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
33Publications
1,514Citations
DNA, Mitochondrial
Mitochondrial Diseases
Mutation
Genetic Variation
Genomics
Rare Diseases
Publications
2025
Pathogenic 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 JD, Ilic D, Padmanarayana M, Fischermanns K, Ranjan M, Boll M, Ka C, Piton A, Mattioli F, Isidor B, Õunap K, Reinson K, Wojcik MH, Marshall CR, Mercimek-Andrews S, Matsumoto N, Miyake N, Stephan BO, Honjo RS, Bertola DR, Kim CA, Yusupov R, Mefford HC, Christodoulou J, Lee J, Heath O, Brown NJ, Baker N, Stark Z, Delatycki M, Lake NJ, Zeidler S, Zuurbier L, Maas SM, de Kruiff CC, Rajabi F, Rodan LH, Coury SA, Platzer K, Oppermann H, Abou Jamra R, Beblo S, Maxton C, Śmigiel R, Underhill H, Dubbs H, Rosen A, Helbig KL, Helbig I, Ruggiero SM, Fitzgerald MP, Kraemer D, Prada CE, 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 VR, Eghbal F, Ghayoor Karimiani E, Heidari M, Neidhardt J, Owczarek-Lipska M, Korenke GC, Bamshad MJ, Campeau PM, Lehman A, Hendon LG, Wentzensen IM, Monaghan KG, Chen Y, Szuto A, Cohn RD, Au PYB, Hübner C, Boschann F, Manickam K, Koboldt DC, Rad A, Oprea G, Bachman KK, Seeley AH, 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 RJ, Washington C, Stevens SJC, Heijligers M, Alkuraya FS, Lisfeld J, Neu A, Paoli Monteiro F, Santos Pessoa AL, Camelo-Filho AE, Kok F, Koeberl D, Riley K, Burglen L, Doummar D, Héron B, Mignot C, Keren B, Charles P, Nava C, Bernhard FP, Kühn AA, Thoms S, Morrie RD, Mekhoubad S, Green EM, Barmada SJ, Gitler AD, Jahn O, Rhee JS, Rosenmund C, Mitkovski M, Sticht H, Sun H, Le Gac G, Taschenberger H, Brose N, Dittman JS, Rauch A, Lipstein N. Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function. Nat Genet 2025, 57: 2691-2704. PMID: 41125872, DOI: 10.1038/s41588-025-02361-5.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, eadk7978. 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
2024
Mitochondrial heteroplasmy improves risk prediction for myeloid neoplasms
Hong Y, Pasca S, Shi W, Puiu D, Lake N, Lek M, Ru M, Grove M, Prizment A, Joshu C, Platz E, Guallar E, Arking D, Gondek L. Mitochondrial heteroplasmy improves risk prediction for myeloid neoplasms. Nature Communications 2024, 15: 10133. PMID: 39578475, PMCID: PMC11584845, DOI: 10.1038/s41467-024-54443-3.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsClonal hematopoiesis of indeterminate potentialClonal hematopoiesisVariant allele fractionHeteroplasmic variantsIndeterminate potentialMyeloid neoplasmsHeteroplasmyMultiple mutationsAllele fractionMutationsHigh-risk groupPathogenic risk factorsMarkersRisk score modelDeleteriousnessSpliceosomeHematologic malignanciesRisk stratificationNeoplasm developmentNeoplasmsNeoplasm incidenceRisk factorsVariantsUpregulation versus loss of function of NTRK2 in 44 affected individuals leads to 2 distinct neurodevelopmental disorders
Berger E, Jauss R, Ranells J, Zonic E, von Wintzingerode L, Wilson A, Wagner J, Tuttle A, Thomas-Wilson A, Schulte B, Rabin R, Pappas J, Odgis J, Muthaffar O, Mendez-Fadol A, Lynch M, Levy J, Lehalle D, Lake N, Krey I, Kozenko M, Knierim E, Jouret G, Jobanputra V, Isidor B, Hunt D, Hsieh T, Holtz A, Haack T, Gold N, Dunstheimer D, Donge M, Deb W, De La Rosa Poueriet K, Danyel M, Christodoulou J, Chopra S, Callewaert B, Busche A, Brick L, Bigay B, Arlt M, Anikar S, Almohammal M, Almanza D, Alhashem A, Bertoli-Avella A, Sticht H, Abou Jamra R. Upregulation versus loss of function of NTRK2 in 44 affected individuals leads to 2 distinct neurodevelopmental disorders. Genetics In Medicine 2024, 27: 101326. PMID: 39540377, DOI: 10.1016/j.gim.2024.101326.Peer-Reviewed Original ResearchAltmetricConceptsDevelopmental delayHeterozygous pathogenic variantsTherapy-refractory epilepsyAffected individualsPhenotype of developmental delayDevelopmental delay/intellectual disabilityGlobal developmental delayRecurrent variant c.Associated with global developmental delayCholesterol-binding motifsTrkB activationVariant c.Pathogenic variantsMuscular hypotoniaFeeding difficultiesSevere phenotypeLoss of functionBinding motifVisual impairmentTransmembrane domainTruncating variantsNeurodevelopmental disordersNTRK2CohortVariantsMitochondrial Heteroplasmy Is a Novel Predictor of Chronic Lymphocytic Leukemia Risk
Pasca S, Hong Y, Shi W, Puiu D, Lake N, Lek M, Guallar E, Arking D, Gondek L. Mitochondrial Heteroplasmy Is a Novel Predictor of Chronic Lymphocytic Leukemia Risk. Blood 2024, 144: 4054-4054. DOI: 10.1182/blood-2024-210250.Peer-Reviewed Original ResearchConceptsMitochondrial heteroplasmyClonal hematopoiesis of indeterminate potentialMtDNA heteroplasmyWhole-exome sequencing dataSomatic mutationsPresence of somatic mutationsExome sequencing dataCancer-associated genesClonal hematopoiesisClonal expansionVariant allele frequencyAssociated with myeloid malignanciesMtDNA variantsMitochondrial DNAPresence of mutationsSequence dataUK Biobank (UKBBiologically significant roleDeleterious mutationsHeteroplasmyChronic lymphocytic leukemia riskAllele frequenciesOncogenic transformationMitochondrial functionMyeloid genes
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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