中國農(nóng)業(yè)大學動物科技學院

丁向東中國農(nóng)業(yè)大學動物科技學院Haplotypeinferenceandhaplotype-basedtransmissiondisequilibriumtest(Hap-TDT)

中國畜牧獸醫(yī)學會信息技術(shù)分會2023年會.哈爾濱OutlineHaplotypeinferenceIntroductionofimportantmethods

Parsimony(Clark,1990)EM(ExcoffierandSlatkin,1995)Bayesian(StephensandDonnelly,2023)HaplotypeinferenceusingfamilyinformationTransmissionDisequilibriumTest(TDT)Haplotype-basedTDT(Hap-TDT)GenotypeandHaplotypeLoc1213Loc216…915…417…19…26Loc7917213619151741926179HaplotypereconstructionChromosomephaseisunkownChromosomephaseiskownHaplotype:AcollectionofallelesfromsamechromosomeAllele&GenotypeHaplotype&diplotypeAlgorithmsforhaplotypeinferenceStatisticalmethodsParsimony(Clark,1990)EMExcoffierandSlatkin(1995);Qinetal.(2023)BayesianStephensandDonnelly(2023);Niuetal.(2023)Rule-basedmethodsMinimumrecombinationprincipleQianandBeckmann(2023);Baruch,etal.(2023)Parsimony(Clark,1990)A1A1A1A2A2A3A3A4A3A5A6A7StartfromahomozygoteDetermineanyotherambiguoussequenceusingthedefinitivehaplotypefrom1ContinuethisprocedureuntilallhaplotypesareresolvedoruntilnomorenewhaplotypescanbefoundEMalgorithmNumericalmethodoffindingmaximumlikelihoodestimatesforparametersgivenincompletedata.Initialparametervalues:haplotypefrequenciesExpectationstep:computeexpectedvaluesofmissingdatabasedoninitialdataMaximizationstep:computeMLEforparametersfromthecompletedataRepeatwithupdatedsetofparametersuntilchangesintheparameterestimatesarenegligible.EMalgorithmefficiencyHeavycomputationalburdenwithlargenumberoflociPartition-ligationalgorithm(Niuetal.,2023)PL-EM(Qinetal.,2023)AccuracyanddeparturesfromHWEAssumptionofHWEinmostEM-basedmethodsRobusttodeparturefromHWE(FallinandSchork,2023)Bayesianmethod

PHASE(StephensandDonnelly,2023)BasedoncoalescentmodelUseGibbssamplingSofar,veryaccurate,butalsocomplicated.fastPHASE(ScheetandStephens,2023)RevisedversionofPHASEMuchfaster,missinggenotypeComparisonofParsimony,EMandPHASEEMPHASEParsimonyPHASEperformsbetterthanparsimonyandEM(Stephen,2023)PHASEandEM-basedmethodsexhibitedsimilarperformances(Zhangetal.2023;Xuetal.2023)Haplotypeinferenceusingfamilydata(1)HaplotypeinferencebasedoncloserelativesReduceshaplotypeambiguityandimprovestheefficiencyRohdeandFuerst(2023)–EMalgorithmFamilieswithbothparentsandtheirchildrenThegenotypedoffspringreducethenumberofpotentialhaplotypepairsforbothparents.Dingetal.(2023)-EMalgorithmFamilieswithonlyoneparentavailableHaplotypeinferenceusingfamilydata(2)Dingetal.–EMalgorithmFamilieswithonlysibsMixedfamilydataCompletefamiliesIncompletefamiliesOneparentOnlysibsgenotypesofsibsParentalinformationHaplotypepairsofsibsMethodnameUsingfamilyinformation?UsingLD?Handlingincompletefamilies?Complete-family-EM(RhodeandFuerst,2023)YESYESNOIncomplete-family-EM(Dingetal.,2023)YESYESYESGENEHUNTER(Kruglyaketal.,1996)YESNOYESPHASE(Stephensetal.,2023)YESYESYESComparisonoffourdifferentstrategies(Dingetal.,

2023)ResultforincompletefamiliesIncomplete-family-EMPHASEGENEHUNTERRunningtimeofPHASE:3.5hsforthewhole100datasetsof30trios,187SNPs(Marchinietal.,2023)RunningtimewillbecomeprohibitiveforlargeSNPsRule-basedmethodMinimumrecombinationprincipleQianandBeckmann(2023);Baruch,etal.(2023)GeneticrecombinationisrareHaplotypewithfewerrecombinantsshouldbepreferredinahaplotypereconstructionRule1Rule2…Wangetal.,2023JointEMandrule-basedalgorithmfor(grand-)daughterdesignAssumptionofnorecombinationEMalgorithmtoconstructdiplotypeTakingintoaccountrecombinationMinimumrecombinationprincipleFindthediplotypeofsirethatminimizesthenumberofrecombinationsinthesirefamily

Possiblediplotypes

recom.events------------------------------------------------1.222221111112.1122222111513.1112222211494.222211111251122222111151-------------------------------------------------Example:Asirefamilywith50offspringphase-unknowngenotypeofsire:(12;12;12;12;12)

Results

HSHAPPedPhaseSimWalk2Errorrateinsires0.007c0.682a0.126bErrorrateinoffspring0.021c0.0330b0.0705aRunningtime(m)8.2110.00660.1710sirefamilieswith30offspringeach10SNPs,0.5centiMorganResults-incompletedataHSHAPPedPhaseSimWalk2Errorrateinsires0.0310c0.8910a0.0930bErrorrateinoffspring0.0159c0.7607a0.2164bRunningtime(m)0.010.00210.6510sirefamilieswith20offspringeach5SNPs,0.5centiMorgan30%individualswithonerandommissinglocus.LinkagevsAssociationLinkageFamily-basedMatching/ethnicitygenerallyunimportantFewmarkersforgenomecoverage(300-400STRs)CanbeweakdesignGoodforinitialdetection;poorforfine-mappingPowerfulforrarevariantsAssociationFamiliesorunrelatedsMatching/ethnicitycrucialManymarkersreqforgenomecoverage(105–106SNPs)PowerfuldesignPoorforinitialdetection;goodforfine-mappingPowerfulforcommonvariants;rarevariantsgenerallyimpossibleTDT(TransmissionDisequilibriumTest)Comparesthedistributionoftransmittedandnon-transmittedallelesbyparentsofaffectedoffspring(Spielmanetal.1993)Non-transmittedalleletotaltransmittedalleleM1M2M1aba+bM2cdc+dtotala+cb+d2nIfthemarkerisunlinkedtothecausativelocusthenweexpectb=c,else,oneofthealleleswilltendtobetransmittedmoreoftenTDTTDT(TransmissionDisequilibriumTest)Goodforfine-mapping,poorforinitialdetectionRobustforpopulationstratification/admixtureWidelyusedingenome-wideassociationstudyExtendedtoallkindsofdatastructureMultiallelicmarkers(ShamandCurtis,1995)Multiplesiblings(Spielman,1998;Boehnke,1998)Missingparentaldata(Sun,1999)Extendedpedigree(Martinetal.,2000)Quantitativetraits(Allison,1997;Dingetal,2023)ComparisonofPDT,QTDTandPTDT#ped#allelesQTLeffectPowerTypeIerrorPDTQTDTPTDTPDTQTDTPTDT1020.159185745150.374618274380.5858192834QuantitativetraitHap-TDTHap-TDT(Haplotype-basedTDT)Haplotypeismoreinformativethan