Methods and systems for genomic analysis

• US 9,727,692 B2
• Filed: 09/30/2015
• Issued: 08/08/2017
• Est. Priority Date: 08/30/2013
• Status: Active Grant

• Current Assignee: Personalis, Inc.
• Original Assignee: Personalis, Inc.
• Inventors: Pratt, Mark R., Chen, Richard, West, John, Harris, Jason, Li, Ming
• Primary Examiner(s): Brusca, John S
• Application Number:
  US14/871,020
• Publication Number:
  US 20160019341A1
• Time in Patent Office: 678 Days
• Field of Search: None
• 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 for genetic analysis of a biological sample of a subject, comprising:

(a) sequencing a first nucleic acid sample from said biological sample of said subject to generate untargeted sequencing data, wherein said untargeted sequencing data comprises less than about 90 gigabases;

(b) sequencing a second nucleic acid sample from said biological sample of said subject to generate target-specific sequencing data;

(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 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 a genome of said subject or a portion of said genome.

2. The method of claim 1, wherein said generating in (d) comprises (1) mapping said untargeted sequencing data onto a first reference sequence to generate a first alignment, and (2) mapping said target-specific sequencing data onto a second reference sequence to generate a second alignment.

3. The method of claim 2, wherein said first reference sequence and said second reference sequence are the same sequence.

4. The method of claim 2, further comprising (i) combining said first alignment and said second alignment to yield a combined sequence, and (ii) mapping said combined sequence onto a reference sequence.

5. The method of claim 1, wherein said target-specific sequencing data is based on targeted sequencing of an exome, specific genes, genomic regions, or a combination thereof.

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

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

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

9. The method of claim 8, wherein said whole genome sequencing data comprises single reads, paired-end reads, or mate-pair reads.

10. 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 included in said non-specific portion of said target-specific sequencing data.

11. The method of claim 10, wherein said untargeted sequencing data is included in said non-specific portion of said target-specific sequencing data.

12. 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 variant data from said untargeted sequencing data and variant data from said target-specific sequencing data into said combined data set.

13. The method of claim 12, wherein said untargeted sequencing data comprises copy number or structural variant data, and wherein said target-specific sequencing data comprises single nucleotide variations (SNV) or insertion deletion polymorphism (indel) data.

14. The method of claim 1, wherein said untargeted sequencing data comprises up to about 10 gigabases.

15. The method of claim 1, wherein said first nucleic acid sample and said second nucleic acid sample are separately subjected to untargeted sequencing and target-specific sequencing, respectively.

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

17. 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 or equal to 90%, wherein said one or more polymorphisms include structural variants that are less than 100,000 bases in length.

18. The method of claim 1, wherein said target-specific sequencing data comprises sequencing data corresponding to less than or equal to about 180,000 exons in an exome of said subject.

19. The method of claim 1, wherein said biological sample is a blood sample or a tissue biopsy.

20. The method of claim 1, wherein said sequencing of (a) and/or (b) is massively parallel sequencing.

21. The method of claim 1, wherein said untargeted sequencing data of (a) and said target-specific sequencing data of (b) comprise sequencing reads, and wherein said combining of (c) comprises combining said sequencing reads.

22. The method of claim 1, wherein said untargeted sequencing data comprises up to about 50 gigabases.

23. The method of claim 1, wherein said untargeted sequencing data is at least about 100 megabases.

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

at least one computer memory comprising untargeted sequencing data and target-specific sequencing data, wherein said untargeted sequencing data is generated by sequencing a first nucleic acid sample from said biological sample of said subject and said target-specific sequencing data is generated by sequencing a second nucleic acid sample from said biological sample of said subject, wherein said untargeted sequencing data comprises less than about 90 gigabases;

a computer processor coupled to said at least one computer memory 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 a genome of said subject or a portion of said genome; and

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

25. The system of claim 24, wherein each of said untargeted sequencing data and said target-specific sequencing data comprises variant data, and wherein said computer processor is programmed to combine variant data from said untargeted sequencing data and variant data from said target-specific sequencing data into said combined data set.

26. The system of claim 25, wherein said untargeted sequencing data comprises copy number or structural variant data, and wherein said target-specific sequencing data comprises single nucleotide variations (SNV) or insertion deletion polymorphism (indel) data.

27. The system of claim 24, further comprising an electronic display coupled to said computer processor, wherein said electronic display provides said output for display.

28. The system of claim 24, wherein said computer processor is programmed to (1) map said untargeted sequencing data onto a first reference sequence in computer memory to generate a first alignment, and (2) map said target-specific sequencing data onto a second reference sequence in computer memory to generate a second alignment.

29. The system of claim 24, wherein said computer processor is programmed to generate said combined data set by (1) combining said untargeted sequencing data and said target-specific sequencing data and (2) removing any redundant sequences.

30. The system of claim 24, wherein said untargeted sequencing data comprises up to about 10 gigabases.

31. The system of claim 24, wherein said target-specific sequencing data comprises sequencing data corresponding to less than or equal to about 180,000 exons in an exome of said subject.

32. The system of claim 24, 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 or equal to 90%, wherein said one or more polymorphisms include structural variants that are less than 100,000 bases in length.

33. The system of claim 24, wherein said sequencing of a first nucleic acid sample and/or said sequencing of a second nucleic acid sample is massively parallel sequencing.

34. The system of claim 24, wherein said untargeted sequencing data and said target-specific sequencing data comprise sequencing reads, and wherein said combining of said untargeted sequencing data and said target-specific sequencing comprises combining said sequencing reads.

35. The system of claim 24, wherein said untargeted sequencing data comprises up to about 50 gigabases.

36. The system of claim 24, wherein said untargeted sequencing data is at least about 100 megabases.