Methods and systems for detecting sequence variants
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Publication Number
US-11837328-B2
Publication Date
2023-12-05
Expiration Date
Abstract
The invention provides methods for identifying rare variants near a structural variation in a genetic sequence, for example, in a nucleic acid sample taken from a subject. The invention additionally includes methods for aligning reads (e.g., nucleic acid reads) to a reference sequence construct accounting for the structural variation, methods for building a reference sequence construct accounting for the structural variation or the structural variation and the rare variant, and systems that use the alignment methods to identify rare variants. The method is scalable, and can be used to align millions of reads to a construct thousands of bases long, or longer.
Core Innovation
The invention describes methods, systems, and non-transitory storage media for identifying a genomic variant as present in a nucleic acid sample using a genomic reference graph. The genomic reference graph represents at least a portion of a genome of an organism and genetic variation of at least the portion of the genome, and includes nodes and edges with a first path representing the portion of the genome and a second path representing at least some of the genetic variation.
Nucleic acid sequence reads associated with the nucleic acid sample are aligned to the genomic reference graph using a dynamic programming algorithm. For a nucleic acid sequence read, the aligning includes determining overlap scores for the read against the genomic reference graph and aligning the read to the genomic reference graph based on the overlap scores.
Variant identification is performed by identifying a first genomic variant as present based on results of the aligning of the reads to the genomic reference graph. In representative embodiments, the genomic reference graph can encode structural variation via nodes and paths, and the first genomic variant can be a deletion, duplication, copy-number variation, insertion, inversion, translocation, or a combination of these.
Claims Coverage
The provided set includes three independent claims: a method for identifying a genomic variant as present, a system configured to perform the method, and a non-transitory storage medium storing instructions to perform the method. Across the independent claims, there are three main inventive features centered on graph-based genomic reference alignment with dynamic-programming overlap scoring and variant presence identification from alignment results, with a scale constraint requiring more than 1,000,000 nucleic acids represented in the graph.
Genomic reference graph with reference and variation paths
Accessing a genomic reference graph representing at least a portion of a genome of an organism and genetic variation of at least the portion of the genome, wherein a first path represents at least the portion of the genome and a second path represents at least some of the genetic variation, the second path including a first node representing a first genomic variant.
Dynamic programming alignment using overlap scores against the genomic reference graph
Aligning one or more nucleic acid sequence reads to the genomic reference graph using a dynamic programming algorithm, the aligning comprising determining overlap scores for the nucleic acid sequence read against the genomic reference graph and aligning the nucleic acid sequence read to the genomic reference graph based on the overlap scores.
Variant presence identification from alignment results
Identifying the first genomic variant as present in the nucleic acid sample based on results of the aligning the one or more nucleic acid sequence reads to the genomic reference graph.
Genomic reference graph scale constraint
The portion of the genome comprising greater than 1,000,000 nucleic acids.
The independent claims consistently require a genomic reference graph with reference and variation paths, read alignment to that graph using dynamic programming based on overlap scores, and identification of a genomic variant as present from the alignment results, with the additional constraint that the represented portion comprises greater than 1,000,000 nucleic acids.
Stated Advantages
Documented Applications
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