Systems and methods for predicting specific genetic loci that affect phenotypic traits

• US 20040146870A1
• Filed: 01/27/2003
• Published: 07/29/2004
• Est. Priority Date: 01/27/2003
• Status: Abandoned Application

• Current Assignee: Sandhill Bio Corporation
• Original Assignee: Sandhill Bio Corporation
• Inventors: Liao, Guochun, Usuka, Jonathan Andrew, Peltz, Gary Allen
• Application Number:
  US10/352,846
• Publication Number:
  US 20040146870A1
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: G16B 20/00 ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/20 Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
• CPC Class Codes: G16B 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 30/00 ICT specially adapted for sequence analysis involving nucleotides or amino acids

Abstract

A database of genetic variations is analyzed to produce a haplotype map of the genome for strains of a single species. A computational method is used to rapidly map complex phenotypes onto the haplotype blocks within the haplotype map. The specific genetic locus regulating three different biologically important phenotypic traits in mice is identified using these systems and methods.

Claims

1. A method of associating a phenotype exhibited by a plurality of different organisms of a single species with one or more specific genetic loci in a genome of said single species, said method comprising:

scoring a haplotype block in a haplotype map, said scoring representing a correspondence between variations in a phenotypic data structure and variations in said haplotype block, wherein

said phenotypic data structure represents a difference in said phenotype exhibited by said plurality of different organisms; and

said haplotype map includes a plurality of haplotype blocks and each haplotype block in said haplotype map represents a different portion of said genome; and

repeating said scoring for each haplotype block in said plurality of haplotype blocks in said haplotype map, thereby identifying one or more haplotype blocks in said plurality of haplotype blocks having a better score than all other haplotype blocks in said plurality of haplotype blocks;

wherein said one or more specific genetic loci is each said different portion of said genome that is represented by said identified one or more haplotype blocks.

2. The method of claim 1 wherein a haplotype block in said plurality of haplotype blocks comprises a plurality of consecutive single nucleotide polymorphisms.

3. The method of claim 2 wherein each single nucleotide polymorphism in said haplotype block is within a threshold distance of another single nucleotide polymorphism in said haplotype block.

4. The method of claim 3 wherein said threshold distance is less than ten megabases.

5. The method of claim 3 wherein said threshold distance is less than one megabase.

6. The method of claim 1 wherein a haplotype block in said plurality of haplotype blocks represents a plurality of haplotypes and less than a cutoff percentage of the haplotypes represented by the haplotype block appear only once in said haplotype block.

7. The method of claim 6 wherein said cutoff percentage is in a range between five percent and thirty percent.

8. The method of claim 6 wherein said cutoff percentage is in a range between fifteen percent and twenty-five percent.

9. The method of claim 1 wherein said method further comprises the step of generating said haplotype map prior to said scoring.

10. The method of claim 9 wherein said generating comprises:

(i) identifying a candidate haplotype block having a plurality of consecutive single nucleotide polymorphisms, wherein each single nucleotide polymorphism in said candidate haplotype block is within a threshold distance of another single nucleotide polymorphism in said candidate haplotype block;

(ii) assigning a score to said candidate haplotype block;

(iii) repeating said identifying step (i) and said assigning step (ii) until all possible candidate haplotype blocks have been identified, thereby creating a set of candidate haplotype blocks;

(iv) selecting for the haplotype map a candidate haplotype block having the highest score in the set of candidate haplotype blocks;

(v) removing from said set of candidate blocks said selected candidate haplotype block and each candidate haplotype block that overlays all or a portion of said selected candidate haplotype block; and

(vi) repeating said selecting step (iv) and said removing step (v) until no candidate haplotype blocks remain in said set of candidate haplotype blocks;

wherein said haplotype map comprises each candidate haplotype block selected in an iteration of step (iv).

11. The method of claim 10 wherein said score is a number of single nucleotide polymorphisms in said candidate haplotype block divided by a square of the number of haplotypes represented by the block.

12. The method of claim 10 wherein said score is a number of single nucleotide polymorphisms in said candidate haplotype block divided by a number of haplotypes represented by the block.

13. The method of claim 1 wherein scoring said haplotype block comprises assigning a score S to said haplotype block wherein

14. The method of claim 1 wherein scoring said haplotype block comprises assigning a score S to said haplotype block wherein

15. The method of claim 1 wherein scoring said haplotype block comprises assigning a score S, wherein S is the negation, inverse, negated inverse, logarithm or negated logarithm of the ratio:

16. The method of claim 15 wherein Σ

D_intra or Σ

D_inter is raised to a power.

17. The method of claim 16 wherein said power is ½

, 2 or 10.

18. The method of claim 1 wherein scoring said haplotype block comprises assigning a score S, wherein S is the negation, inverse, negated inverse, logarithm or negated logarithm of the ratio the ratio:

19. The method of claim 18 wherein said power is ½

, 2 or 10.

20. The method of claim 1 wherein a specific genetic locus in said one or more specific genetic loci has a length that is less than 0.5 of a megabase.

21. The method of claim 1 wherein a specific genetic locus in said one or more specific genetic loci has a length between 0.5 of a megabase and 2.0 megabases.

22. The method of claim 1 wherein a specific genetic locus in said one or more specific genetic loci has a length that is less than 10 megabases

23. The method of claim 1 wherein said phenotype is diabetes, cancer, asthma, schizopherenia, arthritis, multiple sclerosis, or rheumatosis.

24. The method of claim 1 wherein said phenotype is an autoimmune disorder or a genetic disorder.

25. The method of claim 1 wherein said phentotypic data structure is microarray expression data.

26. The method of claim 1 wherein said single species is an animal, a plant, Drosophila, a yeast, a virus, or C. elegans.

27. The method of claim 1 wherein said single species is mouse or human.

28. The method of claim 1 wherein said plurality of different organisms of said single species is between five and 1000 organisms.

29. The method of claim 1 wherein said plurality of different organisms of said single species is between ten and 100 organisms.

30. The method of claim 1 wherein said plurality of different organisms of said single species is between 20 and 75 organisms.

31. The method of claim 1, the method further comprising:

(i) selecting a haplotype in said one or more haplotype blocks in said plurality of haplotype blocks having a better score than all or most other haplotype blocks in said plurality of haplotype blocks;

(ii) generating a secondary haplotype map for said single species using genotypic data for the organisms in said plurality of different organisms of said single species that are represented in said haplotype;

(iii) scoring a haplotype block in said secondary haplotype map, said scoring representing a correspondence between variations in said phenotypic data structure and variations in said haplotype block;

(iv) repeating said scoring step (iii) for each haplotype block in said secondary haplotype map, thereby identifying one or more secondary haplotype blocks having a better score than all other haplotype blocks in said secondary haplotype map; and

(v) constructing a biological pathway for said species that includes (a) a locus in the haplotype block from the haplotype block from which said haplotype was selected and (b) a locus from said one or more secondary haplotype blocks identified in an instance of step (iii).

32. The method of claim 1 wherein said phenotypic data structure represents measurements of a plurality of cellular constituents in said plurality of organisms.

33. The method of claim 1 wherein said phenotype data structure comprises a phenotypic array for each organism in said plurality of organisms and each said phenotypic array comprises a differential expression value for each cellular constituent in a plurality of cellular constituents in the organism represented by said phenotypic array, and each said differential expression value represents a difference between:

(i) a native expression value of a cellular constituent in an organism in said plurality of organisms; and

(ii) an expression value of said cellular constituent in said organism after said organism has been exposed to a perturbation.

34. The method of claim 33 wherein said perturbation is a pharmacological agent.

35. The method of claim 33 wherein said perturbation is a chemical compound having a molecular weight of less than 1000 Daltons.

36. The method of claim 1 wherein an organism in said plurality of different organisms is a member of said single species, a cellular tissue derived from a member of said single species, or a cell culture derived from said member of said single species.

37. The method of claim 1 wherein a haplotype block in said plurality of haplotype blocks comprises a plurality of restriction fragment length polymorphisms, microsatellite markers, short tandem repeats, sequence length polymorphisms, or DNA methylations.

38. A computer program product for use in conjunction with a computer system, the computer program product comprising a computer readable storage medium and a computer program mechanism embedded therein, the computer program mechanism comprising:

a genotypic database for storing variations in genomic sequences of a plurality of different organisms of a single species;

a phenotypic data structure that represents a difference in a phenotype exhibited by said plurality of different organisms;

a haplotype map that comprises a plurality of haplotype blocks, each haplotype block in said haplotype map representing a different portion of the genome of said single species; and

a phenotype/haplotype processing module for associating a phenotype exhibited by said plurality of different organisms with one or more specific genetic loci in the genome of said single species, said phenotype/haplotype processing module comprising a phenotype/haplotype comparison subroutine, said phenotype/haplotype comparison subroutine comprising;

instructions for scoring a haplotype block in said haplotype map, said scoring representing a correspondence between variations in said phenotypic data structure and variations in said haplotype block;

instructions for re-executing said instructions for scoring for each haplotype block in said plurality of haplotype blocks in said haplotype map; and

instructions for identifying one or more haplotype blocks in said plurality of haplotype blocks having a better score than all other haplotype blocks in said plurality of haplotype blocks.

39. The computer program product of claim 38 wherein a haplotype block in said plurality of haplotype blocks comprises a plurality of consecutive single nucleotide polymorphisms.

40. The computer program product of claim 39 wherein each single nucleotide polymorphism in said haplotype block is within a threshold distance of another single nucleotide polymorphism in said haplotype block

41. The computer program product of claim 40 wherein said threshold distance is less than ten megabases.

42. The computer program product of claim 40 wherein said threshold distance is less than one megabase.

43. The computer program product of claim 38 wherein a haplotype block in said plurality of haplotype blocks represents a plurality of haplotypes and less than a cutoff percentage of the haplotypes represented by the haplotype block appear only once in said haplotype block.

44. The computer program product of claim 43 wherein said cutoff percentage is in a range between five percent and thirty percent.

45. The computer program product of claim 43 wherein said cutoff percentage is in a range between fifteen percent and twenty-five percent.

46. The computer program product of claim 38 wherein said phenotype/haplotype processing module further comprises a haplotype map derivation subroutine, wherein said haplotype map derivation subroutine comprises

instructions for generating said haplotype map using said genotypic database.

47. The computer program product of claim 46 wherein said instructions for generating comprise:

(i) instructions for identifying a candidate haplotype block having a plurality of consecutive single nucleotide polymorphisms, wherein each single nucleotide polymorphism in said candidate haplotype block is within a threshold distance of another single nucleotide polymorphism in said candidate haplotype block;

(ii) instructions for assigning a score to said candidate haplotype block;

(iii) instructions for re-executing said instructions for identifying and said instructions for assigning until all possible candidate haplotype blocks in said genotypic database have been identified, thereby creating a set of undiscarded candidate haplotype blocks;

(iv) instructions for selecting for the haplotype map a candidate haplotype block having the highest score in the set of candidate haplotype blocks;

(v) instructions for removing from said set of candidate blocks said selected candidate haplotype block and each candidate haplotype block that overlays all or a portion of said selected candidate haplotype block; and

(vi) instructions for re-executing said instructions for selecting and said instructions for removing step until no candidate haplotype blocks remain in said set of candidate haplotype blocks;

wherein the haplotype map comprises each candidate haplotype block selected.

48. The computer program product of claim 47 wherein said score is a number of single nucleotide polymorphisms in said candidate haplotype block divided by the square of a number of haplotypes represented by the block.

49. The computer program product of claim 47 wherein said score is a number of single nucleotide polymorphisms in said candidate haplotype block divided by a number of haplotypes represented by the block.

50. The computer program product of claim 38 wherein said instructions for scoring said haplotype block comprise instructions for assigning a score S to said haplotype block wherein

51. The computer program product of claim 38 wherein said instructions for scoring comprise instructions for assigning a score S to said haplotype block wherein

52. The computer program product of claim 38 wherein said instructions for scoring comprise instructions for assigning a score S, wherein S is the negation, inverse, negated inverse, logarithm or negated logarithm of the ratio:

53. The computer program product of claim 51 wherein Σ

D_intra or Σ

D_inter is raised to a power.

54. The computer program product of claim 53 wherein said power is ½

, 2 or 10.

55. The computer program product of claim 38 wherein said instruction for scoring said haplotype block comprise instructions for assigning a score S, wherein S is the negation, inverse, negated inverse, logarithm or negated logarithm of the ratio:

56. The computer program product of claim 55 wherein said power is ½

, 2 or 10.

57. The computer program product of claim 38 wherein a specific genetic locus in said one or more specific genetic loci has a length that is less than 0.5 of a megabase.

58. The computer program product of claim 38 wherein a specific genetic locus in said one or more specific genetic loci has a length between 0.5 of a megabase and 2.0 megabases.

59. The computer program product of claim 38 wherein a specific genetic locus in said one or more specific genetic loci has a length that is less than 10 megabases

60. The computer program product of claim 38 wherein said phenotype is diabetes, cancer, asthma, schizopherenia, arthritis, multiple sclerosis, or rheumatosis.

61. The computer program product of claim 38 wherein said phenotype is an autoimmune disorder or a genetic disorder.

62. The computer program product of claim 38 wherein said phentotypic data structure is microarray expression data.

63. The computer program product of claim 38 wherein said single species is an animal, a plant, Drosophila, a yeast, a virus, or C. elegans.

64. The computer program product of claim 38 wherein said single species is mouse or human.

65. The computer program product of claim 38 wherein said plurality of different organisms of said single species is between five and 1000 organisms.

66. The computer program product of claim 38 wherein said plurality of different organisms of said single species is between ten and 100 organisms.

67. The computer program product of claim 38 wherein said plurality of different organisms of said single species is between 20 and 75 organisms.

68. The computer program product of claim 38, the phenotype/haplotype processing module further comprising:

(i) instructions for selecting a haplotype in said one or more haplotype blocks in said plurality of haplotype blocks having a better score than all or most other haplotype blocks in said plurality of haplotype blocks;

(ii) instructions for generating a secondary haplotype map for said single species using genotypic data for the organisms in said plurality of different organisms of said single species that are represented in said haplotype;

(iii) instructions for scoring a haplotype block in said secondary haplotype map, said scoring representing a correspondence between variations in said phenotypic data structure and variations in said haplotype block;

(iv) instructions for re-executing said instructions for scoring (iii) for each haplotype block in said secondary haplotype map, thereby identifying one or more secondary haplotype blocks having a better score than all other haplotype blocks in said secondary haplotype map; and

(v) instructions for constructing a biological pathway for said species that includes (a) a locus in the haplotype block from the haplotype block from which said haplotype was selected and (b) a locus from said one more or more secondary haplotype blocks identified in instances of said instructions for scoring (iii).

69. The computer program product of claim 38 wherein said phenotypic data structure represents measurements of a plurality of cellular constituents in said plurality of organisms.

70. The computer program product of claim 38 wherein said phenotype data structure comprises a phenotypic array for each organism in said plurality of organisms and each said phenotypic array comprises a differential expression value for each cellular constituent in a plurality of cellular constituents in the organism represented by said phenotypic array, and each said differential expression value represents a difference between:

(i) a native expression value of a cellular constituent in an organism in said plurality of organisms; and

(ii) an expression value of said cellular constituent in said organism after said organism has been exposed to a perturbation.

71. The computer program product of claim 70 wherein said perturbation is a pharmacological agent.

72. The computer program product of claim 70 wherein said perturbation is a chemical compound having a molecular weight of less than 1000 Daltons.

73. The computer program product of claim 38 wherein an organism in said plurality of different organisms is a member of said single species, a cellular tissue derived from a member of said single species, or a cell culture derived from said member of said single species.

74. The computer program product of claim 38 wherein a haplotype block in said plurality of haplotype blocks comprises a plurality of restriction fragment length polymorphisms, microsatellite markers, short tandem repeats, sequence length polymorphisms, or DNA methylations.

75. A computer system for associating a phenotype exhibited by a plurality of different organisms with one or more specific genetic loci in the genome of a single species, the computer system comprising:

a central processing unit;

a memory, coupled to the central processing unit, the memory storing;

a genotypic database for storing variations in genomic sequences of said plurality of different organisms of said single species;

a phenotypic data structure that represents a difference in a phenotype exhibited by said plurality of different organisms;

a haplotype map that comprises a plurality of haplotype blocks, each haplotype block in said haplotype map representing a different portion of the genome of said single species; and

a phenotype/haplotype processing module, said phenotype/haplotype processing module comprising a phenotype/haplotype comparison subroutine, said phenotype/haplotype comparison subroutine comprising;

instructions for scoring a haplotype block in said haplotype map, said scoring representing a correspondence between variations in said phenotypic data structure and variations in said haplotype block; and

instructions for re-executing said instructions for scoring for each haplotype block in said plurality of haplotype blocks in said haplotype map, thereby identifying one or more haplotype blocks in said plurality of haplotype blocks having a better score than all other haplotype blocks in said plurality of haplotype blocks.