Methods and processes for non-invasive assessment of genetic variations

1. A computer-implemented method for detecting the presence or absence of a chromosome aneuploidy, comprising:

(a) sequencing test sample nucleic acid into partial sequence reads by assigning one or more nucleotide species from a subset of the nucleotide species present in the sample nucleic acid at some but not all nucleotide positions of the partial sequence reads; wherein:

the partial sequence reads are of a minimum length for unique mapping to a reference genome section,

the test sample nucleic acid comprises circulating cell-free nucleic acid from a pregnant female bearing a fetus, and

thousands to millions of partial sequence reads are generated;

(b) mapping, using a microprocessor, the thousands to millions of partial sequence reads to genomic sections of a reference genome, wherein the genomic sections comprise reference sequences composed of one or more nucleotide species from a subset of the nucleotide species present in the reference genome at some but not all nucleotide positions of the genomic sections;

(c) receiving counts of the thousands to millions of partial sequence reads mapped to the genomic sections of the reference genome;

(d) normalizing the counts of the thousands to millions of partial sequence reads according to guanine and cytosine (GC) content of the genomic sections, thereby providing normalized counts, and

(e) outputting a classification of the presence or absence of a chromosome aneuploidy based on the normalized counts.

2. The method of claim 1 , wherein the partial sequence reads are unary partial reads, for which unary partial reads one nucleotide species is determined at some positions and the other positions can be any one of three other nucleotide species.

3. The method of claim 2 , wherein the partial sequence reads are about 30 base pairs or more in length.

4. The method of claim 1 , wherein the partial sequence reads are ternary partial reads, for which ternary partial reads a first nucleotide species is determined at some positions, a second nucleotide species is determined at other positions and the remaining positions are any one of two nucleotide species other than the first nucleotide species and the second nucleotide species.

5. The method of claim 4 , wherein the partial sequence reads are about 20 base pairs or more in length.

6. The method of claim 1 , wherein the normalizing in (d) comprises performing a local regression on the counts of the partial sequence reads.

7. The method of claim 6 , wherein the local regression comprises a weighted least squares fit.

8. The method of claim 6 , wherein the local regression comprises a LOESS regression.

9. The method of claim 1 , wherein the normalizing in (d) is according to the subset of nucleotide species in the reference sequences.

10. The method of claim 1 , wherein the sequencing in (a) comprises a nanopore process, or a massively parallel sequencing (MPS) process and a nanopore process.

11. The method of claim 1 , wherein the chromosome aneuploidy is a chromosome 21 trisomy.

12. A computer-implemented method for detecting the presence or absence of a chromosome aneuploidy, comprising:

(a) sequencing test sample nucleic acid into partial sequence reads by assigning one or more nucleobase classes at some or all nucleotide positions of the partial sequence reads; wherein:

each nucleobase class represents two or more possible nucleotide species;

the partial sequence reads are of a minimum length for unique mapping to a reference genome section,

the test sample nucleic acid comprises circulating cell-free nucleic acid from a pregnant female bearing a fetus, and

thousands to millions of partial sequence reads are generated;

(b) mapping, using a microprocessor, the thousands to millions of partial sequence reads to genomic sections of a reference genome, wherein the genomic sections comprise reference sequences composed of one or more nucleobase classes at some or all nucleotide positions of the genomic sections;

(c) receiving counts of the thousands to millions of partial sequence reads mapped to the genomic sections of the reference genome;

(d) normalizing the counts of the thousands to millions of partial sequence reads according to guanine and cytosine (GC) content of the genomic sections, thereby providing normalized counts, and

(e) outputting a classification of the presence or absence of a chromosome aneuploidy based on the normalized counts.

13. The method of claim 12 , wherein each nucleobase class comprises two nucleotide species such that the partial sequence reads are binary partial reads, for which binary partial reads a first nucleobase class representing two possible nucleotide species is assigned at some positions and a second nucleobase class representing two nucleotide species is assigned at other positions, wherein the nucleotide species in the first nucleobase class and the nucleobase species in the second nucleobase class are different.

14. The method of claim 13 , wherein the first nucleobase class represents purine nucleotide species and the second nucleobase class represents pyrimidine nucleotide species.

15. The method of claim 13 , wherein the partial sequence reads are about 30 base pairs or more in length.

16. The method of claim 12 , wherein the normalizing in (d) comprises performing a local regression on the counts of the partial sequence reads.

17. The method of claim 16 , wherein the local regression comprises a weighted least squares fit.

18. The method of claim 16 , wherein the local regression comprises a LOESS regression.

19. The method of claim 12 , wherein the normalizing in (d) is according to the number of nucleotide species in each nucleobase class in the reference sequences.

20. The method of claim 12 , wherein the sequencing in (a) comprises a nanopore process, or a massively parallel sequencing (MPS) process and a nanopore process.

21. The method of claim 1 , wherein the sequencing in (a) comprises a massively parallel sequencing (MPS) process.

22. The method of claim 21 , comprising prior to (a) isolating the circulating cell-free nucleic acid from the test sample from the pregnant female.

23. The method of claim 12 , wherein the sequencing in (a) comprises a massively parallel sequencing (MPS) process.

24. The method of claim 23 , comprising prior to (a) isolating the circulating cell-free nucleic acid from the test sample from the pregnant female.