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Systems and methods to detect rare mutations and copy number variation

  • US 10,501,808 B2
  • Filed: 05/14/2018
  • Issued: 12/10/2019
  • Est. Priority Date: 09/04/2012
  • Status: Active Grant
First Claim
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1. A system comprising:

  • a nucleic acid sequencer configured to sequence a nucleic acid library comprising non-uniquely tagged parent polynucleotides and non-uniquely tagged progeny polynucleotides derived therefrom, to generate sequencing reads corresponding to the non-uniquely tagged parent polynucleotides, wherein the non-uniquely tagged parent polynucleotides comprise nucleic acid molecules ligated to non-unique molecular barcodes, wherein the non-unique molecular barcodes have from 2 to 1000 different sequences and lengths of at least 5 nucleotides, wherein the sequencing reads comprise (1) nucleic acid sequences of the nucleic acid molecules, and (2) nucleic acid sequences of the non-unique molecular barcodes attached to the nucleic acid molecules;

    a communication interface that receives, over a communication network, the sequencing reads generated by the nucleic acid sequencer; and

    a computer in communication with the communication interface, wherein the computer comprises one or more computer processors and a computer-readable medium comprising machine-executable code that, upon execution by the one or more computer processors, implements a method comprising;

    (i) receiving, over the communication network, the sequencing reads generated by the nucleic acid sequencer;

    (ii) mapping the sequencing reads to one or more reference sequences from a human genome;

    (iii) grouping the sequencing reads into a plurality of families, wherein a family of the plurality of families comprises sequencing reads comprising identical nucleic acid sequences of the non-unique molecular barcodes and having the same start or stop positions, wherein the family of the plurality of families comprises sequencing reads corresponding to a same original cell-free nucleic acid molecule, wherein the family of the plurality of families comprises sequencing reads of non-uniquely tagged progeny polynucleotides amplified from a unique polynucleotide among the non-uniquely tagged parent polynucleotides; and

    (iv) generating a base call for at least the family of the plurality of families at a genetic locus of a plurality of genetic loci in the one or more reference sequences.

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