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US 11,456,055 B2Granted
Genotyping polyploid loci
AssigneeIllumina, Inc.
InventorRyan Kelley
Life of this patent
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Abstract
Provided are methods, systems, and computer products for genotyping polyploid organisms, as well as diploid organisms. The provided methods use an allele-intensity model to generate cluster definitions. The allele-intensity model relates allele counts of different genotypes to signal intensities generated by the genotyping platform. The model also includes a capability to update cluster positions obtained from a maximum likelihood model using a Bayesian method.
Claims20
A method of genotyping a genomic locus of a polyploid genome of a polyploid organism to be genotyped, the method comprising:
- providing a cluster model for genotyping polyploid organisms produced by:
- (a) identifying a plurality of active genotypes expected to be observed at the genomic locus in the polyploid organisms;
- (b) fitting a plurality of parameters of a first function relating a first signal magnitude produced in a microarray by a first nucleotide type present in a first allele at the genomic locus to a count of the first nucleotide type at the genomic locus, wherein fitting the plurality of parameters of the first function assumes the identified plurality of active genotypes are observed in the polyploid organisms;
- (c) fitting a plurality of parameters of a second function relating a second signal magnitude produced in the microarray by a second nucleotide type present in a second allele at the genomic locus to a count of the second nucleotide type at the genomic locus, wherein fitting the plurality of parameters of the second function assumes the identified plurality of active genotypes are observed in the polyploid organisms,
- wherein fitting the plurality of parameters to the first and second functions is performed using the first and second signal magnitudes obtained by assaying the genomic locus of a plurality of polyploid organisms of a training set, and
- wherein the first and second functions together identify cluster positions for genotypes at the genomic locus;
- and
- (d) adjusting the cluster positions identified by the first and second functions to more closely match observed data from the training set;
- receiving a first signal magnitude produced in a microarray by the first nucleotide type at the genomic locus of the polyploid organism to be genotyped, and receiving a second signal magnitude produced in the microarray by the second nucleotide type at the genomic locus of the polyploid organism to be genotyped, wherein the first and second signal magnitudes together identify a two-dimensional position for a genotype of the genomic locus of the polyploid organism to be genotyped;
- comparing the two-dimensional position to the cluster positions in the cluster model for the genomic locus;
- and
- assigning a genotype to the genomic locus of the polyploid organism to be genotyped based on a distance between the two-dimensional position and a nearest cluster position in the cluster model.
9 more elements
A system for genotyping polyploid organisms, the system comprising:
- a microarray configured to generate a first signal in response to contact with a first nucleotide type present in a first allele at a genomic locus of the polyploid organisms and generate a second signal in response to contact with a second nucleotide type present in a second allele at the genomic locus of the polyploid organisms;
- and
- one or more processors configured to
- (i) receive data representing magnitudes of the first and second signals produced in the microarray by the first and second nucleotide types at the genomic locus of a polyploid organism to be genotyped, wherein the first and second signal magnitudes together identify a two-dimensional position for a genotype of the genomic locus of the polyploid organism to be genotyped;
- (ii) determine a plurality of cluster positions of a cluster model by:
- (a) identifying a plurality of active genotypes expected to be observed at the genomic locus in the polyploid organisms;
- (b) fitting a plurality of parameters of a first function relating the first signal magnitude to a count of the first nucleotide type at the genomic locus, wherein fitting the plurality of parameters of the first function assumes the identified plurality of active genotypes are observed in the polyploid organisms;
- (c) fitting a plurality of parameters of a second function relating the second signal magnitude to a count of the second nucleotide type at the genomic locus, wherein fitting the plurality of parameters of the second function assumes the identified plurality of active genotypes are observed in the polyploid organisms,
- wherein fitting the plurality of parameters to the first and second functions is performed using the first and second signal magnitudes obtained by assaying the genomic locus of a plurality of polyploid organisms of a training set, and
- wherein the first and second functions together identify cluster positions for genotypes at the genomic locus;
- and
- (d) adjusting the cluster positions identified by the first and second functions to more closely match observed data from the training set;
- (iii) compare the two-dimensional position for the genotype of the genomic locus of the polyploid organism to be genotyped to the cluster positions determined by the cluster model for the genomic locus;
- and
- (iv) assign a genotype to the polyploid organism to be determined at the genomic locus based on a distance between the two-dimensional positions and a nearest cluster position in the cluster model.
12 more elements
A computer program product comprising a non-transitory machine readable medium storing program code that, when executed by one or more processors of a computer system, causes the computer system to implement a method for genotyping a genomic locus of a polyploid genome of a polyploid organism to be genotyped, said program code comprising:
- code for providing a cluster model for genotyping polyploid organisms produced by:
- (a) identifying a plurality of active genotypes expected to be observed at the genomic locus in the polyploid organisms;
- (b) fitting a plurality of parameters of a first function relating a first signal magnitude produced in a microarray by a first nucleotide type present in a first allele at the genomic locus to a count of the first nucleotide type at the genomic locus, wherein fitting the plurality of parameters of the first function assumes the identified plurality of active genotypes are observed in the polyploid organisms;
- (c) fitting a plurality of parameters of a second function relating a second signal magnitude produced in the microarray by a second nucleotide type present in a second allele at the genomic locus to a count of the second nucleotide type at the genomic locus, wherein fitting the plurality of parameters of the second function assumes the identified plurality of active genotypes are observed in the polyploid organisms,
- wherein fitting the plurality of parameters to the first and second functions is performed using the first and second signal magnitudes obtained by assaying the genomic locus of a plurality of polyploid organisms of a training set, and
- wherein the first and second functions together identify cluster positions for genotypes at the genomic locus;
- and
- (d) adjusting the cluster positions identified by the first and second functions to more closely match observed data from the training set;
- code for receiving a first signal magnitude produced in a microarray by the first nucleotide type at the genomic locus of the polyploid organism to be genotyped, and receiving a second signal magnitude produced in the microarray by the second nucleotide type at the genomic locus of the polyploid organism to be genotyped, wherein the first and second signal magnitudes together identify a two-dimensional position for a genotype of the genomic locus of the polyploid organism to be genotyped;
- code for comparing the two-dimensional position to the cluster positions in the cluster model for the genomic locus;
- and
- code for assigning a genotype to the genomic locus of the polyploid organism to be genotyped based on a distance between the two-dimensional position and a nearest cluster position in the cluster model.
9 more elements
Dependencies are inferred from the claim text.