Methods for non-invasive prenatal ploidy calling
First Claim
1. A method for determining a ploidy status of a chromosome or chromosome segment in a gestating fetus, the method comprising:
- measuring the DNA in a sample that comprises maternal DNA from the mother of the fetus and fetal DNA from the fetus at a plurality of at least 10 polymorphic loci on the chromosome or chromosome segment;
determining, on a computer, allele counts at the plurality of polymorphic loci from the DNA measurements made on the sample;
generating, on a computer, a plurality of ploidy hypotheses each specifying a different possible ploidy state of the chromosome or chromosome segment;
generating, on a computer, a joint distribution model for the expected allele counts and for the expected linkage between the expected allele counts at the plurality of polymorphic loci on the chromosome or chromosome segment for each ploidy hypothesis;
determining, on a computer, a relative probability of each of the ploidy hypotheses by comparing (i) the joint distribution model for the expected allele counts and for the expected linkage between the expected allele counts at the plurality of polymorphic loci to (ii) the allele counts measured on the sample at the plurality of polymorphic loci; and
outputting the hypothesis with the greatest probability of being true as an indication of the ploidy state of the fetus.
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Abstract
The present disclosure provides methods for determining the ploidy status of a chromosome in a gestating fetus from genotypic data measured from a mixed sample of DNA comprising DNA from both the mother of the fetus and from the fetus, and optionally from genotypic data from the mother and father. The ploidy state is determined by using a joint distribution model to create a plurality of expected allele distributions for different possible fetal ploidy states given the parental genotypic data, and comparing the expected allelic distributions to the pattern of measured allelic distributions measured in the mixed sample, and choosing the ploidy state whose expected allelic distribution pattern most closely matches the observed allelic distribution pattern. The mixed sample of DNA may be preferentially enriched at a plurality of polymorphic loci in a way that minimizes the allelic bias, for example using massively multiplexed targeted PCR.
197 Citations
30 Claims
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1. A method for determining a ploidy status of a chromosome or chromosome segment in a gestating fetus, the method comprising:
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measuring the DNA in a sample that comprises maternal DNA from the mother of the fetus and fetal DNA from the fetus at a plurality of at least 10 polymorphic loci on the chromosome or chromosome segment; determining, on a computer, allele counts at the plurality of polymorphic loci from the DNA measurements made on the sample; generating, on a computer, a plurality of ploidy hypotheses each specifying a different possible ploidy state of the chromosome or chromosome segment; generating, on a computer, a joint distribution model for the expected allele counts and for the expected linkage between the expected allele counts at the plurality of polymorphic loci on the chromosome or chromosome segment for each ploidy hypothesis; determining, on a computer, a relative probability of each of the ploidy hypotheses by comparing (i) the joint distribution model for the expected allele counts and for the expected linkage between the expected allele counts at the plurality of polymorphic loci to (ii) the allele counts measured on the sample at the plurality of polymorphic loci; and outputting the hypothesis with the greatest probability of being true as an indication of the ploidy state 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, 23, 24, 25, 26, 27, 28, 29, 30)
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Specification