Methods and processes for non-invasive assessment of genetic variations
First Claim
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1. A method for determining a fraction of fetal nucleic acid for a test sample, comprising:
- (a) sequencing a test sample, the test sample comprising circulating cell-free nucleic acid from a pregnant female, thereby generating nucleic acid sequence reads, wherein the sequencing is at about 1-fold genome coverage or less, and obtaining counts of the nucleic acid sequence reads mapped to genomic sections of a reference genome;
(b) from the counts in (a), generating an experimental Y chromosome representation, which experimental Y chromosome representation is a ratio of (i) counts of sequence reads mapped to the genomic sections of the reference genome in the Y chromosome, and (ii) counts of sequence reads mapped to genomic sections of the reference genome in a portion of the chromosomes or all of the chromosomes; and
(c) determining the fraction of fetal nucleic acid in the test sample according to the experimental Y chromosome representation generated in (b), a median X chromosome representation for a set of pregnant females bearing a female fetus, and a slope and intercept from a linear regression for X chromosome representations and Y chromosome representations determined for a set of pregnant females bearing a male fetus;
wherein;
each of the X chromosome representations for the set of pregnant females bearing a male fetus is a ratio of (i) counts of sequence reads mapped to the genomic sections of the reference genome in the X chromosome, and (ii) counts of sequence reads mapped to genomic sections of the reference genome in a portion of the chromosomes or all of the chromosomes;
each of the Y chromosome representations for the set of pregnant females bearing a male fetus is a ratio of (i) counts of sequence reads mapped to the genomic sections of the reference genome in the Y chromosome, and (ii) counts of sequence reads mapped to genomic sections of the reference genome in a portion of the chromosomes or all of the chromosomes; and
the median X chromosome representation for the set of pregnant females bearing a female fetus is the median of X chromosome representations, wherein each of the X chromosome representations is a ratio of (i) counts of sequence reads mapped to the genomic sections of the reference genome in the X chromosome, and (ii) counts of sequence reads mapped to genomic sections of the reference genome in a portion of the chromosomes or all of the chromosomes, wherein the portion of the chromosomes is the same for each of the X chromosome representations.
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Abstract
Provided herein are methods, processes and apparatuses for non-invasive assessment of genetic variations.
143 Citations
22 Claims
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1. A method for determining a fraction of fetal nucleic acid for a test sample, comprising:
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(a) sequencing a test sample, the test sample comprising circulating cell-free nucleic acid from a pregnant female, thereby generating nucleic acid sequence reads, wherein the sequencing is at about 1-fold genome coverage or less, and obtaining counts of the nucleic acid sequence reads mapped to genomic sections of a reference genome; (b) from the counts in (a), generating an experimental Y chromosome representation, which experimental Y chromosome representation is a ratio of (i) counts of sequence reads mapped to the genomic sections of the reference genome in the Y chromosome, and (ii) counts of sequence reads mapped to genomic sections of the reference genome in a portion of the chromosomes or all of the chromosomes; and (c) determining the fraction of fetal nucleic acid in the test sample according to the experimental Y chromosome representation generated in (b), a median X chromosome representation for a set of pregnant females bearing a female fetus, and a slope and intercept from a linear regression for X chromosome representations and Y chromosome representations determined for a set of pregnant females bearing a male fetus;
wherein;each of the X chromosome representations for the set of pregnant females bearing a male fetus is a ratio of (i) counts of sequence reads mapped to the genomic sections of the reference genome in the X chromosome, and (ii) counts of sequence reads mapped to genomic sections of the reference genome in a portion of the chromosomes or all of the chromosomes; each of the Y chromosome representations for the set of pregnant females bearing a male fetus is a ratio of (i) counts of sequence reads mapped to the genomic sections of the reference genome in the Y chromosome, and (ii) counts of sequence reads mapped to genomic sections of the reference genome in a portion of the chromosomes or all of the chromosomes; and the median X chromosome representation for the set of pregnant females bearing a female fetus is the median of X chromosome representations, wherein each of the X chromosome representations is a ratio of (i) counts of sequence reads mapped to the genomic sections of the reference genome in the X chromosome, and (ii) counts of sequence reads mapped to genomic sections of the reference genome in a portion of the chromosomes or all of the chromosomes, wherein the portion of the chromosomes is the same for each of the X chromosome representations. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)
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Specification