Featured Publications
Massively parallel approaches for characterizing noncoding functional variation in human evolution
Rong S, Root E, Reilly S. Massively parallel approaches for characterizing noncoding functional variation in human evolution. Current Opinion In Genetics & Development 2024, 88: 102256. PMID: 39217658, PMCID: PMC11648527, DOI: 10.1016/j.gde.2024.102256.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsCis-regulatory elementsFunction of cis-regulatory elementsImpact of sequence variantsHigh-throughput approachNoncoding variationGenome functionNoncoding regionsSequence variantsPhenotypic consequencesCRISPR screensGenetic basisGenetic variantsGenetic differencesDiverse phenotypesGene expressionRegulatory functionsHuman evolutionFunctional variationGenomeUnique phenotypePhenotypeRegulatory impactModel systemVariantsGenesMulticenter integrated analysis of noncoding CRISPRi screens
Yao D, Tycko J, Oh J, Bounds L, Gosai S, Lataniotis L, Mackay-Smith A, Doughty B, Gabdank I, Schmidt H, Guerrero-Altamirano T, Siklenka K, Guo K, White A, Youngworth I, Andreeva K, Ren X, Barrera A, Luo Y, Yardımcı G, Tewhey R, Kundaje A, Greenleaf W, Sabeti P, Leslie C, Pritykin Y, Moore J, Beer M, Gersbach C, Reddy T, Shen Y, Engreitz J, Bassik M, Reilly S. Multicenter integrated analysis of noncoding CRISPRi screens. Nature Methods 2024, 21: 723-734. PMID: 38504114, PMCID: PMC11009116, DOI: 10.1038/s41592-024-02216-7.Peer-Reviewed Original ResearchCis-regulatory elementsCRISPR interferenceSingle guide RNADetection of cis-regulatory elementsGuide RNAsCandidate cis-regulatory elementsNoncoding cis-regulatory elementsDNA strand biasGene regulatory landscapeCis-regulatory mechanismsNoncoding genomeNoncoding elementsTranscribed regionsStrand biasHuman cell linesCRISPR screensFunctional characterizationTranscriptional effectsGenomeK562 cellsRegulatory landscapeCell linesConsortium effortCharacterization CenterRNAMachine-guided design of cell-type-targeting cis-regulatory elements
Gosai S, Castro R, Fuentes N, Butts J, Mouri K, Alasoadura M, Kales S, Nguyen T, Noche R, Rao A, Joy M, Sabeti P, Reilly S, Tewhey R. Machine-guided design of cell-type-targeting cis-regulatory elements. Nature 2024, 634: 1211-1220. PMID: 39443793, PMCID: PMC11525185, DOI: 10.1038/s41586-024-08070-z.Peer-Reviewed Original ResearchConceptsCis-regulatory elementsCell typesActivation of off-target cellsGene expressionCell type-specific expressionSynthetic cis-regulatory elementsCell-type specificityHuman genomeUnique cell typeTissue identityBiotechnological applicationsTissue specificityIn vitro validationCell linesCre activitySequenceGenesNatural sequenceDevelopmental timeExpressionCellsGenomeTested in vivoMotifOff-target cellsThe functional and evolutionary impacts of human-specific deletions in conserved elements
Xue J, Mackay-Smith A, Mouri K, Garcia M, Dong M, Akers J, Noble M, Li X, Lindblad-Toh K, Karlsson E, Noonan J, Capellini T, Brennand K, Tewhey R, Sabeti P, Reilly S, Andrews G, Armstrong J, Bianchi M, Birren B, Bredemeyer K, Breit A, Christmas M, Clawson H, Damas J, Di Palma F, Diekhans M, Dong M, Eizirik E, Fan K, Fanter C, Foley N, Forsberg-Nilsson K, Garcia C, Gatesy J, Gazal S, Genereux D, Goodman L, Grimshaw J, Halsey M, Harris A, Hickey G, Hiller M, Hindle A, Hubley R, Hughes G, Johnson J, Juan D, Kaplow I, Karlsson E, Keough K, Kirilenko B, Koepfli K, Korstian J, Kowalczyk A, Kozyrev S, Lawler A, Lawless C, Lehmann T, Levesque D, Lewin H, Li X, Lind A, Lindblad-Toh K, Mackay-Smith A, Marinescu V, Marques-Bonet T, Mason V, Meadows J, Meyer W, Moore J, Moreira L, Moreno-Santillan D, Morrill K, Muntané G, Murphy W, Navarro A, Nweeia M, Ortmann S, Osmanski A, Paten B, Paulat N, Pfenning A, Phan B, Pollard K, Pratt H, Ray D, Reilly S, Rosen J, Ruf I, Ryan L, Ryder O, Sabeti P, Schäffer D, Serres A, Shapiro B, Smit A, Springer M, Srinivasan C, Steiner C, Storer J, Sullivan K, Sullivan P, Sundström E, Supple M, Swofford R, Talbot J, Teeling E, Turner-Maier J, Valenzuela A, Wagner F, Wallerman O, Wang C, Wang J, Weng Z, Wilder A, Wirthlin M, Xue J, Zhang X. The functional and evolutionary impacts of human-specific deletions in conserved elements. Science 2023, 380: eabn2253. PMID: 37104592, PMCID: PMC10202372, DOI: 10.1126/science.abn2253.Peer-Reviewed Original ResearchConceptsHuman-specific deletionHuman phenotypic traitsParallel reporterEvolutionary impactDevelopmental genesPhenotypic traitsEvolutionary mechanismsGenomic sequencesNew traitsTranscriptomic datasetsSequence altersRegulatory functionsCell typesRegulatory activityRich resourceDeletionSynaptic functionTraitsBrain developmentGenesSpeciesReporterHumansSequenceExpression
2024
Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes
Maury E, Jones A, Seplyarskiy V, Nguyen T, Rosenbluh C, Bae T, Wang Y, Abyzov A, Khoshkhoo S, Chahine Y, Zhao S, Venkatesh S, Root E, Voloudakis G, Roussos P, Network B, Park P, Akbarian S, Brennand K, Reilly S, Lee E, Sunyaev S, Walsh C, Chess A. Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes. Science 2024, 386: 217-224. PMID: 39388546, PMCID: PMC11490355, DOI: 10.1126/science.adq1456.Peer-Reviewed Original ResearchConceptsTranscription factor binding sitesWhole-genome sequencingOpen chromatinMutational processesSomatic mutationsFactor binding sitesSchizophrenia casesSchizophrenia risk genesSomatic mosaicismSomatic variantsRisk genesG mutationGene expressionGermline mutationsBinding sitesGenesMutationsIncreased somatic mutationsChromatinMosaic somatic mutationsPrenatal neurogenesisContext of schizophreniaBrain neuronsSchizophrenia brainVariantsDeciphering the impact of genomic variation on function.
IGVF Consortium. Deciphering the impact of genomic variation on function. Nature 2024, 633: 47-57. PMID: 39232149, DOI: 10.1038/s41586-024-07510-0.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsVocal learning-associated convergent evolution in mammalian proteins and regulatory elements.
Wirthlin ME, Schmid TA, Elie JE, Zhang X, Kowalczyk A, Redlich R, Shvareva VA, Rakuljic A, Ji MB, Bhat NS, Kaplow IM, Schäffer DE, Lawler AJ, Wang AZ, Phan BN, Annaldasula S, Brown AR, Lu T, Lim BK, Azim E, Zoonomia Consortium, Clark NL, Meyer WK, Pond SLK, Chikina M, Yartsev MM, Pfenning AR, Andrews G, Armstrong JC, Bianchi M, Birren BW, Bredemeyer KR, Breit AM, Christmas MJ, Clawson H, Damas J, Di Palma F, Diekhans M, Dong MX, Eizirik E, Fan K, Fanter C, Foley NM, Forsberg-Nilsson K, Garcia CJ, Gatesy J, Gazal S, Genereux DP, Goodman L, Grimshaw J, Halsey MK, Harris AJ, Hickey G, Hiller M, Hindle AG, Hubley RM, Hughes GM, Johnson J, Juan D, Kaplow IM, Karlsson EK, Keough KC, Kirilenko B, Koepfli KP, Korstian JM, Kowalczyk A, Kozyrev SV, Lawler AJ, Lawless C, Lehmann T, Levesque DL, Lewin HA, Li X, Lind A, Lindblad-Toh K, Mackay-Smith A, Marinescu VD, Marques-Bonet T, Mason VC, Meadows JRS, Meyer WK, Moore JE, Moreira LR, Moreno-Santillan DD, Morrill KM, Muntané G, Murphy WJ, Navarro A, Nweeia M, Ortmann S, Osmanski A, Paten B, Paulat NS, Pfenning AR, Phan BN, Pollard KS, Pratt HE, Ray DA, Reilly SK, Rosen JR, Ruf I, Ryan L, Ryder OA, Sabeti PC, Schäffer DE, Serres A, Shapiro B, Smit AFA, Springer M, Srinivasan C, Steiner C, Storer JM, Sullivan KAM, Sullivan PF, Sundström E, Supple MA, Swofford R, Talbot JE, Teeling E, Turner-Maier J, Valenzuela A, Wagner F, Wallerman O, Wang C, Wang J, Weng Z, Wilder AP, Wirthlin ME, Xue JR, Zhang X. Vocal learning-associated convergent evolution in mammalian proteins and regulatory elements. Science 2024, 383: eabn3263. PMID: 38422184, DOI: 10.1126/science.abn3263.Peer-Reviewed Original ResearchGenome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever.
Kotliar D, Raju S, Tabrizi S, Odia I, Goba A, Momoh M, Sandi JD, Nair P, Phelan E, Tariyal R, Eromon PE, Mehta S, Robles-Sikisaka R, Siddle KJ, Stremlau M, Jalloh S, Gire SK, Winnicki S, Chak B, Schaffner SF, Pauthner M, Karlsson EK, Chapin SR, Kennedy SG, Branco LM, Kanneh L, Vitti JJ, Broodie N, Gladden-Young A, Omoniwa O, Jiang PP, Yozwiak N, Heuklom S, Moses LM, Akpede GO, Asogun DA, Rubins K, Kales S, Happi AN, Iruolagbe CO, Dic-Ijiewere M, Iraoyah K, Osazuwa OO, Okonkwo AK, Kunz S, McCormick JB, Khan SH, Honko AN, Lander ES, Oldstone MBA, Hensley L, Folarin OA, Okogbenin SA, Günther S, Ollila HM, Tewhey R, Okokhere PO, Schieffelin JS, Andersen KG, Reilly SK, Grant DS, Garry RF, Barnes KG, Happi CT, Sabeti PC. Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever. Nat Microbiol 2024, 9: 751-762. PMID: 38326571, DOI: 10.1038/s41564-023-01589-3.Peer-Reviewed Original Research
2023
Fine-mapping across diverse ancestries drives the discovery of putative causal variants underlying human complex traits and diseases.
Yuan K, Longchamps RJ, Pardiñas AF, Yu M, Chen TT, Lin SC, Chen Y, Lam M, Liu R, Xia Y, Guo Z, Shi W, Shen C, Schizophrenia Workgroup of Psychiatric Genomics Consortium, Daly MJ, Neale BM, Feng YA, Lin YF, Chen CY, O'Donovan M, Ge T, Huang H. Fine-mapping across diverse ancestries drives the discovery of putative causal variants underlying human complex traits and diseases. MedRxiv 2023 PMID: 36711496, DOI: 10.1101/2023.01.07.23284293.Peer-Reviewed Original Research In PressA genomic timescale for placental mammal evolution.
Foley NM, Mason VC, Harris AJ, Bredemeyer KR, Damas J, Lewin HA, Eizirik E, Gatesy J, Karlsson EK, Lindblad-Toh K, Zoonomia Consortium‡, Springer MS, Murphy WJ. A genomic timescale for placental mammal evolution. Science 2023, 380: eabl8189. PMID: 37104581, DOI: 10.1126/science.abl8189.Peer-Reviewed Original ResearchIntegrating gene annotation with orthology inference at scale.
Kirilenko BM, Munegowda C, Osipova E, Jebb D, Sharma V, Blumer M, Morales AE, Ahmed AW, Kontopoulos DG, Hilgers L, Lindblad-Toh K, Karlsson EK, Zoonomia Consortium‡, Hiller M. Integrating gene annotation with orthology inference at scale. Science 2023, 380: eabn3107. PMID: 37104600, DOI: 10.1126/science.abn3107.Peer-Reviewed Original Research​Comparative genomics of Balto, a famous historic dog, captures lost diversity of 1920s sled dogs.
Moon KL, Huson HJ, Morrill K, Wang MS, Li X, Srikanth K, Zoonomia Consortium, Lindblad-Toh K, Svenson GJ, Karlsson EK, Shapiro B. ​Comparative genomics of Balto, a famous historic dog, captures lost diversity of 1920s sled dogs. Science 2023, 380: eabn5887. PMID: 37104591, DOI: 10.1126/science.abn5887.Peer-Reviewed Original ResearchRelating enhancer genetic variation across mammals to complex phenotypes using machine learning.
Kaplow IM, Lawler AJ, Schäffer DE, Srinivasan C, Sestili HH, Wirthlin ME, Phan BN, Prasad K, Brown AR, Zhang X, Foley K, Genereux DP, Zoonomia Consortium**, Karlsson EK, Lindblad-Toh K, Meyer WK, Pfenning AR. Relating enhancer genetic variation across mammals to complex phenotypes using machine learning. Science 2023, 380: eabm7993. PMID: 37104615, DOI: 10.1126/science.abm7993.Peer-Reviewed Original ResearchThe contribution of historical processes to contemporary extinction risk in placental mammals.
Wilder AP, Supple MA, Subramanian A, Mudide A, Swofford R, Serres-Armero A, Steiner C, Koepfli KP, Genereux DP, Karlsson EK, Lindblad-Toh K, Marques-Bonet T, Munoz Fuentes V, Foley K, Meyer WK, Zoonomia Consortium‡, Ryder OA, Shapiro B. The contribution of historical processes to contemporary extinction risk in placental mammals. Science 2023, 380: eabn5856. PMID: 37104572, DOI: 10.1126/science.abn5856.Peer-Reviewed Original ResearchMammalian evolution of human cis-regulatory elements and transcription factor binding sites.
Andrews G, Fan K, Pratt HE, Phalke N, Zoonomia Consortium§, Karlsson EK, Lindblad-Toh K, Gazal S, Moore JE, Weng Z. Mammalian evolution of human cis-regulatory elements and transcription factor binding sites. Science 2023, 380: eabn7930. PMID: 37104580, DOI: 10.1126/science.abn7930.Peer-Reviewed Original ResearchThree-dimensional genome rewiring in loci with human accelerated regions.
Keough KC, Whalen S, Inoue F, Przytycki PF, Fair T, Deng C, Steyert M, Ryu H, Lindblad-Toh K, Karlsson E, Zoonomia Consortium§, Nowakowski T, Ahituv N, Pollen A, Pollard KS. Three-dimensional genome rewiring in loci with human accelerated regions. Science 2023, 380: eabm1696. PMID: 37104607, DOI: 10.1126/science.abm1696.Peer-Reviewed Original ResearchInsights into mammalian TE diversity through the curation of 248 genome assemblies.
Osmanski AB, Paulat NS, Korstian J, Grimshaw JR, Halsey M, Sullivan KAM, Moreno-Santillán DD, Crookshanks C, Roberts J, Garcia C, Johnson MG, Densmore LD, Stevens RD, Zoonomia Consortium†, Rosen J, Storer JM, Hubley R, Smit AFA, Dávalos LM, Karlsson EK, Lindblad-Toh K, Ray DA. Insights into mammalian TE diversity through the curation of 248 genome assemblies. Science 2023, 380: eabn1430. PMID: 37104570, DOI: 10.1126/science.abn1430.Peer-Reviewed Original ResearchLeveraging base-pair mammalian constraint to understand genetic variation and human disease
Sullivan P, Meadows J, Gazal S, Phan B, Li X, Genereux D, Dong M, Bianchi M, Andrews G, Sakthikumar S, Nordin J, Roy A, Christmas M, Marinescu V, Wang C, Wallerman O, Xue J, Yao S, Sun Q, Szatkiewicz J, Wen J, Huckins L, Lawler A, Keough K, Zheng Z, Zeng J, Wray N, Li Y, Johnson J, Chen J, Paten B, Reilly S, Hughes G, Weng Z, Pollard K, Pfenning A, Forsberg-Nilsson K, Karlsson E, Lindblad-Toh K, Andrews G, Armstrong J, Bianchi M, Birren B, Bredemeyer K, Breit A, Christmas M, Clawson H, Damas J, Di Palma F, Diekhans M, Dong M, Eizirik E, Fan K, Fanter C, Foley N, Forsberg-Nilsson K, Garcia C, Gatesy J, Gazal S, Genereux D, Goodman L, Grimshaw J, Halsey M, Harris A, Hickey G, Hiller M, Hindle A, Hubley R, Hughes G, Johnson J, Juan D, Kaplow I, Karlsson E, Keough K, Kirilenko B, Koepfli K, Korstian J, Kowalczyk A, Kozyrev S, Lawler A, Lawless C, Lehmann T, Levesque D, Lewin H, Li X, Lind A, Lindblad-Toh K, Mackay-Smith A, Marinescu V, Marques-Bonet T, Mason V, Meadows J, Meyer W, Moore J, Moreira L, Moreno-Santillan D, Morrill K, Muntané G, Murphy W, Navarro A, Nweeia M, Ortmann S, Osmanski A, Paten B, Paulat N, Pfenning A, Phan B, Pollard K, Pratt H, Ray D, Reilly S, Rosen J, Ruf I, Ryan L, Ryder O, Sabeti P, Schäffer D, Serres A, Shapiro B, Smit A, Springer M, Srinivasan C, Steiner C, Storer J, Sullivan K, Sullivan P, Sundström E, Supple M, Swofford R, Talbot J, Teeling E, Turner-Maier J, Valenzuela A, Wagner F, Wallerman O, Wang C, Wang J, Weng Z, Wilder A, Wirthlin M, Xue J, Zhang X. Leveraging base-pair mammalian constraint to understand genetic variation and human disease. Science 2023, 380: eabn2937. PMID: 37104612, PMCID: PMC10259825, DOI: 10.1126/science.abn2937.Peer-Reviewed Original ResearchConceptsHuman genomeHuman diseasesCopy-number variationsHeritable human diseasesGenome annotationVariant annotationGenomic positionsGenomic regionsDisease heritabilityFunctional annotationEvolutionary constraintsAssociation studiesCopy-numberGenetic variationGenetic findingsGenomeCell typesRegulatory landscapeDisease mechanismsAnnotationBiological mechanismsCancer dataMammalsPredictor of functionHeritabilityEvolutionary constraint and innovation across hundreds of placental mammals
Christmas M, Kaplow I, Genereux D, Dong M, Hughes G, Li X, Sullivan P, Hindle A, Andrews G, Armstrong J, Bianchi M, Breit A, Diekhans M, Fanter C, Foley N, Goodman D, Goodman L, Keough K, Kirilenko B, Kowalczyk A, Lawless C, Lind A, Meadows J, Moreira L, Redlich R, Ryan L, Swofford R, Valenzuela A, Wagner F, Wallerman O, Brown A, Damas J, Fan K, Gatesy J, Grimshaw J, Johnson J, Kozyrev S, Lawler A, Marinescu V, Morrill K, Osmanski A, Paulat N, Phan B, Reilly S, Schäffer D, Steiner C, Supple M, Wilder A, Wirthlin M, Xue J, Birren B, Gazal S, Hubley R, Koepfli K, Marques-Bonet T, Meyer W, Nweeia M, Sabeti P, Shapiro B, Smit A, Springer M, Teeling E, Weng Z, Hiller M, Levesque D, Lewin H, Murphy W, Navarro A, Paten B, Pollard K, Ray D, Ruf I, Ryder O, Pfenning A, Lindblad-Toh K, Karlsson E, Andrews G, Armstrong J, Bianchi M, Birren B, Bredemeyer K, Breit A, Christmas M, Clawson H, Damas J, Di Palma F, Diekhans M, Dong M, Eizirik E, Fan K, Fanter C, Foley N, Forsberg-Nilsson K, Garcia C, Gatesy J, Gazal S, Genereux D, Goodman L, Grimshaw J, Halsey M, Harris A, Hickey G, Hiller M, Hindle A, Hubley R, Hughes G, Johnson J, Juan D, Kaplow I, Karlsson E, Keough K, Kirilenko B, Koepfli K, Korstian J, Kowalczyk A, Kozyrev S, Lawler A, Lawless C, Lehmann T, Levesque D, Lewin H, Li X, Lind A, Lindblad-Toh K, Mackay-Smith A, Marinescu V, Marques-Bonet T, Mason V, Meadows J, Meyer W, Moore J, Moreira L, Moreno-Santillan D, Morrill K, Muntané G, Murphy W, Navarro A, Nweeia M, Ortmann S, Osmanski A, Paten B, Paulat N, Pfenning A, Phan B, Pollard K, Pratt H, Ray D, Reilly S, Rosen J, Ruf I, Ryan L, Ryder O, Sabeti P, Schäffer D, Serres A, Shapiro B, Smit A, Springer M, Srinivasan C, Steiner C, Storer J, Sullivan K, Sullivan P, Sundström E, Supple M, Swofford R, Talbot J, Teeling E, Turner-Maier J, Valenzuela A, Wagner F, Wallerman O, Wang C, Wang J, Weng Z, Wilder A, Wirthlin M, Xue J, Zhang X. Evolutionary constraint and innovation across hundreds of placental mammals. Science 2023, 380: eabn3943. PMID: 37104599, PMCID: PMC10250106, DOI: 10.1126/science.abn3943.Peer-Reviewed Original ResearchConceptsEncyclopedia of DNA ElementsProtein-coding exonsUltraconserved elementsGenome functionGenomic resourcesOrganismal phenotypesDNA elementsFunctional annotationEvolutionary constraintsHuman genomeRegulatory elementsMammalian traitsGenomeGenetic variantsPlacental mammalsTherapeutic developmentMammalsSpeciesDisease riskExonGenesBiodiversityPhenotypeTraitsRepeats
2021
Transmission from vaccinated individuals in a large SARS-CoV-2 Delta variant outbreak
Siddle K, Krasilnikova L, Moreno G, Schaffner S, Vostok J, Fitzgerald N, Lemieux J, Barkas N, Loreth C, Specht I, Tomkins-Tinch C, Paull J, Schaeffer B, Taylor B, Loftness B, Johnson H, Schubert P, Shephard H, Doucette M, Fink T, Lang A, Baez S, Beauchamp J, Hennigan S, Buzby E, Ash S, Brown J, Clancy S, Cofsky S, Gagne L, Hall J, Harrington R, Gionet G, DeRuff K, Vodzak M, Adams G, Dobbins S, Slack S, Reilly S, Anderson L, Cipicchio M, DeFelice M, Grimsby J, Anderson S, Blumenstiel B, Meldrim J, Rooke H, Vicente G, Smith N, Messer K, Reagan F, Mandese Z, Lee M, Ray M, Fisher M, Ulcena M, Nolet C, English S, Larkin K, Vernest K, Chaluvadi S, Arvidson D, Melchiono M, Covell T, Harik V, Brock-Fisher T, Dunn M, Kearns A, Hanage W, Bernard C, Philippakis A, Lennon N, Gabriel S, Gallagher G, Smole S, Madoff L, Brown C, Park D, MacInnis B, Sabeti P. Transmission from vaccinated individuals in a large SARS-CoV-2 Delta variant outbreak. Cell 2021, 185: 485-492.e10. PMID: 35051367, PMCID: PMC8695126, DOI: 10.1016/j.cell.2021.12.027.Peer-Reviewed Original ResearchConceptsVaccinated individualsPublic health responseEpidemiological dataHealth responseComprehensive public health responseFirst large outbreakHigh vaccination ratesDelta variant outbreakOutbreak-associated casesVaccination ratesCOVID-19 casesDelta variantRobust public health responseVariant outbreakLarge outbreakMultiple settingsOutbreakIndividualsCasesInfectionOnward impactResponse