Nucleic acid amplification

• US 20040126764A1
• Filed: 12/20/2002
• Published: 07/01/2004
• Est. Priority Date: 12/20/2002
• Status: Active Grant

• Current Assignee: Qiagen GmbH (Qiagen NV)
• Original Assignee: Qiagen GmbH (Qiagen NV)
• Inventors: Egholm, Michael, Lasken, Roger S., Alsmadi, Osama A.
• Granted Patent: US 9,487,823 B2
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: C12Q 1/6844 Nucleic acid amplification reactions
• CPC Class Codes: C12Q 1/6858 Allele-specific amplification
• CPC Class Codes: C12Q 2525/151 repeat or repeated sequences, e.g. VNTR, microsatellite, concatemer
• CPC Class Codes: C12Q 2531/119 Strand displacement amplification [SDA]

Abstract

Disclosed are compositions and a method for amplification of nucleic acid sequences of interest. The disclosed method generally involves replication of a complex nucleic acid sample such as genomic samples using one, a few, or more primers such that, during replication, the replicated strands are displaced from the nucleic acid molecules in the sample by strand displacement replication of another replicated strand. It was discovered that highly complex nucleic acid samples can be efficiently amplified using only one or a few primers having specific nucleic acid sequences. The one or few primers are complementary to nucleic acid sequences distributed throughout nucleic acid in the sample.

Claims

1. A method of amplifying genomes, the method comprising,

bringing into contact a single primer, DNA polymerase, and a genomic nucleic acid sample, and incubating the genomic nucleic acid sample under conditions that promote replication of nucleic acid molecules in the genomic nucleic acid sample,

wherein the primer has a specific nucleotide sequence, wherein the genomic nucleic acid sample comprises all or a substantial portion of a genome, wherein replication of nucleic acid molecules in the genomic nucleic acid sample proceeds by strand displacement replication, wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in replication of all or a substantial fraction of the nucleic acid molecules in the genomic nucleic acid sample.

2. The method of claim 1 wherein the genome is a eukaryotic genome.

3. The method of claim 2 wherein the genome is a plant genome.

4. The method of claim 2 wherein the genome is an animal genome.

5. The method of claim 4 wherein the genome is a vertebrate genome.

6. The method of claim 5 wherein the genome is a fish genome.

7. The method of claim 5 wherein the genome is a mammalian genome.

8. The method of claim 7 wherein the genome is a human genome.

9. The method of claim 1 wherein the genome is a microbial genome or a viral genome.

10. The method of claim 1 wherein the amplification bias is less than 20-fold for at least ten nucleic acid sequences in the genomic nucleic acid sample.

11. The method of claim 10 wherein the amplification bias is less than 10-fold for at least ten nucleic acid sequences in the genomic nucleic acid sample.

12. The method of claim 1 wherein the primer has a length of 3 nucleotides, 4 nucleotides, 5 nucleotides, 6 nucleotides, 7 nucleotides, 8 nucleotides, 9 nucleotides, 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, or 30 nucleotides.

13. The method of claim 1 wherein the primer has a length of less than 4 nucleotides, less than 5 nucleotides, less than 6 nucleotides, less than 7 nucleotides, less than 8 nucleotides, less than 9 nucleotides, less than 10 nucleotides, less than 11 nucleotides, less than 12 nucleotides, less than 13 nucleotides, less than 14 nucleotides, less than 15 nucleotides, less than 16 nucleotides, less than 17 nucleotides, less than 18 nucleotides, less than 19 nucleotides, less than 20 nucleotides, less than 21 nucleotides, less than 22 nucleotides, less than 23 nucleotides, less than 24 nucleotides, less than 25 nucleotides, less than 26 nucleotides, less than 27 nucleotides, less than 28 nucleotides, less than 29 nucleotides, less than 30 nucleotides, or less than 31 nucleotides.

14. The method of claim 1 wherein the genomic nucleic acid sample is incubated at 20°

C., 21°

C., 22°

C., 23°

C., 24°

C., 25°

C., 26°

C., 27°

C., 28°

C., 29°

C., 30°

C., 31°

C., 32°

C., 33°

C., 34°

C., 35°

C., 36°

C., 37°

C., 38°

C., 39°

C., 40°

C., 41°

C., 42°

C., 43°

C., 44°

C., 45°

C., 46°

C., 47°

C., 48°

C., 49°

C., 50°

C., 51°

C., 52°

C., 53°

C., 54°

C., 55°

C., 56°

C., 57°

C., 58°

C., 59°

C., 60°

C., 61°

C., 62°

C., 63°

C., 64°

C., 65°

C., 66°

C., 67°

C., 68°

C., 69°

C., 70°

C., 71°

C., 72°

C., 73°

C., 74°

C., 75°

C., 76°

C., 77°

C., 78°

C., 79°

C., or 80°

C.

15. The method of claim 1 wherein the genomic nucleic acid sample is incubated at less than 21°

C., less than 22°

C., less than 23°

C., less than 24°

C., less than 25°

C., less than 26°

C., less than 27°

C., less than 28°

C., less than 29°

C., less than 30°

C., less than 31°

C., less than 32°

C., less than 33°

C., less than 34°

C., less than 35°

C., less than 36°

C., less than 37°

C., less than 38°

C., less than 39°

C., less than 40°

C., less than 41°

C., less than 42°

C., less than 43°

C., less than 44°

C., less than 45°

C., less than 46°

C., less than 47°

C., less than 48°

C., less than 49°

C., less than 50°

C., less than 51°

C., less than 52°

C., less than 53°

C., less than 54°

C., less than 55°

C., less than 56°

C., less than 57°

C., less than 58°

C., less than 59°

C., less than 60°

C., less than 61°

C., less than 62°

C., less than 63°

C., less than 64°

C., less than 65°

C., less than 66°

C., less than 67°

C., less than 68°

C., less than 69°

C., less than 70°

C., less than 71°

C., less than 72°

C., less than 73°

C., less than 74°

C., less than 75°

C., less than 76°

C., less than 77°

C., less than 78°

C., less than 79°

C., or less than 80°

C.

16. The method of claim 1 wherein the genomic nucleic acid sample has a sequence complexity of at least 1×

10³ nucleotides, the genomic nucleic acid sample has a sequence complexity of at least 1×

10⁴ nucleotides, the genomic nucleic acid sample has a sequence complexity of at least 1×

10⁵ nucleotides, the genomic nucleic acid sample has a sequence complexity of at least 1×

10⁶ nucleotides, the genomic nucleic acid sample has a sequence complexity of at least 1×

10⁷ nucleotides, the genomic nucleic acid sample has a sequence complexity of at least 1×

10⁸ nucleotides, or the genomic nucleic acid sample has a sequence complexity of at least 1×

10⁹ nucleotides.

17. The method of claim 1 wherein the primer, DNA polymerase and genomic nucleic acid sample are brought into contact with 1 additional primer, with 2 additional primers, with 3 additional primers, with 4 additional primers, with 5 additional primers, with 6 additional primers, with 7 additional primers, with 8 additional primers, with 9 additional primers, with 10 additional primers, with 11 additional primers, with 12 additional primers, with 13 additional primers, with 14 additional primers, with 15 additional primers, with 16 additional primers, with 17 additional primers, with 18 additional primers, with 19 additional primers, with 20 additional primers, with 21 additional primers, with 22 additional primers, with 23 additional primers, with 24 additional primers, with 25 additional primers, with 26 additional primers, with 27 additional primers, with 28 additional primers, with 29 additional primers, with 30 additional primers, with 31 additional primers, with 32 additional primers, with 33 additional primers, with 34 additional primers, with 35 additional primers, with 36 additional primers, with 37 additional primers, with 38 additional primers, with 39 additional primers, with 40 additional primers, with 41 additional primers, with 42 additional primers, with 43 additional primers, with 44 additional primers, with 45 additional primers, with 46 additional primers, with 47 additional primers, with 48 additional primers, with 49 additional primers, with 50 additional primers, with 51 additional primers, with 52 additional primers, with 53 additional primers, with 54 additional primers, with 55 additional primers, with 56 additional primers, with 57 additional primers, with 58 additional primers, with 59 additional primers, with 60 additional primers, with 61 additional primers, with 62 additional primers, with 63 additional primers, with 75 additional primers, with 100 additional primers, with 150 additional primers, with 200 additional primers, with 300 additional primers, with 400 additional primers, with 500 additional primers, with 750 additional primers, or with 1,000 additional primers, wherein each primer has a different specific nucleotide sequence.

18. The method of claim 17 wherein the primers are all of the same length.

19. The method of claim 1 wherein the primer, DNA polymerase and genomic nucleic acid sample are brought into contact with fewer than 2 additional primers, with fewer than 3 additional primers, with fewer than 4 additional primers, with fewer than 5 additional primers, with fewer than 6 additional primers, with fewer than 7 additional primers, with fewer than 8 additional primers, with fewer than 9 additional primers, with fewer than 10 additional primers, with fewer than 11 additional primers, with fewer than 12 additional primers, with fewer than 13 additional primers, with fewer than 14 additional primers, with fewer than 15 additional primers, with fewer than 16 additional primers, with fewer than 17 additional primers, with fewer than 18 additional primers, with fewer than 19 additional primers, with fewer than 20 additional primers, with fewer than 21 additional primers, with fewer than 22 additional primers, with fewer than 23 additional primers, with fewer than 24 additional primers, with fewer than 25 additional primers, with fewer than 26 additional primers, with fewer than 27 additional primers, with fewer than 28 additional primers, with fewer than 29 additional primers, with fewer than 30 additional primers, with fewer than 31 additional primers, with fewer than 32 additional primers, with fewer than 33 additional primers, with fewer than 34 additional primers, with fewer than 35 additional primers, with fewer than 36 additional primers, with fewer than 37 additional primers, with fewer than 38 additional primers, with fewer than 39 additional primers, with fewer than 40 additional primers, with fewer than 41 additional primers, with fewer than 42 additional primers, with fewer than 43 additional primers, with fewer than 44 additional primers, with fewer than 45 additional primers, with fewer than 46 additional primers, with fewer than 47 additional primers, with fewer than 48 additional primers, with fewer than 49 additional primers, with fewer than 50 additional primers, with fewer than 51 additional primers, with fewer than 52 additional primers, with fewer than 53 additional primers, with fewer than 54 additional primers, with fewer than 55 additional primers, with fewer than 56 additional primers, with fewer than 57 additional primers, with fewer than 58 additional primers, with fewer than 59 additional primers, with fewer than 60 additional primers, with fewer than 61 additional primers, with fewer than 62 additional primers, with fewer than 63 additional primers, with fewer than 64 additional primers, with fewer than 75 additional primers, with fewer than 100 additional primers, with fewer than 150 additional primers, with fewer than 200 additional primers, with fewer than 300 additional primers, with fewer than 400 additional primers, with fewer than 500 additional primers, with fewer than 750 additional primers, or with fewer than 1,000 additional primers, wherein each primer has a different specific nucleotide sequence.

20. The method of claim 19 wherein each primer has a different one of the sequences AGTGGG or AGAGAG.

21. The method of claim 19 wherein each primer has a different one of the sequences AGCCGG, AGTAGG, or AGTTGG.

22. The method of claim 19 wherein each primer has a different one of the sequences AGGCGG, AGTGGG, AGGGAG, or AGTGAG.

23. The method of claim 19 wherein each primer has a different one of the sequences AGTGGG, AGCCAG, AGTTAG, AGTCAG, or AGACAG.

24. The method of claim 19 wherein each primer has a different one of the sequences AGAGGG, AGGCAG, AGCCAG, AGTCAG, or AGACAG.

25. The method of claim 19 wherein each primer has a different one of the sequences AGTAGG, AGGTGG, AGGCAG, AGACAG, or AGTGAG.

26. The method of claim 19 wherein each primer has a different one of the sequences AGGAGG, AGAGGG, AGGGAG, AGTCAG, or AGCGAG.

27. The method of claim 19 wherein each primer has a different one of the sequences CGGTGG, TCACGC, CGAGCG, GCGTGG, ACTCGG, AATCGC, CGGAGG, CCGAGA, GATCGC, AGAGCG, AGCGAG, or ACTCCG.

28. The method of claim 1 wherein the primer has one of the sequences AGTGGG or AGAGAG.

29. The method of claim 1 wherein the primer has one of the sequences AGCCGG, AGTAGG, or AGTTGG.

30. The method of claim 1 wherein the primer has one of the sequences AGGCGG, AGTGGG, AGGGAG, or AGTGAG.

31. The method of claim 1 wherein the primer has one of the sequences AGTGGG, AGCCAG, AGTTAG, AGTCAG, or AGACAG.

32. The method of claim 1 wherein the primer has one of the sequences AGAGGG, AGGCAG, AGCCAG, AGTCAG, or AGACAG.

33. The method of claim 1 wherein the primer has one of the sequences CGGTGG, TCACGC, CGAGCG, GCGTGG, ACTCGG, AATCGC, CGGAGG, CCGAGA, GATCGC, AGAGCG, AGCGAG, or ACTCCG.

34. The method of claim 1 wherein the primer is complementary to a sequence in a repeat sequence.

35. The method of claim 34 wherein the repeat sequence is a microsatellite sequence, a minisatellite sequence, a satellite sequence, a transposon sequence, a ribosomal RNA sequence, a short interspersed nuclear element (SINE), or a long interspersed nuclear element (LINE).

36. The method of claim 1 wherein the primer is complementary to a sequence in a functional consensus sequence.

37. The method of claim 36 wherein the functional consensus sequence is a promoter sequence, an enhancer sequence, a silencer sequence, an upstream regulatory element sequence, a transcription termination site sequence, a transposon regulatory sequence, a ribosomal RNA regulatory sequence, or a polyadenylation site sequence.

38. The method of claim 37 wherein the functional consensus sequence is a microbial promoter sequence, a microbial enhancer sequence, a microbial silencer sequence, a microbial upstream regulatory element sequence, a microbial transcription termination site sequence, a microbial transposon regulatory sequence, a microbial ribosomal RNA regulatory sequence, or a microbial polyadenylation site sequence.

39. The method of claim 1 wherein the primer is a broad coverage primer.

40. The method of claim 39 wherein the primer is complementary to a sequence that occurs every 5,000 nucleotides or less, every 4,000 nucleotides or less, every 3,000 nucleotides or less, every 2,500 nucleotides or less, every 2,000 nucleotides or less, every 1,500 nucleotides or less, every 1,000 nucleotides or less, every 900 nucleotides or less, every 800 nucleotides or less, every 700 nucleotides or less, every 600 nucleotides or less, every 500 nucleotides or less, every 400 nucleotides or less, every 300 nucleotides or less, every 200 nucleotides or less, every 100 nucleotides or less, or every 50 nucleotides or less, on average, in the nucleic acid molecules of the genomic nucleic acid sample.

41. The method of claim 39 wherein the primer has a G+C percentage within 20%, within 15%, within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2%, or within 1% of the G+C percentage of the genomic nucleic acid sample.

42. The method of claim 39 wherein the primer produces a locus representation of at least 10% for at least 5 different loci for the type of genomic nucleic acid sample used.

43. The method of claim 42 wherein the primer produces a locus representation of at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% for at least 5 different loci for the type of genomic nucleic acid sample used.

44. The method of claim 42 wherein the primer produces a locus representation of at least 10% for at least 6 different loci, at least 7 different loci, at least 8 different loci, at least 9 different loci, at least 10 different loci, at least 11 different loci, at least 12 different loci, at least 13 different loci, at least 14 different loci, at least 15 different loci, at least 16 different loci, at least 17 different loci, at least 18 different loci, at least 19 different loci, at least 20 different loci, at least 25 different loci, at least 30 different loci, at least 40 different loci, at least 50 different loci, at least 75 different loci, or at least 100 different loci for the type of genomic nucleic acid sample used.

45. The method of claim 1 wherein the primer produces an amplification bias of less than 50-fold for the type of genomic nucleic acid sample used.

46. The method of claim 45 wherein the primer produces an amplification bias of less than 45-fold, less than 40-fold, less than 35-fold, less than 30-fold, less than 25-fold, less than 20-fold, less than 19-fold, less than 18-fold, less than 17-fold, less than 16-fold, less than 15-fold, less than 14-fold, less than 13-fold, less than 12-fold, less than 11-fold, less than 10-fold, less than 9-fold, less than 8-fold, less than 7-fold, less than 6-fold, less than 5-fold, or less than 4-fold for the type of genomic nucleic acid sample used.

47. The method of claim 45 wherein the primer produces an amplification bias of less than 50-fold for at least 5 different loci, for at least 6 different loci, at least 7 different loci, at least 8 different loci, at least 9 different loci, at least 10 different loci, at least 11 different loci, at least 12 different loci, at least 13 different loci, at least 14 different loci, at least 15 different loci, at least 16 different loci, at least 17 different loci, at least 18 different loci, at least 19 different loci, at least 20 different loci, at least 25 different loci, at least 30 different loci, at least 40 different loci, at least 50 different loci, at least 75 different loci, or at least 100 different loci for the type of genomic nucleic acid sample used.

48. The method of claim 1 wherein the primer does not have an inter-complementary 3′

end.

49. The method of claim 1 wherein the primer does not produce significant replication products in the absence of a nucleic acid sample.

50. The method of claim 1 wherein the DNA polymerase is φ

29 DNA polymerase.

51. The method of claim 1 wherein the genomic nucleic acid sample is not subjected to denaturing conditions.

52. The method of claim 51 wherein the genomic nucleic acid sample is not subjected to heat denaturing conditions.

53. The method of claim 51 wherein the genomic nucleic acid sample is not subjected to alkaline denaturing conditions.

54. The method of claim 1 wherein the genomic nucleic acid sample is subjected to denaturing conditions.

55. The method of claim 54 wherein the genomic nucleic acid sample is subjected to heat denaturing conditions.

56. The method of claim 54 wherein the genomic nucleic acid sample is subjected to alkaline denaturing conditions.

57. The method of claim 1 wherein nucleic acids in the genomic nucleic acid sample are not separated from other material in the genomic nucleic acid sample.

58. The method of claim 1 wherein the genomic nucleic acid sample is a crude cell lysate.

59. The method of claim 1 wherein the genomic nucleic acid sample is produced by exposing cells to alkaline conditions to form a cell lysate, wherein the cell lysate comprises a whole genome, and reducing the pH of the cell lysate to form a stabilized cell lysate.

60. The method of claim 59 wherein the cells are exposed to alkaline conditions by mixing the cells with a lysis solution.

61. The method of claim 60 wherein the lysis solution comprises a base.

62. The method of claim 59 wherein the pH of the cell lysate is reduced by mixing the cell lysate with a stabilization solution.

63. The method of claim 62 wherein the stabilization solution comprises a buffer.

64. The method of claim 62 wherein the stabilization solution comprises an acid.

65. The method of claim 59 wherein nucleic acids in the cell lysate and the stabilized cell lysate are not separated from other material in the cell lysate.

66. The method of claim 59 wherein the cell lysate and the stabilized cell lysate are not subjected to purification prior to the incubation.

67. The method of claim 59 wherein the cell lysate, stabilized cell lysate, or both are subjected to partial purification prior to the incubation.

68. The method of claim 59 wherein the cell lysate and the stabilized cell lysate are not subjected to substantial purification prior to the incubation.

69. The method of claim 59 wherein the incubation is substantially isothermic.

70. The method of claim 69 wherein neither the cell lysate nor the stabilized cell lysate is heated substantially above the temperature of the incubation.

71. The method of claim 69 wherein neither the cell lysate nor the stabilized cell lysate is subjected to substantial heating above the temperature of the incubation.

72. The method of claim 69 wherein the cells are not heated substantially above the temperature of the incubation.

73. The method of claim 69 wherein the cells are not subjected to substantial heating above the temperature of the incubation.

74. The method of claim 69 wherein the cells are not heated substantially above the temperature at which the cells grow.

75. The method of claim 69 wherein the cells are not subjected to substantial heating above the temperature at which the cells grow.

76. The method of claim 59 wherein neither the cell lysate nor the stabilized cell lysate is heated above a temperature and for a time that would cause notable denaturation of the genome.

77. The method of claim 59 wherein neither the cell lysate nor the stabilized cell lysate is subjected to heating above a temperature and for a time that would cause notable denaturation of the genome.

78. The method of claim 59 wherein the cells are not lysed by heat.

79. The method of claim 59 wherein the cells are not heated above a temperature and for a time that would cause substantial cell lysis in the absence of the alkaline conditions.

80. The method of claim 59 wherein the cells are not subjected to heating above a temperature and for a time that would cause substantial cell lysis in the absence of the alkaline conditions.

81. The method of claim 1 further comprising, prior to bringing into contact the primer, the genomic nucleic acid sample and the DNA polymerase,

exposing the genomic nucleic acid sample to conditions that promote substantial denaturation of the nucleic acid molecules in the genomic nucleic acid sample, thereby forming a denatured genomic nucleic acid sample, and altering the conditions to conditions that do not promote substantial denaturation of nucleic acid molecules in the genomic nucleic acid sample to form a denatured genomic nucleic acid sample.

82. The method of claim 81 wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in a longer average fragment length for the replicated nucleic acid molecules than the average fragment length in the genomic nucleic acid sample.

83. The method of claim 81 wherein the genomic nucleic acid sample, the denatured genomic nucleic acid sample, or both are exposed to ionic conditions.

84. The method of claim 81 wherein the genomic nucleic acid sample is exposed to conditions that promote substantial denaturation by mixing the genomic nucleic acid sample with a denaturing solution and by heating the genomic nucleic acid sample to a temperature and for a length of time that substantially denatures the nucleic acid molecules in the genomic nucleic acid sample.

85. The method of claim 1 wherein the primer contains at least one modified nucleotide such that the primer is resistant to 3′

-5′

exonuclease.

86. The method of claim 1 wherein the primer is 6 nucleotides long, wherein the primer contains at least one modified nucleotide such that the primer is nuclease resistant, and wherein the DNA polymerase is φ

29 DNA polymerase.

87. The method of claim 1 wherein the conditions that promote replication of the nucleic acid molecules are substantially isothermic.

88. The method of claim 1 wherein the conditions that promote replication of the nucleic acid molecules do not involve thermal cycling.

89. The method of claim 1 wherein the conditions that promote replication of the nucleic acid molecules do not include thermal cycling.

90. The method of claim 1 wherein the primer comprises nucleotides, wherein one or more of the nucleotides are ribonucleotides.

91. The method of claim 90 wherein from about 10% to about 50% of the nucleotides are ribonucleotides.

92. The method of claim 90 wherein about 50% or more of the nucleotides are ribonucleotides.

93. The method of claim 90 wherein all of the nucleotides are ribonucleotides.

94. The method of claim 1 wherein the primer comprises nucleotides, wherein one or more of the nucleotides are 2′

-O-methyl ribonucleotides.

95. The method of claim 94 wherein from about 10% to about 50% of the nucleotides are 2′

-O-methyl ribonucleotides.

96. The method of claim 94 wherein about 50% or more of the nucleotides are 2′

-O-methyl ribonucleotides.

97. The method of claim 94 wherein all of the nucleotides are 2′

-O-methyl ribonucleotides.

98. The method of claim 1 wherein the primer comprises nucleotides, wherein the nucleotides are a mixture of ribonucleotides and 2′

-O-methyl ribonucleotides.

99. The method of claim 1 wherein the primer comprises nucleotides, wherein the nucleotides are a mixture of deoxyribonucleotides and 2′

-O-methyl ribonucleotides.

100. The method of claim 1 wherein the genomic nucleic acid sample is a blood sample, a urine sample, a semen sample, a lymphatic fluid sample, a cerebrospinal fluid sample, amniotic fluid sample, a biopsy sample, a needle aspiration biopsy sample, a cancer sample, a tumor sample, a tissue sample, a cell sample, a cell lysate sample, a crude cell lysate sample, a forensic sample, an archeological sample, an infection sample, a nosocomial infection sample, a production sample, a drug preparation sample, a biological molecule production sample, a protein preparation sample, a lipid preparation sample, a carbohydrate preparation sample, or a combination thereof.

101. The method of claim 1 wherein the genomic nucleic acid sample is a crude cell lysate.

102. The method of claim 1 wherein the genomic nucleic acid sample is not processed beyond cell lysis.

103. The method of claim 1 wherein the replicated nucleic acid molecules are analyzed.

104. The method of claim 103 wherein the replicated nucleic acid molecules are analyzed using one or more DNA chips.

105. The method of claim 103 wherein the replicated nucleic acid molecules are analyzed by hybridization.

106. The method of claim 103 wherein the replicated nucleic acid molecules are analyzed by nucleic acid sequencing.

107. The method of claim 103 wherein the replicated nucleic acid molecules are stored prior to, following, or both prior to and following their analysis.

108. The method of claim 1 further comprising

bringing into contact the primer, DNA polymerase, and a second genomic nucleic acid sample, and incubating the second genomic nucleic acid sample under conditions that promote replication of nucleic acid molecules in the second genomic nucleic acid sample,

wherein the second genomic nucleic acid sample comprises all or a substantial portion of a genome, wherein replication of nucleic acid molecules in the second genomic nucleic acid sample proceeds by strand displacement replication, wherein replication of the nucleic acid molecules in the second genomic nucleic acid sample results in replication of all or a substantial fraction of the nucleic acid molecules in the second genomic nucleic acid sample.

109. The method of claim 108 wherein the second genomic nucleic acid sample is a sample from the same type of organism as the first genomic nucleic acid sample.

110. The method of claim 108 wherein the second genomic nucleic acid sample is a sample from the same type of tissue as the first genomic nucleic acid sample.

111. The method of claim 108 wherein the second genomic nucleic acid sample is a sample from the same organism as the first genomic nucleic acid sample.

112. The method of claim 111 wherein the second genomic nucleic acid sample is obtained at a different time than the first genomic nucleic acid sample.

113. The method of claim 108 wherein the second genomic nucleic acid sample is a sample from a different organism than the first genomic nucleic acid sample.

114. The method of claim 108 wherein the second genomic nucleic acid sample is a sample from a different type of tissue than the first genomic nucleic acid sample.

115. The method of claim 108 wherein the second genomic nucleic acid sample is a sample from a different species of organism than the first genomic nucleic acid sample.

116. The method of claim 108 wherein the second genomic nucleic acid sample is a sample from a different strain of organism than the first genomic nucleic acid sample.

117. The method of claim 108 wherein the second genomic nucleic acid sample is a sample from a different cellular compartment than the first genomic nucleic acid sample.

118. A method of amplifying genomes, the method comprising,

bringing into contact fewer than 1,000 primers, DNA polymerase, and a genomic nucleic acid sample, and incubating the genomic nucleic acid sample under conditions that promote replication of nucleic acid molecules in the genomic nucleic acid sample,

wherein each primer has a different specific nucleotide sequence, wherein the genomic nucleic acid sample comprises all or a substantial portion of a genome, wherein replication of nucleic acid molecules in the genomic nucleic acid sample proceeds by strand displacement replication, wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in replication of all or a substantial fraction of the nucleic acid molecules in the genomic nucleic acid sample.

119. The method of claim 118 wherein the DNA polymerase and genomic nucleic acid sample are brought into contact with fewer than 2 primers, with fewer than 3 primers, with fewer than 4 primers, with fewer than 5 primers, with fewer than 6 primers, with fewer than 7 primers, with fewer than 8 primers, with fewer than 9 primers, with fewer than 10 primers, with fewer than 11 primers, with fewer than 12 primers, with fewer than 13 primers, with fewer than 14 primers, with fewer than 15 primers, with fewer than 16 primers, with fewer than 17 primers, with fewer than 18 primers, with fewer than 19 primers, with fewer than 20 primers, with fewer than 21 primers, with fewer than 22 primers, with fewer than 23 primers, with fewer than 24 primers, with fewer than 25 primers, with fewer than 26 primers, with fewer than 27 primers, with fewer than 28 primers, with fewer than 29 primers, with fewer than 30 primers, with fewer than 31 primers, with fewer than 32 primers, with fewer than 33 primers, with fewer than 34 primers, with fewer than 35 primers, with fewer than 36 primers, with fewer than 37 primers, with fewer than 38 primers, with fewer than 39 primers, with fewer than 40 primers, with fewer than 41 primers, with fewer than 42 primers, with fewer than 43 primers, with fewer than 44 primers, with fewer than 45 primers, with fewer than 46 primers, with fewer than 47 primers, with fewer than 48 primers, with fewer than 49 primers, with fewer than 50 primers, with fewer than 51 primers, with fewer than 52 primers, with fewer than 53 primers, with fewer than 54 primers, with fewer than 55 primers, with fewer than 56 primers, with fewer than 57 primers, with fewer than 58 primers, with fewer than 59 primers, with fewer than 60 primers, with fewer than 61 primers, with fewer than 62 primers, with fewer than 63 primers, with fewer than 64 primers, with fewer than 75 primers, with fewer than 100 primers, with fewer than 150 primers, with fewer than 200 primers, with fewer than 300 primers, with fewer than 400 primers, with fewer than 500 primers, with fewer than 750 primers, or with fewer than 1,000 primers.

120. A method of amplifying nucleic acid samples of notable sequence complexity, the method comprising,

bringing into contact a single primer, DNA polymerase, and a nucleic acid sample, and incubating the nucleic acid sample under conditions that promote replication of nucleic acid molecules in the nucleic acid sample,

wherein the primer has a specific nucleotide sequence, wherein the nucleic acid sample has a sequence complexity of at least 1×

10⁴ nucleotides, wherein replication of nucleic acid molecules in the nucleic acid sample proceeds by strand displacement replication, wherein replication of the nucleic acid molecules in the nucleic acid sample results in replication of all or a substantial fraction of the nucleic acid molecules in the nucleic acid sample.

121. The method of claim 120 wherein the nucleic acid sample has a sequence complexity of at least 1×

10⁵ nucleotides, the nucleic acid sample has a sequence complexity of at least 1×

10⁶ nucleotides, the nucleic acid sample has a sequence complexity of at least 1×

10⁷ nucleotides, the nucleic acid sample has a sequence complexity of at least 1×

10⁸ nucleotides, or the nucleic acid sample has a sequence complexity of at least 1×

10⁹ nucleotides.

122. The method of claim 120 wherein the nucleic acid sample is or is derived from a genome, a chromosome, a chromosome fragment, an artificial chromosome, a yeast artificial chromosome, a bacterial artificial chromosome, a cosmid, or a combination.

123. The method of claim 120 wherein the nucleic acid sample is or is derived from a blood sample, a urine sample, a semen sample, a lymphatic fluid sample, a cerebrospinal fluid sample, amniotic fluid sample, a biopsy sample, a needle aspiration biopsy sample, a cancer sample, a tumor sample, a tissue sample, a cell sample, a cell lysate sample, a crude cell lysate sample, a forensic sample, an archeological sample, an infection sample, a nosocomial infection sample, a production sample, a drug preparation sample, a biological molecule production sample, a protein preparation sample, a lipid preparation sample, a carbohydrate preparation sample, or a combination thereof.

124. The method of claim 120 wherein the nucleic acid sample is or is derived from a eukaryote, a plant, and animal, a marine animal, a vertebrate, a mammal, or a human.

125. A method of amplifying genomes, the method comprising,

bringing into contact a single primer, DNA polymerase, and a genomic nucleic acid sample, and incubating the genomic nucleic acid sample under conditions that promote replication of nucleic acid molecules in the genomic nucleic acid sample,

wherein the primer has a specific nucleotide sequence, wherein the genomic nucleic acid sample comprises all or a substantial portion of a genome, wherein replication of nucleic acid molecules in the genomic nucleic acid sample proceeds by strand displacement replication, wherein the genomic nucleic acid sample has a sequence complexity of at least 1×

10⁹ nucleotides, wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in replication of at least 0.01% of the nucleic acid sequences in the genomic nucleic acid sample.

126. The method of claim 125 wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in replication of at least 0.1% of the nucleic acid sequences in the genomic nucleic acid sample, at least 1% of the nucleic acid sequences in the genomic nucleic acid sample, at least 5% of the nucleic acid sequences in the genomic nucleic acid sample, at least 10% of the nucleic acid sequences in the genomic nucleic acid sample, at least 20% of the nucleic acid sequences in the genomic nucleic acid sample, at least 30% of the nucleic acid sequences in the genomic nucleic acid sample, at least 40% of the nucleic acid sequences in the genomic nucleic acid sample, at least 50% of the nucleic acid sequences in the genomic nucleic acid sample, at least 60% of the nucleic acid sequences in the genomic nucleic acid sample, at least 70% of the nucleic acid sequences in the genomic nucleic acid sample, at least 80% of the nucleic acid sequences in the genomic nucleic acid sample, at least 90% of the nucleic acid sequences in the genomic nucleic acid sample, at least 95% of the nucleic acid sequences in the genomic nucleic acid sample, at least 96% of the nucleic acid sequences in the genomic nucleic acid sample, at least 97% of the nucleic acid sequences in the genomic nucleic acid sample, at least 98% of the nucleic acid sequences in the genomic nucleic acid sample, or at least 99% of the nucleic acid sequences in the genomic nucleic acid sample.

127. A method of amplifying genomes, the method comprising,

bringing into contact a single primer, DNA polymerase, and a genomic nucleic acid sample, and incubating the genomic nucleic acid sample under conditions that promote replication of nucleic acid molecules in the genomic nucleic acid sample,

wherein the primer has a specific nucleotide sequence, wherein the genomic nucleic acid sample comprises all or a substantial portion of a genome, wherein replication of nucleic acid molecules in the genomic nucleic acid sample proceeds by strand displacement replication, wherein the genomic nucleic acid sample has a sequence complexity of at least 1×

10⁸ nucleotides, wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in replication of at least 0.1% of the nucleic acid sequences in the genomic nucleic acid sample.

128. The method of claim 127 wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in replication of at least 1% of the nucleic acid sequences in the genomic nucleic acid sample, at least 5% of the nucleic acid sequences in the genomic nucleic acid sample, at least 10% of the nucleic acid sequences in the genomic nucleic acid sample, at least 20% of the nucleic acid sequences in the genomic nucleic acid sample, at least 30% of the nucleic acid sequences in the genomic nucleic acid sample, at least 40% of the nucleic acid sequences in the genomic nucleic acid sample, at least 50% of the nucleic acid sequences in the genomic nucleic acid sample, at least 60% of the nucleic acid sequences in the genomic nucleic acid sample, at least 70% of the nucleic acid sequences in the genomic nucleic acid sample, at least 80% of the nucleic acid sequences in the genomic nucleic acid sample, at least 90% of the nucleic acid sequences in the genomic nucleic acid sample, at least 95% of the nucleic acid sequences in the genomic nucleic acid sample, at least 96% of the nucleic acid sequences in the genomic nucleic acid sample, at least 97% of the nucleic acid sequences in the genomic nucleic acid sample, at least 98% of the nucleic acid sequences in the genomic nucleic acid sample, or at least 99% of the nucleic acid sequences in the genomic nucleic acid sample.

129. A method of amplifying genomes, the method comprising,

bringing into contact a single primer, DNA polymerase, and a genomic nucleic acid sample, and incubating the genomic nucleic acid sample under conditions that promote replication of nucleic acid molecules in the genomic nucleic acid sample,

wherein the primer has a specific nucleotide sequence, wherein the genomic nucleic acid sample comprises all or a substantial portion of a genome, wherein replication of nucleic acid molecules in the genomic nucleic acid sample proceeds by strand displacement replication, wherein the genomic nucleic acid sample has a sequence complexity of at least 1×

10⁷ nucleotides, wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in replication of at least 1% of the nucleic acid sequences in the genomic nucleic acid sample.

130. The method of claim 129 wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in replication of at least 5% of the nucleic acid sequences in the genomic nucleic acid sample, at least 10% of the nucleic acid sequences in the genomic nucleic acid sample, at least 20% of the nucleic acid sequences in the genomic nucleic acid sample, at least 30% of the nucleic acid sequences in the genomic nucleic acid sample, at least 40% of the nucleic acid sequences in the genomic nucleic acid sample, at least 50% of the nucleic acid sequences in the genomic nucleic acid sample, at least 60% of the nucleic acid sequences in the genomic nucleic acid sample, at least 70% of the nucleic acid sequences in the genomic nucleic acid sample, at least 80% of the nucleic acid sequences in the genomic nucleic acid sample, at least 90% of the nucleic acid sequences in the genomic nucleic acid sample, at least 95% of the nucleic acid sequences in the genomic nucleic acid sample, at least 96% of the nucleic acid sequences in the genomic nucleic acid sample, at least 97% of the nucleic acid sequences in the genomic nucleic acid sample, at least 98% of the nucleic acid sequences in the genomic nucleic acid sample, or at least 99% of the nucleic acid sequences in the genomic nucleic acid sample.

131. A method of amplifying genomes, the method comprising,

bringing into contact a single primer, DNA polymerase, and a genomic nucleic acid sample, and incubating the genomic nucleic acid sample under conditions that promote replication of nucleic acid molecules in the genomic nucleic acid sample,

wherein the primer has a specific nucleotide sequence, wherein the genomic nucleic acid sample comprises all or a substantial portion of a genome, wherein replication of nucleic acid molecules in the genomic nucleic acid sample proceeds by strand displacement replication, wherein the genomic nucleic acid sample has a sequence complexity of at least 1×

10⁶ nucleotides, wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in replication of at least 10% of the nucleic acid sequences in the genomic nucleic acid sample.

132. The method of claim 131 wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in replication of at least 20% of the nucleic acid sequences in the genomic nucleic acid sample, at least 30% of the nucleic acid sequences in the genomic nucleic acid sample, at least 40% of the nucleic acid sequences in the genomic nucleic acid sample, at least 50% of the nucleic acid sequences in the genomic nucleic acid sample, at least 60% of the nucleic acid sequences in the genomic nucleic acid sample, at least 70% of the nucleic acid sequences in the genomic nucleic acid sample, at least 80% of the nucleic acid sequences in the genomic nucleic acid sample, at least 90% of the nucleic acid sequences in the genomic nucleic acid sample, at least 95% of the nucleic acid sequences in the genomic nucleic acid sample, at least 96% of the nucleic acid sequences in the genomic nucleic acid sample, at least 97% of the nucleic acid sequences in the genomic nucleic acid sample, at least 98% of the nucleic acid sequences in the genomic nucleic acid sample, or at least 99% of the nucleic acid sequences in the genomic nucleic acid sample.

133. A method of amplifying genomes, the method comprising,

bringing into contact a single primer, DNA polymerase, and a genomic nucleic acid sample, and incubating the genomic nucleic acid sample under conditions that promote replication of nucleic acid molecules in the genomic nucleic acid sample,

wherein the primer has a specific nucleotide sequence, wherein the genomic nucleic acid sample comprises all or a substantial portion of a genome, wherein replication of nucleic acid molecules in the genomic nucleic acid sample proceeds by strand displacement replication, wherein the genomic nucleic acid sample has a sequence complexity of at least 1×

10⁵ nucleotides, wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in replication of at least 80% of the nucleic acid sequences in the genomic nucleic acid sample.

134. The method of claim 133 wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in replication of at least 90% of the nucleic acid sequences in the genomic nucleic acid sample, at least 95% of the nucleic acid sequences in the genomic nucleic acid sample, at least 96% of the nucleic acid sequences in the genomic nucleic acid sample, at least 97% of the nucleic acid sequences in the genomic nucleic acid sample, at least 98% of the nucleic acid sequences in the genomic nucleic acid sample, or at least 99% of the nucleic acid sequences in the genomic nucleic acid sample.

135. A method of amplifying genomes, the method comprising,

bringing into contact a single primer, DNA polymerase, and a genomic nucleic acid sample, and incubating the genomic nucleic acid sample under conditions that promote replication of nucleic acid molecules in the genomic nucleic acid sample,

wherein the primer has a specific nucleotide sequence, wherein the genomic nucleic acid sample comprises all or a substantial portion of a genome, wherein replication of nucleic acid molecules in the genomic nucleic acid sample proceeds by strand displacement replication, wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in a locus representation of at least 10% for at least 5 different loci.

136. The method of claim 135 wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in a locus representation of at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% for at least 5 different loci.

137. The method of claim 135 wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in a locus representation of at least 10% for at least 6 different loci, at least 7 different loci, at least 8 different loci, at least 9 different loci, at least 10 different loci, at least 11 different loci, at least 12 different loci, at least 13 different loci, at least 14 different loci, at least 15 different loci, at least 16 different loci, at least 17 different loci, at least 18 different loci, at least 19 different loci, at least 20 different loci, at least 25 different loci, at least 30 different loci, at least 40 different loci, at least 50 different loci, at least 75 different loci, or at least 100 different loci.

138. The method of claim 135 wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in an amplification bias of less than 50-fold.

139. The method of claim 138 wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in an amplification bias of less than 45-fold, less than 40-fold, less than 35-fold, less than 30-fold, less than 25-fold, less than 20-fold, less than 19-fold, less than 18-fold, less than 17-fold, less than 16-fold, less than 15-fold, less than 14-fold, less than 13-fold, less than 12-fold, less than 1′

-fold, less than 10-fold, less than 9-fold, less than 8-fold, less than 7-fold, less than 6-fold, less than 5-fold, or less than 4-fold.

140. The method of claim 138 wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in an amplification bias of less than 50-fold for at least 5 different loci, for at least 6 different loci, at least 7 different loci, at least 8 different loci, at least 9 different loci, at least 10 different loci, at least 11 different loci, at least 12 different loci, at least 13 different loci, at least 14 different loci, at least 15 different loci, at least 16 different loci, at least 17 different loci, at least 18 different loci, at least 19 different loci, at least 20 different loci, at least 25 different loci, at least 30 different loci, at least 40 different loci, at least 50 different loci, at least 75 different loci, or at least 100 different loci.

141. A method of amplifying nucleic acid samples of high sequence complexity, the method comprising,

bringing into contact a single primer, DNA polymerase, and a nucleic acid sample, and incubating the nucleic acid sample under conditions that promote replication of nucleic acid molecules in the nucleic acid sample,

wherein the primer has a specific nucleotide sequence, wherein the nucleic acid sample has a sequence complexity of at least 1×

10³ nucleotides, wherein replication of nucleic acid molecules in the nucleic acid sample proceeds by strand displacement replication, wherein replication of the nucleic acid molecules in the nucleic acid sample results in a sequence representation of at least 10% for at least 5 different target sequences.

142. The method of claim 141 wherein replication of the nucleic acid molecules in the nucleic acid sample results in a sequence representation of at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% for at least 5 different target sequences.

143. The method of claim 141 wherein replication of the nucleic acid molecules in the nucleic acid sample results in a sequence representation of at least 10% for at least 6 different target sequences, at least 7 different target sequences, at least 8 different target sequences, at least 9 different target sequences, at least 10 different target sequences, at least 11 different target sequences, at least 12 different target sequences, at least 13 different target sequences, at least 14 different target sequences, at least 15 different target sequences, at least 16 different target sequences, at least 17 different target sequences, at least 18 different target sequences, at least 19 different target sequences, at least 20 different target sequences, at least 25 different target sequences, at least 30 different target sequences, at least 40 different target sequences, at least 50 different target sequences, at least 75 different target sequences, or at least 100 different target sequences.

144. The method of claim 141 wherein replication of the nucleic acid molecules in the nucleic acid sample results in an amplification bias of less than 50-fold.

145. The method of claim 144 wherein replication of the nucleic acid molecules in the nucleic acid sample results in an amplification bias of less than 45-fold, less than 40-fold, less than 35-fold, less than 30-fold, less than 25-fold, less than 20-fold, less than 19-fold, less than 18-fold, less than 17-fold, less than 16-fold, less than 15-fold, less than 14-fold, less than 13-fold, less than 12-fold, less than 11-fold, less than 10-fold, less than 9-fold, less than 8-fold, less than 7-fold, less than 6-fold, less than 5-fold, or less than 4-fold.

146. The method of claim 144 wherein replication of the nucleic acid molecules in the nucleic acid sample results in an amplification bias of less than 50-fold for at least 5 different target sequences, for at least 6 different target sequences, at least 7 different target sequences, at least 8 different target sequences, at least 9 different target sequences, at least 10 different target sequences, at least 11 different target sequences, at least 12 different target sequences, at least 13 different target sequences, at least 14 different target sequences, at least 15 different target sequences, at least 16 different target sequences, at least 17 different target sequences, at least 18 different target sequences, at least 19 different target sequences, at least 20 different target sequences, at least 25 different target sequences, at least 30 different target sequences, at least 40 different target sequences, at least 50 different target sequences, at least 75 different target sequences, or at least 100 different target sequences.

147. A method of amplifying genomes, the method comprising,

bringing into contact a set of primers, DNA polymerase, and a genomic nucleic acid sample, and incubating the genomic nucleic acid sample under conditions that promote replication of nucleic acid molecules in the genomic nucleic acid sample,

wherein the set of primers comprises one or more selected primers, wherein each selected primer has a specific nucleotide sequence, wherein the genomic nucleic acid sample comprises all or a substantial portion of a genome, wherein replication of nucleic acid molecules in the genomic nucleic acid sample proceeds by strand displacement replication, wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in replication of all or a substantial fraction of the nucleic acid molecules in the genomic nucleic acid sample,

wherein each selected primer in the set can produce replication of at least 80% of the nucleic acid sequences in a selection nucleic acid sample when the primer, DNA polymerase, and the selection nucleic acid sample are brought into contact and incubated under conditions that promote replication of nucleic acid molecules in the selection nucleic acid sample, wherein the selection nucleic acid sample has a sequence complexity of at least 1×

10⁸ nucleotides.

148. The method of claim 147 wherein the set of primers further comprises at least one additional primer.

149. The method of claim 147 wherein the set of primers further comprises at least one non-selected primer, wherein the non-selected primer produces replication of less than 80% of the nucleic acid sequences in a selection nucleic acid sample when the primer, DNA polymerase, and the selection nucleic acid sample are brought into contact and incubated under conditions that promote replication of nucleic acid molecules in the selection nucleic acid sample.

150. A method of amplifying genomes, the method comprising,

bringing into contact a set of primers, DNA polymerase, and a genomic nucleic acid sample, and incubating the genomic nucleic acid sample under conditions that promote replication of nucleic acid molecules in the genomic nucleic acid sample,

wherein the set of primers comprises one or more selected primers, wherein each selected primer has a specific nucleotide sequence, wherein the genomic nucleic acid sample comprises all or a substantial portion of a genome, wherein replication of nucleic acid molecules in the genomic nucleic acid sample proceeds by strand displacement replication, wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in replication of all or a substantial fraction of the nucleic acid molecules in the genomic nucleic acid sample,

wherein each selected primer in the set can produce an amplification bias of less than 20-fold for at least 10 nucleic acid sequences in a selection nucleic acid sample when the primer, DNA polymerase, and the selection nucleic acid sample are brought into contact and incubated under conditions that promote replication of nucleic acid molecules in the selection nucleic acid sample, wherein the selection nucleic acid sample has a sequence complexity of at least 1×

10⁸ nucleotides.

151. A method of amplifying genomes, the method comprising,

bringing into contact a set of primers, DNA polymerase, and a genomic nucleic acid sample, and incubating the genomic nucleic acid sample under conditions that promote replication of nucleic acid molecules in the genomic nucleic acid sample,

wherein the set of primers comprises one or more selected primers, wherein each selected primer has a specific nucleotide sequence, wherein the genomic nucleic acid sample comprises all or a substantial portion of a genome, wherein replication of nucleic acid molecules in the genomic nucleic acid sample proceeds by strand displacement replication, wherein replication of the nucleic acid molecules in the genomic nucleic acid sample results in replication of all or a substantial fraction of the nucleic acid molecules in the genomic nucleic acid sample,

wherein each selected primer in the set can produce a sequence representation of at least 10% for at least 10 nucleic acid sequences in a selection nucleic acid sample when the primer, DNA polymerase, and the selection nucleic acid sample are brought into contact and incubated under conditions that promote replication of nucleic acid molecules in the selection nucleic acid sample, wherein the selection nucleic acid sample has a sequence complexity of at least 1×

10⁸ nucleotides.

152. A method of amplifying nucleic acids, the method comprising,

bringing into contact a set of primers, DNA polymerase, and a nucleic acid sample, and incubating the nucleic acid sample under conditions that promote replication of nucleic acid molecules in the nucleic acid sample,

wherein the set of primers comprises one or more selected primers, wherein each selected primer has a specific nucleotide sequence, wherein replication of nucleic acid molecules in the nucleic acid sample proceeds by strand displacement replication, wherein replication of the nucleic acid molecules in the nucleic acid sample results in replication of all or a substantial fraction of the nucleic acid molecules in the nucleic acid sample,

wherein each selected primer in the set can produce replication of at least 80% of the nucleic acid sequences in a selection nucleic acid sample when the primer, DNA polymerase, and the selection nucleic acid sample are brought into contact and incubated under conditions that promote replication of nucleic acid molecules in the selection nucleic acid sample, wherein the selection nucleic acid sample has a sequence complexity of at least 1×

10⁸ nucleotides.

153. The method of claim 152 wherein the set of primers further comprises at least one additional primer.

154. The method of claim 152 wherein the set of primers further comprises at least one non-selected primer, wherein the non-selected primer produces replication of less than 80% of the nucleic acid sequences in a selection nucleic acid sample when the primer, DNA polymerase, and the selection nucleic acid sample are brought into contact and incubated under conditions that promote replication of nucleic acid molecules in the selection nucleic acid sample.

155. The method of claim 152 wherein the nucleic acid sample has a sequence complexity of at least 1×

10³ nucleotides.

156. A method of amplifying nucleic acids, the method comprising,

bringing into contact a set of primers, DNA polymerase, and a nucleic acid sample, and incubating the nucleic acid sample under conditions that promote replication of nucleic acid molecules in the nucleic acid sample,

wherein the set of primers comprises one or more selected primers, wherein each selected primer has a specific nucleotide sequence, wherein replication of nucleic acid molecules in the nucleic acid sample proceeds by strand displacement replication, wherein replication of the nucleic acid molecules in the nucleic acid sample results in replication of all or a substantial fraction of the nucleic acid molecules in the nucleic acid sample,

wherein each selected primer in the set can produce an amplification bias of less than 20-fold for at least 10 nucleic acid sequences in a selection nucleic acid sample when the primer, DNA polymerase, and the selection nucleic acid sample are brought into contact and incubated under conditions that promote replication of nucleic acid molecules in the selection nucleic acid sample, wherein the selection nucleic acid sample has a sequence complexity of at least 1×

10⁸ nucleotides.

157. A method of amplifying nucleic acids, the method comprising,

bringing into contact a set of primers, DNA polymerase, and a nucleic acid sample, and incubating the nucleic acid sample under conditions that promote replication of nucleic acid molecules in the nucleic acid sample,

wherein the set of primers comprises one or more selected primers, wherein each selected primer has a specific nucleotide sequence, wherein replication of nucleic acid molecules in the nucleic acid sample proceeds by strand displacement replication, wherein replication of the nucleic acid molecules in the nucleic acid sample results in replication of all or a substantial fraction of the nucleic acid molecules in the nucleic acid sample,

wherein each selected primer in the set can produce a sequence representation of at least 10% for at least 10 nucleic acid sequences in a selection nucleic acid sample when the primer, DNA polymerase, and the selection nucleic acid sample are brought into contact and incubated under conditions that promote replication of nucleic acid molecules in the selection nucleic acid sample, wherein the selection nucleic acid sample has a sequence complexity of at least 1×

10⁸ nucleotides.