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Methods and processes for non-invasive assessment of genetic variations

  • US 10,424,394 B2
  • Filed: 03/14/2013
  • Issued: 09/24/2019
  • Est. Priority Date: 10/06/2011
  • Status: Active Grant
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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