Methods for non-invasive prenatal ploidy calling

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 the quantity of one or more alleles at a plurality of polymorphic loci on at least one chromosome that is expected to be disomic in both the mother of the fetus and the fetus in a mixed sample comprising DNA from the fetus and DNA from the mother;
• using the measured quantities of the alleles to determine the ratio of fetal to maternal DNA in the mixed sample;
• determining a number of sequence reads to be obtained from the mixed sample using the ratio of fetal to maternal DNA;
• sequencing the DNA molecules in the mixed sample for at least the determined number of sequence reads to obtain measured genetic data at a plurality of loci on a chromosome or chromosome segment of interest;
• creating a plurality of 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;
• 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 the fetus.

A method for determining the number of copies of a chromosome or chromosome segment of interest in the genome of at least one gestating fetus, the method comprising:

• measuring the quantity of one or more alleles at a plurality of polymorphic loci on at least one chromosome that is expected to be disomic in both the mother and the fetus in a plurality of mixed samples from a plurality of pregnant mothers;
• wherein each mixed sample comprises DNA from a fetus and DNA from the mother of the fetus;
• using the measured quantities of the alleles to determine the ratio of fetal to maternal DNA in each of the mixed samples;
• dividing the mixed samples into a different subsets based on the ratio of fetal to maternal DNA in each of the mixed sample comprising a first subset with at least one mixed sample that has a larger ratio of fetal to maternal DNA and a second subset with at least one mixed sample that has a smaller ratio of fetal to maternal DNA;
• sequencing a first amount of DNA molecules in the mixed samples in the first subset to obtain a first set of measured genetic data at a plurality of loci on a chromosome or chromosome segment of interest;
• sequencing a second amount of DNA molecules in the mixed samples in the second subset to obtain a first set of measured genetic data at a plurality of loci on a chromosome or chromosome segment of interest;
• wherein the second amount of DNA molecules is larger than the first amount of DNA molecules;
• creating a plurality of hypotheses specifying the number of copies of the chromosome or chromosome segment of interest in the genome of at least one of the fetuses;
• determining, on a computer, a first probability of each of the hypotheses using the measured genetic data;
• selecting at least one mixed sample for which the probability of an aneuploid number of copies of the chromosome or chromosome segment of interest is above a threshold value for additional testing;
• sequencing DNA from a second fraction of the selected mixed sample to obtain a second set of measured genetic data at the plurality of loci on the chromosome or chromosome segment of interest;
• determining, on a computer, a second probability for at least one of the hypotheses using the second set of measured genetic data and optionally the first set of measured genetic data;
• and
• selecting the hypothesis with the greatest probability for the second probability determination, thereby determining the number of copies of the chromosome or chromosome segment of interest in the genome of at least one of the fetuses.

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 the quantity of one or more alleles at a plurality of polymorphic loci on at least one chromosome that is expected to be disomic in both the mother of the fetus and the fetus in a mixed sample comprising DNA from the fetus and DNA from the mother;
• using the measured quantities of the alleles to determine the ratio of fetal to maternal DNA in the mixed sample;
• determining a number of sequence reads to be obtained from the mixed sample using the ratio of fetal to maternal DNA;
• sequencing the DNA molecules in the mixed sample for at least the determined number of sequence reads to obtain a first set of measured genetic data at a plurality of loci on a chromosome or chromosome segment of interest;
• creating a plurality of hypotheses specifying the number of copies of the chromosome or chromosome segment of interest in the genome of the fetus;
• determining, on a computer, a first probability of each of the hypotheses using the measured genetic data;
• selecting the mixed sample for additional testing if the probability of an aneuploid number of copies of the chromosome or chromosome segment of interest is above a threshold value;
• sequencing DNA from a second fraction of the selected mixed sample to obtain a second set of measured genetic data at the plurality of loci on the chromosome or chromosome segment of interest;
• determining, on a computer, a second probability for at least one of the hypotheses using the second set of measured genetic data and optionally the first set of measured genetic data;
• and
• selecting the hypothesis with the greatest probability for the second probability determination, thereby determining the number of copies of the chromosome or chromosome segment of interest in the genome of the fetuses.