Methods and compositions for determining ploidy

A method for preparing a DNA fraction from a sample of an individual useful for determining a copy number of a chromosome or chromosomal region of interest in the sample of the individual, the method comprising:

• (i) extracting extracellular circulating cell-free DNA from the sample;
• (ii) producing a fraction of the DNA extracted in step (i) by:
• amplifying at least 200 SNP loci on the chromosome or chromosome region of interest, wherein at least 90% of the at least 200 SNP loci are located within one or more haploblocks and the SNP loci within each haploblock have strong linkage disequilibrium, by forming a reaction mixture comprising the DNA extracted, a polymerase and a pool of primers comprising at least 200 primers or primer pairs that each specifically bind to a primer binding sequence located within an effective distance of one of the at least 200 SNP loci, and subjecting the reaction mixture to amplification conditions, thereby generating a plurality of amplicons;
• and
• (iii) analyzing the fraction of the DNA produced in step (ii) by:
• a. subjecting each of the amplicons to a nucleic acid sequencing reaction to generate the nucleic acid sequencing data for the amplicons, thereby receiving allele frequency data for each SNP of a set of SNPs comprising the at least 200 SNP loci, wherein the allele frequency data comprises the amount of each allele present in the sample at each loci;
• b. estimating the phase of the allele frequency data taking into account an increased statistical correlation of polymorphic loci within the same haploblock;
• c. generating individual likelihoods of allele frequencies for the polymorphic loci for different ploidy states using the allele frequency data;
• d. generating joint likelihoods for the plurality of linked polymorphic loci using the individual likelihoods and the phased allele frequency data;
• and
• e. selecting, based on the joint likelihoods, a best fit model indicative of chromosomal copy number, thereby determining the copy number of the chromosome or chromosome region.