Nicole J. Lake, PhD
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Assistant Professor of GeneticsDownloadHi-Res Photo
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Assistant Professor of Genetics
Biography
Nicole's research career reflects her long-standing interest in understanding how genetic variation contributes to health and disease, and passion for mitochondrial genomics. Nicole completed her Ph.D. in mitochondrial genetics with David Thorburn at the Murdoch Children's Research Institute, where she used computational and experimental methods to discover genetic causes of mitochondrial diseases. Following this, she worked as an analyst in translational and mitochondrial genomics. Nicole then completed her postdoctoral training at Yale University with Monkol Lek, where she built and applied tools to improve the discovery of genetic causes of disease and variant classification, with a focus on the mitochondrial genome. Nicole also holds M.Sc. and B.Sc. degrees in Genetics from the University of Melbourne and University of Edinburgh.
Nicole’s professional experience includes university teaching, clinical genetic testing, media interviews, peer review, science outreach, as well as national, institutional, and departmental committee service and leadership. She established her lab in the Yale School of Medicine in 2024.
Last Updated on August 24, 2024.
Appointments
Genetics
Assistant ProfessorPrimary
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Education & Training
- Postdoctoral Fellow/Associate
- Yale University (2022)
- PhD
- University of Melbourne (2018)
- MSc
- University of Melbourne, Genetics (2012)
- BSc
- University of Melbourne & University of Edinburgh, Genetics (2010)
Research
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Overview
Medical Research Interests
Computational Biology; DNA, Mitochondrial; Gene Editing; Genetic Diseases, Inborn; Genetic Variation; Genetics; Genetics, Medical; Genetics, Population; Genome, Mitochondrial; Genomics; Human Genetics; Mitochondrial Diseases; Mutation; Rare Diseases
ORCID
0000-0003-4103-6387- View Lab Website
Lake Lab
Research at a Glance
Yale Co-Authors
Frequent collaborators of Nicole J. Lake's published research.
Publications Timeline
A big-picture view of Nicole J. Lake's research output by year.
Research Interests
Research topics Nicole J. Lake is interested in exploring.
Monkol Lek, PhD
Justin Cohen, PhD
Shushu Huang, MD, PhD
Cassie Overstreet
Daniel F. Levey, PhD
Francesc Lopez-Giraldez, PhD
36Publications
1,518Citations
DNA, Mitochondrial
Mitochondrial Diseases
Mutation
Genetic Variation
Genomics
Rare Diseases
Publications
2025
Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy
Lai M, Kim K, Zheng Y, Castellani C, Ratliff S, Wang M, Liu X, Haessler J, Huan T, Bonsu K, Newcomb C, McKessy K, Bielak L, Zhao W, Joehanes R, Ma J, Guo X, Manson J, Grove M, Bressler J, Taylor K, Lappalainen T, Kasela S, Blackwell T, Lake N, Faul J, Ferrier K, Ekker S, Hou L, Kooperberg C, Reiner A, Zhang K, Peyser P, Fornage M, Boerwinkle E, Raffield L, Carson A, Rich S, Liu Y, Levy D, Rotter J, Smith J, Arking D, Liu C. Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy. Nature Communications 2025, 16: 10962. PMID: 41330919, PMCID: PMC12689632, DOI: 10.1038/s41467-025-65845-2.Peer-Reviewed Original ResearchAltmetricMeSH Keywords and ConceptsConceptsEpigenome-wide association studiesNuclear DNA methylationDNA methylationHEK293T cellsVariant allele fractionMitochondrial DNAMtDNA mutationsMitochondrial heteroplasmyCpG islandsGene regulationIsland shoresAllele fractionEpigenetic linkBehavioral traitsHeteroplasmyCpGCpGsMethylationMtDNADNAMutationsHEK293TraitsT cellsRegulationAssociation of Epigenetic Age Acceleration and Mitochondrial DNA‐Based Aging Metrics Provides Insights Into Mechanisms of Aging‐Related Diseases
Wang M, Zheng Y, Lai M, Saake E, Liu X, Guo X, Taylor K, Huan T, Joehanes R, Nannini D, Zhang K, Lake N, Castellani C, Rich S, Rotter J, Liu Y, Raffield L, Carson A, Fornage M, Ma J, Arking D, Hou L, Levy D, Liu C. Association of Epigenetic Age Acceleration and Mitochondrial DNA‐Based Aging Metrics Provides Insights Into Mechanisms of Aging‐Related Diseases. Aging Cell 2025, 24: e70279. PMID: 41132105, PMCID: PMC12686565, DOI: 10.1111/acel.70279.Peer-Reviewed Original ResearchAltmetricMeSH Keywords and ConceptsConceptsHeteroplasmic variantsMtDNA-CNLow mtDNA-CNBurden of rare variantsDNA methylation dataMtDNA copy numberGenome sequenceMitochondrial DNAMtDNAMethylation dataEpigenetic age accelerationAging-related diseasesCopy numberMetabolic traitsRare variantsAge-related diseasesFHS participantsDNAVariantsAge accelerationEpigenetic ageHannum methodsHeteroplasmyGenomeSequencePathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function
Asadollahi R, Ahmad A, Boonsawat P, Shahanoor Hinzen J, Lohse M, Bouazza-Arostegui B, Sun S, Utesch T, Sommer J, Ilic D, Padmanarayana M, Fischermanns K, Ranjan M, Boll M, Ka C, Piton A, Mattioli F, Isidor B, Õunap K, Reinson K, Wojcik M, Marshall C, Mercimek-Andrews S, Matsumoto N, Miyake N, Stephan B, Honjo R, Bertola D, Kim C, Yusupov R, Mefford H, Christodoulou J, Lee J, Heath O, Brown N, Baker N, Stark Z, Delatycki M, Lake N, Zeidler S, Zuurbier L, Maas S, de Kruiff C, Rajabi F, Rodan L, Coury S, Platzer K, Oppermann H, Abou Jamra R, Beblo S, Maxton C, Śmigiel R, Underhill H, Dubbs H, Rosen A, Helbig K, Helbig I, Ruggiero S, Fitzgerald M, Kraemer D, Prada C, Tenney J, Jayakar P, Redon S, Lefranc J, Uguen K, Race S, Efthymiou S, Maroofian R, Houlden H, Coppens S, Deconinck N, Ashokkumar B, Varalakshmi P, Gowda K V, Eghbal F, Ghayoor Karimiani E, Heidari M, Neidhardt J, Owczarek-Lipska M, Korenke G, Bamshad M, Campeau P, Lehman A, Hendon L, Wentzensen I, Monaghan K, Chen Y, Szuto A, Cohn R, Au P, Hübner C, Boschann F, Manickam K, Koboldt D, Rad A, Oprea G, Bachman K, Seeley A, Agolini E, Terracciano A, Carmelo P, Bupp C, Grysko B, Rein-Rothschild A, Ben Zeev B, Margolin A, Morrison J, Dagli A, Stolerman E, Louie R, Washington C, Stevens S, Heijligers M, Alkuraya F, Lisfeld J, Neu A, Paoli Monteiro F, Santos Pessoa A, Camelo-Filho A, Kok F, Koeberl D, Riley K, Burglen L, Doummar D, Héron B, Mignot C, Keren B, Charles P, Nava C, Bernhard F, Kühn A, Thoms S, Morrie R, Mekhoubad S, Green E, Barmada S, Gitler A, Jahn O, Rhee J, Rosenmund C, Mitkovski M, Sticht H, Sun H, Le Gac G, Taschenberger H, Brose N, Dittman J, Rauch A, Lipstein N. Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function. Nature Genetics 2025, 57: 2691-2704. PMID: 41125872, PMCID: PMC12597829, DOI: 10.1038/s41588-025-02361-5.Peer-Reviewed Original ResearchAltmetricMeSH Keywords and ConceptsConceptsNeurodevelopmental syndromeSplice-site variantsMechanisms of pathogenicityRegulation of neurotransmitter releaseGain-of-functionMouse hippocampal neuronsCaenorhabditis elegansImpaired regulationVariable degrees of developmental delayPresynaptic proteinsUNC13ADynamics of information transferDegree of developmental delayMessenger signalingRegulation of neurotransmissionNeurotransmitter releaseSynaptic functionVariable degreesHippocampal neuronsTypes A-CProtein expressionNervous system functionDyskinetic movementsVariantsSyndrome subtypesTRPM3-Associated Disorders: Clinical Spectrum and Treatment Options
Becker L, Jolitz L, Helbig I, Ruggiero S, Cohen S, Angelini C, Vallespin E, Michaud V, Gerasimenko A, Cogne B, Isidor B, Keren B, Dyment D, Heron D, Karstensen H, Cuppen I, Christodoulou J, Wilson M, Lake N, Biskup S, Syrbe S, Mori T, Kaindl A. TRPM3-Associated Disorders: Clinical Spectrum and Treatment Options. Neuropediatrics 2025, 56: s1-s24. DOI: 10.1055/s-0045-1812137.Peer-Reviewed Original ResearchReversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations
Huang H, Wang Y, Zsengeller Z, Gorham J, Vemireddy V, Clark A, Pan H, Dreyfuss J, Jotwani V, Shlipak M, Sarnak M, Parikh C, Thiessen-Philbrook H, Katz R, Waikar S, Lake N, Lek M, Shi W, Puiu D, Hong Y, Seidman J, Arking D, Parikh S. Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations. Science 2025, 390: 164-172. PMID: 40906782, DOI: 10.1126/science.adk7978.Peer-Reviewed Original ResearchCitationsAltmetricConceptsHeteroplasmic mtDNA mutationsMtDNA mutationsAdenylate kinase 4Purine biosynthetic enzymesMitochondrial DNA mutationsMetabolically active cellsPurine biosynthesisBiosynthetic enzymesDNA mutationsNucleotide metabolismATP generationMutationsKinase 4NucleotidePhysiological resilienceActive cellsUK Biobank participantsMtDNABiosynthesisCumulative effectBiobank participantsAdenylateMutational burdenEnzymeATPA contextual genomic perspective on physical activity and its relationship to health, well being and illness
Galimberti M, Levey D, Deak J, Adhikari K, Overstreet C, Gupta P, Nitin R, Zhou H, Lake N, Harrington K, Djousse L, Davis L, Gaziano J, Stein M, Gelernter J. A contextual genomic perspective on physical activity and its relationship to health, well being and illness. Nature Genetics 2025, 57: 1860-1871. PMID: 40691405, PMCID: PMC12339386, DOI: 10.1038/s41588-025-02260-9.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsLeisure-time PAPhysical activityLeisure-timeHealth benefitsIndividuals of European ancestryMendelian randomization analysisMillion Veteran ProgramUK Biobank dataLatin American ancestryHealth outcomesVeteran ProgramRandomization analysisBiobank dataRespiratory system diseasesLead variantsCOVID-19 hospitalizationCross-ancestryEuropean ancestryHealthMeta-analysisGenetic analysisAmerican ancestryAfrican ancestryCross-ancestry meta-analysisMetabolic traitsUntargeted proteomics enables ultra-rapid variant prioritisation in mitochondrial and other rare diseases
Hock D, Caruana N, Semcesen L, Lake N, Formosa L, Amarasekera S, Stait T, Tregoning S, Frajman L, Bournazos A, Robinson D, Ball M, Reljic B, Ryder B, Wallis M, Vasudevan A, Beck C, Peters H, Lee J, Tan N, Freckmann M, Karlaftis V, Attard C, Monagle P, Samarasinghe A, Brown R, Bi W, Lek M, McFarland R, Taylor R, Ryan M, Cooper S, Stark Z, Christodoulou J, Compton A, Thorburn D, Stroud D. Untargeted proteomics enables ultra-rapid variant prioritisation in mitochondrial and other rare diseases. Genome Medicine 2025, 17: 58. PMID: 40400026, PMCID: PMC12096736, DOI: 10.1186/s13073-025-01467-z.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsMitochondrial diseaseProteomic dataGenome sequenceDisease genesPathogenicity of novel variantsFunctional validationMitochondrial disease genesMendelian disease genesValidation of genetic variantsGenetic diagnosisInterpretation of variantsPeripheral blood mononuclear cellsVariant prioritisationMitochondrial genesApplication of proteomicsVariant pathogenicityProteomic testBioinformatics toolsNovel variantsGenetic variantsRNA sequencingPathogenic variantsProteomics pipelineProteomicsGenomic testingRevealing secrets of human genetic variation with population databases
Lake N. Revealing secrets of human genetic variation with population databases. Nature Reviews Genetics 2025, 26: 377-377. PMID: 40316690, DOI: 10.1038/s41576-025-00848-9.Peer-Reviewed Original ResearchAltmetricMitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases
Stenton S, Laricchia K, Lake N, Chaluvadi S, Ganesh V, DiTroia S, Osei-Owusu I, Pais L, O’Heir E, Austin-Tse C, O’Leary M, Abu Shanap M, Barrows C, Berger S, Bönnemann C, Bujakowska K, Campagna D, Compton A, Donkervoort S, Fleming M, Gallacher L, Gleeson J, Haliloglu G, Pierce E, Place E, Sankaran V, Shimamura A, Stark Z, Tan T, Thorburn D, White S, Zaki M, Consortium G, Vilain E, Lek M, Rehm H, O’Donnell-Luria A. Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases. Human Genetics And Genomics Advances 2025, 6: 100441. PMID: 40241304, PMCID: PMC12278631, DOI: 10.1016/j.xhgg.2025.100441.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsGenome sequence dataSequence dataUndiagnosed familiesMtDNA variantsRare disease familiesMendelian diseasesDisease familiesDiagnostic variantsNuclear genes POLGSingle nucleotide variantsRare disease cohortsDe novo variantsAnalysis of exomeEvidence of pathogenicityFunctional evidenceRNA sequencing dataDiverse collectionMitochondrial genomeHeteroplasmic variantsNuclear genomeMtDNA replicationNucleotide variantsMtDNA deletionsVariant detectionMtDNAPhenotype Spectrum of TRPM3‐Associated Disorders
Jolitz L, Helbig I, Fitzgerald M, Ruggiero S, Cohen S, Angelini C, Vallespin E, Michaud V, Gerasimenko A, Cogne B, Isidor B, Keren B, Dyment D, Heron D, Karstensen H, Cuppen I, Christodoulou J, Wilson M, Lake N, Biskup S, Syrbe S, Mori T, Becker L, Kaindl A. Phenotype Spectrum of TRPM3‐Associated Disorders. Annals Of Neurology 2025, 97: 561-570. PMID: 39749750, PMCID: PMC11831877, DOI: 10.1002/ana.27141.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsEffective anti-seizure medicationDevelopmental delayGain-of-function variantsDevelopmental delay/intellectual disabilitySpike wave activityAnti-seizure medicationsPreponderance of girlsSystematic literature searchOcular involvementMedian ageMusculoskeletal anomaliesClinical spectrumAxial hypotoniaDysmorphic featuresElectroencephalogram abnormalitiesEffects of treatmentClinical manifestationsTreated patientsEpileptic encephalopathyMonoallelic variantsTreatment optionsFrequent findingPhenotypic spectrumVariant p.Epilepsy phenotype
Academic Achievements & Community Involvement
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Honors
honor Blavatnik Regional Young Scientist Finalist Award
09/17/2024National AwardBlavatnik Family Foundationhonor Excellence in Mitochondrial Research Award
09/14/2020National AwardMito FoundationDetailsAustraliahonor CJ Martin Early Career Fellowship
01/01/2019National AwardAustralian National Health and Medical Research Council (NHMRC)DetailsAustraliahonor Qantas Research Scholar
01/01/2019International AwardAmerican Australian AssociationDetailsUnited Stateshonor AMDF Advocacy Award
08/01/2016National AwardAustralian Mitochondrial Disease FoundationDetailsAustralia
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