Methods and systems for genotyping genetic samples

Inventors

Kural, Deniz

Assignees

Seven Bridges Genomics Inc

Abstract

The invention provides methods and system for making specific base calls at specific loci using a reference sequence construct, e.g., a directed acyclic graph (DAG) that represents known variants at each locus of the genome. Because the sequence reads are aligned to the DAG during alignment, the subsequent step of comparing a mutation, vis-a-vis the reference genome, to a table of known mutations can be eliminated. The disclosed methods and systems are notably efficient in dealing with structural variations within a genome or mutations that are within a structural variation.

Core Innovation

The invention provides a system and method for genotyping a genetic sample by aligning sequencing reads to a reference sequence construct represented as a directed acyclic graph (DAG). The DAG represents a reference sequence of a species and genetic variation of the reference sequence, where different paths through the DAG represent different sequences and alleles. A first path represents a first sequence that includes a first allele stored as a first string of one or more symbols, and a second path represents a second sequence that includes a second allele stored as a second string of one or more symbols.

The invention uses the DAG representation to include genetic structural variation directly in the graph representation, where the second sequence represents a first genetic structural variation. Alignment is performed by comparing a read string corresponding to a first sequence read to the first and second strings associated with the first and second paths at DAG positions. The approach determines a first overlap score corresponding to a first alignment at a first position in the DAG and a second overlap score corresponding to a second alignment at a second position in the DAG, with each overlap score being determined based on, and indicative of, a degree of overlap between the read string and each of the first and second strings.

After computing overlap scores, the invention identifies one of the first and second overlap scores and aligns the first sequence read to the respective first or second position in the DAG. It then determines, based on results of the aligning, whether the first sequence read aligns to the second sequence represented by the second path through the DAG. Upon determining that the first sequence read aligns to the second sequence, the system identifies a presence of the first genetic structural variation within the genetic sample.

Claims Coverage

The document provides three independent claims (system, method, and non-transitory computer-readable storage medium), each centered on DAG-based genotyping using overlap scores to determine alignment to graph paths representing genetic structural variation. Across the independent claims, there are three core inventive features repeated: DAG-based representation of reference sequence and genetic variation, overlap-score-based alignment of reads to DAG positions, and presence detection of genetic structural variation from alignment results.

Each independent claim covers DAG-based genotyping that aligns sequence reads to alternative DAG paths using overlap scores to select DAG positions, and then determines presence of a genetic structural variation from whether reads align to the path representing that structural variation.

Stated Advantages

Documented Applications