Nicole J. Lake, PhD
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Assistant Professor of GeneticsDownloadHi-Res Photo
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Genetics
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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.
Appointments
Genetics
Assistant ProfessorPrimary
Other Departments & Organizations
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
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
Shushu Huang, MD, PhD
Francesc Lopez-Giraldez, PhD
Kaya Bilguvar, MD, PhD
28Publications
1,275Citations
DNA, Mitochondrial
Mutation
Mitochondrial Diseases
Genomics
Genome, Mitochondrial
Publications
2025
Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases.
Stenton SL, Laricchia K, Lake NJ, Chaluvadi S, Ganesh V, DiTroia S, Osei-Owusu I, Pais L, O'Heir E, Austin-Tse C, O'Leary M, Shanap MA, Barrows C, Berger S, Bönnemann CG, Bujakowska KM, Campagna DR, Compton AG, Donkervoort S, Fleming MD, Gallacher L, Gleeson JG, Haliloglu G, Pierce EA, Place EM, Sankaran VG, Shimamura A, Stark Z, Tan TY, Thorburn DR, White SM, Zaki MS, Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium, Vilain E, Lek M, Rehm HL, 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. HGG Adv 2025, 100441. PMID: 40241304, DOI: 10.1016/j.xhgg.2025.100441.Peer-Reviewed Original ResearchPhenotype 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 ResearchAltmetricMeSH 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 ResearchMeSH 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 vs. loss of function of NTRK2 in 44 affected individuals leads to two 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 vs. loss of function of NTRK2 in 44 affected individuals leads to two distinct neurodevelopmental disorders. Genetics In Medicine 2024, 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 genesQuantifying constraint in the human mitochondrial genome
Lake N, Ma K, Liu W, Battle S, Laricchia K, Tiao G, Puiu D, Ng K, Cohen J, Compton A, Cowie S, Christodoulou J, Thorburn D, Zhao H, Arking D, Sunyaev S, Lek M. Quantifying constraint in the human mitochondrial genome. Nature 2024, 635: 390-397. PMID: 39415008, PMCID: PMC11646341, DOI: 10.1038/s41586-024-08048-x.Peer-Reviewed Original ResearchCitationsAltmetricConceptsMitochondrial genomeDeleterious variationMtDNA mutator modelHuman mitochondrial genomeGenome Aggregation DatabaseMtDNA variationMtDNA variantsMitochondrial DNANoncoding regionsMitochondrial proteinsRRNA geneGenetic variationMtDNAThree-dimensional structureMutation modelPathogenic variationDisease relevanceAggregation DatabaseGenomeLarge-scale population datasetRRNAConstrained sitesGenesTRNAPopulation datasetsSaturation mutagenesis-reinforced functional assays for disease-related genes
Ma K, Huang S, Ng K, Lake N, Joseph S, Xu J, Lek A, Ge L, Woodman K, Koczwara K, Cohen J, Ho V, O'Connor C, Brindley M, Campbell K, Lek M. Saturation mutagenesis-reinforced functional assays for disease-related genes. Cell 2024, 187: 6707-6724.e22. PMID: 39326416, PMCID: PMC11568926, DOI: 10.1016/j.cell.2024.08.047.Peer-Reviewed Original ResearchCitationsAltmetricConceptsDisease-related genesDisease-causing genetic variantsGenome-wide resolutionMutation scanning methodsSingle-nucleotide variantsDeep mutational scanning methodFunctional assaysDisease genesComputational predictorsSaturation mutagenesisHuman geneticsGenetic variantsGenesVariantsSmurfAssayMutagenesisLARGE1GeneticsDisease severityThe Australian Genomics Mitochondrial Flagship: A national program delivering mitochondrial diagnoses
Rius R, Compton A, Baker N, Balasubramaniam S, Best S, Bhattacharya K, Boggs K, Boughtwood T, Braithwaite J, Bratkovic D, Bray A, Brion M, Burke J, Casauria S, Chong B, Coman D, Cowie S, Cowley M, de Silva M, Delatycki M, Edwards S, Ellaway C, Fahey M, Finlay K, Fletcher J, Frajman L, Frazier A, Gayevskiy V, Ghaoui R, Goel H, Goranitis I, Haas M, Hock D, Howting D, Jackson M, Kava M, Kemp M, King-Smith S, Lake N, Lamont P, Lee J, Long J, MacShane M, Madelli E, Martin E, Marum J, Mattiske T, McGill J, Metke A, Murray S, Panetta J, Phillips L, Quinn M, Ryan M, Schenscher S, Simons C, Smith N, Stroud D, Tchan M, Tom M, Wallis M, Ware T, Welch A, Wools C, Wu Y, Christodoulou J, Thorburn D. The Australian Genomics Mitochondrial Flagship: A national program delivering mitochondrial diagnoses. Genetics In Medicine 2024, 27: 101271. PMID: 39305161, DOI: 10.1016/j.gim.2024.101271.Peer-Reviewed Original ResearchCitationsAltmetricConceptsGenome sequencePhenocopy genesMitochondrial diseaseMtDNA sequencesMtDNA deletionsMD geneMtDNAChildhood-onset diseaseDiagnostic journeyDiagnostic yieldMolecular diagnosisGenesNational studySequenceGene etiologySuspected MDDiagnostic pathwayIncrease diagnostic yieldPediatric-onsetOnset diseaseAdult onsetAdult patientsChildrenSkeletal muscleScores
2023
P154 The generation of a GNE myopathy patient-derived biobank enables the study of disease-relevant cellular phenotypes across multiple pathogenic variants
Koczwara K, Lake N, Huang S, DeSimone A, Pajusalu S, Branford K, Hallak D, Woodman K, Xu J, Lek A, Best H, Habib A, Avelar J, Martin V, Mozaffar T, Shieh P, Weisleder N, Lek M. P154 The generation of a GNE myopathy patient-derived biobank enables the study of disease-relevant cellular phenotypes across multiple pathogenic variants. Neuromuscular Disorders 2023, 33: s138. DOI: 10.1016/j.nmd.2023.07.286.Peer-Reviewed Original ResearchConceptsPathogenic mutationsCRISPR/Cas9 knockoutDisease-relevant cell typesSialic acid biosynthesis pathwayCellular disease modelsMyogenic cell lineCell linesGNE myopathy patientsPatient-derived cell linesGNE activityWhole-genome sequencingGNE proteinPathogenic variantsBiosynthesis pathwayDisease-relevant cellular phenotypesCellular functionsMyogenic lineageCellular phenotypesRNA sequencingBifunctional enzymeGenome sequencingMultiple pathogenic variantsReduced enzymatic activitySkeletal muscle atrophyMyopathy patientsDeleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality
Hong Y, Battle S, Shi W, Puiu D, Pillalamarri V, Xie J, Pankratz N, Lake N, Lek M, Rotter J, Rich S, Kooperberg C, Reiner A, Auer P, Heard-Costa N, Liu C, Lai M, Murabito J, Levy D, Grove M, Alonso A, Gibbs R, Dugan-Perez S, Gondek L, Guallar E, Arking D. Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality. Nature Communications 2023, 14: 6113. PMID: 37777527, PMCID: PMC10542802, DOI: 10.1038/s41467-023-41785-7.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsSingle nucleotide variantsOwn circular genomeState of heteroplasmyAging-related diseasesNuclear genomeMitochondrial genomeCircular genomeMtDNA single nucleotide variantsMitochondrial DNASomatic cellsMitochondrial mutationsMtDNA heteroplasmyGenomeNucleotide variantsHeteroplasmyDNA moleculesFunctional roleMitochondriaUK BiobankCertain cancersVariantsDNAMutationsCopiesCells
Academic Achievements & Community Involvement
honor Blavatnik Regional Young Scientist Finalist Award
National AwardBlavatnik Family FoundationDetails09/17/2024honor Excellence in Mitochondrial Research Award
National AwardMito FoundationDetails09/14/2020Australiahonor CJ Martin Early Career Fellowship
National AwardAustralian National Health and Medical Research Council (NHMRC)Details01/01/2019Australiahonor Qantas Research Scholar
International AwardAmerican Australian AssociationDetails01/01/2019United Stateshonor AMDF Advocacy Award
National AwardAustralian Mitochondrial Disease FoundationDetails08/01/2016Australia
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