Methods for non-invasive prenatal ploidy calling

摘要

The present disclosure provides methods for determining the ploidy status of a chromosome in a gestating fetus from genotypic data measured from a sample of DNA from the mother of the fetus and from the fetus, and from genotypic data from the mother and optionally also from the father. The ploidy state is determined by using a joint distribution model to create a set 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. In an embodiment, the mixed sample of DNA may be preferentially enriched at a plurality of polymorphic loci in a way that minimizes the allelic bias.

主权项

1. 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:
sequencing DNA from a first fraction of each mixed sample in a plurality of mixed samples from a plurality of pregnant mothers to obtain a first set of measured genetic data at a plurality of loci on a chromosome or chromosome segment of interest; wherein each mixed sample comprises DNA from a fetus and DNA from the mother of the fetus; generating 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 for each of the hypotheses using the first set of measured genetic data; sequencing DNA from a second fraction of a least one of the mixed samples for which the first probability of an aneuploid number of copies of the chromosome or chromosome segment of interest is above a threshold value 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 each of the hypotheses using the second set of measured genetic data and optionally the first set of measured genetic data; selecting the hypothesis with the greatest probability for the second probability determination; and outputting the hypothesis with the greatest probability for the second probability determination as an indication of the number of copies of the chromosome or chromosome segment of interest in the genome of at least one of the fetuses.