2024
Inferring B Cell Phylogenies from Paired H and L Chain BCR Sequences with Dowser.
Jensen C, Sumner J, Kleinstein S, Hoehn K. Inferring B Cell Phylogenies from Paired H and L Chain BCR Sequences with Dowser. The Journal Of Immunology 2024, 212: 1579-1588. PMID: 38557795, PMCID: PMC11073909, DOI: 10.4049/jimmunol.2300851.Peer-Reviewed Original ResearchConceptsPhylogenetic treeL chainsBranch lengthsBCR sequencesTree-building methodsSingle-cell sequencing dataHistory of mutationsSingle-cell sequencingPhylogenetic methodsSequence dataSequencing technologiesL chain sequencesTree accuracyEvolutionary processSingle-cellPhylogenyImmune responseSomatic hypermutationSequenceClonesMutationsB cell clonesHuman immune responseTreesBCR
2020
Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response
Béguelin W, Teater M, Meydan C, Hoehn KB, Phillip JM, Soshnev AA, Venturutti L, Rivas MA, Calvo-Fernández MT, Gutierrez J, Camarillo JM, Takata K, Tarte K, Kelleher NL, Steidl C, Mason CE, Elemento O, Allis CD, Kleinstein SH, Melnick AM. Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response. Cancer Cell 2020, 37: 655-673.e11. PMID: 32396861, PMCID: PMC7298875, DOI: 10.1016/j.ccell.2020.04.004.Peer-Reviewed Original ResearchConceptsFollicular lymphomaB cellsIndolent tumorsCell helpFollicular dendritic cell networksB cell requirementDendritic cell networksFollicular helper cellsGerminal center B cellsGC B cellsHelper cellsImmunological nicheImmune responseMalignant transformationHuman follicular lymphomaEZH2 mutationsPrevents inductionFunction mutationsTumorsCell requirementsCellsMutant EZH2LymphomaMutations
2016
A Model of Somatic Hypermutation Targeting in Mice Based on High-Throughput Ig Sequencing Data
Cui A, Di Niro R, Vander Heiden JA, Briggs AW, Adams K, Gilbert T, O'Connor KC, Vigneault F, Shlomchik MJ, Kleinstein SH. A Model of Somatic Hypermutation Targeting in Mice Based on High-Throughput Ig Sequencing Data. The Journal Of Immunology 2016, 197: 3566-3574. PMID: 27707999, PMCID: PMC5161250, DOI: 10.4049/jimmunol.1502263.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsB-LymphocytesCells, CulturedClonal Selection, Antigen-MediatedDNA RepairFemaleGerminal CenterHigh-Throughput Nucleotide SequencingHumansImmunoglobulin Heavy ChainsImmunoglobulin Variable RegionMiceMice, Inbred BALB CMice, TransgenicModels, GeneticMutationMutation RateSomatic Hypermutation, ImmunoglobulinConceptsSpecific DNA motifsSimilar biological processesObserved mutation patternDNA repair activityIg sequencesNonfunctional sequencesDNA motifsMutation patternsHigh mutation frequencySelection pressureUnselected mutationsSequencing dataBiological processesFunctional sequencesRepair activityTransition mutationsSomatic hypermutation patternsGerminal center B cellsSomatic hypermutationNext-generation methodsHypermutation patternsMutation frequencyMutationsSequenceMotifLong-lived antigen-induced IgM plasma cells demonstrate somatic mutations and contribute to long-term protection
Bohannon C, Powers R, Satyabhama L, Cui A, Tipton C, Michaeli M, Skountzou I, Mittler RS, Kleinstein SH, Mehr R, Lee FE, Sanz I, Jacob J. Long-lived antigen-induced IgM plasma cells demonstrate somatic mutations and contribute to long-term protection. Nature Communications 2016, 7: 11826. PMID: 27270306, PMCID: PMC4899631, DOI: 10.1038/ncomms11826.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAmino Acid MotifsAnimalsAntigensComplementarity Determining RegionsCytidine DeaminaseGerminal CenterImmunityImmunoglobulin Heavy ChainsImmunoglobulin MMice, Inbred C57BLMutationNeutralization TestsOrthomyxoviridaeOrthomyxoviridae InfectionsPlasma CellsSomatic Hypermutation, ImmunoglobulinSpleenConceptsIgM plasma cellsIgG plasma cellsPlasma cellsGerminal centersBone marrowLethal virus challengeProtective host immunitySomatic mutationsActivation-induced cytidine deaminaseHumoral immunityProtective antibodiesVirus challengeLong-term protectionHost immunityB cellsAffinity maturationMarrowLifelong sourceImmunityAntibodiesCellsCytidine deaminaseMutationsReplacement mutationsSpleen
2015
The mutation patterns in B-cell immunoglobulin receptors reflect the influence of selection acting at multiple time-scales
Yaari G, Benichou JI, Heiden J, Kleinstein SH, Louzoun Y. The mutation patterns in B-cell immunoglobulin receptors reflect the influence of selection acting at multiple time-scales. Philosophical Transactions Of The Royal Society B Biological Sciences 2015, 370: 20140242. PMID: 26194756, PMCID: PMC4528419, DOI: 10.1098/rstb.2014.0242.Peer-Reviewed Original ResearchMeSH KeywordsAntibody AffinityAntibody DiversityB-LymphocytesCell LineageClonal Selection, Antigen-MediatedComplementarity Determining RegionsGenes, ImmunoglobulinHumansImmunoglobulin Heavy ChainsImmunoglobulin Variable RegionModels, GeneticModels, ImmunologicalMutationReceptors, Antigen, B-CellSomatic Hypermutation, ImmunoglobulinTime FactorsConceptsLineage treesPositive selectionStrong selection pressureLong-term selectionInfluence of selectionGene familyVariable gene familiesComplementarity determining regionsClone membersMutation patternsSelection pressureB cell populationsImmunoglobulin genesB cellsFramework regionsSomatic hypermutationSomatic mutationsAffinity maturationMutationsClone sizeMaturation processLong trunkAffinity maturation processSignificant diversityMultiple rounds
2014
Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients
Cho MJ, Lo AS, Mao X, Nagler AR, Ellebrecht CT, Mukherjee EM, Hammers CM, Choi EJ, Sharma PM, Uduman M, Li H, Rux AH, Farber SA, Rubin CB, Kleinstein SH, Sachais BS, Posner MR, Cavacini LA, Payne AS. Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients. Nature Communications 2014, 5: 4167. PMID: 24942562, PMCID: PMC4120239, DOI: 10.1038/ncomms5167.Peer-Reviewed Original ResearchConceptsHumoral immune responsePemphigus vulgarisGene usageImmune responseAnti-Dsg3 antibodiesSomatic mutationsRequirement of mutationsPemphigus vulgaris autoantibodiesBlistering diseasePV patientsVH gene usagePatientsDesmoglein 3Unrelated patientsAutoAbsAutoantibodiesAutoreactivityDsg3MutationsGermline sequencesAbReplacement mutationsVDJ recombinationDiseaseAntibodiesIntegrating B Cell Lineage Information into Statistical Tests for Detecting Selection in Ig Sequences
Uduman M, Shlomchik MJ, Vigneault F, Church GM, Kleinstein SH. Integrating B Cell Lineage Information into Statistical Tests for Detecting Selection in Ig Sequences. The Journal Of Immunology 2014, 192: 867-874. PMID: 24376267, PMCID: PMC4363135, DOI: 10.4049/jimmunol.1301551.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibody AffinityAntibody DiversityB-Lymphocyte SubsetsCell LineageClonal Selection, Antigen-MediatedComputer SimulationConfounding Factors, EpidemiologicGene Rearrangement, B-LymphocyteGenes, ImmunoglobulinHumansMiceModels, ImmunologicalModels, StatisticalROC CurveSequence Analysis, DNASomatic Hypermutation, ImmunoglobulinVDJ ExonsConceptsLineage treesHigh-throughput sequencing technologyLineage tree shapesCell lineage informationIg sequencesRatio of replacementTree-shape analysisStatistical frameworkSequence-based methodsBinomial statistical analysisExperimental data setsIndicators of selectionSequencing technologiesLineage informationSequencing depthNumber of generationsData setsHybrid methodVivo selectionSilent mutationsTree shapeStatistical testsSequenceShape analysisMutations
2013
Multiple Transcription Factor Binding Sites Predict AID Targeting in Non-Ig Genes
Duke JL, Liu M, Yaari G, Khalil AM, Tomayko MM, Shlomchik MJ, Schatz DG, Kleinstein SH. Multiple Transcription Factor Binding Sites Predict AID Targeting in Non-Ig Genes. The Journal Of Immunology 2013, 190: 3878-3888. PMID: 23514741, PMCID: PMC3689293, DOI: 10.4049/jimmunol.1202547.Peer-Reviewed Original ResearchConceptsTranscription Factor Binding SitesAID-induced lesionsNon-Ig genesGenome instabilityTranscription factorsAberrant targetingSequence dataCertain genesGenesAID targetingGerminal center B cellsSomatic mutationsLikely targetBinding sitesAID targetsTargetingClassification tree modelMistargetingB cellsLociMechanismTargetMutationsSitesModels of Somatic Hypermutation Targeting and Substitution Based on Synonymous Mutations from High-Throughput Immunoglobulin Sequencing Data
Yaari G, Heiden J, Uduman M, Gadala-Maria D, Gupta N, Stern JN, O’Connor K, Hafler DA, Laserson U, Vigneault F, Kleinstein SH. Models of Somatic Hypermutation Targeting and Substitution Based on Synonymous Mutations from High-Throughput Immunoglobulin Sequencing Data. Frontiers In Immunology 2013, 4: 358. PMID: 24298272, PMCID: PMC3828525, DOI: 10.3389/fimmu.2013.00358.Peer-Reviewed Original ResearchAccurate background modelSynonymous mutationsNon-coding regionsParticular codon usageNon-functional sequencesComputational analysis methodsObserved mutation patternExisting modelsBackground modelInfluence of selectionCodon usageSHM targetingBase compositionImproved modelSequencing dataNucleotide substitutionsAnalysis methodStatistical analysisFunctional sequencesMutation targetingB-cell cancersModelSomatic hypermutation patternsMutationsHypermutation patterns
2011
Somatic hypermutation targeting is influenced by location within the immunoglobulin V region
Cohen RM, Kleinstein SH, Louzoun Y. Somatic hypermutation targeting is influenced by location within the immunoglobulin V region. Molecular Immunology 2011, 48: 1477-1483. PMID: 21592579, PMCID: PMC3109224, DOI: 10.1016/j.molimm.2011.04.002.Peer-Reviewed Original ResearchConceptsObserved mutation patternSpecific DNA motifsBiased codon usageImmunoglobulin V genesMutation accumulationGene positionCodon usageMutation patternsDNA motifsPositive selectionPosition-specific effectsImmunoglobulin V regionsNegative selectionB cellsMutationsMutation frequencyV geneGenesPeripheral B cellsSubstitution typeV regionsTargetingSpecific targetingCellsSequence
2008
Two levels of protection for the B cell genome during somatic hypermutation
Liu M, Duke JL, Richter DJ, Vinuesa CG, Goodnow CC, Kleinstein SH, Schatz DG. Two levels of protection for the B cell genome during somatic hypermutation. Nature 2008, 451: 841-845. PMID: 18273020, DOI: 10.1038/nature06547.Peer-Reviewed Original ResearchConceptsError-free DNA repairB cell genomeGenomic stabilityNumerous oncogenesDNA repairCell genomeBase excisionGenomeMismatch repairImmunoglobulin genesSomatic hypermutationWidespread mutationsHypermutationB-cell tumorsB-cell malignanciesHigh-affinity antibodiesB cellsGenesOncogeneLarge fractionDiversityVital roleMutationsEnzymeRepair
2006
Mutation parameters from DNA sequence data using graph theoretic measures on lineage trees
Magori-Cohen R, Louzoun Y, Kleinstein SH. Mutation parameters from DNA sequence data using graph theoretic measures on lineage trees. Bioinformatics 2006, 22: e332-e340. PMID: 16873490, DOI: 10.1093/bioinformatics/btl239.Peer-Reviewed Original ResearchConceptsLineage treesDNA sequencesDNA sequence dataSomatic hypermutationMaximum likelihood analysisTree shapeBioinformatics methodsSequence dataLethal mutationsMutation rateNumber of generationsLikelihood analysisMutation parametersB cellsSynthetic treeClonal expansionTreesSequenceMutationsHypermutationAffinity maturationCellsImportant linkClonesUnexpected locations