Next-Generation Sequencing (NGS): A Revolutionary Technology in Pharmacogenomics and Personalized Medicine

  • Huixiao Hong
  • Wenqian Zhang
  • Zhenqiang Su
  • Jie Shen
  • Weigong Ge
  • Baitang Ning
  • Hong Fang
  • Roger Perkins
  • Leming Shi
  • Weida Tong


Personalized medicine can improve healthcare by selecting treatments that are more efficacious or induce less adverse responses in stratified cohorts sharing differentiating genetic traits. Personalized medicine has advanced quickly, providing both opportunities and challenges for the pharmaceutical industry and regulatory agencies in the twenty-first century. Pharmacogenomics is the key to the identification of personalized medicine biomarkers useful for efficacy and safety that can ultimately be clinically applied for diagnosis, prognosis, and treatment selection. The requisite technologies and approaches needed for pharmacogenomics have steadily advanced over more than a decade in terms of both capability and cost. In 2005, 454 Life Sciences announced their sequencing-by-synthesis technology, the first next-generation sequencing (NGS) platform, proclaiming the breakthrough in sequencing technology. NGS is revolutionizing pharmacogenomics and personalized medicine, with several NGS platforms commercially available. Illumina, Roche 454, and Applied Biosystems are the current major vendors. This chapter will characterize the technical assessments of NGS, including comparative analyses across platforms, experimental protocols, algorithms for mapping short reads to reference genomes, strategies for quantitatively measuring expression levels, and methods for detecting single nucleotide polymorphisms (SNPs). Different pipelines and software packages for analyzing NGS data will be reviewed. Examples and a prospective outlook on applications of NGS in pharmacogenomics and personalized medicine will be given.


Reference Genome Personalized Medicine KRAS Gene Short Read Sequence Measure Expression Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Ansorge WJ (2009) Next-generation DNA sequencing techniques. Nat Biotechnol 25:195–203Google Scholar
  2. Armstrong B, Stewart M, Mazumder A (2000) Suspension arrays for high throughput, multiplexed single nucleotide polymorphism genotyping. Cytometry 40:102–108PubMedGoogle Scholar
  3. Bao H, Guo H, Wang J, Zhou R, Lu X, Shi S (2009) MapView: visualization of short reads alignment on a desktop computer. Bioinformatics 25:1554–1555PubMedGoogle Scholar
  4. Barany F (1991) Genetic disease detection and DNA amplification using cloned thermostable ligase. Proc Natl Acad Sci USA 88:189–193PubMedCentralPubMedGoogle Scholar
  5. Barbato C, Giorge C, Catalanotto C, Cogoni C (2008) Thinking about RNA? MicroRNAs in the brain. Mamm Genome 19:541–551PubMedGoogle Scholar
  6. Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A (2009) An operational definition of epigenetics. Genes Dev 23:781–783PubMedGoogle Scholar
  7. Beveridge NJ, Gardiner E, Carroll AP et al (2009) Schizophrenia is associated with an increase in cortical microRNA biogenesis. Mol Psychiatry 15:1176–1189PubMedCentralPubMedGoogle Scholar
  8. Bird A (2007) Perceptions of epigenetics. Nature 447:396–398PubMedGoogle Scholar
  9. Brunner AL, Johnson DS, Kim SW et al (2009) Distinct DNA methylation patterns characterize differentiated human embryonic stem cells and developing human fetal liver. Genome Res 19:1044–1056PubMedCentralPubMedGoogle Scholar
  10. Butler J, MacCallum I, Kleber M, Shlyakhter IA, Belmonte MK, Lander ES, Nusbaum C, Jaffe DB (2008) ALLPATHS: de novo assembly of whole-genome shotgun microreads. Genome Res 18:810–820PubMedCentralPubMedGoogle Scholar
  11. Buyse M, Loi S, Van’t Veer L et al (2006) Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst 98:1183–1192PubMedGoogle Scholar
  12. Chaisson MJ, Pevzner PA (2008) Short read fragment assembly of bacterial genomes. Genome Res 18:324–330PubMedCentralPubMedGoogle Scholar
  13. Chaisson MJ, Brinza D, Pevzner PA (2009) De novo fragment assembly with short mate-paired reads: does the read length matter? Genome Res 19:336–346PubMedCentralPubMedGoogle Scholar
  14. Chepelev I, Wei G, Tang Q, Zhao K (2009) Detection of single nucleotide variations in expressed exons of the human genome using RNA-Seq. Nucleic Acids Res 37:e106PubMedCentralPubMedGoogle Scholar
  15. Chevreux B, Pfisterer T, Drescher B, Driesel AJ, Müller WEG et al (2004) Using the miraEST assembler for reliable and automated mRNA transcript assembly and SNP detection in sequenced ESTs. Genome Res 14:1147–1159PubMedCentralPubMedGoogle Scholar
  16. Chistoserdova L (2010) Recent progress and new challenges in metagenomics for biotechnology. Biotechnol Lett 32:1351–1359PubMedGoogle Scholar
  17. Cloonan N, Forrest AR, Kolle G et al (2008) Stem cell transcriptome profiling via massive-scale mRNA sequencing. Nat Methods 5:613–619PubMedGoogle Scholar
  18. Cronin MT, Fucini RV, Kim SM, Masino RS, Wespi RM, Miyada CG (1996) Cystic fibrosis mutation detection by hybridization to light-generated DNA probe arrays. Hum Mutat 7:244–255PubMedGoogle Scholar
  19. Daly AK, Donaldson PT, Bhatnagar P et al (2009) HLA-B*5701 genotype is a major determinant of drug induced liver injury due to flucloxacillin. Nat Genet 41:816–819PubMedGoogle Scholar
  20. Das SK, Austin MD, Akana MC, Deshpande P, Cao H, Xiao M (2010) Single molecule linear analysis of DNA in nano-channel labeled with sequence specific fluorescent probes. Nucleic Acids Res 38:e177PubMedCentralPubMedGoogle Scholar
  21. Denoeud F, Aury JM, Da Silva C et al (2008) Annotating genomes with massive-scale RNA sequencing. Genome Biol 9:R175PubMedCentralPubMedGoogle Scholar
  22. Dreyer JL (2010) New insights into the roles of microRNAs in drug addiction and neuroplasticity. Genome Med 2:92PubMedCentralPubMedGoogle Scholar
  23. Duffy MJ, Napieralski R, Martens JW et al (2009) Methylated genes as new cancer biomarkers. Eur J Cancer 45:335–346PubMedGoogle Scholar
  24. Fasanaro P, Greco S, Ivan M, Capogrossi MC, Martelli F (2010) MicroRNA: emerging therapeutic targets in acute ischemic diseases. Pharmacol Ther 125:92–104PubMedGoogle Scholar
  25. Fierer N, Lauber C, Zhou N et al (2010) Forensic identification using skin bacterial communities. Proc Natl Acad Sci USA 107:6477–6481PubMedCentralPubMedGoogle Scholar
  26. Frazer KA, Murray SS, Schork NJ, Topol EJ (2009) Human genetic variation and its contribution to complex traits. Nat Rev Genet 10:241–251PubMedGoogle Scholar
  27. Glas AM, Floore A, Delahaye LJ et al (2006) Converting a breast cancer microarray signature into a high-throughput diagnostic test. BMC Genomics 7:278PubMedCentralPubMedGoogle Scholar
  28. Goldstein JA, Blaisdell J (1996) Genetic tests which identify the principal defects in CYP2C19 responsible for the polymorphism in mephenytoin metabolism. Methods Enzymol 272:210–218PubMedGoogle Scholar
  29. Goldstein LJ, Gray R, Badve S et al (2008) Prognostic utility of the 21-gene assay in hormone receptor-positive operable breast cancer compared with classical clinicopathologic features. J Clin Oncol 26:4063–4071PubMedCentralPubMedGoogle Scholar
  30. Guttman M, Amit I, Garber M et al (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458:223–227PubMedCentralPubMedGoogle Scholar
  31. Guttman M, Garber M, Levin JZ et al (2010) Ab initio reconstruction of cell type-specific transcriptomes in mouse reveals the conserved multi-exonic structure of lincRNAs. Nat Biotechnol 28:503–510PubMedCentralPubMedGoogle Scholar
  32. Harris L, Fritsche H, Mennel R et al (2007) American Society of Clinical Oncology 2007 update of recommendations for the use of tumour markers in breast cancer. J Clin Oncol 25:5287–5312PubMedGoogle Scholar
  33. Harris TD, Buzby PR, Babcock H et al (2008) Single-molecule DNA sequencing of a viral genome. Science 320:106–109PubMedGoogle Scholar
  34. He L, Thomson JM, Hemann MT et al (2005) A microRNA polycistron as a potential human oncogene. Nature 435:828–833PubMedGoogle Scholar
  35. Hennessy E, O’Driscoll L (2008) Molecular medicine of microRNAs: structure, function, and implications for diabetes. Expert Rev Mol Med 10:e24PubMedGoogle Scholar
  36. Hernandez D, François P, Farinelli L, Osterås M, Schrenzel J (2008) De novo bacterial genome sequencing: millions of very short reads assembled on a desktop. Genome Res 18:802–809PubMedCentralPubMedGoogle Scholar
  37. Higuchi R, Dollinger G, Walsh PS, Griffith R (1992) Simultaneous amplification and detection of specific DNA sequences. Biotechnology (N Y) 10:413–417Google Scholar
  38. Hiller D, Jiang H, Xu W, Wong WH (2009) Identifiability of isoform deconvolution from junction arrays and RNA-Seq. Bioinformatics 25:3056–3059PubMedCentralPubMedGoogle Scholar
  39. Hittinger CT, Johnston M, Tossberg JT, Rokas A (2010) Leveraging skewed transcript abundance by RNA-Seq to increase the genomic depth of the tree of life. Proc Natl Acad Sci USA 107:1476–1481PubMedCentralPubMedGoogle Scholar
  40. Hodges E, Xuan Z, Balija V et al (2007) Genome-wide in situ exon capture for selective re-sequencing. Nat Genet 39:1522–1527PubMedGoogle Scholar
  41. Holland PM, Abramson RD, Watson R, Gelfand DH (1991) Detection of specific polymerase chain reaction product by utilizing the 5′–3′ exonuclease activity of Thermus aquaticus DNA polymerase. Proc Natl Acad Sci USA 88:7276–7280PubMedCentralPubMedGoogle Scholar
  42. Hong H, Goodsaid F, Shi L, Tong W (2010) Molecular biomarkers: a US FDA effort. Biomarkers Med 4:215–225Google Scholar
  43. Hormozdiari F, Alkan C, Eichler EE, Sahinalp SC (2009) Combinatorial algorithms for structural variation detection in high-throughput sequenced genomes. Genome Res 19:1270–1278PubMedCentralPubMedGoogle Scholar
  44. Huang W, Marth G (2008) EagleView: a genome assembly viewer for next-generation sequencing technologies. Genome Res 18:1538–1543PubMedCentralPubMedGoogle Scholar
  45. International Human Genome Sequencing Consortium (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921Google Scholar
  46. Irizarry RA, Ladd-Acosta C, Wen B et al (2009) The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 41:178–186PubMedCentralPubMedGoogle Scholar
  47. Jacquier A (2009) The complex eukaryotic transcriptome: unexpected pervasive transcription and novel small RNAs. Nat Rev Genet 10:833–844PubMedGoogle Scholar
  48. Ji W, Foo JN, O’Roak BJ et al (2008) Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet 40:592–599PubMedCentralPubMedGoogle Scholar
  49. Jiang H, Wong WH (2008) SeqMap: mapping massive amount of oligonucleotides to the genome. Bioinformatics 24:2395–2396PubMedCentralPubMedGoogle Scholar
  50. Jiang Q, Wang Y, Hao Y et al (2009) miR2Disease: a manually curated database for microRNA deregulation in human disease. Nucleic Acids Res 37:D98–D104PubMedCentralPubMedGoogle Scholar
  51. Johnson DS, Mortazavi A, Myers RM, Wold B (2007) Genome-wide mapping of in vivo protein-DNA interactions. Science 316:1497–1502PubMedGoogle Scholar
  52. Jorgensen JT (2009) New era of personalized medicine: a 10-year anniversary. Oncologist 14:557–558PubMedGoogle Scholar
  53. Kahn SL, Ronnett BM, Gravitt PE, Gustafson KS (2008) Quantitative methylation-specific PCR for the detection of aberrant DNA methylation in liquid-based Pap tests. Cancer 114:57–64PubMedCentralPubMedGoogle Scholar
  54. Kato K (2009) Impact of the next generation DNA sequences. Int J Clin Exp Med 2:193–202PubMedCentralPubMedGoogle Scholar
  55. Kaufmann K, Muino JM, Osteras M et al (2010) Chromatin immunoprecipitation (ChIP) of plant transcription factors followed by sequencing (ChIP-SEQ) or hybridization to whole genome arrays (ChIP-CHIP). Nat Protoc 5:457–472PubMedGoogle Scholar
  56. Kharchenko PV, Tolstorukov MY, Park PJ (2008) Design and analysis of ChIP-seq experiments for DNA-binding proteins. Nat Biotechnol 26:1351–1359PubMedCentralPubMedGoogle Scholar
  57. Kim MJ, Huang SM, Meyer UA, Rahman A, Lesko LJ (2009) A regulatory science perspective on warfarin therapy: a pharmacogenetic opportunity. J Clin Pharmacol 49:138–146PubMedGoogle Scholar
  58. Kindmark A, Jawaid A, Harbron CG et al (2008) Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J 8:186–195PubMedGoogle Scholar
  59. Kondo Y, Shen L, Cheng AS et al (2008) Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. Nat Genet 40:741–750PubMedGoogle Scholar
  60. Kranenburg O (2005) The KRAS oncogene: past, present, and future. Biochim Biophys Acta 1756:81–82PubMedGoogle Scholar
  61. Langmead B, Trapnell C, Pop M, Salzberg SL (2009) Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 10:R25PubMedCentralPubMedGoogle Scholar
  62. Langreth R, Waldholz M (1999) New era of personalized medicine: targeting drugs for each unique genetic profile. Oncologist 4:426–427PubMedGoogle Scholar
  63. Lavedan C, Licamele L, Volpi S et al (2008) Association of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study. Mol Psychiatry 14:804–819PubMedGoogle Scholar
  64. Lee W, Jiang Z, Liu J et al (2010) The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature 465:473–477PubMedGoogle Scholar
  65. Li R, Li Y, Kristiansen K, Wang J (2008a) SOAP: short oligonucleotide alignment program. Bioinformatics 24:713–714PubMedGoogle Scholar
  66. Li H, Ruan J, Durbin R (2008b) Mapping short DNA sequencing reads and calling variants using mapping quality scores. Genome Res 18:1851–1858PubMedCentralPubMedGoogle Scholar
  67. Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754–1760PubMedCentralPubMedGoogle Scholar
  68. Li JB, Levanon EY, Yoon JK et al (2009a) Genome-wide identification of human RNA editing sites by parallel DNA capturing and sequencing. Science 324:1210–1213PubMedGoogle Scholar
  69. Li R, Li Y, Fang X, Yang H, Wang J, Kristiansen K, Wang J (2009b) SNP detection for massively parallel whole-genome re-sequencing. Genome Res 19:1124–1132PubMedCentralPubMedGoogle Scholar
  70. Li H, Homer N (2010) A survey of sequence alignment algorithms for next-generation sequencing. Brief Bioinform 11:473–483PubMedCentralPubMedGoogle Scholar
  71. Li R, Zhu H, Ruan J, Qian W, Fang X, Shi Z et al (2010a) De novo assembly of human genomes with massively parallel short read sequencing. Genome Res 20:265–272PubMedCentralPubMedGoogle Scholar
  72. Li R, Fan W, Tian G et al (2010b) The sequence and de novo assembly of the giant panda genome. Nature 463:311–317PubMedGoogle Scholar
  73. Li B, Ruotti V, Stewart RM, Thomson JA, Dewey CN (2010c) RNA-Seq gene expression estimation with read mapping uncertainty. Bioinformatics 26:493–500PubMedCentralPubMedGoogle Scholar
  74. Licatalosi DD, Darnell RB (2010) RNA processing and its regulation: global insights into biological networks. Nat Rev Genet 11:75–87PubMedCentralPubMedGoogle Scholar
  75. Lipson D, Capelletti M, Yelensky R et al (2012) Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med 18:382–384PubMedGoogle Scholar
  76. Lockhart DJ, Dong H, Byrne MC et al (1996) Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat Biotechnol 14:1675–1680PubMedGoogle Scholar
  77. Lu J, Getz G, Miska EA et al (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838PubMedGoogle Scholar
  78. Lucas A, Nolan D, Mallal S (2007) HLA-B*5701 screening for susceptibility to abacavir hypersensitivity. J Antimicrob Chemother 59:591–593PubMedGoogle Scholar
  79. Mallal S, Phillips E, Carosi G et al (2008) HLA-B*5701 screening for susceptibility to abacavir hypersensitivity. N Engl J Med 358:568–569PubMedGoogle Scholar
  80. Margulies M, Egholm M, Altman WE et al (2005) Genome sequencing in microfabricated high-density picolitre reactors. Nature 437:376–380PubMedCentralPubMedGoogle Scholar
  81. Marioni JC, Mason CE, Mane SM, Stephens M, Gilad Y (2008) RNA-seq: an assessment of technical reproducibility and comparison with gene expression arrays. Genome Res 18:1509–1517PubMedCentralPubMedGoogle Scholar
  82. McGrath JP, Capon DJ, Smith DH et al (1983) Structure and organization of the human Ki-ras proto-oncogene and a related processed pseudogene. Nature 304:501–506PubMedGoogle Scholar
  83. Medina PP, Slack FJ (2008) MicroRNAs and cancer: an overview. Cell Cycle 7:2485–2492PubMedGoogle Scholar
  84. Metzker ML (2010) Sequencing technologies – the next generation. Nat Rev Genet 11:31–46PubMedGoogle Scholar
  85. Mocali S, Benedetti A (2010) Exploring research frontiers in microbiology: the challenge of metagenomics in soil microbiology. Res Microbiol 161:497–505PubMedGoogle Scholar
  86. Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B (2008) Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods 5:621–628PubMedGoogle Scholar
  87. Motulsky AG (1957) Drug reactions enzymes and biochemical genetics. J Am Med Assoc 165:835–837PubMedGoogle Scholar
  88. Nagalakshmi U, Wang Z, Waern K, Shou C, Raha D, Gerstein M, Snyder M (2008) The transcriptional landscape of the yeast genome defined by RNA sequencing. Science 320:1344–1349PubMedCentralPubMedGoogle Scholar
  89. Nana-Sinkam SP, Croce CM (2011) MicroRNAs as therapeutic targets in cancer. Transl Res 157:216–225PubMedGoogle Scholar
  90. Newton CR, Graham A, Heptinstall LE et al (1989) Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res 17:2503–2516PubMedCentralPubMedGoogle Scholar
  91. Ozcelik H, Shi X, Mc C et al (2012) Long-range PCR and next-generation sequencing of Brca1 and Brca2 in breast cancer. J Mol Diagn 14:467–475PubMedGoogle Scholar
  92. Paik S, Shak S, Tang G et al (2004) A multi-gene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817–2826PubMedGoogle Scholar
  93. Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ (2008) Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet 40:1413–1415PubMedGoogle Scholar
  94. Park PJ (2009) ChIP–seq: advantages and challenges of a maturing technology. Nat Rev Genet 10:669–680PubMedCentralPubMedGoogle Scholar
  95. Perkins TT, Kingsley RA, Fookes MC et al (2009) A strand-specific RNA-Seq analysis of the transcriptome of the typhoid bacillus Salmonella typhi. PLoS Genet 5:e1000569PubMedCentralPubMedGoogle Scholar
  96. Pleasance ED, Cheetham RK, Stephens PJ et al (2010) A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463:191–196PubMedCentralPubMedGoogle Scholar
  97. President’s Council of Advisors on Science Technology (2008) Priorities for personalised medicine. Accessed 28 Aug 2012
  98. Reis-Filho JS (2009) Next-generation sequencing. Breast Cancer Res 11(Suppl 3):S12PubMedCentralPubMedGoogle Scholar
  99. Robertson G, Hirst M, Bainbridge M et al (2007) Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nat Methods 4:651–657PubMedGoogle Scholar
  100. Robinson JT, Thorvaldsdóttir H, Winckler W, Guttman M, Lander ES, Getz G, Mesirov JP (2011) Integrative genomics viewer. Nat Biotechnol 29:24–26PubMedCentralPubMedGoogle Scholar
  101. Sanderson S, Emery J, Higgins J (2005) CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet™ systemic review and meta-analysis. Genet Med 7:97–104PubMedGoogle Scholar
  102. Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74:5463–5467PubMedCentralPubMedGoogle Scholar
  103. Schena M, Shalon D, Davis RW, Brown PO (1995) Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270:467–470PubMedGoogle Scholar
  104. Schmidt D, Wilson MD, Ballester B et al (2010) Five-vertebrate ChIP–seq reveals the evolutionary dynamics of transcription factor binding. Science 328:1036–1040PubMedCentralPubMedGoogle Scholar
  105. Schulte JH, Marschall T, Martin M et al (2010) Deep sequencing reveals differential expression of microRNAs in favorable versus unfavorable neuroblastoma. Nucleic Acids Res 38:5919–5928PubMedCentralPubMedGoogle Scholar
  106. Shah SP, Morin RD, Khattra J et al (2009) Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 461:809–813PubMedGoogle Scholar
  107. Shendure J, Ji H (2008) Next-generation DNA sequencing. Nat Biotechnol 26:1135–1145PubMedGoogle Scholar
  108. Simpson JT, Wong K, Jackman SD, Schein JE, Jones SJ, Birol I (2009) ABySS: a parallel assembler for short read sequence data. Genome Res 19:1117–1123PubMedCentralPubMedGoogle Scholar
  109. Sinicropi D, Qu K, Collin F et al (2012) Whole transcriptome RNA-Seq analysis of breast cancer recurrence risk using formalin-fixed paraffin- embedded tumor tissue. PLoS One 7:e40092PubMedCentralPubMedGoogle Scholar
  110. Sonnhammer EL, Hollich V (2005) Scoredist: a simple and robust protein sequence distance estimator. BMC Bioinformatics 6:108PubMedCentralPubMedGoogle Scholar
  111. Sorek R, Cossart P (2010) Prokaryotic transcriptomics: a new view on regulation, physiology and pathogenicity. Nat Rev Genet 11:9–16PubMedGoogle Scholar
  112. Sultan M, Schulz MH, Richard H et al (2008) A global view of gene activity and alternative splicing by deep sequencing of the human transcriptome. Science 32:956–960Google Scholar
  113. Syvanen AC, Aalto-Setala K, Harju L, Kontula K, Soderlund H (1990) A primer-guided nucleotide incorporation assay in the genotyping of apolipoprotein E. Genomics 8:684–692PubMedGoogle Scholar
  114. Takahashi H, Wilkinson GR, Nutescu EA et al (2006) Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance doses of warfarin in Japanese, Caucasians and African Americans. Pharmacogenet Genomics 16:101–110PubMedGoogle Scholar
  115. Takeuchi F, McGinnis R, Bourgeois S et al (2009) A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet 5, E1000433PubMedCentralPubMedGoogle Scholar
  116. Tang F, Barbacioru C, Wang Y et al (2009) MRNA-Seq whole-transcriptome analysis of a single cell. Nat Methods 6:377–382PubMedGoogle Scholar
  117. The International HapMap Consortium (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449:851–862PubMedCentralGoogle Scholar
  118. Tran B, Brown AM, Bedard PL et al (2013) Feasibility of real time next generation sequencing of cancer genes linked to drug response: results from a clinical trial. Int J Cancer 132:1547–1555. doi: 10.1002/ ijc.27817 PubMedGoogle Scholar
  119. Trapnell C, Pachter L, Salzberg SL (2009) TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25:1105–1111PubMedCentralPubMedGoogle Scholar
  120. Trapnell C, Williams BA, Pertea G et al (2010) Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol 28:511–515PubMedCentralPubMedGoogle Scholar
  121. Turnbaugh PJ, Quince C, Faith JJ et al (2010) Organismal, genetic, and transcriptional variation in the deeply sequenced gut microbiomes of identical twins. Proc Natl Acad Sci USA 107:7503–7508PubMedCentralPubMedGoogle Scholar
  122. Turner ST, Bailey KR, Fridley BL et al (2008) Genomic association analysis suggests chromosome 12 locus influencing antihypertensive response to thiazide diuretic. Hypertension 52:359–365PubMedCentralPubMedGoogle Scholar
  123. US Food and Drug Administration (2012) Table of valid genomic biomarkers in the context of approved drug labels. Accessed 28 Aug 2012
  124. Van’t Veer LJ, Dai H, van de Vijver MJ et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536Google Scholar
  125. van de Vijver MJ, He YD, Van’t Veer LJ et al (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999–2009PubMedGoogle Scholar
  126. van Rooij E, Sutherland LB, Liu N et al (2006) A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci USA 103:18255–18260PubMedCentralPubMedGoogle Scholar
  127. Venter JC, Adams MD, Myers EW et al (2001) The sequence of the human genome. Science 291:1304–1351PubMedGoogle Scholar
  128. Voelkerding KV, Dames SA, Durtschi JD (2009) Next-generation sequencing: from basic research to diagnostics. Clin Chem 55:641–658PubMedGoogle Scholar
  129. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, Kingsmore SF, Schroth GP, Burge CB (2008a) Alternative isoform regulation in human tissue transcriptomes. Nature 456:470–476PubMedCentralPubMedGoogle Scholar
  130. Wang J, Wang W, Li R et al (2008b) The diploid genome sequence of an Asian individual. Nature 456:60–65PubMedCentralPubMedGoogle Scholar
  131. Wang Z, Gerstein M, Snyder M (2009) RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet 10:57–63PubMedCentralPubMedGoogle Scholar
  132. Warren RL, Butterfield YS, Morin RD, Siddiqui AS, Marra MA, Jones SJM (2005) Management and visualization of whole genome shotgun assemblies using SAM. Biotechniques 38:715–720PubMedGoogle Scholar
  133. Weisenberger DJ, Siegmund KD, Campan M et al (2006) CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38:787–793PubMedGoogle Scholar
  134. Wheeler DA, Srinivasan M, Egholm M et al (2008) The complete genome of an individual by massively parallel DNA sequencing. Nature 452:872–876PubMedGoogle Scholar
  135. Wilhelm BT, Marguerat S, Goodhead I, Bahler J (2010) Defining transcribed regions using RNA-seq. Nat Protoc 5:255–266PubMedGoogle Scholar
  136. Yeager M, Xiao N, Hayes RB et al (2008) Comprehensive re-sequence analysis of a 136 kb region of human chromosome 8q24 associated with prostate and colon cancers. Hum Genet 124:161–170PubMedCentralPubMedGoogle Scholar
  137. Yi X, Liang Y, Huerta-Sanchez E et al (2010) Sequencing of 50 human exomes reveals adaptation to high altitude. Science 329:75–78PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer India 2013

Authors and Affiliations

  • Huixiao Hong
    • 1
  • Wenqian Zhang
    • 2
  • Zhenqiang Su
    • 1
  • Jie Shen
    • 1
  • Weigong Ge
    • 1
  • Baitang Ning
    • 3
  • Hong Fang
    • 4
  • Roger Perkins
    • 1
  • Leming Shi
    • 1
  • Weida Tong
    • 1
  1. 1.Division of Bioinformatics and Biostatistics, National Center for Toxicological ResearchUS Food and Drug AdministrationJeffersonUSA
  2. 2.Beijing Genomic InstituteShenzhenChina
  3. 3.Division of Systems Biology, National Center for Toxicological ResearchUS Food and Drug AdministrationJeffersonUSA
  4. 4.Office of Scientific Coordination, National Center for Toxicological ResearchUS Food and Drug AdministrationJeffersonUSA

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