Methods for non-invasive prenatal ploidy calling
DCFirst Claim
1. A method for determining the number of copies of a chromosome or chromosome segment of interest in the genome of a gestating fetus, the method comprising:
- measuring genetic data at a plurality of polymorphic loci on at least one chromosome that is expected to be disomic in both the mother and the fetus and a plurality of polymorphic loci on at least chromosome or chromosome segment of interest, which comprises amplifying at least 500 polymorphic loci from a mixed sample comprising DNA derived from the fetus and DNA derived from the mother, wherein the mixed sample is prepared from a maternal blood or plasma sample that comprises free floating fetal and maternal DNA;
determining a ratio of DNA derived from the fetus to DNA derived from the mother from the measured genetic data at the plurality of polymorphic loci on the at least one chromosome that is expected to be disomic in both the mother and the fetus;
creating hypotheses specifying the number of copies of the chromosome or chromosome segment of interest in the genome of the fetus;
determining, on a computer, the probability of each of the hypotheses using the measured genetic data for the chromosome or chromosome segment of interest and the ratio of DNA derived from the fetus to DNA derived from the mother; and
selecting the hypothesis with the greatest probability, thereby determining the number of copies of the chromosome or chromosome segment of interest in the genome of the fetus.
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Litigations
1 Petition
Accused Products
Abstract
Disclosed herein are methods for determining the copy number of a chromosome in a fetus in the context of non-invasive prenatal diagnosis. In an embodiment, the measured genetic data from a sample of genetic material that contains both fetal DNA and maternal DNA is analyzed, along with the genetic data from the biological parents of the fetus, and the copy number of the chromosome of interest is determined. In an embodiment, the maternal serum is measured using a single-nucleotide polymorphism (SNP) microarray, along with parental genomic data, and the determination of the chromosome copy number is used to make clinical decisions pertaining to the fetus.
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Citations
26 Claims
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1. A method for determining the number of copies of a chromosome or chromosome segment of interest in the genome of a gestating fetus, the method comprising:
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measuring genetic data at a plurality of polymorphic loci on at least one chromosome that is expected to be disomic in both the mother and the fetus and a plurality of polymorphic loci on at least chromosome or chromosome segment of interest, which comprises amplifying at least 500 polymorphic loci from a mixed sample comprising DNA derived from the fetus and DNA derived from the mother, wherein the mixed sample is prepared from a maternal blood or plasma sample that comprises free floating fetal and maternal DNA; determining a ratio of DNA derived from the fetus to DNA derived from the mother from the measured genetic data at the plurality of polymorphic loci on the at least one chromosome that is expected to be disomic in both the mother and the fetus; creating hypotheses specifying the number of copies of the chromosome or chromosome segment of interest in the genome of the fetus; determining, on a computer, the probability of each of the hypotheses using the measured genetic data for the chromosome or chromosome segment of interest and the ratio of DNA derived from the fetus to DNA derived from the mother; and selecting the hypothesis with the greatest probability, thereby determining the number of copies of the chromosome or chromosome segment of interest in the genome of the fetus. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 24)
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23. A method for determining the number of copies of a chromosome or chromosome segment of interest in the genome of a gestating fetus, the method comprising:
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obtaining a plurality primers to a locus (i) that is known to be polymorphic in the human population and (i) that is likely to be informative based on the rate of SNP heterozygosity in the human population for the locus;
wherein an informative polymorphic loci is a SNP locus on at least one chromosome that is expected to be disomic in both the mother and the fetus where the mother is homozygous for a first allele at that locus, and the father is (i) heterozygous for the first allele and a second allele or (ii) homozygous for a second allele at that locus;amplifying at least 500 SNPs from DNA in a mixed sample comprising DNA derived from the fetus and DNA derived from the mother by using the plurality of primers to obtain amplified products comprising the plurality of polymorphic loci on the at least one chromosome that is expected to be disomic, wherein the mixed sample is prepared from a maternal blood or plasma sample that comprises free floating fetal and maternal DNA; measuring an amount of the amplified products to obtain a measured quantity of each allele at the plurality of polymorphic loci on the at least one chromosome that is expected to be disomic; determining a ratio of DNA derived from the fetus to DNA derived from the mother using (i) the measured quantity of the second allele or (ii) the measured quantity of the first and second alleles for each of the polymorphic loci on the at least one chromosome that is expected to be disomic; measuring genetic data at a plurality of loci on a chromosome or chromosome segment of interest in the mixed sample; creating one or more hypotheses specifying the number of copies of the chromosome or chromosome segment of interest in the genome of the fetus; determining, on a computer, the probability of each of the hypotheses using the measured genetic data for the chromosome or chromosome segment of interest and the ratio of DNA derived from the fetus to DNA derived from the mother; and selecting the hypothesis with the greatest probability, thereby determining the number of copies of the chromosome or chromosome segment of interest in the genome of the fetus. - View Dependent Claims (25, 26)
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Specification