Methods and systems for genomic analysis

• US 9,183,496 B2
• Filed: 08/29/2014
• Issued: 11/10/2015
• Est. Priority Date: 08/30/2013
• Status: Active Grant

• Current Assignee: Personalis, Inc.
• Original Assignee: Personalis, Inc.
• Inventors: Harris, Jason, Pratt, Mark R., West, John, Chen, Richard, Li, Ming
• Primary Examiner(s): Brusca, John S
• Application Number:
  US14/474,034
• Publication Number:
  US 20150066824A1
• Time in Patent Office: 438 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: C12Q 1/68 involving nucleic acids
• CPC Class Codes: C12Q 1/6869 Methods for sequencing
• CPC Class Codes: G06N 3/126 Evolutionary algorithms, e.g. genetic algorithms or genetic programming
• CPC Class Codes: G16B 20/00 ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/20 Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
• CPC Class Codes: G16B 30/00 ICT specially adapted for sequence analysis involving nucleotides or amino acids
• CPC Class Codes: G16B 30/10 Sequence alignment; Homology search
• CPC Class Codes: G16H 50/00 ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics

Abstract

A computer-implemented method for processing and/or analyzing nucleic acid sequencing data comprises receiving a first data input and a second data input. The first data input comprises untargeted sequencing data generated from a first nucleic acid sample obtained from a subject. The second data input comprises target-specific sequencing data generated from a second nucleic acid sample obtained from the subject. Next, with the aid of a computer processor, the first data input and the second data input are combined to produce a combined data set. Next, an output derived from the combined data set is generated. The output is indicative of the presence or absence of one or more polymorphisms of the first nucleic acid sample and/or the second nucleic acid sample.

Claims

1. A method of genetic analysis of a biological sample of a subject, comprising:

a. sequencing a first nucleic acid sample derived from said biological sample of said subject by untargeted sequencing to generate untargeted sequencing data, wherein said untargeted sequencing data comprises from about 300 megabases to 10 gigabases and has a coverage that is less than 100% of a full coverage of a genome of said subject in said biological sample;

b. sequencing a second nucleic acid sample derived from said biological sample of said subject by target-specific sequencing to generate target-specific sequencing data, wherein said target-specific sequencing comprises target-specific whole exome sequencing;

c. combining, with the aid of a computer processor, said untargeted sequencing data and said target-specific sequencing data to produce a combined data set; and

d. generating, with the aid of a computer processor, an output derived from said combined data set, wherein said output is indicative of a presence or absence of one or more polymorphisms in said first nucleic acid sample and said second nucleic acid sample, thereby identifying a presence or absence of one or more polymorphisms in said biological sample of said subject.

2. The method of claim 1, wherein said output comprises a first alignment, wherein said first alignment is generated by mapping said untargeted sequencing data onto a first reference sequence.

3. The method of claim 2, wherein said output further comprises a second alignment, wherein said second alignment is generated by mapping said target-specific sequencing data onto a second reference sequence.

4. The method of claim 1, wherein said output comprises a uniform alignment, wherein said uniform alignment is generated by mapping said combined data set onto a reference sequence.

5. The method of claim 1, wherein said target-specific sequencing data is generated using one or more non-random primers or hybridization probes.

6. The method of claim 5, wherein said non-random primers comprise primers targeting one or more genes, exons, untranslated regions, or a combination thereof.

7. The method of claim 1, wherein said untargeted sequencing data is whole genome sequencing data.

8. The method of claim 1, wherein said first nucleic acid sample and said second nucleic acid sample are derived from the same biological sample of said subject.

9. The method of claim 1, wherein said target-specific sequencing data comprises a specific portion and a non-specific portion, and wherein at least a portion of said untargeted sequencing data is the non-specific portion of the target-specific sequencing data.

10. The method of claim 1, wherein each of said untargeted sequencing data and said target-specific sequencing data comprises variant data, and wherein said combining comprises combining said variant data from said untargeted sequencing data and said target-specific sequencing data into said combined data set.

11. The method of claim 10, wherein said untargeted sequencing data comprises copy number and/or structural variant data, and wherein said target-specific sequencing data comprises single nucleotide variations (SNV) and/or insertion deletion polymorphism (indel) data.

20. The method of claim 3, wherein said first reference sequence and said second reference sequence are the same sequence.

21. The method of claim 1, wherein said combining comprises removing any redundant sequences.

22. The method of claim 1, wherein said coverage of said untargeted sequencing data is from about 1 gigabase to about 10 gigabases of said first nucleic acid sample, which coverage is less than a full coverage of a genome of said subject in said biological sample.

23. The method of claim 1, wherein generating said output comprises using a computer processor to identify said one or more polymorphisms at a sensitivity greater than 90%, wherein said one or more polymorphisms include structural variants that are less than 50,000 bases in length.

12. A system for genetic analysis of a biological sample of a subject, comprising:

a. at least one memory location comprising untargeted sequencing data and target-specific sequencing data, wherein said untargeted sequencing data is generated by untargeted sequencing of a first nucleic acid sample derived from said biological sample of said subject and said target-specific sequencing data is generated by target-specific sequencing of a second nucleic acid sample derived from said biological sample of said subject, wherein said target-specific sequencing data comprises target-specific whole exome sequencing, and wherein said untargeted sequencing data comprises from about 300 megabases to 10 gigabases and has a coverage that is less than 100% of a full coverage of a genome of said subject in said biological sample;

b. a computer processor operably coupled to said at least one memory location and programmed to (i) combine said untargeted sequencing data and said target-specific sequencing data to produce a combined data set and (ii) generate an output from at least a portion of said combined data set, wherein said output is indicative of a presence or absence of one or more polymorphisms in said genome of said subject or a portion of said genome; and

c. an electronic display coupled to said computer processor, wherein said electronic display provides said output for display to a user.

13. The system of claim 12, wherein each of said untargeted sequencing data and said target-specific sequencing data comprises variant data, and wherein said computer processor combines said variant data from said untargeted sequencing data and said target-specific sequencing data into said combined data set.

14. The system of claim 13, wherein said untargeted sequencing data comprises copy number and/or structural variant data, and wherein said target-specific sequencing data comprises single nucleotide variations (SNV) and/or insertion deletion polymorphism (indel) data.

15. The system of claim 12, wherein said computer processor is programmed to map said untargeted sequencing data onto a first reference sequence in memory to generate a first alignment.

16. The system of claim 15, wherein said computer processor is programmed to map said target-specific sequencing data onto a second reference sequence in memory to generate a second alignment.

24. The system of claim 12, wherein said computer processor is programmed to generate said combined data set by combining said untargeted sequencing data and said target-specific sequencing and removing any redundant sequences.

25. The system of claim 12, wherein said coverage of said untargeted sequencing data is from about 1 gigabase to about 10 gigabases of said first nucleic acid sample, which coverage is less than a full coverage of a genome of said subject in said biological sample.

26. The system of claim 12, wherein said computer processor is programmed to generate said output, that is indicative of the presence or absence of said one or more polymorphisms, at a sensitivity greater than 90%, wherein said one or more polymorphisms include structural variants that are less than 50,000 bases in length.

17. A system for genetic analysis of a biological sample of a subject, comprising:

a. at least one memory location comprising untargeted sequencing data and target-specific sequencing data, wherein said untargeted sequencing data is generated by untargeted sequencing of a first nucleic acid sample derived from said biological sample of said subject and said target-specific sequencing data is generated by target-specific sequencing of a second nucleic acid sample derived from said biological sample of said subject, wherein said target-specific sequencing comprises target-specific whole exome sequencing, and wherein said untargeted sequencing data comprises from about 300 megabases to 10 gigabases and has a coverage that is less than 100% of a full coverage of a genome of said subject in said biological sample;

b. a computer processor coupled to said at least one memory location and programmed to (i) combine said untargeted sequencing data and said target-specific sequencing data to produce a combined data set, and (ii) generate an output from at least a portion of said combined data set, wherein said output is indicative of a presence or absence of one or more polymorphisms in said genome of said subject or a portion of said genome; and

c. an electronic data storage unit coupled to said computer processor, wherein said electronic data storage unit comprises said combined data set and/or said output.

18. The system of claim 17, wherein each of said untargeted sequencing data and said target-specific sequencing data comprises variant data, and wherein said computer processor combines said variant data from said untargeted sequencing data and said target-specific sequencing data into said combined data set.

19. The system of claim 18, wherein said untargeted sequencing data comprises copy number and/or structural variant data, and wherein said target-specific sequencing data comprises single nucleotide variations (SNV) and/or insertion deletion polymorphism (indel) data.

27. The system of claim 17, wherein said computer processor is programmed to generate said combined data set by combining said untargeted sequencing data and said target-specific sequencing and removing any redundant sequences.

28. The system of claim 17, wherein said coverage of said untargeted sequencing data is from about 1 gigabase to about 10 gigabases of said first nucleic acid sample, which coverage is less than a full coverage of a genome of said subject in said biological sample.

29. The system of claim 17, wherein said computer processor is programmed to generate said output, that is indicative of the presence or absence of said one or more polymorphisms, at a sensitivity greater than 90%, wherein said one or more polymorphisms include structural variants that are less than 50,000 bases in length.