Systems and methods for detecting homopolymer insertions/deletions

A system for identifying variants in nucleic acid sequence reads, comprising:

• a processor configured to:
• map a plurality of reads to a reference genome, wherein the plurality of reads for a sample are provided by a base caller;
• identify a potential variant position in a homopolymer region of the mapped reads;
• calculate a plurality of base calling residuals corresponding to the mapped reads that span the homopolymer region using measured values and predicted signal values, wherein the predicted signal values are based on a phasing model for a read and the measured values are based on normalized measurements of sequencing data from a nucleic acid sequencing device;
• determine a distribution of the base calling residuals;
• and detect presence of an insertion/deletion in the homopolymer region and heterozygosity in the sample based on the distribution of the base calling.

A method for determining a presence or absence of an insertion/deletion variant in a reference homopolymer, comprising:

• obtaining sequencing data by a processor, the sequencing data relating to a plurality of template polynucleotide strands disposed in a sample processing unit of a nucleic acid sequencing device, the template polynucleotide strands having been exposed to a series of flows of nucleotide species;
• generating one or more preliminary sequences of called bases by performing a preliminary base calling for at least some of the plurality of template polynucleotide strands using the sequencing data;
• identifying one or more candidate variant sequences in the one or more preliminary sequences of called bases by mapping the one or more preliminary sequences of called bases against a reference genome;
• and
• calling one or more variants using a distribution of base calling residuals based on measured and model-predicted signal values of the sequencing data, including retrieving, for at least one of the one or more candidate variant sequences, a called sequence c and corresponding normalized measurements y from the sequencing data covering a reference homopolymer hA.

A system, including:

• a machine-readable memory;
• and
• a processor configured to execute machine-readable instructions, which, when executed by the processor, cause the system to perform a method for determining a presence or absence of an insertion/deletion variant in a reference homopolymer comprising:
• receiving at the processor sequencing data relating to a plurality of template polynucleotide strands disposed in a sample processing unit of a nucleic acid sequencing device, the template polynucleotide strands having been exposed to a series of flows of nucleotide species;
• generating one or more preliminary sequences of called bases by performing a preliminary base calling for at least some of the plurality of template polynucleotide strands using the sequencing data;
• identifying one or more candidate variant sequences in the one or more preliminary sequences of called bases by mapping the one or more preliminary sequences of called bases against a reference genome;
• and
• calling one or more variants using a distribution of base calling residuals based on measured and model-predicted signal values of the sequencing data, including retrieving, for at least one of the one or more candidate variant sequences, a called sequence c and corresponding normalized measurements y from the sequencing data covering a reference homopolymer hA.