genomic region.