Methods and genotyping panels for detecting alleles, genomes, and transcriptomes

1. A method of obtaining and analyzing a fetal genome from a mixture of maternal and fetal cells, comprising:

a) obtaining a maternal blood sample comprising a mixture of maternal and fetal cells;

b) enriching said sample from step a) for said fetal cells, wherein fetal cells in the mixture of maternal and fetal cells are enriched to between 1 in 100 and 1 in 100,000 fetal cells per maternal cells;

c) dividing said enriched sample from step b) into at least about 1,000 subsamples, wherein each subsample has an average of less than one cell;

d) performing whole genome amplification on each at least about 1,000 subsamples from step c) to provide an amplified product for each subsample, wherein each amplified product has an amplified genome from an average of about one cell, and wherein at least 99% of the amplified genomes in said amplified product are not from a fetal cell;

e) dividing each of said amplified product from step d) into aliquots, wherein each aliquot contains at least one copy of said amplified genome from said cell, and wherein at least 99% of the amplified genomes in said aliquots are not from a fetal cell;

f) screening or genotyping an aliquot from step e) for the presence of a fetal identifier, wherein said screening or genotyping comprises:

i) determining a maternal genotype and a fetal genotype at at least 1 SNP(s) per chromosome-specific SNP panel on at least 10 chromosome-specific panels;

ii) selecting as test loci from step i) at least 1 SNP(s) per chromosome-specific panel on at least 10 chromosome-specific panels where the maternal genotype is homozygous and the fetal genotype is heterozygous;

iii) screening or genotyping said aliquot from step e) for a genotype differing from a maternal genotype at at least one of said test loci from step ii), wherein the presence of said genotype differing from said maternal genotype indicates the possible presence of an informative paternal allele in said aliquot and thus said corresponding subsample;

iv) screening or genotyping an aliquot from a subsample having an informative paternal allele from step iii) for a genotype differing from a maternal genotype at at least 1 test loci per chromosome-specific panel on at least 10 chromosome-specific panels from step ii), wherein the presence of said genotype differing from said maternal genotype indicates the presence of an informative paternal allele in said aliquot,

g) identifying the presence of a fetal cell in at least one subsample from step c) whose aliquot contains an informative paternal allele from step f) iv); and

h) analyzing another aliquot from step e) from said at least one subsample from step g) identified as containing fetal cell to detect a genetic variation in said genome of said fetal cell.

2. The method of claim 1 , wherein said genetic variation is selected from the group consisting of a chromosomal rearrangement, a copy number variation, and a polymorphism.

3. The method of claim 1 , wherein said analyzing to detect a genetic variation comprises determining a ratio of maternally- and paternally-inherited alleles, wherein said ratio is analyzed to determine the presence of a genetic variation.

4. The method of claim 1 , wherein said analyzing to detect a genetic variation comprises determining a copy number of alleles in said aliquot, wherein said copy number of alleles is analyzed to determine the presence of a genetic variation.

5. The method of claim 1 , wherein said maternal genotype and fetal genotype are determined from a mixture of maternal and fetal nucleic acids from a mixture of cell-free nucleic acids.

6. The method of claim 5 , wherein the source of said maternal and fetal cell-free nucleic acid sample is blood, serum, plasma, urine, cervical swab, cervical lavage, uterine lavage, or culdocentesis from a pregnant female.

7. The method of claim 1 , further comprising pooling an aliquot from two or more subsamples prior to screening or genotyping an aliquot for the presence of a fetal identifier, wherein said screening or genotyping further comprises:

individually screening or genotyping a second aliquot from the subsamples whose pooled aliquots contained an informative paternal allele.

8. The method of claim 7 , wherein said pooling comprises the use of an indexed system of rows and columns of wells comprising said aliquots.

9. The method of claim 1 , wherein aliquots from two or more subsamples identified as containing a fetal cell are pooled prior to said analyzing another aliquot from said at least one subsample identified as containing fetal cell to detect a genetic variation in said fetal cell.

10. The method of claim 7 , wherein aliquots from two or more subsamples identified as containing a fetal cell are pooled prior to said analyzing another aliquot from said at least one subsample identified as containing fetal cell to detect a genetic variation in said fetal cell.

11. The method of claim 1 , wherein the loci used to determine the presence of an informative paternal allele is not the same loci used to detect a genetic variation.