2025
Association of clinical manifestations and immune alterations with genetic variants of uncertain significance in patients concerned for inborn errors of immunity
Novotny S, Yoo N, Chen J, Granoth M, Kohli-Pamnani A, Hsu F, Rodenas M, Steele R, Kaman K, Soffer G, Price C, Kuster J, Kang I, Osmani L, Shin J. Association of clinical manifestations and immune alterations with genetic variants of uncertain significance in patients concerned for inborn errors of immunity. Clinical Immunology 2025, 277: 110513. PMID: 40354868, DOI: 10.1016/j.clim.2025.110513.Peer-Reviewed Original ResearchInborn errors of immunityErrors of immunityGenetic variantsInborn errorsAssociation of clinical manifestationsGene clusterGene functionStudy evaluated associationsImmune alterationsDiagnostic challengeClinical manifestationsImmunological profileGenetic testingVUSGenesImmunological characteristicsImmune functionLaboratory dataImmunityVariantsAssociationPatientsA compendium of human gene functions derived from evolutionary modelling
Ramsey J, Siegele D, Chisholm R, Fey P, Giglio M, Nadendla S, Antonazzo G, Attrill H, Brown N, Garapati P, Marygold S, Ahmed S, Asanitthong P, Buitrago D, Erdol M, Gage M, Huang S, Kadhum M, Li K, Long M, Michalak A, Pesala A, Pritazahra A, Saverimuttu S, Su R, Xu Q, Lovering R, Blake J, Christie K, Corbani L, Dolan M, Ni L, Sitnikov D, Smith C, Lera-Ramirez M, Rutherford K, Wood V, D’Eustachio P, Demos W, De Pons J, Dwinell M, Hayman G, Kaldunski M, Kwitek A, Laulederkind S, Smith J, Tutaj M, Vedi M, Wang S, Engel S, Karra K, Miyasato S, Nash R, Skrzypek M, Weng S, Wong E, Achsel T, Andres-Alonso M, Bagni C, Bayés À, Biederer T, Brose N, Chua J, Coba M, Cornelisse L, de Juan-Sanz J, Goldschmidt H, Gundelfinger E, Huganir R, Imig C, Jahn R, Jung H, Kaeser P, Kim E, Koopmans F, Kreutz M, Lipstein N, MacGillavry H, McPherson P, O’Connor V, Pielot R, Ryan T, Sala C, Sheng M, Smalla K, Smit A, Toonen R, van Weering J, Verhage M, Verpelli C, Bakker E, Berardini T, Reiser L, Auchincloss A, Axelsen K, Argoud-Puy G, Blatter M, Boutet E, Breuza L, Bridge A, Casals-Casas C, Coudert E, Estreicher A, Famiglietti M, Gos A, Gruaz-Gumowski N, Hulo C, Hyka-Nouspikel N, Jungo F, Le Mercier P, Lieberherr D, Masson P, Morgat A, Pedruzzi I, Pourcel L, Poux S, Rivoire C, Sundaram S, Bowler-Barnett E, Bye-A-Jee H, Denny P, Ignatchenko A, Ishtiaq R, Lock A, Lussi Y, Magrane M, Martin M, Orchard S, Raposo P, Speretta E, Tyagi N, Warner K, Zaru R, Chan J, Diamantakis S, Raciti D, Fisher M, James-Zorn C, Ponferrada V, Zorn A, Ramachandran S, Ruzicka L, Westerfield M. A compendium of human gene functions derived from evolutionary modelling. Nature 2025, 640: 146-154. PMID: 40011791, PMCID: PMC11964926, DOI: 10.1038/s41586-025-08592-0.Peer-Reviewed Original ResearchHuman gene functionHuman protein-coding genesProtein-coding genesGene functionFunctional repertoireGene Ontology enrichment analysisGene Ontology ConsortiumOntology enrichment analysisHuman genomeHuman genesEvolutionary timeEvolutionary originGenomic techniquesEvolutionary modeling approachExpert-curatedEnrichment analysisGenesRegulatory functionsFunctional characteristicsEvolutionary modelsBiomedical researchGenomeRepertoireOrganisms1,2Body of informationCoupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits
Scherer N, Fässler D, Borisov O, Cheng Y, Schlosser P, Wuttke M, Haug S, Li Y, Telkämper F, Patil S, Meiselbach H, Wong C, Berger U, Sekula P, Hoppmann A, Schultheiss U, Mozaffari S, Xi Y, Graham R, Schmidts M, Köttgen M, Oefner P, Knauf F, Eckardt K, Grünert S, Estrada K, Thiele I, Hertel J, Köttgen A. Coupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits. Nature Genetics 2025, 57: 193-205. PMID: 39747595, PMCID: PMC11735408, DOI: 10.1038/s41588-024-01965-7.Peer-Reviewed Original ResearchConceptsWhole-exome sequencing dataGene-metabolite associationsHuman traitsHuman metabolic reactionsSequence dataAllelic seriesGene functionExome sequencingFunctional variantsGenetic studiesInborn errors of metabolismHeterozygous variantsErrors of metabolismMusculoskeletal traitsMetabolic reactionsHuman heightUrine metabolitesHeterozygous stateSulfate reabsorptionInborn errorsTraitsAggregation testVariantsHuman metabolismMetabolomics
2024
A disease-associated PPP2R3C-MAP3K1 phospho-regulatory module controls centrosome function
Ganga A, Sweeney L, Rubio Ramos A, Wrinn C, Bishop C, Hamel V, Guichard P, Breslow D. A disease-associated PPP2R3C-MAP3K1 phospho-regulatory module controls centrosome function. Current Biology 2024, 34: 4824-4834.e6. PMID: 39317195, PMCID: PMC11496028, DOI: 10.1016/j.cub.2024.08.058.Peer-Reviewed Original ResearchCentrosome functionKinase-phosphatase pairSystems genetics approachDisorders of gonadal developmentCentriolar localizationCentriole proteinsGrowth defectSystems geneticsPhosphatase subunitFunctional partnersCentrosomal proteinsGene functionMicrotubule organizationCentrosome regulationGenetic approachesPPP2R3CJNK signalingCell signalingKinase activityCentrosome biogenesisAcute overexpressionGonadal developmentRegulatory mechanismsMAP3K1Gonadal dysgenesisContext-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes
Long E, Yin J, Shin J, Li Y, Li B, Kane A, Patel H, Sun X, Wang C, Luong T, Xia J, Han Y, Byun J, Zhang T, Zhao W, Landi M, Rothman N, Lan Q, Chang Y, Yu F, Amos C, Shi J, Lee J, Kim E, Choi J. Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes. Nature Communications 2024, 15: 7995. PMID: 39266564, PMCID: PMC11392933, DOI: 10.1038/s41467-024-52356-9.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesGenome-wide association study lociSusceptibility genesLung cancer susceptibility genesTranscription factor footprintsChromatin accessibility mapsCis-regulatory elementsRisk-associated variantsRare cell typesRegulate gene expressionCell typesCell type-specificCancer susceptibility genesCausal variantsAssociation studiesGene regulationGene functionMultiomics approachTarget genesLociGene expressionGenesType-specificHuman lung cellsCCREsInsights into the evolution, virulence and speciation of Babesia MO1 and Babesia divergens through multiomics analyses
Singh P, Vydyam P, Fang T, Estrada K, Gonzalez L, Grande R, Kumar M, Chakravarty S, Berry V, Ranwez V, Carcy B, Depoix D, Sánchez S, Cornillot E, Abel S, Ciampossin L, Lenz T, Harb O, Sanchez-Flores A, Montero E, Le Roch K, Lonardi S, Mamoun C. Insights into the evolution, virulence and speciation of Babesia MO1 and Babesia divergens through multiomics analyses. Emerging Microbes & Infections 2024, 13: 2386136. PMID: 39148308, PMCID: PMC11370697, DOI: 10.1080/22221751.2024.2386136.Peer-Reviewed Original ResearchLeveraging genomic informationHuman babesiosisTick-borne diseasesDiseases of significanceCases of human babesiosisGenomic divergenceGenome sequenceGenomic informationMultigene familyGene functionBabesia divergensMammalian hostsAnimal healthMultiomics analysisZoonotic pathogensBabesiosisProtozoan parasitesVirulent strainsPathogensVertebrate hostsEnvironmental changesVirulenceReplication rateAntiparasitic drugsParasitesInvestigating gene functions and single-cell expression profiles of de novo variants in orofacial clefts
Itai T, Yan F, Liu A, Dai Y, Iwaya C, Curtis S, Leslie E, Simon L, Jia P, Chen X, Iwata J, Zhao Z. Investigating gene functions and single-cell expression profiles of de novo variants in orofacial clefts. Human Genetics And Genomics Advances 2024, 5: 100313. PMID: 38807368, PMCID: PMC11318074, DOI: 10.1016/j.xhgg.2024.100313.Peer-Reviewed Original ResearchDe novo variantsCPO geneOMIM genesGene functionScRNA-seq data analysisOrofacial cleftsMan (OMIMScRNA-seq analysisOnline Mendelian InheritanceSingle-cell RNA sequencingSingle-cell expression profilesInvestigate gene functionCleft palateScRNA-seqGene setsCellular expression profilesMendelian inheritanceGenetic variantsRNA sequencingOrofacial clefting genesContextual geneGenesExpression patternsCongenital birth defectsExpression profilesCritical reasoning on the co-expression module QTL in the dorsolateral prefrontal cortex
Cote A, Young H, Huckins L. Critical reasoning on the co-expression module QTL in the dorsolateral prefrontal cortex. Human Genetics And Genomics Advances 2024, 5: 100311. PMID: 38773772, PMCID: PMC11214266, DOI: 10.1016/j.xhgg.2024.100311.Peer-Reviewed Original ResearchConceptsExpression quantitative trait lociGene co-expressionCo-expressionExpression quantitative trait locus methodGenetic variantsComplex trait heritabilityMultiple testing burdenGene-based testsQuantitative trait lociTrans-eQTLsCis-eQTLsRegulatory variationSequencing datasetsTrait lociGene regulationTrait heritabilityGene functionGene modulesReal-data applicationModule genesGenesTesting burdenDorsolateral prefrontal cortexVariantsComparison to prior studiesConserved genes regulating human sex differentiation, gametogenesis and fertilization
Fakhro K, Awwad J, Garibova S, Saraiva L, Avella M. Conserved genes regulating human sex differentiation, gametogenesis and fertilization. Journal Of Translational Medicine 2024, 22: 473. PMID: 38764035, PMCID: PMC11103854, DOI: 10.1186/s12967-024-05162-2.Peer-Reviewed Original ResearchConceptsFertility phenotypesReproductive biologyMechanisms of gene functionNewly-discovered genesHuman reproductive biologyCharacterization of genesLoss-of-function mutationsFundamental reproductive processesNext-generation sequencingGenome editing technologyConserved genesFunctional genomicsGene functionFunctional characterizationConsanguineous populationsSex differentiationGenesReproductive tissuesMonogenic causeMolecular mechanismsHuman reproductive tissuesEditing technologyReproductive processesPhenotypeFertility disordersMetagenomic analysis of the intestinal microbiome reveals the potential mechanism involved in Bacillus amyloliquefaciens in treating schistosomiasis japonica in mice
Chen H, Huang S, Zhao Y, Sun R, Wang J, Yao S, Huang J, Yu Z. Metagenomic analysis of the intestinal microbiome reveals the potential mechanism involved in Bacillus amyloliquefaciens in treating schistosomiasis japonica in mice. Microbiology Spectrum 2024, 12: e03735-23. PMID: 38441977, PMCID: PMC10986500, DOI: 10.1128/spectrum.03735-23.Peer-Reviewed Original ResearchConceptsTaxonomic compositionGut microbiomeIntestinal microbiomeFunctional genesKEGG OrthologyMetagenomic analysisIntestinal microbiotaRegulatory mechanismsFunction of gut microbiomeComposition of gut microbiotaAbundance of functional genesMetagenomic sequencingGene functionGut microbiotaPotential regulatory mechanismSpecies levelIntervention of probioticsBacillus amyloliquefaciensMicrobiomeGenesMicrobiotaHost immune responseProbiotic interventionMetabolic reactionsSchistosoma japonicum</i>
2023
KidneyNetwork: using kidney-derived gene expression data to predict and prioritize novel genes involved in kidney disease
Boulogne F, Claus L, Wiersma H, Oelen R, Schukking F, de Klein N, Li S, Westra H, van der Zwaag B, van Reekum F, Sierks D, Schönauer R, Li Z, Bijlsma E, Bos W, Halbritter J, Knoers N, Besse W, Deelen P, Franke L, van Eerde A. KidneyNetwork: using kidney-derived gene expression data to predict and prioritize novel genes involved in kidney disease. European Journal Of Human Genetics 2023, 31: 1300-1308. PMID: 36807342, PMCID: PMC10620423, DOI: 10.1038/s41431-023-01296-x.Peer-Reviewed Original ResearchConceptsCo-expression networkTissue-specific expressionCandidate genesGene functionPhenotypic consequences of genetic variationPathogenic variantsConsequences of genetic variationInterpretation of genetic variantsGenetic causeRare variantsGene-phenotype associationsHereditary kidney diseaseExome sequencing dataDisease-associated genesGene expression dataPlausible candidate genesCandidate gene prioritizationKidney disease phenotypesUnbiased mannerCystic kidneysNovel genesGenetic variationPhenotypic consequencesGene prioritizationSequence dataChapter 5 Measurement and meaning in gene expression evolution
Diaz R, Wang Z, Townsend J. Chapter 5 Measurement and meaning in gene expression evolution. 2023, 111-129. DOI: 10.1016/b978-0-323-91810-7.00008-x.ChaptersGene expressionPhenotypic evolutionGene expression evolutionMessenger RNAEffects of epistasisIndividual gene expressionRibonucleic acid sequencingExpression evolutionNonmodel speciesFunctional genomicsGenomic scaleTranscriptional networksGene functionRelative mRNA abundancePhenotypic variationPopulation geneticsReference genomeTranscriptome profilingBiological traitsMolecular adjustmentsQuantitative traitsPhenotypic varianceGene interactionsGenetic controlExpression variation
2022
High-content CRISPR screening
Bock C, Datlinger P, Chardon F, Coelho M, Dong M, Lawson K, Lu T, Maroc L, Norman T, Song B, Stanley G, Chen S, Garnett M, Li W, Moffat J, Qi L, Shapiro R, Shendure J, Weissman J, Zhuang X. High-content CRISPR screening. Nature Reviews Methods Primers 2022, 2: 8. DOI: 10.1038/s43586-021-00093-4.Peer-Reviewed Original ResearchCRISPR screeningCRISPR screensBiological discoverySingle-cell RNA sequencingPooled CRISPR screensList of genesHigh-content methodBiological challengesGene functionCell competitionUnbiased interrogationGuide RNARNA sequencingBioinformatics analysisDetailed biological insightsTarget genesBasic biologyPool of cellsBiological insightsCRISPR technologyMolecular mechanismsSuch screensGenesMedical GeneticsBroad utilityMeasuring mRNA Decay with Roadblock‐qPCR
Watson MJ, Thoreen CC. Measuring mRNA Decay with Roadblock‐qPCR. Current Protocols 2022, 2: e344. PMID: 35041257, PMCID: PMC8830782, DOI: 10.1002/cpz1.344.Peer-Reviewed Original ResearchConceptsMRNA stabilityPost-transcriptional regulatory stepsPre-existing mRNAsMRNA decay kineticsQuantitative PCRN-ethylmaleimideGene functionGene regulationGeneral transcriptionNascent mRNARegulatory stepEndogenous mRNACDNA poolsGene expressionLiving cellsTranscriptionCell functionMRNAReverse transcriptionCDNA synthesisMRNA levelsCellsTranscriptsRNACommon strategy
2021
Renal plasticity revealed through reversal of polycystic kidney disease in mice
Dong K, Zhang C, Tian X, Coman D, Hyder F, Ma M, Somlo S. Renal plasticity revealed through reversal of polycystic kidney disease in mice. Nature Genetics 2021, 53: 1649-1663. PMID: 34635846, PMCID: PMC9278957, DOI: 10.1038/s41588-021-00946-4.Peer-Reviewed Original ResearchConceptsPKD genesAutosomal dominant polycystic kidney diseaseCyst cell proliferationGene functionPolycystic kidney diseaseCell shapeGenesKidney diseaseExtracellular matrix depositionCell proliferationKidney tubule cellsNormal lumensDominant polycystic kidney diseaseUnexpected capacityPhenotypic featuresCyst progressionMatrix depositionCellsPlasticityCyst formationCystic tubulesMyofibroblast activationProliferationSquamoid cellsKidney resultsPleiotropic effects of telomere length loci with brain morphology and brain tissue expression
Pathak GA, Wendt FR, Levey DF, Mecca AP, van Dyck CH, Gelernter J, Polimanti R. Pleiotropic effects of telomere length loci with brain morphology and brain tissue expression. Human Molecular Genetics 2021, 30: 1360-1370. PMID: 33831179, PMCID: PMC8255129, DOI: 10.1093/hmg/ddab102.Peer-Reviewed Original ResearchConceptsMethylation expressionGenetic variantsMapping gene functionTelomere lengthChromatin associationChromatin profilesGene functionGenetic colocalizationGene mappingGenomic relationshipsNeuropsychiatric traitsPleiotropic rolesDrug-gene interactionsCertain lociBrain tissue expressionGenesLociPleiotropic effectsBrain morphology measuresNucleotide polymorphismsAncestry populationsTissue expressionPhenotypic associationsPleiotropyAncestry groupsAlt-RPL36 downregulates the PI3K-AKT-mTOR signaling pathway by interacting with TMEM24
Cao X, Khitun A, Luo Y, Na Z, Phoodokmai T, Sappakhaw K, Olatunji E, Uttamapinant C, Slavoff SA. Alt-RPL36 downregulates the PI3K-AKT-mTOR signaling pathway by interacting with TMEM24. Nature Communications 2021, 12: 508. PMID: 33479206, PMCID: PMC7820019, DOI: 10.1038/s41467-020-20841-6.Peer-Reviewed Original ResearchMeSH KeywordsAlternative SplicingAmino Acid SequenceBase SequenceBiological TransportCell MembraneDown-RegulationEndoplasmic ReticulumHEK293 CellsHumansMembrane ProteinsMutationPhosphatidylinositol 3-KinasesPhosphatidylinositol 4,5-DiphosphateProtein BindingProto-Oncogene Proteins c-aktRibosomal ProteinsSignal TransductionTOR Serine-Threonine KinasesConceptsPI3K-AktEndoplasmic reticulumMTOR signalingHuman gene functionAlternative open reading framesOpen reading framePI3K signalingDifferent molecular mechanismsCanonical proteinsGene functionCell sizeReading framePrecursor phosphatidylinositolPlasma membraneTMEM24Upstream regulatorMolecular mechanismsPhosphoserine residuesK signalingPoint mutationsSignalingPhosphatidylinositolProteinReticulumRPL36
2020
A CRISPR Interference Platform for Selective Downregulation of Gene Expression in Borrelia burgdorferi
Takacs CN, Scott M, Chang Y, Kloos ZA, Irnov I, Rosa PA, Liu J, Jacobs-Wagner C. A CRISPR Interference Platform for Selective Downregulation of Gene Expression in Borrelia burgdorferi. Applied And Environmental Microbiology 2020, 87: e02519-20. PMID: 33257311, PMCID: PMC7851697, DOI: 10.1128/aem.02519-20.Peer-Reviewed Original ResearchCRISPR interference platformDifferent antibiotic resistance markersGene functionAntibiotic resistance markersGene expressionHomologous recombination-based methodsCell morphogenesis genesCell wall elongationNative expression levelsBasic cellular processesRecombination-based methodGene function studiesCryo-electron tomographyFuture genetic studiesMorphogenesis genesResistance markersRepression efficiencyCell straighteningGenetic toolsCellular processesWall elongationPeriplasmic flagellaCell filamentationCell divisionCellular motilityHypothalamic oestrogen receptor alpha establishes a sexually dimorphic regulatory node of energy expenditure
van Veen JE, Kammel LG, Bunda PC, Shum M, Reid MS, Massa MG, Arneson D, Park JW, Zhang Z, Joseph AM, Hrncir H, Liesa M, Arnold AP, Yang X, Correa SM. Hypothalamic oestrogen receptor alpha establishes a sexually dimorphic regulatory node of energy expenditure. Nature Metabolism 2020, 2: 351-363. PMID: 32377634, PMCID: PMC7202561, DOI: 10.1038/s42255-020-0189-6.Peer-Reviewed Original ResearchConceptsFemale-biased expressionMale-biased expressionSex-biased expressionSingle-cell RNA transcriptomicsPrecise neuronal populationsEstrogen receptor alphaReceptor alphaGene functionVentromedial hypothalamusRegulatory nodesRNA transcriptomicsMale developmentNeuronal populationsMouse ventromedial hypothalamusSitu hybridizationEnergy homeostasisEnergy expenditureCore temperatureExpressionTachykinin-1RPRMReduced core temperatureVMH neuronsChemogenetic activationPhysical activity
2019
De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes
Watkins WS, Hernandez EJ, Wesolowski S, Bisgrove BW, Sunderland RT, Lin E, Lemmon G, Demarest BL, Miller TA, Bernstein D, Brueckner M, Chung WK, Gelb BD, Goldmuntz E, Newburger JW, Seidman CE, Shen Y, Yost HJ, Yandell M, Tristani-Firouzi M. De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes. Nature Communications 2019, 10: 4722. PMID: 31624253, PMCID: PMC6797711, DOI: 10.1038/s41467-019-12582-y.Peer-Reviewed Original ResearchConceptsChromatin-modifying genesCilia-related genesGene classesDe novo variantsDistinct gene functionsDamaging de novo variantsBackground mutation rateGene burden analysisNovo variantsGene functionGenetic architectureRecessive formPediatric Cardiac Genomics ConsortiumSporadic congenital heart diseaseMode of inheritancePhenotypic landscapeGene pathwaysDisease genesGenomics ConsortiumMutation rateGenesRecessive genotypeDe novoCompound heterozygous genotypeDe novo forms
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