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
Position-Dependent Differential Targeting of Somatic Hypermutation
Zhou JQ, Kleinstein SH. Position-Dependent Differential Targeting of Somatic Hypermutation. The Journal Of Immunology 2020, 205: 3468-3479. PMID: 33188076, PMCID: PMC7726104, DOI: 10.4049/jimmunol.2000496.Peer-Reviewed Original ResearchConceptsSomatic hypermutationSHM targetingIg sequencesSame DNA motifTranscription start siteAllele-specific effectsInfluence of selectionGene familyVariable gene familiesDNA motifsSequence neighborhoodError-prone repairStart siteAb diversityDNA lesionsDifferential targetingUnique motifMotifSequenceTargetingHypermutationEffective humoral immunityIntrinsic biasesAffinity maturationLarge collection
2018
Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers
Rydyznski CE, Cranert SA, Zhou JQ, Xu H, Kleinstein SH, Singh H, Waggoner SN. Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers. Cell Reports 2018, 24: 3367-3373.e4. PMID: 30257198, PMCID: PMC6192537, DOI: 10.1016/j.celrep.2018.08.075.Peer-Reviewed Original ResearchConceptsNK cellsGC B cell frequencyNatural killer cell suppressionAntigen-reactive B cellsB cell frequenciesNatural killer cellsFollicular helper TAntigen-specific immunoglobulinsAdministration of alumGerminal center reactionVaccine elicitationHelper TKiller cellsHumoral immunityProtective antibodiesHigh-affinity antibodiesCell suppressionGerminal centersB cellsCell frequencyCenter reactionSomatic hypermutationGC developmentGC reactionAntibody affinity
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 frequencyMutationsSequenceMotif
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 roundsSalmonella Infection Drives Promiscuous B Cell Activation Followed by Extrafollicular Affinity Maturation
Di Niro R, Lee SJ, Vander Heiden J, Elsner RA, Trivedi N, Bannock JM, Gupta NT, Kleinstein SH, Vigneault F, Gilbert TJ, Meffre E, McSorley SJ, Shlomchik MJ. Salmonella Infection Drives Promiscuous B Cell Activation Followed by Extrafollicular Affinity Maturation. Immunity 2015, 43: 120-131. PMID: 26187411, PMCID: PMC4523395, DOI: 10.1016/j.immuni.2015.06.013.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalB-LymphocytesClonal Selection, Antigen-MediatedGerminal CenterImmunoglobulin GLymphocyte ActivationMiceMice, Inbred BALB CMice, Inbred C57BLMice, KnockoutReceptors, Antigen, B-CellSalmonella InfectionsSalmonella typhimuriumSomatic Hypermutation, ImmunoglobulinSpleenConceptsB cell receptorExtrafollicular sitesGerminal centersAffinity maturationInfection of miceB cell responsesB cell activationDetectable antibodiesSomatic hypermutationExtrafollicular responseAntigen microarraysSalmonella infectionAntigen targetsCell activationSalmonella typhimuriumCell responsesBCR specificityFlow cytometryCell receptorMonoclonal antibodiesUndetectable affinityClonal selectionInfectionAntibodiesLaser microdissectionChange-O: a toolkit for analyzing large-scale B cell immunoglobulin repertoire sequencing data
Gupta NT, Vander Heiden JA, Uduman M, Gadala-Maria D, Yaari G, Kleinstein SH. Change-O: a toolkit for analyzing large-scale B cell immunoglobulin repertoire sequencing data. Bioinformatics 2015, 31: 3356-3358. PMID: 26069265, PMCID: PMC4793929, DOI: 10.1093/bioinformatics/btv359.Peer-Reviewed Original ResearchConceptsHigh-throughput sequencing technologyB cell immunoglobulinLarge-scale characterizationLineage treesSpecialized computational methodsSelection pressureSequencing technologiesSomatic diversityClonal populationsIg repertoireSomatic hypermutationIg sequencesDiversityNon-commercial useSuite of utilitiesRepertoire diversityGermlineComputational methodsAllelesHypermutationA model of somatic hypermutation targeting in mice based on high-throughput immunoglobulin sequencing data (TECH2P.910)
Cui A, Diniro R, Briggs A, Adams K, Vander Heiden J, O'Connor K, Vigneault F, Shlomchik M, Kleinstein S. A model of somatic hypermutation targeting in mice based on high-throughput immunoglobulin sequencing data (TECH2P.910). The Journal Of Immunology 2015, 194: 206.20-206.20. DOI: 10.4049/jimmunol.194.supp.206.20.Peer-Reviewed Original ResearchSimilar biological processesNon-functional sequencesObserved mutation patternDNA repair activityMutation patternsDNA motifsNext-generation sequencingHigh mutation frequencyUnselected mutationsSelection pressureSequencing dataBiological processesFunctional sequencesImmunoglobulin genesRepair activitySomatic hypermutation patternsSomatic hypermutationHypermutation patternsMutation frequencyIg sequencesT transitionSequenceHeavy chain transgenic miceMotifTransgenic miceAutomated analysis of high-throughput B-cell sequencing data reveals a high frequency of novel immunoglobulin V gene segment alleles
Gadala-Maria D, Yaari G, Uduman M, Kleinstein SH. Automated analysis of high-throughput B-cell sequencing data reveals a high frequency of novel immunoglobulin V gene segment alleles. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: e862-e870. PMID: 25675496, PMCID: PMC4345584, DOI: 10.1073/pnas.1417683112.Peer-Reviewed Original Research
2012
Identification of Core DNA Elements That Target Somatic Hypermutation
Kohler KM, McDonald JJ, Duke JL, Arakawa H, Tan S, Kleinstein SH, Buerstedde JM, Schatz DG. Identification of Core DNA Elements That Target Somatic Hypermutation. The Journal Of Immunology 2012, 189: 5314-5326. PMID: 23087403, PMCID: PMC3664039, DOI: 10.4049/jimmunol.1202082.Peer-Reviewed Original ResearchMeSH Keywords3' Flanking RegionAnimalsB-LymphocytesCells, CulturedChickensChromatin ImmunoprecipitationCytidine DeaminaseDNAEnhancer Elements, GeneticGenes, ImmunoglobulinGenetic LociImmunoassayImmunoglobulin Variable RegionMutationPhosphorylationRNA Polymerase IISerineSomatic Hypermutation, ImmunoglobulinTranscription, GeneticConceptsActivation-induced deaminaseDNA elementsSomatic hypermutationChicken DT40 B cellsIg lociChromatin immunoprecipitation experimentsDT40 B cellsRNA polymerase IISystematic deletion analysisL chain lociNon-Ig genesCore DNA elementSerine 5Epigenetic marksPolymerase IITranscriptional elongationMutational machineryDeletion analysisReporter cassetteImmunoprecipitation experimentsDeoxycytosine residuesIg genesDNA damageChain locusLociQuantifying selection in high-throughput Immunoglobulin sequencing data sets
Yaari G, Uduman M, Kleinstein SH. Quantifying selection in high-throughput Immunoglobulin sequencing data sets. Nucleic Acids Research 2012, 40: e134-e134. PMID: 22641856, PMCID: PMC3458526, DOI: 10.1093/nar/gks457.Peer-Reviewed Original ResearchConceptsQuantifying selectionDifferent selection pressuresHigh-throughput immunoglobulinSomatic hypermutationNext-generation sequencing dataDNA mutation patternsSomatic mutation patternsGroups of sequencesAntigen-driven selection processMutation patternsSequence dataSelection pressureSequencing dataB cell affinity maturationB-cell cancersNegative selection
2009
Activated Germinal-Center B Cells Undergo Directed Migration
O'Connor M, Hauser A, Haberman A, Kleinstein S. Activated Germinal-Center B Cells Undergo Directed Migration. 2009, 327-331. DOI: 10.1109/bibm.2009.61.Peer-Reviewed Original Research
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