2025
Protein Quality Control is a Master Modulator of Molecular Evolution in Bacteria
Arenas C, Alvarez M, Wilson R, Shakhnovich E, Ogbunugafor C. Protein Quality Control is a Master Modulator of Molecular Evolution in Bacteria. Genome Biology And Evolution 2025, 17: evaf010. PMID: 39837347, PMCID: PMC11789785, DOI: 10.1093/gbe/evaf010.Peer-Reviewed Original ResearchConceptsProtein quality controlMolecular evolutionProtein translation machineryProteome homeostasisTranslation machineryHost-parasite interactionsProtein spaceOrganismal developmentProtein foldingBacterial systemsCellular processesPromote proteostasisEvolutionary biologyMechanistic basesProteostasisProteinQuality controlEpistasisChaperoneProteomicsGenesBacteriaProteaseMachineryPhenotype
2023
Environmental modulation of global epistasis in a drug resistance fitness landscape
Diaz-Colunga J, Sanchez A, Ogbunugafor C. Environmental modulation of global epistasis in a drug resistance fitness landscape. Nature Communications 2023, 14: 8055. PMID: 38052815, PMCID: PMC10698197, DOI: 10.1038/s41467-023-43806-x.Peer-Reviewed Original ResearchConceptsGlobal epistasisEnvironmental variationGene-by-gene interactionsFitness landscapeGenotype-phenotype mapAdaptive trajectoriesEvolution of drug resistanceEssential enzymeEpistasisFitness effectsGenetic backgroundMutationsAntimicrobial drugsDrug resistanceEnvironmental modulationDrug doseLandscapeGenesPathogensDrugFitnessEvolutionEpistasis and pleiotropy shape biophysical protein subspaces associated with drug resistance
Ogbunugafor C, Guerrero R, Miller-Dickson M, Shakhnovich E, Shoulders M. Epistasis and pleiotropy shape biophysical protein subspaces associated with drug resistance. Physical Review E 2023, 108: 054408. PMID: 38115433, PMCID: PMC10935598, DOI: 10.1103/physreve.108.054408.Peer-Reviewed Original ResearchConceptsProtein spaceAmino acid sequenceAmino acid substitutionsGenotype-phenotype mapAcid sequenceProtein variantsBacterial enzymesAcid substitutionsProtein phenotypesEngineered proteinsDHFR enzymeProteinEpistasisDrug resistanceMutationsAminoProcess of evolutionEnzymePhenotypeTraitsPleiotropySequenceVariantsBiophysical components
2022
The mutation effect reaction norm (mu‐rn) highlights environmentally dependent mutation effects and epistatic interactions
Ogbunugafor C. The mutation effect reaction norm (mu‐rn) highlights environmentally dependent mutation effects and epistatic interactions. Evolution 2022, 76: 37-48. PMID: 34989399, DOI: 10.1111/evo.14428.Peer-Reviewed Original ResearchConceptsReaction normsFitness effects of mutationsPhenotypic consequences of mutationsEvolution of antimicrobial resistanceEffects of mutationsConsequences of mutationsGenetic interactionsPopulation geneticsEpistatic interactionsPhenotypic consequencesGenetic informationMutational effectsFunction of environmental contextUnpredictability of evolutionFitness effectsMutationsAntimicrobial resistanceLayer of complexityEnvironmental contextModern SynthesisPerformance of genotypesReverse evolutionEpistasisGeneticsPublic health
2019
Lexical Landscapes as large in silico data for examining advanced properties of fitness landscapes
Meszaros V, Miller-Dickson M, Ogbunugafor C. Lexical Landscapes as large in silico data for examining advanced properties of fitness landscapes. PLOS ONE 2019, 14: e0220891. PMID: 31404101, PMCID: PMC6690511, DOI: 10.1371/journal.pone.0220891.Peer-Reviewed Original ResearchConceptsFitness landscapeHigher-order epistasisProperties of fitness landscapesEmpirical fitness landscapesEvolutionary geneticsIn silico approachDevelopment of evolutionary theoryIn silico dataEvolutionary biologyClonal competitionIn silicoAstronomical numberEnvironment interactionGoogle’s Ngram corpusEvolutionary theoryLandscapeEpistasisLandscape approachProteostasis Environment Shapes Higher-Order Epistasis Operating on Antibiotic Resistance
Guerrero R, Scarpino S, Rodrigues J, Hartl D, Ogbunugafor C. Proteostasis Environment Shapes Higher-Order Epistasis Operating on Antibiotic Resistance. Genetics 2019, 212: 565-575. PMID: 31015194, PMCID: PMC6553834, DOI: 10.1534/genetics.119.302138.Peer-Reviewed Original ResearchConceptsHigher-order epistasisSNPs associated with resistancePatterns of epistasisControlled genetic backgroundSets of mutationsProteostasis environmentComplex traitsEpistatic interactionsBacterial enzymesEssential enzymeCell physiologyGenotypic contextEpistasisAntibiotic resistanceGenetic backgroundBackground sequencesAntimicrobial resistanceProteostasisBacterial resistanceGenetic modification technologyMutationsProteinEnzymeTraitsAntibiotics
2018
Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk
Consortium I, Mitrovič M, Patsopoulos N, Beecham A, Dankowski T, Goris A, Dubois B, D’hooghe M, Lemmens R, Van Damme P, Søndergaard H, Sellebjerg F, Sorensen P, Ullum H, Thørner L, Werge T, Saarela J, Cournu-Rebeix I, Damotte V, Fontaine B, Guillot-Noel L, Lathrop M, Vukusik S, Gourraud P, Andlauer T, Pongratz V, Buck D, Gasperi C, Bayas A, Heesen C, Kümpfel T, Linker R, Paul F, Stangel M, Tackenberg B, Bergh F, Warnke C, Wiendl H, Wildemann B, Zettl U, Ziemann U, Tumani H, Gold R, Grummel V, Hemmer B, Knier B, Lill C, Luessi F, Dardiotis E, Agliardi C, Barizzone N, Mascia E, Bernardinelli L, Comi G, Cusi D, Esposito F, Ferrè L, Comi C, Galimberti D, Leone M, Sorosina M, Mescheriakova J, Hintzen R, van Duijn C, Theunissen C, Bos S, Myhr K, Celius E, Lie B, Spurkland A, Comabella M, Montalban X, Alfredsson L, Stridh P, Hillert J, Jagodic M, Piehl F, Jelčić I, Martin R, Sospedra M, Ban M, Hawkins C, Hysi P, Kalra S, Karpe F, Khadake J, Lachance G, Neville M, Santaniello A, Caillier S, Calabresi P, Cree B, Cross A, Davis M, Haines J, de Bakker P, Delgado S, Dembele M, Edwards K, Fitzgerald K, Hakonarson H, Konidari I, Lathi E, Manrique C, Pericak-Vance M, Piccio L, Schaefer C, McCabe C, Weiner H, Goldstein J, Olsson T, Hadjigeorgiou G, Taylor B, Tajouri L, Charlesworth J, Booth D, Harbo H, Ivinson A, Hauser S, Compston A, Stewart G, Zipp F, Barcellos L, Baranzini S, Martinelli-Boneschi F, D’Alfonso S, Ziegler A, Oturai A, McCauley J, Sawcer S, Oksenberg J, De Jager P, Kockum I, Hafler D, Cotsapas C. Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. Cell 2018, 175: 1679-1687.e7. PMID: 30343897, PMCID: PMC6269166, DOI: 10.1016/j.cell.2018.09.049.Peer-Reviewed Original ResearchConceptsRare coding variationsGenome-wide association studiesNon-coding variationCommon variant signalsSubstantial linkage disequilibriumLow-frequency variantsNovel genesCell homeostasisAssociation studiesComplex neurological diseasesLinkage disequilibriumGenetic variantsCommon variantsHeritabilityRich resourceGenesVariantsKey pathogenic roleIndividual familiesEpistasisAdditive effectBiologyHomeostasisMutationsNeurological diseasesAnalysis of mutation, selection, and epistasis: an informed approach to cancer clinical trials
Wilkins JF, Cannataro VL, Shuch B, Townsend JP. Analysis of mutation, selection, and epistasis: an informed approach to cancer clinical trials. Oncotarget 2018, 9: 22243-22253. PMID: 29854275, PMCID: PMC5976461, DOI: 10.18632/oncotarget.25155.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsStrength of selectionMutation rateSomatic variantsSynergistic epistasisAnalysis of mutationsDetailed mechanistic knowledgeGenetic architectureContribution of mutationsLineage selectionDrug development effortsEvolutionary principlesTherapeutic potentialDrug developmentMechanistic knowledgeEpistasisMutationsCancer typesVariant frequencyVariantsGenesSelectionClinical trialsPotential therapeutic benefitSubstantial clinical benefitRigorous guidance
2016
Quantifying Deception
Eppstein M, Ogbunugafor C. Quantifying Deception. 2016, 101-108. DOI: 10.1145/2908812.2908821.Peer-Reviewed Original ResearchEmpirical fitness landscapesSign epistasisRuggedness of fitness landscapesEvolution of antimicrobial drug resistanceFitness landscapeWithin-host evolutionEvolutionary geneticistsEvolutionary biologistsAntimicrobial drug resistanceEvolutionary dynamicsAnti-malarial drugsEpistasisPopulation modelLandscapeDrug resistanceDiscrete population modelGenetic algorithmPlasmodium falciparumPopulation distributionGeneticistsBiologistsGlobal optimumImproved understanding
2015
COMT and MAO-A Polymorphisms and Obsessive-Compulsive Disorder: A Family-Based Association Study
Sampaio A, Hounie A, Petribú K, Cappi C, Morais I, Vallada H, do Rosário M, Stewart S, Fargeness J, Mathews C, Arnold P, Hanna G, Richter M, Kennedy J, Fontenelle L, de Bragança Pereira C, Pauls D, Miguel E. COMT and MAO-A Polymorphisms and Obsessive-Compulsive Disorder: A Family-Based Association Study. PLOS ONE 2015, 10: e0119592. PMID: 25793616, PMCID: PMC4368617, DOI: 10.1371/journal.pone.0119592.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAllelesCatechol O-MethyltransferaseChildEpistasis, GeneticFamilyFemaleGene FrequencyGenetic Association StudiesGenetic Predisposition to DiseaseGenotypeHaplotypesHumansLinkage DisequilibriumMaleMonoamine OxidaseObsessive-Compulsive DisorderPhenotypePolymorphism, Single NucleotideYoung AdultConceptsAssociation studiesBroad spectrum phenotypesTransmission disequilibrium analysisSingle geneSingle nucleotide polymorphismsGenetic association studiesGene-gene interactionsGenesClassical case-control designDisequilibrium analysisGenetic componentAssociation investigationsEpistatic influencesPhenotypePolymorphismSpectrum phenotypeEpistasisOCD susceptibilityAlternative strategyRoleNarrow phenotype
2014
Evolutionary Systems Biology: Shifting Focus to the Context‐Dependency of Genetic Effects
Pavličev M, Wagner G. Evolutionary Systems Biology: Shifting Focus to the Context‐Dependency of Genetic Effects. 2014, 91-108. DOI: 10.1002/9781118398814.ch6.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsGenetics of Complex Traits in Psychiatry
Gelernter J. Genetics of Complex Traits in Psychiatry. Biological Psychiatry 2014, 77: 36-42. PMID: 25444161, PMCID: PMC4282183, DOI: 10.1016/j.biopsych.2014.08.005.Peer-Reviewed Original ResearchConceptsComplex traitsNext-generation high-throughput sequencingGenome-wide association studiesHigh-throughput sequencingSingle nucleotide polymorphismsEpigenetic effectsRisk allelesAssociation studiesExpression dataMultiple risk allelesPsychiatric geneticsPsychiatric traitsNumber variantsNucleotide polymorphismsTraitsGeneticsNew mutationsTrait riskAllelesEpistasisMinor effectMethylationKind of variationVariantsSequencing
2011
A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility
Bush WS, McCauley JL, DeJager PL, Dudek SM, Hafler DA, Gibson RA, Matthews PM, Kappos L, Naegelin Y, Polman CH, Hauser SL, Oksenberg J, Haines JL, Ritchie MD. A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility. Genes & Immunity 2011, 12: 335-340. PMID: 21346779, PMCID: PMC3136581, DOI: 10.1038/gene.2011.3.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesGene-gene interactionsCytoskeleton regulatory proteinsCytoskeletal regulationGenetic architectureGene clusterInteraction analysisSingle-locus analysisGWAS dataRegulatory proteinsBiological contextRelated genesAssociation studiesSusceptibility lociWeak main effectsPhospholipase CGenetic effectsΒ isoformsComplex diseasesBiological mechanismsNeurodegenerative mechanismsNew genetic effectsEpistasisACTN1Genes
2010
On the possible role of robustness in the evolution of infectious diseases
Ogbunugafor CB, Pease JB, Turner PE. On the possible role of robustness in the evolution of infectious diseases. Chaos An Interdisciplinary Journal Of Nonlinear Science 2010, 20: 026108. PMID: 20590337, PMCID: PMC2909313, DOI: 10.1063/1.3455189.Peer-Reviewed Original ResearchConceptsRole of epistasisMaintenance of phenotypeInfectious disease evolutionGenetic robustnessMutational inputPhenotypic constancyEvolutionary biologyEnvironmental robustnessModel RNA virusRNA genomeEnvironmental variationRNA virusesMalaria parasite infectionEpistasisDisease systemsModel systemParasite infectionDisease agentsAdaptive constraintsInfectious disease systemsDifferent disease agentsImmune evasionBiological systemsPossible roleAntibiotic resistance
2001
Epistasis and the Mutation Load: A Measurement-Theoretical Approach
Hansen T, Wagner G. Epistasis and the Mutation Load: A Measurement-Theoretical Approach. Genetics 2001, 158: 477-485. PMID: 11333254, PMCID: PMC1461645, DOI: 10.1093/genetics/158.1.477.Peer-Reviewed Original ResearchConceptsMutation-selection equilibriumGene interactionsEpistatic interactionsMutation loadStrength of epistasisMutation-selection balanceGenomic mutation rateHigher-order gene interactionsSynergistic epistasisMean fitnessOptimal genotypeEpistatic effectsTwofold disadvantageEpistasisMutation rateGenetic backgroundSynergistic interactionSystematic relationshipGenesLociInteraction intensityInteractionFitnessInteraction densityGenotypesModeling Genetic Architecture: A Multilinear Theory of Gene Interaction
Hansen T, Wagner G. Modeling Genetic Architecture: A Multilinear Theory of Gene Interaction. Theoretical Population Biology 2001, 59: 61-86. PMID: 11243929, DOI: 10.1006/tpbi.2000.1508.Peer-Reviewed Original ResearchConceptsGenotype-phenotype mapGene interactionsQuantitative genetic variationEffects of epistasisGenetic canalizationGenetic experimentsGenetic variationGene substitutionGenetic backgroundEpistasisTractable modelComplex functionsCentral importanceLociBiologyCanalizationPhenotypeGenotypesInteractionSum of linear
1998
Genetic measurement theory of epistatic effects
Wagner G, Laubichler M, Bagheri-Chaichian H. Genetic measurement theory of epistatic effects. Genetica 1998, 102-103: 569-580. PMID: 9766965, DOI: 10.1023/a:1017088321094.Peer-Reviewed Original ResearchConceptsEpistatic effectsGenotype-phenotype mapMendelian genetic systemMathematical population geneticsAverage additive effectPairs of lociGenetic architecturePopulation geneticsEvolutionary changeEvolutionary phenomenaGenetic systemGenotypic varianceMetabolic fluxSecond locusEpistasisGene substitutionMutation effectsAdditive effectAdult body weightGene effectsSecond mutationLocus BLociMutationsNegative interactionsGenetic measurement theory of epistatic effects
Wagner G, Laubichler M, Bagheri-Chaichian H. Genetic measurement theory of epistatic effects. Contemporary Issues In Genetics And Evolution 1998, 7: 569-580. DOI: 10.1007/978-94-011-5210-5_43.Peer-Reviewed Original ResearchEpistatic effectsGenotype-phenotype mapMendelian genetic systemMathematical population geneticsAverage additive effectPairs of lociGenetic architecturePopulation geneticsEvolutionary changeEvolutionary phenomenaGenetic systemGenotypic varianceMetabolic fluxSecond locusEpistasisGene substitutionMutation effectsAdditive effectAdult body weightGene effectsSecond mutationLocus BLociMutationsNegative interactions
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