Blum SM, Zlotoff DA, Smith NP
… +37 more, Kernin IJ, Ramesh S, Zubiri L, Caplin J, Samanta N, Martin S, Wang M, Tirard A, Song Y, Xu KH, Barth J, Sen P, Slowikowski K, Tantivit J, Manakongtreecheep K, Arnold BY, Nasrallah M, Pinto CJ, McLoughlin D, Jackson M, Chan P, Lawless A, Michaud WA, Sharova T, Nieman LT, Gainor JF, Wu CJ, Juric D, Mino-Kenudson M, Oliveira G, Sullivan RJ, Boland GM, Stone JR, Thomas MF, Neilan TG, Reynolds KL, Villani AC
Immune checkpoint inhibitors are widely used anticancer therapies that can cause morbid and potentially fatal immune-related adverse events such as immune-related myocarditis (irMyocarditis). The pathogenesis of irMyocar...Immune checkpoint inhibitors are widely used anticancer therapies that can cause morbid and potentially fatal immune-related adverse events such as immune-related myocarditis (irMyocarditis). The pathogenesis of irMyocarditis and its relationship to antitumour immunity remain poorly understood. Here we sought to define immune responses in heart, tumour and blood in patients with irMyocarditis by leveraging single-cell RNA sequencing coupled with T cell receptor (TCR) sequencing, microscopy and proteomics analyses of samples from 28 patients with irMyocarditis and 41 unaffected individuals. Analyses of 84,576 cardiac cells by single-cell RNA sequencing combined with multiplexed microscopy demonstrated increased frequencies and co-localization of cytotoxic T cells, conventional dendritic cells and inflammatory fibroblasts in irMyocarditis heart tissue. Analyses of 366,066 blood cells revealed decreased frequencies of plasmacytoid dendritic cells, conventional dendritic cells and B lineage cells but an increased frequency of other mononuclear phagocytes in irMyocarditis. Fifty-two heart-expanded TCR clones from eight patients did not recognize the putative cardiac autoantigens α-myosin, troponin I or troponin T. Additionally, TCRs enriched in heart tissue were largely nonoverlapping with those enriched in paired tumour tissue. The presence of heart-expanded TCRs in a cycling blood CD8 T cell population was associated with fatal irMyocarditis case status. Collectively, these findings highlight crucial biology driving irMyocarditis and identify putative biomarkers.
Jee J, Fong C, Pichotta K
… +66 more, Tran TN, Luthra A, Waters M, Fu C, Altoe M, Liu SY, Maron SB, Ahmed M, Kim S, Pirun M, Chatila WK, de Bruijn I, Pasha A, Kundra R, Gross B, Mastrogiacomo B, Aprati TJ, Liu D, Gao J, Capelletti M, Pekala K, Loudon L, Perry M, Bandlamudi C, Donoghue M, Satravada BA, Martin A, Shen R, Chen Y, Brannon AR, Chang J, Braunstein L, Li A, Safonov A, Stonestrom A, Sanchez-Vela P, Wilhelm C, Robson M, Scher H, Ladanyi M, Reis-Filho JS, Solit DB, Jones DR, Gomez D, Yu H, Chakravarty D, Yaeger R, Abida W, Park W, O'Reilly EM, Garcia-Aguilar J, Socci N, Sanchez-Vega F, Carrot-Zhang J, Stetson PD, Levine R, Rudin CM, Berger MF, Shah SP, Schrag D, Razavi P, Kehl KL, Li BT, Riely GJ, Schultz N, MSK Cancer Data Science Initiative Group
The digitization of health records and growing availability of tumour DNA sequencing provide an opportunity to study the determinants of cancer outcomes with unprecedented richness. Patient data are often stored in unstr...The digitization of health records and growing availability of tumour DNA sequencing provide an opportunity to study the determinants of cancer outcomes with unprecedented richness. Patient data are often stored in unstructured text and siloed datasets. Here we combine natural language processing annotations with structured medication, patient-reported demographic, tumour registry and tumour genomic data from 24,950 patients at Memorial Sloan Kettering Cancer Center to generate a clinicogenomic, harmonized oncologic real-world dataset (MSK-CHORD). MSK-CHORD includes data for non-small-cell lung (n = 7,809), breast (n = 5,368), colorectal (n = 5,543), prostate (n = 3,211) and pancreatic (n = 3,109) cancers and enables discovery of clinicogenomic relationships not apparent in smaller datasets. Leveraging MSK-CHORD to train machine learning models to predict overall survival, we find that models including features derived from natural language processing, such as sites of disease, outperform those based on genomic data or stage alone as tested by cross-validation and an external, multi-institution dataset. By annotating 705,241 radiology reports, MSK-CHORD also uncovers predictors of metastasis to specific organ sites, including a relationship between SETD2 mutation and lower metastatic potential in immunotherapy-treated lung adenocarcinoma corroborated in independent datasets. We demonstrate the feasibility of automated annotation from unstructured notes and its utility in predicting patient outcomes. The resulting data are provided as a public resource for real-world oncologic research.
The Caucasus and surrounding areas, with their rich metal resources, became a crucible of the Bronze Age and the birthplace of the earliest steppe pastoralist societies. Yet, despite this region having a large influence...The Caucasus and surrounding areas, with their rich metal resources, became a crucible of the Bronze Age and the birthplace of the earliest steppe pastoralist societies. Yet, despite this region having a large influence on the subsequent development of Europe and Asia, questions remain regarding its hunter-gatherer past and its formation of expansionist mobile steppe societies. Here we present new genome-wide data for 131 individuals from 38 archaeological sites spanning 6,000 years. We find a strong genetic differentiation between populations north and south of the Caucasus mountains during the Mesolithic, with Eastern hunter-gatherer ancestry in the north, and a distinct Caucasus hunter-gatherer ancestry with increasing East Anatolian farmer admixture in the south. During the subsequent Eneolithic period, we observe the formation of the characteristic West Eurasian steppe ancestry and heightened interaction between the mountain and steppe regions, facilitated by technological developments of the Maykop cultural complex. By contrast, the peak of pastoralist activities and territorial expansions during the Early and Middle Bronze Age is characterized by long-term genetic stability. The Late Bronze Age marks another period of gene flow from multiple distinct sources that coincides with a decline of steppe cultures, followed by a transformation and absorption of the steppe ancestry into highland populations.
Rossi C, Sinding MS, Mullin VE
… +48 more, Scheu A, Erven JAM, Verdugo MP, Daly KG, Ciucani MM, Mattiangeli V, Teasdale MD, Diquelou D, Manin A, Bangsgaard P, Collins M, Lord TC, Zeibert V, Zorzin R, Vinter M, Timmons Z, Kitchener AC, Street M, Haruda AF, Tabbada K, Larson G, Frantz LAF, Gehlen B, Alhaique F, Tagliacozzo A, Fornasiero M, Pandolfi L, Karastoyanova N, Sørensen L, Kiryushin K, Ekström J, Mostadius M, Grandal-d'Anglade A, Vidal-Gorosquieta A, Benecke N, Kropp C, Grushin SP, Gilbert MTP, Merts I, Merts V, Outram AK, Rosengren E, Kosintsev P, Sablin M, Tishkin AA, Makarewicz CA, Burger J, Bradley DG
Now extinct, the aurochs (Bos primigenius) was a keystone species in prehistoric Eurasian and North African ecosystems, and the progenitor of cattle (Bos taurus), domesticates that have provided people with food and labo...Now extinct, the aurochs (Bos primigenius) was a keystone species in prehistoric Eurasian and North African ecosystems, and the progenitor of cattle (Bos taurus), domesticates that have provided people with food and labour for millennia. Here we analysed 38 ancient genomes and found 4 distinct population ancestries in the aurochs-European, Southwest Asian, North Asian and South Asian-each of which has dynamic trajectories that have responded to changes in climate and human influence. Similarly to Homo heidelbergensis, aurochsen first entered Europe around 650 thousand years ago, but early populations left only trace ancestry, with both North Asian and European B. primigenius genomes coalescing during the most recent glaciation. North Asian and European populations then appear separated until mixing after the climate amelioration of the early Holocene. European aurochsen endured the more severe bottleneck during the Last Glacial Maximum, retreating to southern refugia before recolonizing from Iberia. Domestication involved the capture of a small number of individuals from the Southwest Asian aurochs population, followed by early and pervasive male-mediated admixture involving each ancestral strain of aurochs after domestic stocks dispersed beyond their cradle of origin.
Islam M, Yang Y, Simmons AJ
… +23 more, Shah VM, Musale KP, Xu Y, Tasneem N, Chen Z, Trinh LT, Molina P, Ramirez-Solano MA, Sadien ID, Dou J, Rolong A, Chen K, Magnuson MA, Rathmell JC, Macara IG, Winton DJ, Liu Q, Zafar H, Kalhor R, Church GM, Shrubsole MJ, Coffey RJ, Lau KS
Temporal ordering of cellular events offers fundamental insights into biological phenomena. Although this is traditionally achieved through continuous direct observations, an alternative solution leverages irreversible g...Temporal ordering of cellular events offers fundamental insights into biological phenomena. Although this is traditionally achieved through continuous direct observations, an alternative solution leverages irreversible genetic changes, such as naturally occurring mutations, to create indelible marks that enables retrospective temporal ordering. Using a multipurpose, single-cell CRISPR platform, we developed a molecular clock approach to record the timing of cellular events and clonality in vivo, with incorporation of cell state and lineage information. Using this approach, we uncovered precise timing of tissue-specific cell expansion during mouse embryonic development, unconventional developmental relationships between cell types and new epithelial progenitor states by their unique genetic histories. Analysis of mouse adenomas, coupled to multiomic and single-cell profiling of human precancers, with clonal analysis of 418 human polyps, demonstrated the occurrence of polyclonal initiation in 15-30% of colonic precancers, showing their origins from multiple normal founders. Our study presents a multimodal framework that lays the foundation for in vivo recording, integrating synthetic or natural indelible genetic changes with single-cell analyses, to explore the origins and timing of development and tumorigenesis in mammalian systems.
Amrute JM, Luo X, Penna V
… +33 more, Yang S, Yamawaki T, Hayat S, Bredemeyer A, Jung IH, Kadyrov FF, Heo GS, Venkatesan R, Shi SY, Parvathaneni A, Koenig AL, Kuppe C, Baker C, Luehmann H, Jones C, Kopecky B, Zeng X, Bleckwehl T, Ma P, Lee P, Terada Y, Fu A, Furtado M, Kreisel D, Kovacs A, Stitziel NO, Jackson S, Li CM, Liu Y, Rosenthal NA, Kramann R, Ason B, Lavine KJ
Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction. However, the molecular mechanisms driving immune-fibroblast cell communication in human cardiac disease remain unexplored and there...Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction. However, the molecular mechanisms driving immune-fibroblast cell communication in human cardiac disease remain unexplored and there are at present no approved treatments that directly target cardiac fibrosis. Here we performed multiomic single-cell gene expression, epitope mapping and chromatin accessibility profiling in 45 healthy donor, acutely infarcted and chronically failing human hearts. We identified a disease-associated fibroblast trajectory that diverged into distinct populations reminiscent of myofibroblasts and matrifibrocytes, the latter expressing fibroblast activator protein (FAP) and periostin (POSTN). Genetic lineage tracing of FAP fibroblasts in vivo showed that they contribute to the POSTN lineage but not the myofibroblast lineage. We assessed the applicability of experimental systems to model cardiac fibroblasts and demonstrated that three different in vivo mouse models of cardiac injury were superior compared with cultured human heart and dermal fibroblasts in recapitulating the human disease phenotype. Ligand-receptor analysis and spatial transcriptomics predicted that interactions between C-C chemokine receptor type 2 (CCR2) macrophages and fibroblasts mediated by interleukin-1β (IL-1β) signalling drove the emergence of FAP/POSTN fibroblasts within spatially defined niches. In vivo, we deleted the IL-1 receptor on fibroblasts and the IL-1β ligand in CCR2 monocytes and macrophages, and inhibited IL-1β signalling using a monoclonal antibody, and showed reduced FAP/POSTN fibroblasts, diminished myocardial fibrosis and improved cardiac function. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and preserve organ function.
Nordmann TM, Anderton H, Hasegawa A
… +31 more, Schweizer L, Zhang P, Stadler PC, Sinha A, Metousis A, Rosenberger FA, Zwiebel M, Satoh TK, Anzengruber F, Strauss MT, Tanzer MC, Saito Y, Gong T, Thielert M, Kimura H, Silke N, Rodriguez EH, Restivo G, Nguyen HH, Gross A, Feldmeyer L, Joerg L, Levesque MP, Murray PJ, Ingen-Housz-Oro S, Mund A, Abe R, Silke J, Ji C, French LE, Mann M
Toxic epidermal necrolysis (TEN) is a fatal drug-induced skin reaction triggered by common medications and is an emerging public health issue. Patients with TEN undergo severe and sudden epidermal detachment caused by ke...Toxic epidermal necrolysis (TEN) is a fatal drug-induced skin reaction triggered by common medications and is an emerging public health issue. Patients with TEN undergo severe and sudden epidermal detachment caused by keratinocyte cell death. Although molecular mechanisms that drive keratinocyte cell death have been proposed, the main drivers remain unknown, and there is no effective therapy for TEN. Here, to systematically map molecular changes that are associated with TEN and identify potential druggable targets, we utilized deep visual proteomics, which provides single-cell-based, cell-type-resolution proteomics. We analysed formalin-fixed, paraffin-embedded archived skin tissue biopsies of three types of cutaneous drug reactions with varying severity and quantified more than 5,000 proteins in keratinocytes and skin-infiltrating immune cells. This revealed a marked enrichment of type I and type II interferon signatures in the immune cell and keratinocyte compartment of patients with TEN, as well as phosphorylated STAT1 activation. Targeted inhibition with the pan-JAK inhibitor tofacitinib in vitro reduced keratinocyte-directed cytotoxicity. In vivo oral administration of tofacitinib, baricitinib or the JAK1-specific inhibitors abrocitinib or upadacitinib ameliorated clinical and histological disease severity in two distinct mouse models of TEN. Crucially, treatment with JAK inhibitors (JAKi) was safe and associated with rapid cutaneous re-epithelialization and recovery in seven patients with TEN. This study uncovers the JAK/STAT and interferon signalling pathways as key pathogenic drivers of TEN and demonstrates the potential of targeted JAKi as a curative therapy.
Gopee NH, Winheim E, Olabi B
… +68 more, Admane C, Foster AR, Huang N, Botting RA, Torabi F, Sumanaweera D, Le AP, Kim J, Verger L, Stephenson E, Adão D, Ganier C, Gim KY, Serdy SA, Deakin C, Goh I, Steele L, Annusver K, Miah MU, Tun WM, Moghimi P, Kwakwa KA, Li T, Basurto Lozada D, Rumney B, Tudor CL, Roberts K, Chipampe NJ, Sidhpura K, Englebert J, Jardine L, Reynolds G, Rose A, Rowe V, Pritchard S, Mulas I, Fletcher J, Popescu DM, Poyner E, Dubois A, Guy A, Filby A, Lisgo S, Barker RA, Glass IA, Park JE, Vento-Tormo R, Nikolova MT, He P, Lawrence JEG, Moore J, Ballereau S, Hale CB, Shanmugiah V, Horsfall D, Rajan N, McGrath JA, O'Toole EA, Treutlein B, Bayraktar O, Kasper M, Progatzky F, Mazin P, Lee J, Gambardella L, Koehler KR, Teichmann SA, Haniffa M
Human prenatal skin is populated by innate immune cells, including macrophages, but whether they act solely in immunity or have additional functions in morphogenesis is unclear. Here we assembled a comprehensive multi-om...Human prenatal skin is populated by innate immune cells, including macrophages, but whether they act solely in immunity or have additional functions in morphogenesis is unclear. Here we assembled a comprehensive multi-omics reference atlas of prenatal human skin (7-17 post-conception weeks), combining single-cell and spatial transcriptomics data, to characterize the microanatomical tissue niches of the skin. This atlas revealed that crosstalk between non-immune and immune cells underpins the formation of hair follicles, is implicated in scarless wound healing and is crucial for skin angiogenesis. We systematically compared a hair-bearing skin organoid (SkO) model derived from human embryonic stem cells and induced pluripotent stem cells to prenatal and adult skin. The SkO model closely recapitulated in vivo skin epidermal and dermal cell types during hair follicle development and expression of genes implicated in the pathogenesis of genetic hair and skin disorders. However, the SkO model lacked immune cells and had markedly reduced endothelial cell heterogeneity and quantity. Our in vivo prenatal skin cell atlas indicated that macrophages and macrophage-derived growth factors have a role in driving endothelial development. Indeed, vascular network remodelling was enhanced following transfer of autologous macrophages derived from induced pluripotent stem cells into SkO cultures. Innate immune cells are therefore key players in skin morphogenesis beyond their conventional role in immunity, a function they achieve through crosstalk with non-immune cells.
The human hippocampus and prefrontal cortex play critical roles in learning and cognition, yet the dynamic molecular characteristics of their development remain enigmatic. Here we investigated the epigenomic and three-di...The human hippocampus and prefrontal cortex play critical roles in learning and cognition, yet the dynamic molecular characteristics of their development remain enigmatic. Here we investigated the epigenomic and three-dimensional chromatin conformational reorganization during the development of the hippocampus and prefrontal cortex, using more than 53,000 joint single-nucleus profiles of chromatin conformation and DNA methylation generated by single-nucleus methyl-3C sequencing (snm3C-seq3). The remodelling of DNA methylation is temporally separated from chromatin conformation dynamics. Using single-cell profiling and multimodal single-molecule imaging approaches, we have found that short-range chromatin interactions are enriched in neurons, whereas long-range interactions are enriched in glial cells and non-brain tissues. We reconstructed the regulatory programs of cell-type development and differentiation, finding putatively causal common variants for schizophrenia strongly overlapping with chromatin loop-connected, cell-type-specific regulatory regions. Our data provide multimodal resources for studying gene regulatory dynamics in brain development and demonstrate that single-cell three-dimensional multi-omics is a powerful approach for dissecting neuropsychiatric risk loci.
Bai Z, Feng B, McClory SE
… +21 more, de Oliveira BC, Diorio C, Gregoire C, Tao B, Yang L, Zhao Z, Peng L, Sferruzza G, Zhou L, Zhou X, Kerr J, Baysoy A, Su G, Yang M, Camara PG, Chen S, Tang L, June CH, Melenhorst JJ, Grupp SA, Fan R
Despite a high response rate in chimeric antigen receptor (CAR) T cell therapy for acute lymphocytic leukaemia (ALL), approximately 50% of patients relapse within the first year, representing an urgent question to addres...Despite a high response rate in chimeric antigen receptor (CAR) T cell therapy for acute lymphocytic leukaemia (ALL), approximately 50% of patients relapse within the first year, representing an urgent question to address in the next stage of cellular immunotherapy. Here, to investigate the molecular determinants of ultralong CAR T cell persistence, we obtained a single-cell multi-omics atlas from 695,819 pre-infusion CAR T cells at the basal level or after CAR-specific stimulation from 82 paediatric patients with ALL enrolled in the first two CAR T ALL clinical trials and 6 healthy donors. We identified that elevated type 2 functionality in CAR T infusion products is significantly associated with patients maintaining a median B cell aplasia duration of 8.4 years. Analysis of ligand-receptor interactions revealed that type 2 cells regulate a dysfunctional subset to maintain whole-population homeostasis, and the addition of IL-4 during antigen-specific activation alleviates CAR T cell dysfunction while enhancing fitness at both transcriptomic and epigenomic levels. Serial proteomic profiling of sera after treatment revealed a higher level of circulating type 2 cytokines in 5-year or 8-year relapse-free responders. In a leukaemic mouse model, type 2 CAR T cell products demonstrated superior expansion and antitumour activity, particularly after leukaemia rechallenge. Restoring antitumour efficacy in type 2 CAR T cells was attainable by enhancing their type 2 functionality, either through incorporating IL-4 into the manufacturing process or by priming manufactured CAR T products with IL-4 before infusion. Our findings provide insights into the mediators of durable CAR T therapy response and suggest potential therapeutic strategies to sustain long-term remission by boosting type 2 functionality in CAR T cells.
Down syndrome predisposes individuals to haematological abnormalities, such as increased number of erythrocytes and leukaemia in a process that is initiated before birth and is not entirely understood. Here, to understan...Down syndrome predisposes individuals to haematological abnormalities, such as increased number of erythrocytes and leukaemia in a process that is initiated before birth and is not entirely understood. Here, to understand dysregulated haematopoiesis in Down syndrome, we integrated single-cell transcriptomics of over 1.1 million cells with chromatin accessibility and spatial transcriptomics datasets using human fetal liver and bone marrow samples from 3 fetuses with disomy and 15 fetuses with trisomy. We found that differences in gene expression in Down syndrome were dependent on both cell type and environment. Furthermore, we found multiple lines of evidence that haematopoietic stem cells (HSCs) in Down syndrome are 'primed' to differentiate. We subsequently established a Down syndrome-specific map linking non-coding elements to genes in disomic and trisomic HSCs using 10X multiome data. By integrating this map with genetic variants associated with blood cell counts, we discovered that trisomy restructured regulatory interactions to dysregulate enhancer activity and gene expression critical to erythroid lineage differentiation. Furthermore, as mutations in Down syndrome display a signature of oxidative stress, we validated both increased mitochondrial mass and oxidative stress in Down syndrome, and observed that these mutations preferentially fell into regulatory regions of expressed genes in HSCs. Together, our single-cell, multi-omic resource provides a high-resolution molecular map of fetal haematopoiesis in Down syndrome and indicates significant regulatory restructuring giving rise to co-occurring haematological conditions.
Crop translational genomics applies breeding techniques based on genomic datasets to improve crops. Technological breakthroughs in the past ten years have made it possible to sequence the genomes of increasing numbers of...Crop translational genomics applies breeding techniques based on genomic datasets to improve crops. Technological breakthroughs in the past ten years have made it possible to sequence the genomes of increasing numbers of crop varieties and have assisted in the genetic dissection of crop performance. However, translating research findings to breeding applications remains challenging. Here we review recent progress and future prospects for crop translational genomics in bringing results from the laboratory to the field. Genetic mapping, genomic selection and sequence-assisted characterization and deployment of plant genetic resources utilize rapid genotyping of large populations. These approaches have all had an impact on breeding for qualitative traits, where single genes with large phenotypic effects exert their influence. Characterization of the complex genetic architectures that underlie quantitative traits such as yield and flowering time, especially in newly domesticated crops, will require further basic research, including research into regulation and interactions of genes and the integration of genomic approaches and high-throughput phenotyping, before targeted interventions can be designed. Future priorities for translation include supporting genomics-assisted breeding in low-income countries and adaptation of crops to changing environments.
SAR11 bacteria are the most abundant microorganisms in the surface ocean and have global biogeochemical importance. To thrive in their competitive oligotrophic environment, these bacteria rely heavily on solute-binding p...SAR11 bacteria are the most abundant microorganisms in the surface ocean and have global biogeochemical importance. To thrive in their competitive oligotrophic environment, these bacteria rely heavily on solute-binding proteins that facilitate uptake of specific substrates via membrane transporters. The functions and properties of these transport proteins are key factors in the assimilation of dissolved organic matter and biogeochemical cycling of nutrients in the ocean, but they have remained largely inaccessible to experimental investigation. Here we performed genome-wide experimental characterization of all solute-binding proteins in a prototypical SAR11 bacterium, revealing specific functions and general trends in their properties that contribute to the success of SAR11 bacteria in oligotrophic environments. We found that the solute-binding proteins of SAR11 bacteria have extremely high binding affinity (dissociation constant >20 pM) and high binding specificity, revealing molecular mechanisms of oligotrophic adaptation. Our functional data have uncovered new carbon sources for SAR11 bacteria and enable accurate biogeographical analysis of SAR11 substrate uptake capabilities throughout the ocean. This study provides a comprehensive view of the substrate uptake capabilities of ubiquitous marine bacteria, providing a necessary foundation for understanding their contribution to assimilation of dissolved organic matter in marine ecosystems.
Moreno-Mayar JV, Sousa da Mota B, Higham T
… +12 more, Klemm S, Gorman Edmunds M, Stenderup J, Iraeta-Orbegozo M, Laborde V, Heyer E, Torres Hochstetter F, Friess M, Allentoft ME, Schroeder H, Delaneau O, Malaspinas AS
Rapa Nui (also known as Easter Island) is one of the most isolated inhabited places in the world. It has captured the imagination of many owing to its archaeological record, which includes iconic megalithic statues calle...Rapa Nui (also known as Easter Island) is one of the most isolated inhabited places in the world. It has captured the imagination of many owing to its archaeological record, which includes iconic megalithic statues called moai. Two prominent contentions have arisen from the extensive study of Rapa Nui. First, the history of the Rapanui has been presented as a warning tale of resource overexploitation that would have culminated in a major population collapse-the 'ecocide' theory. Second, the possibility of trans-Pacific voyages to the Americas pre-dating European contact is still debated. Here, to address these questions, we reconstructed the genomic history of the Rapanui on the basis of 15 ancient Rapanui individuals that we radiocarbon dated (1670-1950 CE) and whole-genome sequenced (0.4-25.6×). We find that these individuals are Polynesian in origin and most closely related to present-day Rapanui, a finding that will contribute to repatriation efforts. Through effective population size reconstructions and extensive population genetics simulations, we reject a scenario involving a severe population bottleneck during the 1600s, as proposed by the ecocide theory. Furthermore, the ancient and present-day Rapanui carry similar proportions of Native American admixture (about 10%). Using a Bayesian approach integrating genetic and radiocarbon dates, we estimate that this admixture event occurred about 1250-1430 CE.