Bambam: parallel comparative analysis of high-throughput sequencing data

• US 9,646,134 B2
• Filed: 11/18/2011
• Issued: 05/09/2017
• Est. Priority Date: 05/25/2010
• Status: Active Grant

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Sanborn, John Zachary, Haussler, David
• Primary Examiner(s): Patel, Neha
• Assistant Examiner(s): DURANT, JONATHAN W
• Application Number:
  US13/373,550
• Publication Number:
  US 20120066001A1
• Time in Patent Office: 1,999 Days
• CPC Class Codes: G06F 3/04845 for image manipulation, e.g. dragging, rotation, expansion or change of colour
• CPC Class Codes: G06F 40/169 Annotation, e.g. comment data or footnotes
• CPC Class Codes: G06N 7/01 Probabilistic graphical models, e.g. probabilistic networks
• CPC Class Codes: G16B 20/00 ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/10 Ploidy or copy number detection
• CPC Class Codes: G16B 20/20 Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
• CPC Class Codes: G16B 20/40 Population genetics; Linkage disequilibrium
• 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: G16B 50/00 ICT programming tools or database systems specially adapted for bioinformatics
• CPC Class Codes: G16B 50/30 Data warehousing; Computing architectures
• CPC Class Codes: G16H 10/40 for data related to laboratory analysis, e.g. patient specimen analysis
• CPC Class Codes: G16H 10/60 for patient-specific data, e.g. for electronic patient records
• CPC Class Codes: G16H 50/20 for computer-aided diagnosis, e.g. based on medical expert systems
• CPC Class Codes: G16H 50/30 for calculating health indices; for individual health risk assessment
• CPC Class Codes: Y02A 90/10 Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

A differential sequence object is constructed on the basis of alignment of sub-strings via incremental synchronization of sequence strings using known positions of the sub-strings relative to a reference genome sequence. An output file is then generated that comprises only relevant changes with respect to the reference genome.

Claims

1. A processor-based method of deriving a differential genetic sequence object, the method comprising:

providing access to a genetic database storing (a) a first genetic sequence string representing a first tissue and (b) a second genetic sequence string representing a second tissue, wherein the first and second sequence strings have a plurality of corresponding sub-strings;

providing access to a sequence analysis engine coupled with the genetic database;

producing, using the sequence analysis engine, a local alignment using a known position of at least one of a plurality of corresponding sub-strings;

determining base probabilities of possible locations of sequence reads in the first and second genetic sequence strings as a function of error rates of at least one sequencer;

identifying a difference between the first set and the second set of genetic sequence strings by comparing genotypes from the first and the second sets that, overlapping at a particular genomic position, maximize a likelihood probability function identifying the genotypes as being different and that are located at the particular genomic position, where the likelihood probability function operates as a probability distribution of a likelihood that unmapped sequence reads of both the first set, representing the first tissue, and the second set, representing the second tissue, align to possible junction sequences, modeled over the base probabilities and associated sequence reads;

using the local alignment and the identifying the difference to generate a local differential string between the first and second sequence strings within the local alignment; and

using, by the sequence analysis engine, the local differential string to update a differential genetic sequence object in a differential sequence database with information according to the local differential string; and

generating a patient specific clinical instruction based on the information of the differential genetic sequence object.

2. The method of claim 1 wherein the first and second genetic sequence strings represent at least 10% of a genome, transcriptome, or proteome of the first and second tissues, respectively.

3. The method of claim 1 wherein the first and second genetic sequence strings represent at least 50% of a genome, transcriptome, or proteome of the first and second tissues, respectively.

4. The method of claim 1 wherein the first and second genetic sequence strings represent substantially the entire genome, transcriptome, or proteome of the first and second tissues, respectively.

5. The method of claim 1 wherein the first and second tissues originate from the same biological entity, the biological entity selected from the group consisting of a patient, a healthy individual, a cell line, a stem cell, an experimental animal model, a recombinant bacterial cell, and a virus.

6. The method of claim 1 wherein the first tissue is a healthy tissue and wherein the second is a diseased tissue.

7. The method of claim 6 wherein the diseased tissue comprises a tumor tissue.

8. The method of claim 1 wherein the corresponding sub-strings comprise homozygous alleles.

9. The method of claim 1 wherein the corresponding sub-strings comprise heterozygous alleles.

10. The method of claim 1 wherein the step of synchronizing comprises aligning at least one of the plurality of sub-strings is based on an a priori known location within the first string.

11. The method of claim 1 wherein the step of synchronizing comprises aligning at least one of the plurality of sub-strings based on a known reference string comprising known locations for the at least one of the plurality of sub-strings.

12. The method of claim 11 wherein the known reference string is a consensus sequence.

13. The method of claim 1 wherein the step of synchronizing comprises aligning the at least one of the plurality of sub-strings within a window having a length of less than a length of the at least one of the plurality of sub-strings.

14. The method of claim 1 further comprising iteratively incrementally synchronizing the first and second sequence strings throughout the entire length of the first sequence string.

15. The method of claim 1 wherein the differential genetic sequence object represents a plurality of local differential strings for at least one chromosome.

16. The method of claim 1 wherein the differential genetic sequence object represents a plurality of local differential strings for substantially the entire genome of the first tissue.

17. The method of claim 1 wherein the differential genetic sequence object comprises an attribute comprising metadata describing the differential genetic sequence object.

18. The method of claim 17 wherein the attribute comprises a state of at least one of the first and second tissues.

19. The method of claim 18 wherein the state comprises a physiological state of at least one of the first and second tissues.

20. The method of claim 19 wherein the physiological state comprises a state selected from the group consisting of neoplastic growth, apoptosis, state of differentiation, tissue age, and responsiveness to treatment.

21. The method of claim 18 wherein the state comprises genetic status.

22. The method of claim 21 wherein the genetic status comprises a status selected from the group consisting of at least one ploidy, gene copy number, repeat copy number, inversion, deletion, insertion of viral genes, somatic mutation, germline mutation, structural rearrangement, transposition, and loss of heterozygosity.

23. The method of claim 18 wherein the state comprises pathway model information associated with a signaling pathway within the tissues.

24. The method of claim 23 wherein the signaling pathway is selected from the group consisting of a growth factor signaling pathway, a transcription factor signaling pathway, an apoptosis pathway, a cell cycle pathway, and a hormone response pathway.

25. The method of claim 1 wherein the differential genetic sequence object comprises a file.

26. The method of claim 25 wherein the file conforms to a standardized format.

27. The method of claim 26 wherein the file conforms to a SAM/BAM format.

28. The method of claim 1 wherein a patient or person associated with the patient specific clinical instruction is selected from the group consisting of a patient or person diagnosed with a condition, the condition selected from the group consisting of a disease and a disorder.

29. The method of claim 28 wherein the condition is selected from the group consisting of acquired immunodeficiency syndrome (AIDS), Addison'"'"'s disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis, benign prostatic hyperplasia, bronchitis, Chediak-Higashi syndrome, cholecystitis, Crohn'"'"'s disease, atopic dermatitis, dermatomyositis, diabetes mellitus, emphysema, erythroblastosis fetalis, erythema nodosum, atrophic gastritis, glomerulonephritis, Goodpasture'"'"'s syndrome, gout, chronic granulomatous diseases, Graves'"'"' disease, Hashimoto'"'"'s thyroiditis, hypereosinophilia, irritable bowel syndrome, multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, osteoarthritis, osteoporosis, pancreatitis, polycystic ovary syndrome, polymyositis, psoriasis, Reiter'"'"'s syndrome, rheumatoid arthritis, scleroderma, severe combined immunodeficiency disease (SCID), Sjogren'"'"'s syndrome, systemic anaphylaxis, systemic lupus erythematosus, systemic sclerosis, thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome, complications of cancer, hemodialysis, and extracorporeal circulation, viral, bacterial, fungal, parasitic, protozoal, and helminthic infection;

and adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, cancers of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus, akathesia, Alzheimer'"'"'s disease, amnesia, amyotrophic lateral sclerosis (ALS), ataxias, bipolar disorder, catatonia, cerebral palsy, cerebrovascular disease Creutzfeldt-Jakob disease, dementia, depression, Down'"'"'s syndrome, tardive dyskinesia, dystonias, epilepsy, Huntington'"'"'s disease, multiple sclerosis, muscular dystrophy, neuralgias, neurofibromatosis, neuropathies, Parkinson'"'"'s disease, Pick'"'"'s disease, retinitis pigmentosa, schizophrenia, seasonal affective disorder, senile dementia, stroke, Tourette'"'"'s syndrome and cancers including adenocarcinomas, melanomas, and teratocarcinomas, particularly of the brain.

30. The method of claim 28 wherein the condition is selected from the group consisting of cancers including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, cancers of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus;

immune disorders including acquired immunodeficiency syndrome (AIDS), Addison'"'"'s disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis, bronchitis, cholecystitis, contact dermatitis, Crohn'"'"'s disease, atopic dermatitis, dermatomyositis, diabetes mellitus, emphysema, episodic lymphopenia with lymphocytotoxins, erythroblastosis fetalis, erythema nodosum, atrophic gastritis, glomerulonephritis, Goodpasture'"'"'s syndrome, gout, Graves'"'"' disease, Hashimoto'"'"'s thyroiditis, hypereosinophilia, irritable bowel syndrome, multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, osteoarthritis, osteoporosis, pancreatitis, polymyositis, psoriasis, Reiter'"'"'s syndrome, rheumatoid arthritis, scleroderma, Sjogren'"'"'s syndrome, systemic anaphylaxis, systemic lupus erythematosus, systemic sclerosis, thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome, complications of cancer, hemodialysis, and extracorporeal circulation, viral, bacterial, fungal, parasitic, protozoal, and helminthic infections, trauma, X-linked agammaglobinemia of Bruton, common variable immunodeficiency (CVI), DiGeorge'"'"'s syndrome (thymic hypoplasia), thymic dysplasia, isolated IgA deficiency, severe combined immunodeficiency disease (SCID), immunodeficiency with thrombocytopenia and eczema (Wiskott-Aldrich syndrome), Chediak-Higashi syndrome, chronic granulomatous diseases, hereditary angioneurotic edema, and immunodeficiency associated with Cushing'"'"'s disease; and

developmental disorders including renal tubular acidosis, anemia, Cushing'"'"'s syndrome, achondroplastic dwarfism, Duchenne and Becker muscular dystrophy, epilepsy, gonadal dysgenesis, WAGR syndrome (Wilms'"'"' tumor, aniridia, genitourinary abnormalities, and mental retardation), Smith-Magenis syndrome, myelodysplastic syndrome, hereditary mucoepithelial dysplasia, hereditary keratodermas, hereditary neuropathies including Charcot-Marie-Tooth disease and neurofibromatosis, hypothyroidism, hydrocephalus, seizure disorders including s Syndenham'"'"'s chorea and cerebral palsy, spina bifida, anencephaly, craniorachischisis, congenital glaucoma, cataract, sensorineural hearing loss, and any disorder associated with cell growth and differentiation, embryogenesis, and morphogenesis involving any tissue, organ, or system of a subject, for example, the brain, adrenal gland, kidney, skeletal or reproductive system.

31. The method of claim 28 wherein the condition is selected from the group consisting of endocrinological disorders including disorders associated with hypopituitarism including hypogonadism, Sheehan syndrome, diabetes insipidus, Kallman'"'"'s disease, Hand-Schuller-Christian disease, Letterer-Siwe disease, sarcoidosis, empty sella syndrome, and dwarfism;

hyperpituitarism including acromegaly, giantism, and syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH); and

disorders associated with hypothyroidism including goiter, myxedema, acute thyroiditis associated with bacterial infection, subacute thyroiditis associated with viral infection, autoimmune thyroiditis (Hashimoto'"'"'s disease), and cretinism;

disorders associated with hyperthyroidism including thyrotoxicosis and its various forms, Grave'"'"'s disease, pretibial myxedema, toxic multinodular goiter, thyroid carcinoma, and Plummer'"'"'s disease; and

disorders associated with hyperparathyroidism including Conn disease (chronic hypercalemia);

respiratory disorders including allergy, asthma, acute and chronic inflammatory lung diseases, ARDS, emphysema, pulmonary congestion and edema, COPD, interstitial lung diseases, and lung cancers;

cancer including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, cancers of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus; and

immunological disorders including acquired immunodeficiency syndrome (AIDS), Addison'"'"'s disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis, bronchitis, cholecystitis, contact dermatitis, Crohn'"'"'s disease, atopic dermatitis, dermatomyositis, diabetes mellitus, emphysema, episodic lymphopenia with lymphocytotoxins, erythroblastosis fetalis, erythema nodosum, atrophic gastritis, glomerulonephritis, Goodpasture'"'"'s syndrome, gout, Graves'"'"' disease, Hashimoto'"'"'s thyroiditis, hypereosinophilia, irritable bowel syndrome, multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, osteoarthritis, osteoporosis, pancreatitis, polymyositis, psoriasis, Reiter'"'"'s syndrome, rheumatoid arthritis, scleroderma, Sjogren'"'"'s syndrome, systemic anaphylaxis, systemic lupus erythematosus, systemic sclerosis, thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome, complications of cancer, hemodialysis, and extracorporeal circulation, viral, bacterial, fungal, parasitic, protozoal, and helminthic infections, and trauma.