Methods for identifying DNA copy number changes
View Patent ↗Methods of identifying allele-specific changes in genomic DNA copy number are disclosed. Methods for identifying homozygous deletions and genetic amplifications are disclosed. An array of probes designed to detect presence or absence of a plurality of different sequences is also disclosed. The probes are designed to hybridize to sequences that are predicted to be present in a reduced complexity sample. The methods may be used to detect copy number changes in cancerous tissue compared to normal tissue. The methods may be used to diagnose cancer and other diseases associated with chromosomal anomalies.
1. A system for identifying regions of copy number variation in a test sample comprising:
a computer readable storage medium having computer program logic recorded thereon, wherein said computer program logic comprises instructions comprising:
(a) input instructions for (i) receiving a plurality of probe intensity values for each of a plurality of perfect match probes for a first allele and each of a plurality of perfect match probes for a second allele for each of a plurality of polymorphisms;
(ii) instructing a processor to execute computer code to calculate a first summary intensity value for the first allele and a second summary intensity value for the second allele for each polymorphism in the plurality of polymorphisms using one or more of the probe intensity values received in (a);
(iii) normalizing the first summary intensity value for the first allele for each polymorphism using a normalization value for the first allele obtained from a reference set of samples of known genotype;
(iv) normalizing the second summary probe intensity value for the second allele for each polymorphism using a normalization value for the second allele obtained from a reference set of samples of known genotype;
(v) estimating copy number for said first allele for each polymorphism;
(vi) estimating copy number for said second allele for each polymorphism; and
(vii) estimating the copy number for each of a plurality of genomic regions, wherein each genomic region contains at least one of the polymorphism in the plurality of polymorphisms by combining the estimated copy number for said first allele and the estimated copy number for said second allele for each polymorphism;
(b) instructions for comparing the estimated total copy number for each genomic region in the test sample to the reference set of samples; and
(c) instructions for outputing a copy number estimate for each of a plurality of genomic regions in the test sample and for outputting genomic regions in the test sample where the copy number estimate for that region varies from the copy number of that region in the reference set of samples.
2. The system of claim 1 , further comprising: instructions for displaying an indication of total copy number for a plurality of genomic regions.
3. The system of claim 1 , further comprising: instructions for displaying an indication of allele-specific copy number for a plurality of genomic regions.
4. The system of claim 1 , further comprising a graphical user interface and instructions for displaying the copy number estimates for the plurality of genomic regions using the graphical user interface.
5. The system of claim 4 , wherein the graphical user interface comprises graphical elements to display the estimated copy number of genomic regions.
6. The system of claim 1 , wherein each of the normalization values comprises a standard deviation value.
7. The system of claim 1 , wherein each polymorphism is a single nucleotide polymorphism and wherein for each polymorphism the reference set of samples is divided into subgroups having the same genotpype at that polymorphism and the test sample is compared at that SNP to a distribution of reference samples that are matched in genotype to the test sample at that SNP.
8. The system of claim 1 wherein the reference set of samples comprises more than 100 normal individuals.
9. The system of claim 1 wherein the reference set of samples comprises more than 200 normal individuals.
10. The system of claim 1 wherein the reference set of samples comprises more than 500 normal individuals.