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ADVISORY BOARD Joseph A. Caruso University of Cincinnati, Cincinnati, OH, USA Hendrik Emons Joint Research Centre, Geel, Belgium Gary Hieftje Indiana University, Bloomington, IN, USA Kiyokatsu Jinno Toyohashi University of Technology, Toyohashi, Japan Uwe Karst University of Mu¨nster, Mu¨nster, Germany Gyro¨gy Marko-Varga AstraZeneca, Lund, Sweden Janusz Pawliszyn University of Waterloo, Waterloo, Ont., Canada Susan Richardson US Environmental Protection Agency, Athens, GA, USA Elsevier TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UK Radarweg29,POBox211,1000AEAmsterdam,TheNetherlands Copyright©2014ElsevierB.V.Allrightsreserved. Nopartofthispublicationmaybereproduced,storedinaretrievalsystemortransmittedin anyformorbyanymeanselectronic,mechanical,photocopying,recordingorotherwisewithout thepriorwrittenpermissionofthepublisher PermissionsmaybesoughtdirectlyfromElsevier’sScience&TechnologyRightsDepartment inOxford,UK:phone(+44)(0)1865843830;fax(+44)(0)1865853333;email: permissions@elsevier.com.Alternativelyyoucansubmityourrequestonlinebyvisitingthe Elsevierwebsiteathttp://elsevier.com/locate/permissions,andselecting ObtainingpermissiontouseElseviermaterial Notice Noresponsibilityisassumedbythepublisherforanyinjuryand/ordamagetopersonsorproperty asamatterofproductsliability,negligenceorotherwise,orfromanyuseoroperationofany methods,products,instructionsorideascontainedinthematerialherein.Becauseofrapid advancesinthemedicalsciences,inparticular,independentverificationofdiagnosesanddrug dosagesshouldbemade BritishLibraryCataloguinginPublicationData AcatalogrecordforthisbookisavailablefromtheBritishLibrary LibraryofCongressCataloging-in-PublicationData AcataloguerecordforthisbookisavailablefromtheLibraryofCongress ISBN:978-0-444-62651-6 ISSN:0166-526X ForinformationonallElsevierpublications visitourwebsiteatstore.elsevier.com PrintedandboundinPoland 14 15 16 17 10 9 8 7 6 5 4 3 2 1 Contributors to Volume 63 SaraAibar,BioinformaticsandFunctionalGenomicsGroup,CancerResearchCenter (CiC-IBMCC, CSIC/USAL), Salamanca, Spain Benjamin Balluff, Center for Proteomics and Metabolomics, Leiden University Medical Center,Leiden, The Netherlands Salvatore Cappadona, Proteomics Unit, Centre for Genomic Regulation (CRG) and Universitat Pompeu Fabra(UPF), Barcelona, Spain Ricardo J. Carreira, Center for Proteomics and Metabolomics, Leiden University Medical Center,Leiden, The Netherlands Richard D. Cummings, Department of Biochemistry and the Glycomics Center, Emory UniversitySchool ofMedicine, Atlanta, Georgia, USA SayaniDasgupta,DepartmentofMolecularPharmacology,AlbertEinsteinCollegeof Medicine, Bronx, New York,USA Noelia Dasilva, Centro de Investigacioń del Cańcer/IBMCC (USAL/CSIC), IBSAL, Departamento de Medicina Unidad de Proteomica & Servicio General de Citometr´ıa,Universityof Salamanca, Salamanca,Spain Javier De Las Rivas, Bioinformatics and Functional Genomics Group, Cancer Research Center (CiC-IBMCC,CSIC/USAL), Salamanca,Spain RubeńD´ıaz,HospitalSantJoandeDeu,Endocrinology,FundacioperlaRecercaSant Joan de Deu,Barcelona, Spain Paula Diez, Centro de Investigacioń del Cańcer/IBMCC (USAL/CSIC), IBSAL, Departamento de Medicina Unidad de Proteomica & Servicio General de Citometr´ıa,Universityof Salamanca, Salamanca,Spain Vahid Farrokhi, Department of Chemistry, University of Connecticut, Storrs, Connecticut, USA LloydD.Fricker,DepartmentofMolecularPharmacology,AlbertEinsteinCollegeof Medicine, Bronx, New York,USA ManuelFuentes,CentrodeInvestigaciońdelCańcer/IBMCC(USAL/CSIC),IBSAL, Departamento de Medicina Unidad de Proteomica & Servicio General de Citometr´ıa,Universityof Salamanca, Salamanca,Spain VirginiaGarc´ıa-Canãs,LaboratoryofFoodomics,InstituteofFoodScienceResearch (CIAL), CSIC.Nicola´s Cabrera 9,Madrid, Spain Helen G. Gika, Department of Chemical Engineering, Aristotle University Thessaloniki, Thessaloniki, Greece I. Gobernado,Servicio dePsiquiatr´ıa,Hospital Ramońy Cajal,Madrid, Spain xiii xiv ContributorstoVolume63 Maria Gonzalez-Gonzalez, Centro de Investigacioń del Cańcer/IBMCC (USAL/ CSIC), IBSAL, Departamento de Medicina Unidad de Proteomica & Servicio General deCitometr´ıa,Universityof Salamanca,Salamanca, Spain ClaraIbań˜ez,Laboratory ofFoodomics,InstituteofFoodScience Research (CIAL), CSIC.Nicola´s Cabrera 9,Madrid,Spain Ricardo Jara-Acevedo, ImmunoStep, Edificio Centro de Investigacioń del Cańcer, Avda.Coimbra s/n, Campus Miguelde Unamuno,Salamanca, Spain A.Jimenez-Escrig,Serviciode Neurolog´ıa, HospitalRamoń y Cajal,Madrid,Spain JosepC.Jimeńez-Chillaroń,HospitalSantJoandeDeu,Endocrinology,Fundacioper laRecerca SantJoan deDeu, Barcelona, Spain Paul C.H. Li, Department of Chemistry, Simon Fraser University, Burnaby, British Columbia,Canada Song Li, Department of Chemistry, University of Connecticut, Storrs, Connecticut, USA Lucia Lourido, Instituto de Investigacioń Biomedica da Corunã (INIBIC), Hospital UniversitarioACorunã,ACorunã, Spain Jacob W. Malcom, Department of Molecular and Cell Biology, University of Connecticut,Storrs, Connecticut, USA John H. Malone, Department of Molecular and Cell Biology, University of Connecticut,Storrs, Connecticut, USA FrancescoM.Mancuso,ProteomicsUnit,CentreforGenomicRegulation(CRG)and UniversitatPompeu Fabra(UPF), Barcelona, Spain Liam A. McDonnell, Center for Proteomics and Metabolomics, Leiden University Medical Center,Leiden, The Netherlands Adam J. McShane, Department of Chemistry, University of Connecticut, Storrs, Connecticut,USA Tyler J. Moss, Department of Systems Biology, UT MD Anderson Cancer Center, Houston,Texas, USA G.A. Nagana Gowda, Department of Anesthesiology and Pain Medicine, Northwest MetabolomicsResearchCenter,UniversityofWashington,Seattle,Washington,USA RezaNemati,DepartmentofChemistry,UniversityofConnecticut,Storrs,Connecti- cut,USA Alberto Orfao, Centro de Investigacioń del Cańcer/IBMCC (USAL/CSIC), IBSAL, Departamento de Medicina Unidad de Proteomica & Servicio General de Citometr´ıa,University ofSalamanca, Salamanca, Spain Daniel Raftery, Department of Anesthesiology and Pain Medicine, Northwest Metabolomics Research Center, University of Washington, and Public Health SciencesDivision,FredHutchinsonCancerResearchCenter,Seattle,Washington, USA PrahladT.Ram,DepartmentofSystemsBiology,UTMDAndersonCancerCenter, Houston,Texas, USA ContributorstoVolume63 xv Marta Ramoń-Krauel, Hospital Sant Joan de Deu, Endocrinology, Fundacio per la Recerca Sant Joande Deu, Barcelona, Spain Beatriz Roson, Bioinformatics and Functional Genomics Group, Cancer Research Center (CiC-IBMCC, CSIC/USAL), Salamanca, Spain Eduard Sabido´, Proteomics Unit, Centre for Genomic Regulation (CRG) and Universitat Pompeu Fabra(UPF), Barcelona, Spain A. Sanchez-Herranz, Servicio de Neurobiolog´ıa-Investigacioń, Unidad Central de Geno´micaTranslacional, Hospital Ramoń yCajal, Madrid,Spain Alex Sańchez-Pla, Statistics Department, Facultat de Biologia, University of Barcelona, and Statistics and Bioinformatics Unit, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain Ram Sasisekharan, Department of Biological Engineering, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA J.M. Sayagues, Centro de Investigacioń del Cańcer/IBMCC (USAL/CSIC), IBSAL, Departamento de Medicina Unidad de Proteomica & Servicio General de Citometr´ıa,Universityof Salamanca, Salamanca,Spain Philippe Schmitt-Kopplin, Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum Mu¨nchen, German Research Center for Environmental Health, Neuherberg, and Chair of Analytical Food Chemistry, Technische Universita¨t Mu¨nchen, Freising-Weihenstephan, Germany Abootaleb Sedighi, Department of Chemistry, Simon Fraser University, Burnaby, British Columbia,Canada VasudhaSehgal,DepartmentofSystemsBiology, UTMDAndersonCancerCenter, Houston, Texas, USA CarolinaSimo´,LaboratoryofFoodomics,InstituteofFoodScienceResearch(CIAL), CSIC.Nicola´sCabrera 9,Madrid,Spain David F. Smith, Department of Biochemistry and the Glycomics Center, Emory University Schoolof Medicine, Atlanta, Georgia, USA Xuezheng Song, Department of Biochemistry and the Glycomics Center, Emory University Schoolof Medicine, Atlanta, Georgia, USA Nathan W. Stebbins, Department of Biological Engineering, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA GeorgiosA.Theodoridis,DepartmentofChemistry,AristotleUniversityThessaloniki, Thessaloniki,Greece AlbertoValde´s,LaboratoryofFoodomics,InstituteofFoodScienceResearch(CIAL), CSIC.Nicola´sCabrera 9,Madrid,Spain Ian D. Wilson, Department of Surgery and Cancer, Faculty of Medicine, Imperial College, SouthKensington, London, UnitedKingdom xvi ContributorstoVolume63 Michael Witting, Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum Mu¨nchen,GermanResearchCenterforEnvironmentalHealth,Neuherberg,Germany XudongYao,DepartmentofChemistry,UniversityofConnecticut,Storrs,Connecticut, USA Ying Yu, Department of Biochemistry and the Glycomics Center, Emory University Schoolof Medicine,Atlanta, Georgia, USA Chapter 1 DNA Microarrays Technology: Overview and Current Status Alex Sańchez-Pla*,{ *StatisticsDepartment,FacultatdeBiologia,UniversityofBarcelona,Barcelona,Spain {StatisticsandBioinformaticsUnit,Valld’HebronInstitutdeRecerca(VHIR),Barcelona,Spain Chapter Outline 1. IntroductionandOverview 1 3.3. CGHArrays for 1.1. ABriefHistoryof ComparativeGenomic Microarrays 3 Hybridization 17 2. TypesofDNAMicroarrays 4 3.4. ChIP-on-ChipArraysfor 2.1. SpottedorPrinted TranscriptionFactor Microarrays 4 BindingAnalysis 17 2.2. InSituSynthesized 3.5. ArraysfortheAnalysis Microarrays 5 ofAlternativeSplicing 2.3. High-DensityBeadArrays9 andRelatedIssues 18 3. ApplicationsofMicroarrays 11 4. MicroarrayBioinformatics 18 3.1. MicroarraysforGene 4.1. TheMIAMEStandard 19 ExpressionAnalysis 11 4.2. MicroarrayDatabases 19 3.2. SNPArraysfor 5. Discussion andConcluding VariationAnalysisand Remarks 20 Genotyping 16 References 21 1 INTRODUCTION AND OVERVIEW Since the early days of molecular biology, life scientists have been interested inbeing abletomeasure gene expressionor toquantify gene variation,either at the nucleotide level or by the number of copies of a gene. Techniques to measure the expression level of a gene, such as the Northern blot (1), or to quantify DNA variation, such as restriction fragment length polymorphism (2), have been in use for decades and have become part of the biologist’s standard toolbox. These techniques, which were considered revolutionary when they were introduced, became much less attractive when the ComprehensiveAnalyticalChemistry,Vol.63.http://dx.doi.org/10.1016/B978-0-444-62651-6.00001-5 Copyright©2014ElsevierB.V.Allrightsreserved. 1 2 FundamentalsofAdvancedOmicsTechnologies:FromGenestoMetabolites information on genomic sequences increased exponentially as a result of sequencing projects. However, with the availability of sequence information also came the solution. The development of microarray technology allowed to enter a new era of high-throughput data generation and analysis where gene expression or gene variation could be measured simultaneously at hundredsorthousandsofgenes (forgene expression)oreven millionsofloci (for gene variation). Microarrays are a group of technologies designed to perform high- throughput screening by exposing amounts of biological material to a slide ofplastic orglasswhereknownDNAsequencesorproteinsthatactasdetec- torshavebeenpreviouslydeposited.DNAsequencesfromthebiologicalsam- ple, usually known as targets, are transformed into a stable DNA form, such as complementary DNA (cDNA), and in the process they are labeled with a fluorescent dye. Labeled target molecules are exposed to all the sequences ontheslide,usuallyknownasprobes.Itisexpectedthatduringthisexposure, target molecules have the chance to hybridize with their complementary sequences on the slide. The detection of target sequences that have been hybridized to their respective probes is done by stimulating the microarrays with the appropriate laser light,scanningthe resulting images, and, by means ofimageanalysis,identifyingandquantifyingthesignalsemittedbythosetar- get molecules that have hybridized to the probes (Figure 1) (3). Research “on” microarrays, especially on techniques for microarray data analysis, and “with” microarrays, that is, applications that use microarrays, has been very active during the first decade of the century (4,5), and thousands of papers on their use, applications, and analysis have been published, as can be seen by searching PubMed for references with the term “microarray” in their title (see Figure 2) (6). In this chapter the basic Labeled target (sample) Fixed probes Different features (e.g., bind different genes) Fully complementary Partially complementary strands bind strongly strands bind weakly FIGURE1 GeneraloverviewofthefunctioningofDNAmicroarrays. Chapter 1 DNAMicroarraysTechnology:OverviewandCurrentStatus 3 Number of published papers on expression or genotyping microarrays Years 1992–2012 7000 6000 5000 4000 Count 3000 2000 1000 0 Year 1993 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 FIGURE2 Evolutionofthenumberofpublishedmicroarrayarticles.Thenumberofpaperspub- lishedonmicroarraysincreasedexponentiallyduringthedecade1999–2008andisnowrelatively stable. ThedatafromtheimagehasbeenobtainedfromaPubMedsearchperformedwiththe following terms: “microarray” OR “gene expression array” OR “(microarrays AND gene)” OR“(microarrayANDgene).” principles underlying the technology of microarrays are described. In the following sections, the main different types of arrays and their applications are considered, and an overview of the current state and of future perspectives is presented. 1.1 A Brief History of Microarrays The approach of cloning multiple sequences in one process has been used in biology for a long time. It can be traced to well-established techniques such astheSouthernblot(7).InthistechniquefragmentedDNAisboundtoasub- strate, either of nitrocellulose or a nylon membrane. The DNA is denatured, dried, and then exposed to a labeled hybridization probe in an appropriate buffer. The blot is then extensively washed and analyzed by X-ray film, autoradiography, or membrane chromogen detection, depending on the type of probe label employed. Although in recent years this technique has been replaced by improved approaches, it can still be an option, especially in cases where the length of the expanded DNA is greater than the usual ampli- ficationabilityofpolymerasechainreaction(PCR).Adifferentapproach,the Grunstein and Hogness method (8), was also introduced in 1975 to identify plasmid clones by colony hybridization. The method was quickly extended by Gergen et al. (9) to create small 144-well microplates able to produce