Whole‐Genome Sequencing in Personalized Therapeutics

Eleven years since the initial drafts of the human genome were published, we have begun to see the first examples of the application of whole‐genome sequencing to personalized diagnosis and therapeutics. The exponential decline in sequencing costs and the constant improvement in these technologies promise to further advance the use of a patient's full genetic profile in the clinic. However, realizing the potential benefit of such sequencing will require a concerted effort by science, medicine, law, and management. In this review, we discuss current approaches to decoding the 6 billion–letter genetic code of a whole genome in a clinical context, give current examples of translating this information into therapy‐guiding knowledge, and list the challenges that will need to be surmounted before these powerful data can be fully exploited to forward the goals of personalized medicine.

[1]  R. Green,et al.  Design of a randomized trial of diabetes genetic risk testing to motivate behavior change: The Genetic Counseling/Lifestyle Change (GC/LC) Study for Diabetes Prevention , 2011, Clinical trials.

[2]  William Stafford Noble,et al.  Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project , 2007, Nature.

[3]  P. Shannon,et al.  Exome sequencing identifies the cause of a Mendelian disorder , 2009, Nature Genetics.

[4]  D. Cooper,et al.  Human Gene Mutation Database , 1996, Human Genetics.

[5]  Emily H Turner,et al.  Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome , 2010, Nature Genetics.

[6]  Michael DiCuccio,et al.  Public data archives for genomic structural variation , 2010, Nature Genetics.

[7]  L. Feuk,et al.  Detection of large-scale variation in the human genome , 2004, Nature Genetics.

[8]  Robert B. Hartlage,et al.  This PDF file includes: Materials and Methods , 2009 .

[9]  G. Rosner,et al.  Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition. , 2012, Genome research.

[10]  K. Sirotkin,et al.  The NCBI dbGaP database of genotypes and phenotypes , 2007, Nature Genetics.

[11]  K. Frazer,et al.  Human genetic variation and its contribution to complex traits , 2009, Nature Reviews Genetics.

[12]  Judy H. Cho,et al.  Finding the missing heritability of complex diseases , 2009, Nature.

[13]  Shashi Amur,et al.  Pharmacogenomic Biomarker Information in Drug Labels Approved by the United States Food and Drug Administration: Prevalence of Related Drug Use , 2008, Pharmacotherapy.

[14]  Christian Gilissen,et al.  De novo mutations of SETBP1 cause Schinzel-Giedion syndrome , 2010, Nature Genetics.

[15]  J. O’Connell,et al.  Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. , 2009, JAMA.

[16]  K. Becker,et al.  The Genetic Association Database , 2004, Nature Genetics.

[17]  T. Hudson,et al.  A genome-wide association study identifies novel risk loci for type 2 diabetes , 2007, Nature.

[18]  David S. Wishart,et al.  DrugBank 3.0: a comprehensive resource for ‘Omics’ research on drugs , 2010, Nucleic Acids Res..

[19]  Thomas Berg,et al.  IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy , 2009, Nature Genetics.

[20]  Loy En Yun,et al.  Genome‐wide Association Studies: The Success, Failure and Future , 2009 .

[21]  Toshihiro Tanaka The International HapMap Project , 2003, Nature.

[22]  L. Feuk,et al.  Development of bioinformatics resources for display and analysis of copy number and other structural variants in the human genome , 2006, Cytogenetic and Genome Research.

[23]  D. Pinto,et al.  Structural variation of chromosomes in autism spectrum disorder. , 2008, American journal of human genetics.

[24]  David R. Murdock,et al.  Whole-Genome Sequencing for Optimized Patient Management , 2011, Science Translational Medicine.

[25]  D. Carlini,et al.  Synonymous SNPs Provide Evidence for Selective Constraint on Human Exonic Splicing Enhancers , 2005, Journal of Molecular Evolution.

[26]  J Oyston,et al.  Online Mendelian Inheritance in Man. , 1998, Anesthesiology.

[27]  Kenneth G. C. Smith,et al.  Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake , 2008, The Journal of experimental medicine.

[28]  Amin Zia,et al.  Ranking insertion, deletion and nonsense mutations based on their effect on genetic information , 2011, BMC Bioinformatics.

[29]  F. Collins,et al.  Potential etiologic and functional implications of genome-wide association loci for human diseases and traits , 2009, Proceedings of the National Academy of Sciences.

[30]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.

[31]  I. Bièche,et al.  ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[32]  Ken Chen,et al.  Use of whole-genome sequencing to diagnose a cryptic fusion oncogene. , 2011, JAMA.

[33]  N. Schork,et al.  Effect of direct-to-consumer genomewide profiling to assess disease risk. , 2011, The New England journal of medicine.

[34]  Atul J. Butte,et al.  An Environment-Wide Association Study (EWAS) on Type 2 Diabetes Mellitus , 2010, PloS one.

[35]  A. Daly,et al.  Pharmacogenomics of anticoagulants: steps toward personal dosage , 2009, Genome Medicine.

[36]  P. Visscher,et al.  Rare chromosomal deletions and duplications increase risk of schizophrenia , 2008, Nature.

[37]  Elisa Rossi,et al.  Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. , 2005, Journal of the National Cancer Institute.

[38]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[39]  Jonathan Scott Friedlaender,et al.  A Human Genome Diversity Cell Line Panel , 2002, Science.

[40]  M. Daly,et al.  HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin , 2009, Nature Genetics.

[41]  Sarah E. Johnstone,et al.  Stress and the epigenetic landscape: a link to the pathobiology of human diseases? , 2010, Nature Reviews Genetics.

[42]  W J Kleijer,et al.  Inversion of the IDS gene resulting from recombination with IDS-related sequences is a common cause of the Hunter syndrome. , 1995, Human molecular genetics.

[43]  Alexander A. Morgan,et al.  Clinical assessment incorporating a personal genome , 2010, The Lancet.

[44]  S. Baylin,et al.  Cancer epigenetics: linking basic biology to clinical medicine , 2011, Cell Research.

[45]  J. Witte Genome-wide association studies and beyond. , 2010, Annual review of public health.

[46]  R. Collins,et al.  SLCO1B1 variants and statin-induced myopathy--a genomewide study. , 2008, The New England journal of medicine.

[47]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[48]  M. McCarthy,et al.  Genome-wide association studies for complex traits: consensus, uncertainty and challenges , 2008, Nature Reviews Genetics.

[49]  Ian N M Day,et al.  dbSNP in the detail and copy number complexities , 2010, Human mutation.

[50]  A. Koike,et al.  Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C , 2009, Nature Genetics.

[51]  Michelle Whirl-Carrillo,et al.  From pharmacogenomic knowledge acquisition to clinical applications: the PharmGKB as a clinical pharmacogenomic biomarker resource. , 2011, Biomarkers in medicine.

[52]  Steven Henikoff,et al.  SIFT: predicting amino acid changes that affect protein function , 2003, Nucleic Acids Res..

[53]  P. Stankiewicz,et al.  Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. , 2010, The New England journal of medicine.

[54]  P. Bork,et al.  A method and server for predicting damaging missense mutations , 2010, Nature Methods.

[55]  P. Stenson,et al.  The Human Gene Mutation Database: 2008 update , 2009, Genome Medicine.

[56]  Anaïs Mottaz,et al.  Bioinformatics Applications Note Databases and Ontologies Easy Retrieval of Single Amino-acid Polymorphisms and Phenotype Information Using Swissvar , 2022 .

[57]  Omar E. Cornejo,et al.  Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence , 2011, PLoS genetics.

[58]  F E Preston,et al.  Factor VIII gene inversions in severe hemophilia A: results of an international consortium study. , 1995, Blood.

[59]  L. Shulman,et al.  Genome-wide association study identifies novel breast cancer susceptibility loci , 2008 .

[60]  Dan M Roden,et al.  A rare variant in MYH6 is associated with high risk of sick sinus syndrome , 2011, Nature Genetics.

[61]  D. Mccormick Sequence the Human Genome , 1986, Bio/Technology.

[62]  H. Goldschmidt,et al.  Genetic factors underlying the risk of thalidomide-related neuropathy in patients with multiple myeloma. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[63]  Lester L. Peters,et al.  Genome-wide association study identifies novel breast cancer susceptibility loci , 2007, Nature.

[64]  Alexander A. Morgan,et al.  Likelihood ratios for genome medicine , 2010, Genome Medicine.

[65]  Judy H. Cho,et al.  A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene , 2006, Science.

[66]  D. Valle,et al.  Online Mendelian Inheritance In Man (OMIM) , 2000, Human mutation.

[67]  R. Shiekhattar,et al.  Long non-coding RNAs and enhancers. , 2011, Current opinion in genetics & development.

[68]  R. Weinshilboum,et al.  Sulfotransferase gene copy number variation: pharmacogenetics and function , 2009, Cytogenetic and Genome Research.

[69]  E. Hing,et al.  Electronic health record systems and intent to apply for meaningful use incentives among office-based physician practices: United States, 2001-2011. , 2011, NCHS data brief.

[70]  Lee T. Sam,et al.  Personalized Oncology Through Integrative High-Throughput Sequencing: A Pilot Study , 2011, Science Translational Medicine.

[71]  E. van de Steeg,et al.  Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. , 2012, The Journal of clinical investigation.

[72]  Ryan E. Mills,et al.  Small insertions and deletions (INDELs) in human genomes. , 2010, Human molecular genetics.

[73]  Hugo Y. K. Lam,et al.  Personal Omics Profiling Reveals Dynamic Molecular and Medical Phenotypes , 2012, Cell.

[74]  A. Butte,et al.  Non-Synonymous and Synonymous Coding SNPs Show Similar Likelihood and Effect Size of Human Disease Association , 2010, PloS one.

[75]  David B. Goldstein,et al.  Rare Variants Create Synthetic Genome-Wide Associations , 2010, PLoS biology.

[76]  M. Boyd,et al.  A Frameshift Mutation and Alternate Splicing in Human Brain Generate a Functional Form of the Pseudogene Cytochrome P4502D7 That Demethylates Codeine to Morphine* , 2004, Journal of Biological Chemistry.

[77]  Stephan J Sanders,et al.  Whole exome sequencing identifies recessive WDR62 mutations in severe brain malformations , 2010, Nature.

[78]  Patrizia Sola,et al.  Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS , 2011, Neuron.

[79]  M. Rieder,et al.  A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. , 2008, Blood.

[80]  P. Shannon,et al.  Analysis of Genetic Inheritance in a Family Quartet by Whole-Genome Sequencing , 2010, Science.

[81]  A. Hinks,et al.  Association of the 5-aminoimidazole-4-carboxamide ribonucleotide transformylase gene with response to methotrexate in juvenile idiopathic arthritis , 2011, Annals of the rheumatic diseases.

[82]  Ying Cheng,et al.  The European Nucleotide Archive , 2010, Nucleic Acids Res..