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Methods in Molecular Biology 2590 Brock A. Peters · Radoje Drmanac Editors Haplotyping Methods and Protocols M M B ETHODS IN OLECULAR IO LO GY SeriesEditor JohnM.Walker School of Lifeand MedicalSciences University ofHertfordshire Hatfield, Hertfordshire, UK Forfurther volumes: http://www.springer.com/series/7651 For over 35 years, biological scientists have come to rely on the research protocols and methodologiesinthecriticallyacclaimedMethodsinMolecularBiologyseries.Theserieswas thefirsttointroducethestep-by-stepprotocolsapproachthathasbecomethestandardinall biomedicalprotocolpublishing.Eachprotocolisprovidedinreadily-reproduciblestep-by- step fashion, opening with an introductory overview, a list of the materials and reagents neededtocompletetheexperiment,andfollowedbyadetailedprocedurethatissupported with a helpful notes section offering tips and tricks of the trade as well as troubleshooting advice. These hallmark features were introduced by series editor Dr. John Walker and constitutethekeyingredientineachandeveryvolumeoftheMethodsinMolecularBiology series. Tested and trusted, comprehensive and reliable, all protocols from the series are indexedinPubMed. Haplotyping Methods and Protocols Edited by Brock A. Peters and Radoje Drmanac Advanced Genomics Technology Laboratory, Complete Genomics/MGI, San Jose, CA, USA Editors BrockA.Peters RadojeDrmanac AdvancedGenomicsTechnology AdvancedGenomicsTechnology Laboratory Laboratory CompleteGenomics/MGI CompleteGenomics/MGI SanJose,CA,USA SanJose,CA,USA ISSN1064-3745 ISSN1940-6029 (electronic) MethodsinMolecularBiology ISBN978-1-0716-2818-8 ISBN978-1-0716-2819-5 (eBook) https://doi.org/10.1007/978-1-0716-2819-5 ©TheEditor(s)(ifapplicable)andTheAuthor(s),underexclusivelicensetoSpringerScience+BusinessMedia,LLC,part ofSpringerNature2023 Chapters2and8arelicensedunderthetermsoftheCreativeCommonsAttribution4.0InternationalLicense(http:// creativecommons.org/licenses/by/4.0/).Forfurtherdetailsseelicenseinformationinthechapter. Thisworkissubjecttocopyright.AllrightsaresolelyandexclusivelylicensedbythePublisher,whetherthewholeorpart of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting,reproductionon microfilmsorinanyotherphysicalway,andtransmissionorinformation storageand retrieval,electronicadaptation, computersoftware,orbysimilar ordissimilar methodologynow knownorhereafter developed. Theuseofgeneraldescriptivenames,registerednames,trademarks,servicemarks,etc.inthispublicationdoesnotimply, evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevantprotectivelawsandregulations andthereforefreeforgeneraluse. Thepublisher,theauthors,andtheeditorsaresafetoassumethattheadviceandinformationinthisbookarebelievedto betrueandaccurateatthedateofpublication.Neitherthepublishernortheauthorsortheeditorsgiveawarranty, expressedorimplied,withrespecttothematerialcontainedhereinorforanyerrorsoromissionsthatmayhavebeen made.Thepublisherremainsneutralwithregardtojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations. ThisHumanaimprintispublishedbytheregisteredcompanySpringerScience+BusinessMedia,LLC,partofSpringer Nature. Theregisteredcompanyaddressis:1NewYorkPlaza,NewYork,NY10004,U.S.A. Preface The term haplotype was first coined in 1965 by R. Ceppellini and used “to indicate the productsofasinglelocusinhaploidform”[1].Putanotherway,ahaplotypeisasegmentof genomicDNAcarryingaspecificcollectionofpolymorphismsinheritedfromasingleparent inmultiploidorganisms.Typically,thesepolymorphismsareincloseproximitytoeachother suchthatovergenerationstheyhavenotbeenseparatedbyrecombinationevents.Theresult isthatthegenomeofanindividualcanbethoughtofasauniquecombinationofhaplotypes inheritedfromeachparent.Inaddition,manyhaplotypesareuniquetospecificsubpopula- tionswithinaspecies,oftenasaresultofselectivepressuresovernumerousgenerations.In thisbook,wewillexploreallthingshaplotypesstartingwithwhyhaplotypesareimportant, howtheycanbeusedindifferentareasofresearch,andhowhaplotypeinformationcanbe generatedandanalyzedusingdifferentsourcesofinputmaterialanddata. Earlystudiesofhaplotypingfocused primarilyonthehumanleukocyteantigen (HLA) complex and were primarily used for finding suitable matches between organ donors and recipients[1].Inaddition,earlystudiesdiscoveredindividualsharboringspecifichaplotypes of the HLA region had different disease susceptibilities [2]. Haplotype use expanded after theinitialsequencingofthehumangenomeandthecreationofDNAmicroarrays.Thiswas a result of the realization that a small subset of the entire collection of human single nucleotidepolymorphisms(SNPs)couldbeusedtodetecthaplotypesthatcodedforspecific phenotypes without the need to detect the SNP that was causative for the phenotype [3]. This led to the discovery of many marker SNPs that could be used to study and predict certain traits in humans [4] and later other species, as well as the use of haplotype data to better understandhumanpopulationhistory[5]. At the time of this writing, it is well accepted that whole genome sequencing is incompleteandsubstantiallylessinformativewithoutalsocollectingthecompletehaplotype structure of the genome (due to gene activity regulation from distant enhancers and other genomicelementstonameoneexample,seeChap.1for furtherdiscussionandexamples). This has resulted in much effort being placed in the development of novel haplotyping technologies,manyofwhicharedescribedinthisedition.However,toquoteourcolleague Margret Hoehe, “while novel or improved haplotyping methods usually receive notable attention, the application of haplotyping methods to obtain more insight into the nature and structure of diploid genomes still tends to be ignored.” Along these lines, we observe thattheroutineuseofhaplotypeinformationinclinicalsequencingispracticallynonexistent except for very specific cases and conditions. In general, we still find that any extra cost associated with generating haplotype information results in most investigators opting for cheapersequencingwithouthaplotypedata.Perhapsamorecompleteunderstandingofour genomes, further reductions in the cost of sequencing whole genomes, and continued refinements in haplotyping technologies will lead to the increased uptake and use of haplotypeinformationinclinicalandresearchsettings.Atleastwecanhope. Despitethisrelativelackofuseofcurrenthaplotypingtechnologies,thereisstillarobust interest in improving and marketing current haplotyping methods. Not mentioned else- whereinthisbook(notforlackofaninvitationfromus)areseveralcommercialprovidersof various forms of haplotyping data. These fall into two categories: short range and long v vi Preface range. A provider of short-range haplotyping information similar to methods described in Chaps.2,3,and4isLoopGenomicsfor thosewhodecidetheywouldprefersomeoneelse togeneratethistypeofdataforthem.Inaddition,PacificBiosciencesCCSreadscandirectly generatedataofthistypeupto20kbinlength,althoughthisisoneofthemoreexpensive options available. Providers of long-range haplotyping information, similar to those describedinChaps.5,6,and7,includeArimaGenomics,DovetailGenomics,BGIGeno- mics, Phase Genomics, and many local providers and university core sequencing labs. In addition,directsequencingusingOxfordNanoporeorPacificBiosciencescanalsogenerate haplotypedata,althoughqualityoftheseresultscanvaryduetothehigherrawerrorratesof thesetechnologies. Oncedatahasbeengeneratedusingahaplotypeawaremethod,itbecomesnecessaryto use bioinformatic techniques to make sense of it. Indeed, often the bioinformatic analyses takesignificantlymoretimeandeffortthanthewetlabtechniquesusedtogeneratethedata. Fortunately,over thepastseveralyears,manynewandhelpfulbioinformaticmethodshave been developed for haplotype analysis. In this edition, we have dedicated a much larger portionofchaptersthanpreviouseditionstomethodsdescribingbioinformaticanalysesthat canbeperformedtobothgeneratefinalhaplotypesandtousethishaplotypedata.Chapters 8, 9, 10, 11, 12, 13, and 14 describe methods for generating haplotypes from multiple differentsourcesofsequencingdata.Chapters15,16,and17explainvariousmethodsand strategiesforusinghaplotypedataonceyouhaveobtainedit.Wehopethisbookhelpsyou discover theusefulnessofhaplotypesinyour research.Cheers! SanJose,CA,USA BrockA.Peters RadojeDrmanac References 1. AmosB,WardFE,ZmijewskiCM,HattlerBG,SeiglerHF(1968)Graftdonorselectionbasedupon singlelocus(haplotype)analysiswithinfamilies.Transplantation6(4):524–534.https://doi.org/10. 1097/00007890-196807000-00003 2. MatzarakiV,KumarV,WijmengaC,ZhernakovaA(2017)TheMHClocusandgeneticsusceptibility to autoimmune and infectious diseases. Genome Biol 18(1):76. https://doi.org/10.1186/s13059- 017-1207-1 3. JohnsonGC,EspositoL,BarrattBJ,SmithAN,HewardJ,DiGenovaG,UedaH,CordellHJ,Eaves IA,DudbridgeF,TwellsRC,PayneF,HughesW,NutlandS,StevensH,CarrP,Tuomilehto-WolfE, TuomilehtoJ,GoughSC,ClaytonDG,ToddJA(2001)Haplotypetaggingfor theidentificationof commondiseasegenes.NatGenet29(2):233–237.https://doi.org/10.1038/ng1001-233 4. International HapMap C (2003) The international HapMap project. Nature 426(6968):789–796. https://doi.org/10.1038/nature02168 5. GenomesProjectC,AutonA,BrooksLD,DurbinRM,GarrisonEP,KangHM,KorbelJO,Marchini JL, McCarthy S, McVean GA, Abecasis GR (2015) A global reference for human genetic variation. Nature526(7571):68–74.https://doi.org/10.1038/nature15393 Contents Preface ..................................................................... v Contributors................................................................. ix 1 InterrogatingtheHumanDiplome:ComputationalMethods,Emerging Applications,andChallenges ........ ....... ....... ........ ....... ........ 1 AgnesP.Chan,YongwookChoi,AdityaRangan,GuangfaZhang, AvijitPodder,MichaelBerens,SunilSharma,PatrickPirrotte, SaraByron,DaveDuggan,andNicholasJ.Schork 2 TargetedLocusAmplificationandHaplotyping...... ........ ....... ........ 31 JulietW.Lefferts,VeraBoersma,MarneC.Hagemeijer, KarimaHajo,Jeffrey M.Beekman,andErikSplinter 3 Full-LengthTranscriptPhasingwithThird-GenerationSequencing........... 49 NenadSvrzikapaandRamakrishnaBoyanapalli 4 Large-ScaleCompleteSequencingandHaplotypingof1–10kbDNA MoleculesUsingShortMassivelyParallelReads ..... ........ ....... ........ 59 YoutaoLiu,FeiFan,RadojeDrmanac,BrockA.Peters,andOuWang 5 AccurateSequencingandHaplotypingfrom10CellsUsingLong FragmentRead(LFR)Technology.......... ....... ........ ....... ........ 71 MarkA.McElwainandBrockA.Peters 6 Low-CostGenome-ScalePhasingwithBarcode-LinkedSequencing .......... 85 DavidRedin 7 ASimpleCost-EffectiveMethodforWhole-GenomeSequencing, Haplotyping,andAssembly ......... ....... ....... ........ ....... ........ 101 OuWang,XiaofangCheng,RadojeDrmanac,andBrockA.Peters 8 Read-BasedPhasingandAnalysisofPhasedVariantswithWhatsHap.......... 127 MarcelMartin,PeterEbert,andTobiasMarschall 9 HapCUT2:AMethodforPhasingGenomesUsingExperimental SequenceData...... ...... ......... ....... ....... ........ ....... ........ 139 VikasBansal 10 DeterminingCompleteChromosomalHaplotypesbymLinker....... ........ 149 SumitSinhaandCheng-ZhongZhang 11 Haplotyping-AssistedDiploidAssemblyandVariantDetection withLinkedReads ......... ........ ....... ....... ........ ....... .... .... 161 YunfeiHu,ChaoYang,LuZhang,andXinZhou 12 Chromosome-LengthHaplotypeswithStrandPhaseRandStrand-seq......... 183 VincentC.T.Hanlon,DavidPorubsky,andPeterM.Lansdorp 13 GameteBinningtoAchieveHaplotype-ResolvedGenomeAssembly.......... 201 HequanSun,JoseÁ.Campoy,andKorbinianSchneeberger vii viii Contents 14 PhasingDNAMethylation.......... ....... ....... ........ ....... ........ 219 VahidAkbariandStevenJ.M.Jones 15 Analysisof1276Haplotype-ResolvedGenomesAllowsCharacterization ofCis-andTrans-AbundantGenes ......... ....... ........ ....... ........ 237 MargretR.HoeheandRalfHerwig 16 PhasedGenomeAssemblies......... ....... ....... ........ ... .... ........ 273 JorgeDuitama 17 Haplotype-AssistedNoninvasivePrenatalDiagnosisofGeneticDiseases byMassivelyParallelSequencingofMaternalPlasmaCell-FreeDNA.......... 287 JiaJu,FengxiaSu,ChaoChen,JunSun,andYaGao Index ...................................................................... 295 Contributors VAHIDAKBARI • Canada’sMichaelSmithGenomeSciencesCentre,BCCancer,Vancouver, BC,Canada;DepartmentofMedicalGenetics,UniversityofBritishColumbia,Vancouver, BC,Canada VIKASBANSAL • SchoolofMedicine,UniversityofCaliforniaSanDiego,LaJolla,CA,USA JEFFREYM.BEEKMAN • DepartmentofPediatricRespiratoryMedicine,Wilhelmina Children’sHospital,UniversityMedicalCenterUtrecht,Utrecht,TheNetherlands; RegenerativeMedicineCenter,Center forLivingTechnologies,UniversityMedicalCenter Utrecht,Utrecht,TheNetherlands MICHAELBERENS • TheTranslationalGenomicsResearchInstitute(TGen),partoftheCity ofHopeNationalMedicalCenter,Phoenix,AZ,USA;TheCityofHopeNationalMedical Center,Duarte,CA,USA VERABOERSMA • CergentisBV,Utrecht,TheNetherlands RAMAKRISHNA BOYANAPALLI • WaveLifeSciences,Cambridge,MA,USA SARABYRON • TheTranslationalGenomicsResearchInstitute(TGen),partoftheCityof HopeNationalMedicalCenter,Phoenix,AZ,USA;TheCityofHopeNationalMedical Center,Duarte,CA,USA JOSE´ A.CAMPOY • DepartmentofChromosomeBiology,MaxPlanckInstituteforPlant BreedingResearch,Cologne,Germany AGNESP.CHAN • TheTranslationalGenomicsResearchInstitute(TGen),partoftheCityof HopeNationalMedicalCenter,Phoenix,AZ,USA CHAOCHEN • BGIGenomics,BGI-Shenzhen,Shenzhen,China;TianjinMedical Laboratory,BGI-Tianjin,BGI-Shenzhen,Tianjin,China XIAOFANGCHENG • MGI,Shenzhen,GuangdongProvince,People’sRepublicofChina YONGWOOKCHOI • TheTranslationalGenomicsResearchInstitute(TGen),partoftheCity ofHopeNationalMedicalCenter,Phoenix,AZ,USA RADOJEDRMANAC • AdvancedGenomicsTechnologyLaboratory,CompleteGenomics/MGI, SanJose,CA,USA DAVEDUGGAN • TheTranslationalGenomicsResearchInstitute(TGen),partoftheCityof HopeNationalMedicalCenter,Phoenix,AZ,USA;TheCityofHopeNationalMedical Center,Duarte,CA,USA JORGEDUITAMA • SystemsandComputingEngineeringDepartment,Universidaddelos Andes,Bogota´,Colombia PETEREBERT • InstituteforMedicalBiometryandBioinformatics,MedicalFaculty, HeinrichHeineUniversityDu¨sseldorf,Du¨sseldorf,Germany FEIFAN • BGI-Shenzhen,Shenzhen,GuangdongProvince,PRChina YAGAO • BGI-Shenzhen,Shenzhen,China;ShenzhenEngineeringLaboratoryforBirth DefectsScreening,Shenzhen,China MARNEC.HAGEMEIJER • DepartmentofPediatricRespiratoryMedicine,Wilhelmina Children’sHospital,UniversityMedicalCenterUtrecht,Utrecht,TheNetherlands; RegenerativeMedicineCenter,Center forLivingTechnologies,UniversityMedicalCenter Utrecht,Utrecht,TheNetherlands;DepartmentofClinicalGenetics,CenterforLysosomal andMetabolicDiseases,ErasmusUniversityMedicalCenter,Rotterdam,TheNetherlands ix