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1. WO2020113079 - SYSTÈMES ET PROCÉDÉS PERMETTANT DE DÉDUIRE UN ÉTAT DE CELLULE

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

What is claimed:

1. A method of deconvolving a first clonal population comprising a first plurality of cells of a species, the method comprising:

at a computer system having one or more processors, and memory storing one or more programs for execution by the one or more processors:

(A) obtaining a set of nucleic acid sequence reads from each cell in the first plurality of cells of the first clonal population through a single cell sequencing process, thereby obtaining a first plurality of sets of nucleic acid sequence reads, wherein each respective set of nucleic acid sequence reads in the first plurality of sets of nucleic acid sequence reads is from a single cell in the first plurality of cells;

(B) mapping a nucleic acid sequence of each respective sequence read in each respective set of sequence reads onto a corresponding bin in a plurality of bins, wherein each respective bin in the plurality of bins represents a different portion of a reference genome of the species, thereby obtaining a nucleic acid sequence read count for each respective bin in the plurality of bins for each respective cell in the first plurality of cells;

(C) for each respective cell in the first plurality of cells, assigning the respective cell into one of a plurality of groups based upon a pattern of sequence read counts of the respective cell across the plurality of bins, wherein

a first group in the plurality of groups represents a first mitotic stage,

a second group in the plurality of groups represents a non-mitotic stage, and

the assigning (C) determines whether the respective cell is to be assigned to the first group by applying a first mitotic filter to the nucleic acid read count of respective bins in the plurality of bins obtained for the respective cell, thereby deconvolving the first clonal population.

2. The method of claim 1, wherein the single cell sequencing process is a single cell DNA sequencing process and each nucleic acid sequence read in each set in the plurality of sets of nucleic acid sequence reads is a DNA sequence.

3. The method of claim 1, wherein the single cell sequencing process is a single cell RNA sequencing process and each nucleic acid sequence read in each set in the plurality of sets of nucleic acid sequence reads is an RNA sequence.

4. The method of claim 1, wherein

the mapping (B) normalizes the nucleic acid sequence read counts for each respective bin in the plurality of bins for each respective cell in the first plurality of cells,

the first mitotic filter is a first predetermined pattern of read counts across a first subset of the plurality of bins that has been previously associated with the first mitotic stage, and

a respective cell in the first plurality of cells is assigned to the first group when the predetermined pattern of read counts across the first subset of the bins of the first mitotic filter is exhibited by the normalized nucleic acid sequence read counts for the respective cell across the first subset of the plurality of bins.

5. The method of claim 4, wherein

a third group in the plurality of groups represents a second mitotic stage,

the assigning (C) determines whether the respective cell is to be assigned to the third group by applying a second mitotic filter to the nucleic acid read count of respective bins in the plurality of bins obtained for the respective cell,

the second mitotic filter is a second predetermined pattern of read counts across a second subset of the plurality of bins that has been previously associated with the second mitotic stage, and

a respective cell in the first plurality of cells is assigned to the second group when the predetermined pattern of read counts across the subset of the bins of the second mitotic filter is exhibited by the normalized nucleic acid sequence read counts for the respective cell across the second subset of the plurality of bins.

6. The method of claim 1, wherein

the species is human,

each bin in the plurality of bins is the same size and the plurality of bins collectively encompass at least three percent of the entire human genome, and

the plurality of bins consists of between one hundred and two thousand bins.

7. The method of any one of claims 1-6, the method further comprising exposing the first plurality of cells to a perturbation prior to the obtaining step (A).

8. The method of claim 7, wherein the first plurality of cells are exposed to the perturbation for at least one hour prior to performing the obtaining step (A).

9. The method of claim 7, wherein the perturbation is a compound.

10. The method of claim 9, wherein the compound is an organic compound having a molecular weight of less than 2000 Daltons.

11. The method of claim 9, wherein the compound is an organic compound that satisfies the Lipinski rule of five criteria.

12. The method of claim 9, wherein the compound is an organic compound that satisfies at least three criteria of the Lipinski rule of five criteria.

13. The method of claim 9, wherein the compound is a checkpoint blockade immunotherapy.

14. The method of claim 13, wherein the checkpoint blockade immunotherapy is an anti-CTLA-4, anti-PDl, anti-PD-Ll, anti-LAG3, anti-TIM-3, anti-GITR, anti-OX40, anti-CD40, anti-TIGIT, anti4-lBB, anti-B7-H3, anti-B7-H4, or anti-BTLA compound.

15. The method of any one of claims 7-14, the method further comprising:

(D) obtaining a set of nucleic acid sequence reads from each cell in a second clonal population comprising a second plurality of cells of the species through a single cell sequencing process, thereby obtaining a second plurality of sets of nucleic acid sequence reads, wherein each respective set of nucleic acid sequence reads in the second plurality of sets of nucleic acid sequence reads is from a single cell in the second plurality of cells;

(E) mapping a nucleic acid sequence of each respective sequence read in each respective set of sequence reads in the second plurality of sets of nucleic acid sequence reads onto a corresponding bin in the plurality of bins;

(F) for each respective cell in the second plurality of cells, assigning the respective cell into one of the plurality of groups based upon a pattern of sequence read counts of the respective cell across the plurality of bins, wherein the assigning (F) determines whether the respective cell is to be assigned to the first group by applying the first mitotic filter to the nucleic acid read count of respective bins in the plurality of bins obtained for the respective cell; and

(G) comparing a relative assignment of cells in (i) the first plurality of cells and (ii) the second plurality of cells to individual groups in the first plurality of groups.

16. The method of any one of claims 1-15, wherein the first plurality of cells is

heterogeneous.

17. The method of any one of claims 1-16, wherein the first plurality of cells is from a tumor biopsy.

18. A computer system having one or more processors, and memory storing one or more programs for execution by the one or more processors, the one or more programs comprising instructions for performing the method of any one of claims 1-17.

19. A non-transitory computer readable storage medium, wherein the non-transitory computer readable storage medium stores instructions, which when executed by a computer system, cause the computer system to perform a method of any one of claims 1-17.

20. A method of evaluating a DNA repair inhibitor, the method comprising:

at a computer system having one or more processors, and memory storing one or more programs for execution by the one or more processors:

(A) obtaining a set of nucleic acid sequence reads from each cell in a first plurality of cells through a single cell sequencing process, wherein the first plurality of cells is from an organism of a species that has been exposed to the DNA repair inhibitor, thereby obtaining a first plurality of sets of nucleic acid sequence reads, wherein each respective set of nucleic acid sequence reads in the first plurality of sets of nucleic acid sequence reads is from a single cell in the first plurality of cells;

(B) mapping a nucleic acid sequence of each respective sequence read in each respective set of sequence reads onto a corresponding bin in a plurality of bins, wherein each respective bin in the plurality of bins represents a different portion of a reference genome of the species, thereby obtaining a nucleic acid sequence read count for each respective bin in the plurality of bins for each respective cell in the first plurality of cells;

(C) independently segregating each respective cell in the first plurality of cells into one of a plurality of cell classes based on a presence, absence, or amount of a marker or a marker set in the respective cell;

(D) for each respective cell class in the plurality of classes, evaluating an average sequence read count for a predetermined subset of the plurality of bins across the cells of the respective cell class in the first plurality of cells; and

(E) comparing an average sequence read count for the predetermined subset of the plurality of bins across the plurality of cell classes identified by the evaluating (D) thereby evaluating the DNA repair inhibitor.

21. The method of claim 20 wherein the single cell sequencing process is a single cell DNA sequencing process and each nucleic acid sequence read in each set in the first plurality of sets of nucleic acid sequence reads is a DNA sequence.

22. The method of claim 20 wherein the single cell sequencing process is a single cell RNA sequencing process and each nucleic acid sequence read in each set in the first plurality of sets of nucleic acid sequence reads is an RNA sequence.

23. The method of claim 20 wherein the marker or the marker set comprises a predetermined genetic mutation and the segregating (C) determines whether the respective cell includes the predetermined genetic mutation, wherein, when the respective cell includes the predetermined genetic mutation the respective cell is deemed to belong to a first class in the plurality of cell classes and when the respective cell does not include the predetermined genetic mutation, the respective cell is deemed to belong in a class in the plurality of cell classes other than the first class.

24. The method of claim 23 wherein the predetermined genetic mutation is a single nucleotide polymorphism, an insertion, a deletion, or an inversion.

25. The method of claim 20 wherein the marker or the marker set is a plurality of

predetermined genetic mutations and the segregating (C) determines whether the respective cell includes each predetermined genetic mutation in the plurality of predetermined genetic mutations, wherein, when the respective cell includes each predetermined genetic mutation in the plurality of predetermined genetic mutations, the respective cell is deemed to belong to a first class in the plurality of cell classes and when the respective cell does not include each predetermined genetic mutation in the plurality of predetermined genetic mutations the respective cell is deemed to belong in a class in the plurality of cell classes other than the first class.

26. The method of claim 25 wherein each predetermined genetic mutation in the plurality of predetermined genetic mutations is a single nucleotide polymorphism, an insertion, a deletion, or an inversion.

27. The method of claim 20, wherein the marker is a threshold number of genetic mutations mapping to one or more predetermined portions of the reference genome and the segregating (C) determines whether the respective cell includes the threshold number of genetic mutations, wherein, when the respective cell includes the threshold number of genetic mutations, the respective cell is deemed to belong to a first class in the plurality of cell classes and when the respective cell does not include the threshold number of genetic mutations, the respective cell is deemed to belong in a class in the plurality of cell classes other than the first class.

28. The method of claim 27 wherein the threshold number is determined by evaluating an average number and standard deviation of the average number of mutations in the one or more predetermined portions of the reference genome across a population of cells of the species that have not been exposed to the DNA repair inhibitor.

29. The method of claim 27 wherein the threshold number is determined by evaluating an average number and standard deviation of the average number of mutations in the one or more predetermined portions of the reference genome across the first plurality of cells.

30. The method of claim 27 wherein each genetic mutation mapping to the one or more predetermined portions of the reference genome is a single nucleotide polymorphism, an insertion, a deletion, or an inversion in the one or more predetermined portions of the reference genome.

31. The method of claim 27 wherein the one or more predetermined portions of the reference genome consists of the X-Ray Repair Cross Complementing 2 (XRCC2) gene, the X-Ray Repair Cross Complementing 3 (XRCC3) gene, the RAD54 gene, the H2AX gene, the phosphatase and tensin homolog gene, and/or the ATM gene.

32. The method of claim 20 wherein

the species is human,

each bin in the plurality of bins is the same size and the plurality of bins collectively encompass at least three percent of the entire human genome, and

the plurality of bins consists of between one hundred and two thousand bins.

33. The method of claim 20, wherein the organism is exposed to the DNA repair inhibitor for at least one hour prior to performing the obtaining step (A).

34. The method of claim 20, wherein the DNA repair inhibitor is a compound.

35. The method of claim 34, wherein the compound is an organic compound having a molecular weight of less than 2000 Daltons.

36. The method of claim 34, wherein the compound is an organic compound that satisfies the Lipinski rule of five criteria.

37. The method of claim 34, wherein the compound is an organic compound that satisfies at least three criteria of the Lipinski rule of five criteria.

38. The method of claim 34, wherein the compound is a poly ADP ribose polymerase (PARP) inhibitor.

39. The method of any one of claims 20-38, the method further comprising:

(F) obtaining a set of nucleic acid sequence reads from each cell in a second plurality of cells of the species through a single cell sequencing process, thereby obtaining a second plurality of sets of nucleic acid sequence reads, wherein each respective set of nucleic acid sequence reads in the second plurality of sets of nucleic acid sequence reads is from a single cell in the second plurality of cells;

(G) mapping a nucleic acid sequence of each respective sequence read in each respective set of sequence reads in the second plurality of sets of nucleic acid sequence reads onto a corresponding bin in the plurality of bins;

(H) for each respective cell in the second plurality of cells, independently segregating the respective cell into one of the plurality of cell classes based on the presence, absence, or amount of the marker or the marker set in the respective cell;

(I) for each respective cell class in the plurality of classes, evaluating an average sequence read count for a predetermined subset of the plurality of bins across the cells of the respective cell class in the second plurality of cells; and

(J) comparing, for each respective cell class in the plurality of cell classes, an average sequence read count for the respective cell class for the predetermined subset of the plurality of bins obtained from the first plurality of cells versus the second plurality of cells.

40. The method of any one of claims 20-39, wherein the first plurality of cells is

heterogeneous.

41. The method of any one of claims 20-40, wherein the first plurality of cells is from a tumor biopsy.

42. A computer system having one or more processors, and memory storing one or more programs for execution by the one or more processors, the one or more programs comprising instructions for performing the method of any one of claims 20-41.

43. A non-transitory computer readable storage medium, wherein the non-transitory computer readable storage medium stores instructions, which when executed by a computer system, cause the computer system to perform a method of any one of claims 20-41.

44. A method of deconvolving a heterogeneous population of cells comprising a first plurality of cells, the method comprising:

at a computer system having one or more processors, and memory storing one or more programs for execution by the one or more processors:

(A) obtaining a set of nucleic acid sequence reads from each cell in the first plurality of cells through a single cell sequencing process, thereby obtaining a first plurality of sets of nucleic acid sequence reads, wherein each respective set of nucleic acid sequence reads in the first plurality of sets of nucleic acid sequence reads is from a single cell in the first plurality of cells;

(B) mapping a nucleic acid sequence of each respective sequence read in each respective set of sequence reads onto a corresponding bin in a plurality of bins, wherein each respective bin in the plurality of bins represents a different portion of a reference genome of the species, thereby obtaining a nucleic acid sequence read count for each respective bin in the plurality of bins for each respective cell in the first plurality of cells;

(C) independently segregating each respective cell in the first plurality of cells into one of a plurality of cell classes based on a presence, absence, or amount of a marker or a marker set in the respective cell;

(D) for each respective cell in each respective cell class in the plurality of cell classes, assigning the respective cell into one of a plurality of groups based upon a pattern of sequence read counts of the respective cell across the plurality of bins, wherein

a first group in the plurality of groups represents a first mitotic stage,

a second group in the plurality of groups represents a non-mitotic stage, and

the assigning (D) determines whether the respective cell is to be assigned to the first group by applying a first mitotic filter to the nucleic acid read count of respective bins in the plurality of bins obtained for the respective cell; and

(E) comparing a proportion of cells in each cell class in the plurality of cell classes that are in the first mitotic stage.

45. The method of claim 44 wherein the single cell sequencing process is a single cell DNA sequencing process and each nucleic acid sequence read in each set in the first plurality of sets of nucleic acid sequence reads is a DNA sequence.

46. The method of claim 44 wherein the single cell sequencing process is a single cell RNA sequencing process and each nucleic acid sequence read in each set in the first plurality of sets of nucleic acid sequence reads is an RNA sequence.

47. The method of claim 44 wherein the marker or the marker set comprises a predetermined genetic mutation and the segregating (C) determines whether the respective cell includes the predetermined genetic mutation, wherein, when the respective cell includes the predetermined genetic mutation the respective cell is deemed to belong to a first class in the plurality of cell classes and when the respective cell does not include the predetermined genetic mutation, the respective cell is deemed to belong in a class in the plurality of cell classes other than the first class.

48. The method of claim 47 wherein the predetermined genetic mutation is a single nucleotide polymorphism, an insertion, a deletion, or an inversion.

49. The method of claim 44 wherein the marker or marker set is a plurality of predetermined genetic mutations and the segregating (C) determines whether the respective cell includes each predetermined genetic mutation in the plurality of predetermined genetic mutations, wherein, when the respective cell includes each predetermined genetic mutation in the plurality of predetermined genetic mutations, the respective cell is deemed to belong to a first class in the plurality of cell classes and when the respective cell does not include each predetermined genetic mutation in the plurality of predetermined genetic mutations the respective cell is deemed to belong in a class in the plurality of cell classes other than the first class.

50. The method of claim 49 wherein each predetermined genetic mutation in the plurality of predetermined genetic mutations is a single nucleotide polymorphism, an insertion, a deletion, or an inversion.

51. The method of claim 49 wherein the marker is a threshold number of genetic mutations mapping to one or more predetermined portions of the reference genome and the segregating (C) determines whether the respective cell includes the threshold number of genetic mutations, wherein, when the respective cell includes the threshold number of genetic mutations, the respective cell is deemed to belong to a first class in the plurality of cell classes and when the respective cell does not include the threshold number of genetic mutations, the respective cell is deemed to belong in a class in the plurality of cell classes other than the first class.

52. The method of claim 51 wherein the threshold number is determined by evaluating an average number and standard deviation of the average number of mutations in the one or more predetermined portions of the reference genome across the first plurality of cells.

53. The method of claim 51 wherein each genetic mutation mapping to the one or more predetermined portions of the reference genome is a single nucleotide polymorphism, an insertion, a deletion, or an inversion in the one or more predetermined portions of the reference genome.

54. The method of claim 51 wherein each genetic mutation mapping to the one or more predetermined portions of the reference genome is a single nucleotide polymorphism, an insertion, a deletion, or an inversion in the one or more predetermined portions of the reference genome.

55. The method of claim 51 wherein the one or more predetermined portions of the reference genome consists of the X-Ray Repair Cross Complementing 2 (XRCC2) gene, the X-Ray Repair Cross Complementing 3 (XRCC3) gene, the RAD54 gene, the H2AX gene, the phosphatase and tensin homolog gene, and/or the ATM gene.

56. The method of claim 44 wherein

the species is human,

each bin in the plurality of bins is the same size and the plurality of bins collectively encompass at least three percent of the entire human genome, and

the plurality of bins consists of between one hundred and two thousand bins.

57. The method of any one of claims 44-56, the method further comprising:

(F) obtaining a set of nucleic acid sequence reads from each cell in a second plurality of cells of the species through a single cell sequencing process, thereby obtaining a second plurality of sets of nucleic acid sequence reads, wherein each respective set of nucleic acid sequence reads in the second plurality of sets of nucleic acid sequence reads is from a single cell in the second plurality of cells and the second plurality of cells has been exposed to a compound;

(G) mapping a nucleic acid sequence of each respective sequence read in each respective set of sequence reads in the second plurality of sets of nucleic acid sequence reads onto a corresponding bin in the plurality of bins;

(H) for each respective cell in the second plurality of cells, independently segregating the respective cell into one of the plurality of cell classes based on the presence, absence, or amount of the marker or the marker set in the respective cell;

(I) for each respective cell in each respective cell class in the plurality of cell classes for the second plurality of cells, assigning the respective cell into one of the plurality of groups based upon a pattern of sequence read counts of the respective cell across the plurality of bins by applying the first mitotic filter to the nucleic acid read count of respective bins in the plurality of bins obtained for the respective cell; and

(J) comparing a proportion of cells in each cell class in the plurality of cell classes that are in the first mitotic stage between the first plurality of cells and the second plurality of cells.

58. The method of claim 57, wherein the second plurality of cells is exposed to the compound for at least one hour prior to performing the obtaining (F).

59. The method of claim 57, wherein the compound is DNA repair inhibitor.

60. The method of claim 57, wherein the compound is an organic compound having a molecular weight of less than 2000 Daltons.

61. The method of claim 57, wherein the compound is an organic compound that satisfies the Lipinski rule of five criteria.

62. The method of claim 57, wherein the compound is an organic compound that satisfies at least three criteria of the Lipinski rule of five criteria.

63. The method of claim 57, wherein the compound is a poly ADP ribose polymerase (PARP) inhibitor.

64. The method of any one of claims 44-63, wherein the first plurality of cells is

heterogeneous.

65. The method of any one of claims 44-63, wherein the first plurality of cells is from a tumor biopsy.

66. A computer system having one or more processors, and memory storing one or more programs for execution by the one or more processors, the one or more programs comprising instructions for performing the method of any one of claims 44-65.

67. A non-transitory computer readable storage medium, wherein the non-transitory computer readable storage medium stores instructions, which when executed by a computer system, cause the computer system to perform a method of any one of claims 44-65.

68. A method for treating a cancer state in a subject in need thereof, the method comprising: deconvolving a mitotic profile for a first clonal population comprising a first plurality of cells from a first tumor biopsy from the subject by:

(A) obtaining a set of nucleic acid sequence reads from each cell in the first plurality of cells of the first clonal population through a single cell sequencing process, thereby obtaining a first plurality of sets of nucleic acid sequence reads, wherein each respective set of nucleic acid sequence reads in the first plurality of sets of nucleic acid sequence reads is from a single cell in the first plurality of cells;

(B) mapping a nucleic acid sequence of each respective sequence read in each respective set of sequence reads onto a corresponding bin in a plurality of bins, wherein each respective bin in the plurality of bins represents a different portion of a reference genome of the species, thereby obtaining a nucleic acid sequence read count for each respective bin in the plurality of bins for each respective cell in the first plurality of cells;

(C) for each respective cell in the first plurality of cells, assigning the respective cell into one of a plurality of groups based upon a pattern of sequence read counts of the respective cell across the plurality of bins, wherein

a first group in the plurality of groups represents a first mitotic stage, a second group in the plurality of groups represents a non-mitotic stage, and

the assigning (C) determines whether the respective cell is to be assigned to the first group by applying a first mitotic filter to the nucleic acid read count of respective bins in the plurality of bins obtained for the respective cell, thereby deconvolving the mitotic profile for the first clonal population; and

(D) determining whether the deconvolved mitotic profile for the first clonal population resembles a mitotic profile associated with a first cancer state or a mitotic state associated with a second cancer state, and

when the deconvolved mitotic profile for the first clonal population resembles a mitotic profile associated with a first cancer state, administering a therapy for treatment of the first cancer state to the subject, and

when the deconvolved mitotic profile for the first clonal population resembles a mitotic profile associated with a second cancer state, administering a second therapy for treatment of the second cancer state to the subject.

69. The method of claim 68, wherein:

the first cancer state is a malignant state for the tumor,

the first therapy for treatment of the first cancer state is a chemotherapeutic agent, the second cancer state is a benign state for the tumor, and

the second therapy for treatment of the second cancer state is a therapy other than a chemotherapeutic agent.

70. The method of claim 68, wherein:

the first cancer state is a first type of cancer, and

the second cancer state is a second type of cancer.

71. The method of claim 68, wherein:

the first cancer state is a first prognosis for cancer in the subject, and

the second cancer state is a second prognosis for cancer in the subject.

72. The method of any one of claims 68-71, wherein the single cell sequencing process is a single cell DNA sequencing process and each nucleic acid sequence read in each set in the plurality of sets of nucleic acid sequence reads is a DNA sequence.

73. The method of any one of claims 68-71, wherein the single cell sequencing process is a single cell RNA sequencing process and each nucleic acid sequence read in each set in the plurality of sets of nucleic acid sequence reads is an RNA sequence.

74. The method of any one of claims 68-71, wherein

the mapping (B) normalizes the nucleic acid sequence read counts for each respective bin in the plurality of bins for each respective cell in the first plurality of cells,

the first mitotic filter is a first predetermined pattern of read counts across a first subset of the plurality of bins that has been previously associated with the first mitotic stage, and

a respective cell in the first plurality of cells is assigned to the first group when the predetermined pattern of read counts across the first subset of the bins of the first mitotic filter is exhibited by the normalized nucleic acid sequence read counts for the respective cell across the first subset of the plurality of bins.

75. The method of claim 74, wherein

a third group in the plurality of groups represents a second mitotic stage,

the assigning (C) determines whether the respective cell is to be assigned to the third group by applying a second mitotic filter to the nucleic acid read count of respective bins in the plurality of bins obtained for the respective cell,

the second mitotic filter is a second predetermined pattern of read counts across a second subset of the plurality of bins that has been previously associated with the second mitotic stage, and

a respective cell in the first plurality of cells is assigned to the second group when the predetermined pattern of read counts across the subset of the bins of the second mitotic filter is exhibited by the normalized nucleic acid sequence read counts for the respective cell across the second subset of the plurality of bins.

76. The method of any one of claims 68-75, wherein

the species is human,

each bin in the plurality of bins is the same size and the plurality of bins collectively encompass at least three percent of the entire human genome, and

the plurality of bins consists of between one hundred and two thousand bins.

77. The method of any one of claims 68-76, the method further comprising exposing the first plurality of cells to a perturbation prior to the obtaining step (A).

78. The method of claim 77, wherein the first plurality of cells are exposed to the

perturbation for at least one hour prior to performing the obtaining step (A).

79. The method of claim 77, wherein the perturbation is a compound.

80. The method of claim 79, wherein the compound is an organic compound having a molecular weight of less than 2000 Daltons.

81. The method of claim 79, wherein the compound is an organic compound that satisfies the Lipinski rule of five criteria.

82. The method of claim 79, wherein the compound is an organic compound that satisfies at least three criteria of the Lipinski rule of five criteria.

83. The method of claim 79, wherein the compound is a checkpoint blockade

immunotherapy.

84. The method of claim 83, wherein the checkpoint blockade immunotherapy is an anti-CTLA-4, anti-PDl, anti-PD-Ll, anti-LAG3, anti-TIM-3, anti-GITR, anti-OX40, anti-CD40, anti-TIGIT, anti4-lBB, anti-B7-H3, anti-B7-H4, or anti-BTLA compound.

85. The method of any one of claims 77-84, the method further comprising:

(D) obtaining a set of nucleic acid sequence reads from each cell in a second clonal population comprising a second plurality of cells of the species through a single cell sequencing process, thereby obtaining a second plurality of sets of nucleic acid sequence reads, wherein each respective set of nucleic acid sequence reads in the second plurality of sets of nucleic acid sequence reads is from a single cell in the second plurality of cells;

(E) mapping a nucleic acid sequence of each respective sequence read in each respective set of sequence reads in the second plurality of sets of nucleic acid sequence reads onto a corresponding bin in the plurality of bins;

(F) for each respective cell in the second plurality of cells, assigning the respective cell into one of the plurality of groups based upon a pattern of sequence read counts of the respective cell across the plurality of bins, wherein the assigning (F) determines whether the respective cell is to be assigned to the first group by applying the first mitotic filter to the nucleic acid read count of respective bins in the plurality of bins obtained for the respective cell; and

(G) comparing a relative assignment of cells in (i) the first plurality of cells and (ii) the second plurality of cells to individual groups in the first plurality of groups.

86. The method of any one of claims 68-85, wherein the first plurality of cells is

heterogeneous.

87. The method of any one of claims 68-86, wherein the second plurality of cells is from a second tumor biopsy.

88. A computer system having one or more processors, and memory storing one or more programs for execution by the one or more processors, the one or more programs comprising instructions for performing the method of any one of claims 68-87.

89. A non-transitory computer readable storage medium, wherein the non-transitory computer readable storage medium stores instructions, which when executed by a computer system, cause the computer system to perform a method of any one of claims 68-87.

90. A method for treating cancer in a subject in need thereof, the method comprising:

deconvolving a mitotic profile for a first clonal population comprising a first plurality of cells from a first tumor biopsy from the subject by:

(A) obtaining a set of nucleic acid sequence reads from each cell in the first plurality of cells of the first clonal population through a single cell sequencing process, thereby obtaining a first plurality of sets of nucleic acid sequence reads, wherein each respective set of nucleic acid sequence reads in the first plurality of sets of nucleic acid sequence reads is from a single cell in the first plurality of cells;

(B) mapping a nucleic acid sequence of each respective sequence read in each respective set of sequence reads onto a corresponding bin in a plurality of bins, wherein each respective bin in the plurality of bins represents a different portion of a reference genome of the species, thereby obtaining a nucleic acid sequence read count for each respective bin in the plurality of bins for each respective cell in the first plurality of cells;

(C) for each respective cell in the first plurality of cells, assigning the respective cell into one of a plurality of groups based upon a pattern of sequence read counts of the respective cell across the plurality of bins, wherein

a first group in the plurality of groups represents a first mitotic stage, a second group in the plurality of groups represents a non-mitotic stage, and

the assigning (C) determines whether the respective cell is to be assigned to the first group by applying a first mitotic filter to the nucleic acid read count of respective bins in the plurality of bins obtained for the respective cell, thereby deconvolving the mitotic profile for the first clonal population; and

(D) determining whether the deconvolved mitotic profile for the first clonal population resembles a mitotic profile for a population of cancerous cells that are sensitive to a first type of therapy, and

when the deconvolved mitotic profile for the first clonal population resembles a mitotic profile for a population of cancerous cells that are sensitive to a first type of therapy,

administering the first type of therapy to the subject, and

when the deconvolved mitotic profile for the first clonal population does not resemble a mitotic profile for a population of cancerous cells that are sensitive to a first type of therapy, administering a second type of therapy to the subject.

91. The method of claim 90, wherein:

the first type of therapy is a DNA repair inhibitor chemotherapeutic agent;

the second type of therapy is a chemotherapeutic agent other than a DNA repair inhibitor; and

the mitotic profile for a population of cancerous cells that are sensitive to the first type of therapy indicates a homologous recombination repair deficiency.

92. The method of claim 91, wherein the DNA repair inhibitor chemotherapeutic inhibitor is a PARP inhibitor.

93. The method of any one of claims 90-92, wherein the single cell sequencing process is a single cell DNA sequencing process and each nucleic acid sequence read in each set in the plurality of sets of nucleic acid sequence reads is a DNA sequence.

94. The method of any one of claims 90-92, wherein the single cell sequencing process is a single cell RNA sequencing process and each nucleic acid sequence read in each set in the plurality of sets of nucleic acid sequence reads is an RNA sequence.

95. The method of any one of claims 90-92, wherein

the mapping (B) normalizes the nucleic acid sequence read counts for each respective bin in the plurality of bins for each respective cell in the first plurality of cells,

the first mitotic filter is a first predetermined pattern of read counts across a first subset of the plurality of bins that has been previously associated with the first mitotic stage, and

a respective cell in the first plurality of cells is assigned to the first group when the predetermined pattern of read counts across the first subset of the bins of the first mitotic filter is exhibited by the normalized nucleic acid sequence read counts for the respective cell across the first subset of the plurality of bins.

96. The method of claim 95, wherein

a third group in the plurality of groups represents a second mitotic stage,

the assigning (C) determines whether the respective cell is to be assigned to the third group by applying a second mitotic filter to the nucleic acid read count of respective bins in the plurality of bins obtained for the respective cell,

the second mitotic filter is a second predetermined pattern of read counts across a second subset of the plurality of bins that has been previously associated with the second mitotic stage, and

a respective cell in the first plurality of cells is assigned to the second group when the predetermined pattern of read counts across the subset of the bins of the second mitotic filter is exhibited by the normalized nucleic acid sequence read counts for the respective cell across the second subset of the plurality of bins.

97. The method of any one of claims 90-92, wherein

the species is human,

each bin in the plurality of bins is the same size and the plurality of bins collectively encompass at least three percent of the entire human genome, and

the plurality of bins consists of between one hundred and two thousand bins.

98. The method of any one of claims 90-97, the method further comprising exposing the first plurality of cells to a perturbation prior to the obtaining step (A).

99. The method of claim 98, wherein the first plurality of cells are exposed to the

perturbation for at least one hour prior to performing the obtaining step (A).

100. The method of claim 97, wherein the perturbation is a compound.

101. The method of claim 100, wherein the compound is an organic compound having a molecular weight of less than 2000 Daltons.

102. The method of claim 100, wherein the compound is an organic compound that satisfies the Lipinski rule of five criteria.

103. The method of claim 100, wherein the compound is an organic compound that satisfies at least three criteria of the Lipinski rule of five criteria.

104. The method of claim 100, wherein the compound is a checkpoint blockade

immunotherapy.

105. The method of claim 104, wherein the checkpoint blockade immunotherapy is an anti-CTLA-4, anti-PDl, anti-PD-Ll, anti-LAG3, anti-TIM-3, anti-GITR, anti-OX40, anti-CD40, anti-TIGIT, anti4-lBB, anti-B7-H3, anti-B7-H4, or anti-BTLA compound.

106. The method of any one of claims 90-105, wherein the first plurality of cells is

heterogeneous.

107. The method of any one of claims 90-106, the method further comprising:

(D) obtaining a set of nucleic acid sequence reads from each cell in a second clonal population comprising a second plurality of cells of the species through a single cell sequencing process, thereby obtaining a second plurality of sets of nucleic acid sequence reads, wherein each respective set of nucleic acid sequence reads in the second plurality of sets of nucleic acid sequence reads is from a single cell in the second plurality of cells;

(E) mapping a nucleic acid sequence of each respective sequence read in each respective set of sequence reads in the second plurality of sets of nucleic acid sequence reads onto a corresponding bin in the plurality of bins;

(F) for each respective cell in the second plurality of cells, assigning the respective cell into one of the plurality of groups based upon a pattern of sequence read counts of the respective cell across the plurality of bins, wherein the assigning (F) determines whether the respective cell is to be assigned to the first group by applying the first mitotic filter to the nucleic acid read count of respective bins in the plurality of bins obtained for the respective cell; and

(G) comparing a relative assignment of cells in (i) the first plurality of cells and (ii) the second plurality of cells to individual groups in the first plurality of groups.

108. The method of claim 107, wherein the second plurality of cells is from a second tumor biopsy.

109. A computer system having one or more processors, and memory storing one or more programs for execution by the one or more processors, the one or more programs comprising instructions for performing the method of any one of claims 90-108.

110. A non-transitory computer readable storage medium, wherein the non-transitory computer readable storage medium stores instructions, which when executed by a computer system, cause the computer system to perform a method of any one of claims 90-108.

111. A method for treating cancer in a subject in need thereof, the method comprising:

deconvolving a mitotic profile for a first clonal population comprising a first plurality of cells from a first tumor biopsy from a subject being treated for cancer with a first type of therapy, by:

(A) obtaining a set of nucleic acid sequence reads from each cell in the first plurality of cells of the first clonal population through a single cell sequencing process, thereby obtaining a first plurality of sets of nucleic acid sequence reads, wherein each respective set of nucleic acid sequence reads in the first plurality of sets of nucleic acid sequence reads is from a single cell in the first plurality of cells;

(B) mapping a nucleic acid sequence of each respective sequence read in each respective set of sequence reads onto a corresponding bin in a plurality of bins, wherein each respective bin in the plurality of bins represents a different portion of a reference genome of the species, thereby obtaining a nucleic acid sequence read count for each respective bin in the plurality of bins for each respective cell in the first plurality of cells;

(C) for each respective cell in the first plurality of cells, assigning the respective cell into one of a plurality of groups based upon a pattern of sequence read counts of the respective cell across the plurality of bins, wherein

a first group in the plurality of groups represents a first mitotic stage, a second group in the plurality of groups represents a non-mitotic stage, and

the assigning (C) determines whether the respective cell is to be assigned to the first group by applying a first mitotic filter to the nucleic acid read count of respective bins in the plurality of bins obtained for the respective cell, thereby deconvolving the mitotic profile for the first clonal population; and

(D) comparing the deconvolved mitotic profile for the first clonal population to a deconvolved mitotic profile for a second clonal population comprising a second plurality of cells from a second tumor biopsy obtained from the subject prior to being treated for cancer with the first type of therapy, and

when a change in the deconvolved mitotic profile for the first clonal population, relative to the deconvolved mitotic profile for the second clonal population, indicates that the first type of therapy is not producing at least a threshold level of efficacy, administering a second type of therapy to the subject, and

when a change in the deconvolved mitotic profile for the first clonal population, relative to the deconvolved mitotic profile for the second clonal population, indicates that the first type of therapy is producing at least a threshold level of efficacy, continue administering the first type of therapy to the subject.

112. The method of claim 111, wherein, when:

the first type of therapy is a DNA repair inhibitor chemotherapeutic agent;

the second type of therapy is a chemotherapeutic agent other than a DNA repair inhibitor; and

a change in the deconvolved mitotic profile for the first clonal population, relative to the deconvolved mitotic profile for the second clonal population, indicates that the first type of therapy is not producing at least a threshold level of efficacy, changing the therapy for the subject from the first type of therapy to the second type of therapy.

113. The method of claim 112, wherein the DNA repair inhibitor chemotherapeutic inhibitor is a PARP inhibitor.

114. The method of any one of claims 111-113, wherein the single cell sequencing process is a single cell DNA sequencing process and each nucleic acid sequence read in each set in the plurality of sets of nucleic acid sequence reads is a DNA sequence.

115. The method of any one of claims 111-113, wherein the single cell sequencing process is a single cell RNA sequencing process and each nucleic acid sequence read in each set in the plurality of sets of nucleic acid sequence reads is an RNA sequence.

116. The method of any one of claims 111-113, wherein

the mapping (B) normalizes the nucleic acid sequence read counts for each respective bin in the plurality of bins for each respective cell in the first plurality of cells,

the first mitotic filter is a first predetermined pattern of read counts across a first subset of the plurality of bins that has been previously associated with the first mitotic stage, and

a respective cell in the first plurality of cells is assigned to the first group when the predetermined pattern of read counts across the first subset of the bins of the first mitotic filter is exhibited by the normalized nucleic acid sequence read counts for the respective cell across the first subset of the plurality of bins.

117. The method of claim 116, wherein

a third group in the plurality of groups represents a second mitotic stage,

the assigning (C) determines whether the respective cell is to be assigned to the third group by applying a second mitotic filter to the nucleic acid read count of respective bins in the plurality of bins obtained for the respective cell,

the second mitotic filter is a second predetermined pattern of read counts across a second subset of the plurality of bins that has been previously associated with the second mitotic stage, and

a respective cell in the first plurality of cells is assigned to the second group when the predetermined pattern of read counts across the subset of the bins of the second mitotic filter is exhibited by the normalized nucleic acid sequence read counts for the respective cell across the second subset of the plurality of bins.

118. The method of any one of claims 111-113, wherein

the species is human,

each bin in the plurality of bins is the same size and the plurality of bins collectively encompass at least three percent of the entire human genome, and

the plurality of bins consists of between one hundred and two thousand bins.

119. The method of any one of claims 111-118, the method further comprising exposing the first plurality of cells to a perturbation prior to the obtaining step (A).

120. The method of claim 119, wherein the first plurality of cells are exposed to the perturbation for at least one hour prior to performing the obtaining step (A).

121. The method of claim 119 or 120, wherein the perturbation is a compound.

122. The method of claim 121, wherein the compound is an organic compound having a molecular weight of less than 2000 Daltons.

123. The method of claim 121, wherein the compound is an organic compound that satisfies the Lipinski rule of five criteria.

124. The method of claim 121, wherein the compound is an organic compound that satisfies at least three criteria of the Lipinski rule of five criteria.

125. The method of claim 121, wherein the compound is a checkpoint blockade

immunotherapy.

126. The method of claim 125, wherein the checkpoint blockade immunotherapy is an anti-CTLA-4, anti-PDl, anti-PD-Ll, anti-LAG3, anti-TIM-3, anti-GITR, anti-OX40, anti-CD40, anti-TIGIT, anti4-lBB, anti-B7-H3, anti-B7-H4, or anti-BTLA compound.

127. The method of any one of claims 111-126, wherein the first plurality of cells is heterogeneous.

128. The method of any one of claims 111-127, the method further comprising:

(D) obtaining a set of nucleic acid sequence reads from each cell in a second clonal population comprising a second plurality of cells of the species through a single cell sequencing process, thereby obtaining a second plurality of sets of nucleic acid sequence reads, wherein each respective set of nucleic acid sequence reads in the second plurality of sets of nucleic acid sequence reads is from a single cell in the second plurality of cells;

(E) mapping a nucleic acid sequence of each respective sequence read in each respective set of sequence reads in the second plurality of sets of nucleic acid sequence reads onto a corresponding bin in the plurality of bins;

(F) for each respective cell in the second plurality of cells, assigning the respective cell into one of the plurality of groups based upon a pattern of sequence read counts of the respective cell across the plurality of bins, wherein the assigning (F) determines whether the respective cell is to be assigned to the first group by applying the first mitotic filter to the nucleic acid read count of respective bins in the plurality of bins obtained for the respective cell; and

(G) comparing a relative assignment of cells in (i) the first plurality of cells and (ii) the second plurality of cells to individual groups in the first plurality of groups.

129. The method of claim 128, wherein the second plurality of cells is from a second tumor biopsy.

130. A computer system having one or more processors, and memory storing one or more programs for execution by the one or more processors, the one or more programs comprising instructions for performing the method of any one of claims 111-129.

131. A non-transitory computer readable storage medium, wherein the non-transitory computer readable storage medium stores instructions, which when executed by a computer system, cause the computer system to perform a method of any one of claims 111-129.