Methods and compositions for determining gene function

• US 20040048264A1
• Filed: 09/24/2003
• Published: 03/11/2004
• Est. Priority Date: 07/05/2000
• Status: Active Grant

• Current Assignee: Microsoft Technology Licensing LLC (Microsoft Corporation)
• Original Assignee: Microsoft Corporation
• Inventors: Stoughton, Roland, Hughes, Timothy R.
• Granted Patent: US 7,657,379 B2
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: C12Q 1/6809 Methods for determination or identification of nucleic acids involving differential detection
• CPC Class Codes: C12Q 1/6837 using probe arrays or probe chips C12Q1/6874 takes precedence
• CPC Class Codes: C12Q 2521/107 RNA dependent DNA polymerase,(i.e. reverse transcriptase)
• CPC Class Codes: C12Q 2539/113 Differential Display Analysis [DDA]
• CPC Class Codes: C12Q 2545/114 involving a quantitation step
• CPC Class Codes: C40B 30/04 by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 33/5005 involving human or animal cells immunoassay G01N33/56966; immunoassays of protozoa G01N33/56905; protozoa in screening assays C12Q1/025
• CPC Class Codes: G16B 20/00 ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/50 Mutagenesis
• CPC Class Codes: G16B 25/00 ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression
• CPC Class Codes: G16B 25/10 Gene or protein expression profiling; Expression-ratio estimation or normalisation
• CPC Class Codes: G16B 40/00 ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
• CPC Class Codes: G16B 40/30 Unsupervised data analysis

Abstract

The invention relates to methods and systems (e.g., computer systems and computer program products) for characterizing cellular constituents, particularly genes and gene products. In particular, the invention provides methods for assigning or determining the biological function of uncharacterized genes and gene products by using “response profiles,” i.e., measurements of pluralities of cellular constituents in cells having a modified gene or gene product, as phenotypic markers for the gene or gene product. Methods are provided for clustering such response profiles so that similar or correlated response profiles are organized into the same cluster. The invention also provides databases or “compendiums” of response profiles to which the response profile of an uncharacterized gene or gene product can compared.

Claims

1. A method for characterizing a cellular constituent as being associated or not being associated with a biological function, said method comprises identifying one or more response profiles associated with a known biological function as either correlating or not correlating with a response profile for the cellular constituent being characterized, wherein:

(a) each of said one or more response profiles associated with said known biological function comprises changes of a plurality of cellular constituents in a biological sample in which a particular cellular constituent, other than the cellular constituent being characterized, that is associated with said known biological function is perturbed,

(b) said response profile for the cellular constituent being characterized comprises changes of measured amounts of a plurality cellular constituents in a biological sample in which the cellular constituent being characterized is perturbed, and

(c) either the cellular constituent being characterized is characterized as being associated with said known biological function if said response profile for said cellular constituent being characterized correlates with said response profile associated with said known biological function, or the cellular constituent being characterized is characterized as not being associated with said known biological function if said response profile for said cellular constituent being characterized does not correlate with said response profile associated with said known biological function.

2. The method of claim 1 wherein the cellular constituent being characterized is a gene or gene product.

3. The method of claim 2 wherein the perturbation to the cellular constituent being characterized comprises a mutation of said gene.

4. The method of claim 2 wherein the perturbation to the cellular constituent being characterized comprises modifying abundances of mRNA transcripts of said gene.

5. The method of claim 4 wherein abundances of mRNA transcripts are modified by antisense nucleic acids.

6. The method of claim 4 wherein abundances of mRNA transcripts are modified by ribozymes.

7. The method of claim 2 wherein the perturbation to the cellular constituent being characterized comprises modifying abundances or activities of said gene product.

8. The method of claim 7 wherein abundances or activities of said gene product are modified by antibodies.

9. The method of claim 1 wherein a particular cellular constituent associated with a known biological function is a gene or gene product associated with said known biological function.

10. The method of claim 9 wherein the perturbation to said gene or gene product associated with said known biological function comprises a mutation of said gene associated with said known biological function.

11. The method of claim 9 wherein the perturbation to said gene or gene product associated with said known biological function comprises modifying abundances of mRNA transcripts of said gene associated with said known biological function.

12. The method of claim 11 wherein abundances of mRNA transcripts are modified by antisense nucleic acids.

13. The method of claim 11 wherein abundances of mRNA transcripts are modified by ribozymes.

14. The method of claim 9 wherein the perturbation to the gene or gene product associated with said known biological function comprises modifying abundances or activities of said gene product associated with said known biological function.

15. The method of claim 14 wherein abundances or activities of said gene product associated with said known biological function are modified by antibodies.

16. The method of claim 1 wherein said changes of measured amounts of a plurality of cellular constituents in a biological sample comprise changes in abundances of mRNA species in said biological sample.

17. The method of claim 16 wherein abundances of mRNA species in said biological sample are provided by a method comprising:

(a) reverse transcribing mRNA species extracted from cells to form cDNA species; and

(b) measuring abundances of said cDNA species.

18. The method of claim 16 wherein abundances of mRNA species in said biological sample are provided by a method comprising:

(a) reverse transcribing mRNA species extracted from cells to form cDNA species;

(b) transcribing said cDNA species to form cRNA species; and

(c) measuring abundances of said cRNA species.

19. The method of claim 16 wherein abundances of mRNA species in said biological sample are provided by a method which comprises measuring abundances of polynucleotide species on a microarray, said microarray comprising

(a) a surface, and

(b) binding sites for a plurality of polynucleotide species attached to said surface wherein said binding sites are attached to said surface such that the identity of a binding site can be determined from its position on the surface.

20. The method of claim 1 wherein said changes of measured amounts of a plurality of cellular constituents in a biological sample comprise changes in protein abundances in said biological sample.

21. The method of claim 1 wherein the one or more response profiles associated with a known biological function that correlate with the response profile for the cellular constituent being characterized are identified by a method which comprises:

(a) clustering a plurality of response profiles so that response profiles that are correlated are located within a particular cluster; and

(b) identifying response profiles that cluster with the response profile for the cellular constituent being characterized.

22. The method of claim 21 wherein said plurality of response profiles is clustered by means of an agglomerative hierarchical clustering algorithm.

82. The method of claim 1, wherein said one or more response profiles associated with said known biological function that either correlates or does not correlate with said response profile for the cellular constituent being characterized is a consensus profile associated with said known biological function.

23. A method for characterizing a cellular constituent as being associated or not associated with a particular biological function, in which said method comprises:

(a) clustering a plurality of response profiles, wherein

each response profile in said plurality of response profiles comprises changes in measured amounts of a plurality of cellular constituents in a biological sample in which a particular cellular constituent is perturbed or modified, and

said plurality of response profiles includes a response profile for the cellular constituent being characterized, said response profile for the cellular constituent being characterized comprising changes in measured amounts of a plurality of cellular constituents expressed in a biological sample in which the cellular constituent being characterized is perturbed or modified; and

(b) identifying one or more response profiles in said plurality of response profiles that cluster with the response profiles for the cellular constituent being characterized, said identified response profiles being associated with a known biological function, or identifying one or more response profiles in said plurality of response profiles that do not cluster with the response profiles for the cellular constituent being characterized, said identified response profiles being associated with a known biological function,

wherein if said response profile associated with the cellular constituent being characterized is identified as clustering with said response profiles being associated with a known biological function, said cellular constituent is characterized as being associated with said known biological function, and if said response profile associated with the cellular constituent being characterized is identified as not clustering with said response profiles being associated with a known biological function, said cellular constituent is characterized as not being associated with said known biological function.

24. The method of claim 23, wherein the cellular constituent being characterized is a gene or gene product.

25. The method of claim 24 wherein the perturbation to the cellular constituent being characterized comprises a mutation of said gene.

26. The method of claim 24 wherein the perturbation to the cellular constituent being characterized comprises modifying abundances of mRNA transcripts of said gene.

27. The method of claim 26 wherein said abundances of mRNA transcripts are modified by antisense nucleic acids.

28. The method of claim 26 wherein said abundances of mRNA transcripts are modified by ribozymes.

29. The method of claim 23 wherein said changes of measured amounts of a plurality of cellular constituents in a biological sample comprise changes in abundances of mRNA species in said biological sample.

30. The method of claim 29 wherein said changes in abundances of a plurality of mRNA species in said biological sample are provided by a method comprising:

(a) reverse transcribing mRNA species extracted from cells to form cDNA species; and

(b) measuring abundances of said cDNA species.

31. The method of claim 29 wherein said changes in abundances of mRNA species in said biological sample are provided by a method comprising:

(a) reverse transcribing mRNA species extracted from cells to form cDNA species;

(b) transcribing said cDNA species to form cRNA species; and

(c) measuring abundances of said cRNA species.

32. The method of claim 29 wherein abundances of mRNA species in said biological sample are provided by a method which comprises measuring abundances of polynucleotide species on a microarray, said microarray comprising:

(a) a surface; and

(b) binding sites for a plurality of polynucleotide species attached to said surface,

wherein said binding sites are attached to said surface such that the identity of a binding site can be determined from its position on the surface.

83. The method of claim 23, wherein said one or more response profiles associated with a known biological function that either cluster or do not cluster with said response profile for said cellular constituent being characterized is a consensus profile associated with said known biological function.

33. A computer system for characterizing cellular constituents, said computer system comprising:

one or more processor units; and

one or more memory units connected to said one or more processor units,

said one or more memory units containing one or more programs which cause said one or more processor units to execute steps of;

(a) receiving a data structure for a response profile of a cellular constituent to be characterized, said response profile of a cellular constituent to be characterized comprising changes of measured amounts of a plurality of cellular constituents in a biological sample in which the cellular constituent to be characterized is perturbed; and

(b) identifying one or more response profiles associated with a known biological function that correlate or do not correlate with said response profile of the cellular constituent to be characterized, wherein each of the one or more response profiles associated with said known biological function comprises changes of a plurality of cellular constituents in a biological sample in which a particular cellular constituent, other than the cellular constituent to be characterized, that is associated with said known biological function is perturbed,

wherein if said response profile of the cellular constituent to be characterized correlates with said one or more response profiles associated with a known biological function, the cellular constituent to be characterized is characterized as being associated with said known biological function, and if said response profile of the cellular constituent to be characterized does not correlate with said one or more response profiles associated with a known biological function, the cellular constituent to be characterized is characterized as not being associated with said known biological function.

34. The computer system of claim 33 wherein said programs further cause the one or more processor units to execute steps of:

(a) clustering a plurality of response profiles so that response profiles that are correlated are located within a particular cluster; and

(b) identifying response profiles that cluster with the response profile for the cellular constituent to be characterized.

35. The computer system of claim 34 wherein said programs cause the one or more processor units to execute said step of clustering by means of an agglomerative hierarchical clustering algorithm.

36. A computer program product for use in conjunction with a computer having one or more memory units and one or more processor units, the computer program product comprising a computer readable storage medium having a computer program mechanism encoded thereon, wherein said computer program mechanism can be loaded into the one or more memory units of a computer and cause the one or more processor units of the computer to execute steps of:

(a) receiving a data structure for a response profile of a cellular constituent to be characterized, said response profile of a cellular constituent to be characterized comprising changes of measured amounts of a plurality of cellular constituents in a biological sample in which the cellular constituent to be characterized is perturbed; and

(b) identifying one or more response profiles associated with a known biological function that correlate with said response profile of the cellular constituent to be characterized, wherein each of the one or more response profiles associated with said known biological function comprises changes of a plurality of cellular constituents in a biological sample in which a particular cellular constituent, other than the cellular constituent to be characterized, that is associated with said known biological function is perturbed.

37. The computer program product of claim 36 wherein said computer program mechanism can further cause the one or more processor units to execute steps of:

(a) clustering a plurality of response profiles so that response profiles that are correlated are located within a particular cluster; and

(b) identifying response profiles that cluster with the response profile for the cellular constituent to be characterized.

38. The computer program product of claim 37 wherein said computer program mechanism causes the one or more processor units to execute said step of clustering by means of an agglomerative hierarchical clustering algorithm.

39. A method for determining a biological function with which a cellular constituent of a cell type or organism is associated, comprising:

(a) determining measured amounts of a plurality of cellular constituents in a first cell of said cell type or of said organism in which said cellular constituent has been perturbed to create a first response profile;

(b) comparing said first response profile, or a predicted response profile derived therefrom, to a database comprising a plurality of landmark response profiles to determine the one or more landmark response profiles most similar to said first or predicted response profile, each landmark response profile comprising measured amounts of a plurality of cellular constituents in a second cell of said cell type or type of organism having a perturbation in a cellular constituent associated with a known biological function,

wherein the known biological function of the cellular constituent perturbed in the one or more landmark response profiles determined in step (b) is the biological function with which said cellular constituent is associated.

41. The method of claim 39 or 40, wherein the cellular constituent being characterized is a gene or gene product.

42. The method of claim 41, wherein the perturbation to the cellular constituent being characterized comprises a mutation of said gene.

43. The method of claim 41, wherein the perturbation to the cellular constituent being characterized comprises modifying abundances of mRNA transcripts of said gene.

44. The method of claim 41, wherein the perturbation to the cellular constituent being characterized comprises modifying abundances or activities of said gene product.

45. The method of claim 39 or 40, wherein a particular cellular constituent associated with a known biological function is a gene or gene product associated with said known biological function.

46. The method of claim 45, wherein the perturbation to said gene or gene product associated with said known biological function comprises a mutation of said gene associated with said known biological function.

47. The method of claim 45, wherein the perturbation to said gene or gene product associated with said known biological function comprises modifying abundances of mRNA transcripts of said gene associated with said known biological function.

48. The method of claim 45, wherein the perturbation to said gene or gene product associated with said known biological function comprises modifying abundances or activities of said gene product associated with said known biological function.

49. The method of claim 39 or 40, wherein said changes of measured amounts of the plurality of cellular constituents in a biological sample comprise changes in abundances of mRNA species in said biological sample.

50. The method of claim 39 or 40, wherein said changes of measured amounts of a plurality of cellular constituents in a biological sample comprise changes in protein abundances in said biological sample.

51. The method of claim 49, wherein abundances of mRNA species in said biological sample are provided by a method comprising measuring abundances of polynucleotide species on a microarray, said microarray comprising:

(a) a surface, and

(b) binding sites for a plurality of polynucleotide species attached to said surface

wherein said binding sites are attached to said surface such that the identity of a binding site can be determined from its position on the surface.

52. The method of claim 39 or 40, wherein the one or more landmark response profiles associated with a known biological function that correlate with the first response profile for the cellular constituent being characterized are identified by a method comprising:

(a) clustering a plurality of response profiles so that response profiles that are correlated are located within a particular cluster; and

(b) identifying landmark response profiles that cluster with the first response profile for the cellular constituent being characterized.

53. The method of claim 52, wherein said plurality of response profiles is clustered by means of an agglomerative hierarchical clustering algorithm.

54. The method of claim 39 or 40, wherein the measured amounts of the plurality of cellular constituents in said first cell of said cell type or of said organism are determined in comparison to a wild-type cell of said cell type or of said organism, and wherein the measured amounts of the plurality of cellular constituents in said second cell of said cell type or of said organism are determined in comparison to a wild-type cell of said cell type or of said organism.

55. The method of claim 39 or 40, wherein the measured amounts of the plurality of cellular constituents in said first cell of said cell type or of said organism and the measured amounts of the plurality of cellular constituents in said second cell of said cell type or of said organism are absolute amounts of the pluralities of cellular constituents.

84. The method of claim 39 or 40, wherein said one or more landmark response profiles determined to be most similar to said first or predicted response profile is a consensus profile for perturbation to a cellular constituent associated with said known biological function.

40. A method for determining a biological function with which a cellular constituent of a cell type or organism is associated, comprising:

comparing a first response profile or a predicted response profile derived therefrom to a database comprising a plurality of landmark response profiles to determine the one or more landmark response profiles most similar to said first or predicted response profile;

wherein said first response profile comprises measured amounts of a plurality of cellular constituents in a first cell of said cell type or of said organism in which said cellular constituent has been perturbed;

wherein each landmark response profile comprises measured amounts of a plurality of cellular constituents in a second cell of said cell type or type of organism having a perturbation to a cellular constituent associated with a known biological function; and

wherein the known biological function of the cellular constituent perturbed in the one or more landmark response profiles determined to be most similar is the biological function with which said cellular constituent is associated.

56. A method for characterizing a cellular constituent as being associated with a particular biological function, comprising:

(a) determining measured amounts of a plurality of cellular constituents in a first cell of a cell type or organism in which said cellular constituent being characterized is perturbed or modified to create a first response profile;

(b) clustering a plurality of response profiles, which comprise said first response profile and a plurality of landmark response profiles, each landmark response profile comprising measured amounts of a plurality of cellular constituents in a second cell of said cell type or type of organism having a perturbation or modification in a cellular constituent associated with a known biological function; and

(c) identifying one or more landmark response profiles in said plurality of landmark response profiles that cluster with the first response profile for the cellular constituent being characterized, said identified landmark response profiles being associated with a known biological function,

wherein the cellular constituent being characterized is characterized as being associated with said known biological function.

58. The method of claim 56 or 57, wherein the cellular constituent being characterized is a gene or gene product.

59. The method of claim 58, wherein the perturbation to the cellular constituent being characterized comprises a mutation of said gene.

60. The method of claim 58, wherein the perturbation to the cellular constituent being characterized comprises modifying abundances of mRNA transcripts of said gene.

61. The method of claim 58 wherein the perturbation to the cellular constituent being characterized comprises modifying abundances or activities of said gene product.

62. The method of claim 56 or 57 wherein a particular cellular constituent associated with a known biological function is a gene or gene product associated with said known biological function.

63. The method of claim 62 wherein the perturbation to said gene or gene product associated with said known biological function comprises a mutation of said gene associated with said known biological function.

64. The method of claim 62 wherein the perturbation to said gene or gene product associated with said known biological function comprises modifying abundances of mRNA transcripts of said gene associated with said known biological function.

65. The method of claim 62 wherein the perturbation to the gene or gene product associated with said known biological function comprises modifying abundances or activities of said gene product associated with said known biological function.

66. The method of claim 56 or 57 wherein said changes of a plurality of cellular constituents in a biological sample comprise changes in abundances of mRNA species in said biological sample.

67. The method of claim 66, wherein abundances of mRNA species in said biological sample are provided by a method comprising measuring abundances of polynucleotide species on a microarray, said microarray comprising:

(a) a surface; and

(b) binding sites for a plurality of polynucleotide species attached to said surface,

wherein said binding sites are attached to said surface such that the identity of a binding site can be determined from its position on the surface.

68. The method of claim 56 or 57, wherein the measured amounts of the plurality of cellular constituents in said first cell of said cell type or of said organism are determined in comparison to a wild-type cell of said cell type or of said organism, and wherein the measured amounts of the plurality of cellular constituents in said second cell of said cell type or of said organism are determined in comparison to a wild-type cell of said cell type or of said organism.

69. The method of claim 56 or 57, wherein the measured amounts of the plurality of cellular constituents in said first cell of said cell type or of said organism and the measured amounts of the plurality of cellular constituents in said second cell of said cell type or of said organism are absolute amounts of the pluralities of cellular constituents.

85. The method of claim 56 or 57, wherein said one or more landmark response profiles identified as clustering with said first response profile are one or more consensus profiles for perturbation or modification to a cellular constituent associated with said known biological function.

57. A method for characterizing a cellular constituent as being associated with a particular biological function, comprising:

(a) clustering a plurality of response profiles, which comprise;

(i) a first response profile comprising measured amounts of a plurality of cellular constituents in a first cell of a cell type or organism in which said cellular constituent being characterized is perturbed or modified; and

(ii) a plurality of landmark response profiles, each landmark response profile comprising measured amounts of a plurality of cellular constituents in a second cell of said cell type or type of organism having a perturbation or modification in a cellular constituent associated with a known biological function; and

(c) identifying one or more landmark response profiles in said plurality of landmark response profiles that cluster with the first response profile for the cellular constituent being characterized, said identified landmark response profiles being associated with a known biological function,

wherein the cellular constituent being characterized is characterized as being associated with said known biological function.

70. A computer system for identifying a biological function with which a cellular constituent is associated, said computer system comprising:

one or more processor units; and

one or more memory units connected to said one or more processor units, said one or more memory units containing one or more programs which cause said one or more processor units to execute steps of;

(a) receiving a data structure for a first response profile comprising measured amounts of a plurality of cellular constituents in a first cell of said cell type or of said organism in which said cellular constituent has been perturbed; and

(b) comparing said first response profile, or a predicted response profile derived therefrom, to a database comprising a plurality of landmark response profiles to determine the one or more landmark response profiles most similar to said first or predicted response profile, each landmark response profile comprising measured amounts of a plurality of cellular constituents in a second cell of said cell type or type of organism having a perturbation in a cellular constituent associated with a known biological function,

wherein the known biological function of the cellular constituent perturbed in the one or more landmark response profiles determined in step (b) is the biological function with which said cellular constituent is associated.

72. The computer system of claim 70 or 71, wherein said programs further cause the one or more processor units to execute steps of:

(a) clustering a plurality of response profiles so that response profiles that are correlated are located within a particular cluster; and

(b) identifying landmark response profiles that cluster with the first response profile for the cellular constituent being characterized.

73. The computer system of claim 72, wherein said programs cause the one or more processor units to execute said step of clustering by means of an agglomerative hierarchical clustering algorithm.

74. The computer system of claim 70 or 71, wherein the measured amounts of the plurality of cellular constituents in said first cell of said cell type or of said organism are determined in comparison to a wild-type cell of said cell type or of said organism, and wherein the measured amounts of the plurality of cellular constituents in said second cell of said cell type or of said organism are determined in comparison to a wild-type cell of said cell type or of said organism.

75. The computer system of claim 70 or 71, wherein the measured amounts of the plurality of cellular constituents in said first cell of said cell type or of said organism and the measured amounts of the plurality of cellular constituents in said second cell of said cell type or of said organism are absolute amounts of the pluralities of cellular constituents.

71. A computer system for identifying a biological function with which a cellular constituent is associated, said computer system comprising:

one or more processor units; and

one or more memory units connected to said one or more processor units, said one or more memory units containing one or more programs which cause said one or more processor units to execute steps of;

comparing a first response profile or a predicted response profile derived therefrom to a database comprising a plurality of landmark response profiles to determine the one or more landmark response profiles most similar to said first or predicted response profile;

wherein said first response profile comprises measured amounts of a plurality of cellular constituents in a first cell of said cell type or of said organism in which said cellular constituent has been perturbed;

wherein each landmark response profile comprises measured amounts of a plurality of cellular constituents in a second cell of said cell type or type of organism having a perturbation to a cellular constituent associated with a known biological function; and

wherein the known biological function of the cellular constituent perturbed in the one or more landmark response profiles determined to be most similar is the biological function with which said cellular constituent is associated.

76. A computer program product for use in conjunction with a computer having one or more memory units and one or more processor units, the computer program product comprising a computer readable storage medium having a computer program mechanism encoded thereon, wherein said computer program mechanism can be loaded into the one or more memory units of a computer and cause the one or more processor units of the computer to execute steps of:

(a) receiving a data structure for a first response profile comprising measured amounts of a plurality of cellular constituents in a first cell of said cell type or of said organism in which said cellular constituent has been perturbed; and

(b) comparing said first response profile, or a predicted response profile derived therefrom, to a database comprising a plurality of landmark response profiles to determine the one or more landmark response profiles most similar to said first or predicted response profile, each landmark response profile comprising measured amounts of a plurality of cellular constituents in a second cell of said cell type or type of organism having a perturbation in a cellular constituent associated with a known biological function,

wherein the known biological function of the cellular constituent perturbed in the one or more landmark response profiles determined in step (b) is the biological function with which said cellular constituent is associated.

78. The computer program product of claim 76 or 77, wherein said computer program mechanism can further cause the one or more processor units to execute steps of:

(a) clustering a plurality of response profiles so that response profiles that are correlated are located within a particular cluster; and

(b) identifying landmark response profiles that cluster with the first response profile for the cellular constituent being characterized.

79. The computer program product of claim 76 or 77, wherein said computer program mechanism causes the one or more processor units to execute said step of clustering by means of an agglomerative hierarchical clustering algorithm.

80. The computer program product of claim 76 or 77, wherein the measured amounts of the plurality of cellular constituents in said first cell of said cell type or of said organism are determined in comparison to a wild-type cell of said cell type or of said organism, and wherein the measured amounts of the plurality of cellular constituents in said second cell of said cell type or of said organism are determined in comparison to a wild-type cell of said cell type or of said organism.

81. The computer program product of claim 76 or 77, wherein the measured amounts of the plurality of cellular constituents in said first cell of said cell type or of said organism and the measured amounts of the plurality of cellular constituents in said second cell of said cell type or of said organism are absolute amounts of the pluralities of cellular constituents.

77. A computer program product for use in conjunction with a computer having one or more memory units and one or more processor units, the computer program product comprising a computer readable storage medium having a computer program mechanism encoded thereon, wherein said computer program mechanism can be loaded into the one or more memory units of a computer and cause the one or more processor units of the computer to execute steps of:

comparing a first response profile or a predicted response profile derived therefrom to a database comprising a plurality of landmark profiles to determine the one or more landmark response profiles most similar to said first or predicted response profile;

wherein said first response profile comprises measured amounts of a plurality of cellular constituents in a first cell of said cell type or of said organism in which said cellular constituent has been perturbed;

wherein each landmark response profile comprises measured amounts of a plurality of cellular constituents in a second cell of said cell type or type of organism having a perturbation to a cellular constituent associated with a known biological function; and

wherein the known biological function of the cellular constituent perturbed in the one or more landmark response profiles determined to be most similar is the biological function with which said cellular constituent is associated.