RESUMO
The Open Targets Platform (https://www.targetvalidation.org/) provides users with a queryable knowledgebase and user interface to aid systematic target identification and prioritisation for drug discovery based upon underlying evidence. It is publicly available and the underlying code is open source. Since our last update two years ago, we have had 10 releases to maintain and continuously improve evidence for target-disease relationships from 20 different data sources. In addition, we have integrated new evidence from key datasets, including prioritised targets identified from genome-wide CRISPR knockout screens in 300 cancer models (Project Score), and GWAS/UK BioBank statistical genetic analysis evidence from the Open Targets Genetics Portal. We have evolved our evidence scoring framework to improve target identification. To aid the prioritisation of targets and inform on the potential impact of modulating a given target, we have added evaluation of post-marketing adverse drug reactions and new curated information on target tractability and safety. We have also developed the user interface and backend technologies to improve performance and usability. In this article, we describe the latest enhancements to the Platform, to address the fundamental challenge that developing effective and safe drugs is difficult and expensive.
Assuntos
Antineoplásicos/uso terapêutico , Drogas em Investigação/uso terapêutico , Bases de Conhecimento , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Software , Antineoplásicos/química , Bases de Dados Factuais , Conjuntos de Dados como Assunto , Descoberta de Drogas/métodos , Drogas em Investigação/química , Humanos , Internet , Neoplasias/classificação , Neoplasias/genética , Neoplasias/patologiaRESUMO
CRISPR genetic screens in cancer cell models are a powerful tool to elucidate oncogenic mechanisms and to identify promising therapeutic targets. The Project Score database (https://score.depmap.sanger.ac.uk/) uses genome-wide CRISPR-Cas9 dropout screening data in hundreds of highly annotated cancer cell models to identify genes required for cell fitness and prioritize novel oncology targets. The Project Score database currently allows users to investigate the fitness effect of 18 009 genes tested across 323 cancer cell models. Through interactive interfaces, users can investigate data by selecting a specific gene, cancer cell model or tissue type, as well as browsing all gene fitness scores. Additionally, users can identify and rank candidate drug targets based on an established oncology target prioritization pipeline, incorporating genetic biomarkers and clinical datasets for each target, and including suitability for drug development based on pharmaceutical tractability. Data are freely available and downloadable. To enhance analyses, links to other key resources including Open Targets, COSMIC, the Cell Model Passports, UniProt and the Genomics of Drug Sensitivity in Cancer are provided. The Project Score database is a valuable new tool for investigating genetic dependencies in cancer cells and the identification of candidate oncology targets.
Assuntos
Biomarcadores Tumorais/genética , Bases de Dados Factuais , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Neoplasias/genética , Software , Antineoplásicos/uso terapêutico , Sistemas CRISPR-Cas , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Aptidão Genética , Humanos , Internet , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , OncogenesRESUMO
SUMMARY: The evolutionary history of gene families can be complex due to duplications and losses. This complexity is compounded by the large number of genomes simultaneously considered in contemporary comparative genomic analyses. As provided by several orthology databases, hierarchical orthologous groups (HOGs) are sets of genes that are inferred to have descended from a common ancestral gene within a species clade. This implies that the set of HOGs defined for a particular clade correspond to the ancestral genes found in its last common ancestor. Furthermore, by keeping track of HOG composition along the species tree, it is possible to infer the emergence, duplications and losses of genes within a gene family of interest. However, the lack of tools to manipulate and analyse HOGs has made it difficult to extract, display and interpret this type of information. To address this, we introduce interactive HOG analysis method, an interactive JavaScript widget to visualize and explore gene family history encoded in HOGs and python HOG analysis method, a python library for programmatic processing of genes families. These complementary open source tools greatly ease adoption of HOGs as a scalable and interpretable concept to relate genes across multiple species. AVAILABILITY AND IMPLEMENTATION: iHam's code is available at https://github.com/DessimozLab/iHam or can be loaded dynamically. pyHam's code is available at https://github.com/DessimozLab/pyHam and or via the pip package 'pyham'.
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Software , Evolução Biológica , GenomaRESUMO
The Open Targets Platform integrates evidence from genetics, genomics, transcriptomics, drugs, animal models and scientific literature to score and rank target-disease associations for drug target identification. The associations are displayed in an intuitive user interface (https://www.targetvalidation.org), and are available through a REST-API (https://api.opentargets.io/v3/platform/docs/swagger-ui) and a bulk download (https://www.targetvalidation.org/downloads/data). In addition to target-disease associations, we also aggregate and display data at the target and disease levels to aid target prioritisation. Since our first publication two years ago, we have made eight releases, added new data sources for target-disease associations, started including causal genetic variants from non genome-wide targeted arrays, added new target and disease annotations, launched new visualisations and improved existing ones and released a new web tool for batch search of up to 200 targets. We have a new URL for the Open Targets Platform REST-API, new REST endpoints and also removed the need for authorisation for API fair use. Here, we present the latest developments of the Open Targets Platform, expanding the evidence and target-disease associations with new and improved data sources, refining data quality, enhancing website usability, and increasing our user base with our training workshops, user support, social media and bioinformatics forum engagement.
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Biologia Computacional/métodos , Bases de Dados Genéticas , Genômica/métodos , Armazenamento e Recuperação da Informação/métodos , Terapia de Alvo Molecular/métodos , Biologia Computacional/tendências , Perfilação da Expressão Gênica/métodos , Genômica/tendências , Humanos , Armazenamento e Recuperação da Informação/tendências , Internet , Reprodutibilidade dos Testes , SoftwareRESUMO
We discuss how we designed the Open Targets Platform (www.targetvalidation.org), an intuitive application for bench scientists working in early drug discovery. To meet the needs of our users, we applied lean user experience (UX) design methods: we started engaging with users very early and carried out research, design and evaluation activities within an iterative development process. We also emphasize the collaborative nature of applying lean UX design, which we believe is a foundation for success in this and many other scientific projects.
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Descoberta de Drogas , Internet , Comportamento Cooperativo , Humanos , PesquisadoresRESUMO
Transcriptional dysregulation induced by aberrant transcription factors (TF) is a key feature of cancer, but its global influence on drug sensitivity has not been examined. Here, we infer the transcriptional activity of 127 TFs through analysis of RNA-seq gene expression data newly generated for 448 cancer cell lines, combined with publicly available datasets to survey a total of 1,056 cancer cell lines and 9,250 primary tumors. Predicted TF activities are supported by their agreement with independent shRNA essentiality profiles and homozygous gene deletions, and recapitulate mutant-specific mechanisms of transcriptional dysregulation in cancer. By analyzing cell line responses to 265 compounds, we uncovered numerous TFs whose activity interacts with anticancer drugs. Importantly, combining existing pharmacogenomic markers with TF activities often improves the stratification of cell lines in response to drug treatment. Our results, which can be queried freely at dorothea.opentargets.io, offer a broad foundation for discovering opportunities to refine personalized cancer therapies.Significance: Systematic analysis of transcriptional dysregulation in cancer cell lines and patient tumor specimens offers a publicly searchable foundation to discover new opportunities to refine personalized cancer therapies. Cancer Res; 78(3); 769-80. ©2017 AACR.
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Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Farmacogenética , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição/genética , Apoptose , Proliferação de Células , Humanos , Neoplasias/genética , Neoplasias/patologia , Fatores de Transcrição/metabolismo , Células Tumorais CultivadasRESUMO
We have designed and developed a data integration and visualization platform that provides evidence about the association of known and potential drug targets with diseases. The platform is designed to support identification and prioritization of biological targets for follow-up. Each drug target is linked to a disease using integrated genome-wide data from a broad range of data sources. The platform provides either a target-centric workflow to identify diseases that may be associated with a specific target, or a disease-centric workflow to identify targets that may be associated with a specific disease. Users can easily transition between these target- and disease-centric workflows. The Open Targets Validation Platform is accessible at https://www.targetvalidation.org.
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Biologia Computacional/métodos , Terapia de Alvo Molecular , Ferramenta de Busca , Software , Bases de Dados Factuais , Humanos , Terapia de Alvo Molecular/métodos , Reprodutibilidade dos Testes , Navegador , Fluxo de TrabalhoRESUMO
UNLABELLED: There is an increasing need for rich and dynamic biological data visualizations in bioinformatic web applications. New standards in web technologies, like SVG or Canvas, are now supported by most modern web browsers allowing the blossoming of powerful visualizations in biological data analysis. The exploration of different ways to visualize genomic data is still challenging due to the lack of flexible tools to develop them. Here, I present a set of libraries aimed at creating powerful tree- and track-based visualizations for the web. Its modularity and rich API facilitate the development of many different visualizations ranging from simple species trees to complex visualizations comprising per-node data annotations or even simple genome browsers. AVAILABILITY AND IMPLEMENTATION: The TnT libraries have been written in Javascript, licensed under the APACHE 2.0 license and hosted at https://github.com/tntvis CONTACT: mp@ebi.ac.uk.
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Biologia Computacional , Curadoria de Dados , Navegador , Gráficos por Computador , Genômica , Internet , SoftwareRESUMO
Annotation of orthologous and paralogous genes is necessary for many aspects of evolutionary analysis. Methods to infer these homology relationships have traditionally focused on protein-coding genes and evolutionary models used by these methods normally assume the positions in the protein evolve independently. However, as our appreciation for the roles of non-coding RNA genes has increased, consistently annotated sets of orthologous and paralogous ncRNA genes are increasingly needed. At the same time, methods such as PHASE or RAxML have implemented substitution models that consider pairs of sites to enable proper modelling of the loops and other features of RNA secondary structure. Here, we present a comprehensive analysis pipeline for the automatic detection of orthologues and paralogues for ncRNA genes. We focus on gene families represented in Rfam and for which a specific covariance model is provided. For each family ncRNA genes found in all Ensembl species are aligned using Infernal, and several trees are built using different substitution models. In parallel, a genomic alignment that includes the ncRNA genes and their flanking sequence regions is built with PRANK. This alignment is used to create two additional phylogenetic trees using the neighbour-joining (NJ) and maximum-likelihood (ML) methods. The trees arising from both the ncRNA and genomic alignments are merged using TreeBeST, which reconciles them with the species tree in order to identify speciation and duplication events. The final tree is used to infer the orthologues and paralogues following Fitch's definition. We also determine gene gain and loss events for each family using CAFE. All data are accessible through the Ensembl Comparative Genomics ('Compara') API, on our FTP site and are fully integrated in the Ensembl genome browser, where they can be accessed in a user-friendly manner. Database URL: http://www.ensembl.org.
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Biologia Computacional/métodos , RNA não Traduzido/genética , Vertebrados/genética , Algoritmos , Animais , Ciona intestinalis , Ciprinodontiformes , Evolução Molecular , Variação Genética , Genoma , Genômica , Humanos , Funções Verossimilhança , Camundongos , Conformação de Ácido Nucleico , Fases de Leitura Aberta , Filogenia , Ratos , Peixe-ZebraRESUMO
Evolution provides the unifying framework with which to understand biology. The coherent investigation of genic and genomic data often requires comparative genomics analyses based on whole-genome alignments, sets of homologous genes and other relevant datasets in order to evaluate and answer evolutionary-related questions. However, the complexity and computational requirements of producing such data are substantial: this has led to only a small number of reference resources that are used for most comparative analyses. The Ensembl comparative genomics resources are one such reference set that facilitates comprehensive and reproducible analysis of chordate genome data. Ensembl computes pairwise and multiple whole-genome alignments from which large-scale synteny, per-base conservation scores and constrained elements are obtained. Gene alignments are used to define Ensembl Protein Families, GeneTrees and homologies for both protein-coding and non-coding RNA genes. These resources are updated frequently and have a consistent informatics infrastructure and data presentation across all supported species. Specialized web-based visualizations are also available including synteny displays, collapsible gene tree plots, a gene family locator and different alignment views. The Ensembl comparative genomics infrastructure is extensively reused for the analysis of non-vertebrate species by other projects including Ensembl Genomes and Gramene and much of the information here is relevant to these projects. The consistency of the annotation across species and the focus on vertebrates makes Ensembl an ideal system to perform and support vertebrate comparative genomic analyses. We use robust software and pipelines to produce reference comparative data and make it freely available. Database URL: http://www.ensembl.org.
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Biologia Computacional/métodos , Genoma , Genômica , Algoritmos , Animais , DNA Complementar/genética , Bases de Dados Genéticas , Evolução Molecular , Etiquetas de Sequências Expressas , Humanos , Filogenia , Controle de Qualidade , RNA não Traduzido/genética , Alinhamento de Sequência , Análise de Sequência de RNA , SoftwareRESUMO
The Ensembl project (http://www.ensembl.org) is a system for genome annotation, analysis, storage and dissemination designed to facilitate the access of genomic annotation from chordates and key model organisms. It provides access to data from 87 species across our main and early access Pre! websites. This year we introduced three newly annotated species and released numerous updates across our supported species with a concentration on data for the latest genome assemblies of human, mouse, zebrafish and rat. We also provided two data updates for the previous human assembly, GRCh37, through a dedicated website (http://grch37.ensembl.org). Our tools, in particular the VEP, have been improved significantly through integration of additional third party data. REST is now capable of larger-scale analysis and our regulatory data BioMart can deliver faster results. The website is now capable of displaying long-range interactions such as those found in cis-regulated datasets. Finally we have launched a website optimized for mobile devices providing views of genes, variants and phenotypes. Our data is made available without restriction and all code is available from our GitHub organization site (http://github.com/Ensembl) under an Apache 2.0 license.
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Bases de Dados Genéticas , Genômica , Anotação de Sequência Molecular , Animais , Genes , Variação Genética , Humanos , Internet , Camundongos , Proteínas/genética , Ratos , Sequências Reguladoras de Ácido Nucleico , SoftwareRESUMO
The mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understanding of regulatory evolution in mammals. Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation. We report that rapid evolution of enhancers is a universal feature of mammalian genomes. Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather than lineage-specific expansions of repeat elements. In contrast, almost all liver promoters are partially or fully conserved across these species. Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annotating regulatory adaptations in genomic sequences. These results provide important insight into the functional genetics underpinning mammalian regulatory evolution.
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Elementos Facilitadores Genéticos , Evolução Molecular , Fígado/metabolismo , Mamíferos/classificação , Mamíferos/genética , Regiões Promotoras Genéticas , Animais , Código das Histonas , Humanos , Fatores de Transcrição/metabolismoRESUMO
MOTIVATION: We present a Web service to access Ensembl data using Representational State Transfer (REST). The Ensembl REST server enables the easy retrieval of a wide range of Ensembl data by most programming languages, using standard formats such as JSON and FASTA while minimizing client work. We also introduce bindings to the popular Ensembl Variant Effect Predictor tool permitting large-scale programmatic variant analysis independent of any specific programming language. AVAILABILITY AND IMPLEMENTATION: The Ensembl REST API can be accessed at http://rest.ensembl.org and source code is freely available under an Apache 2.0 license from http://github.com/Ensembl/ensembl-rest.
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Biologia Computacional/métodos , Bases de Dados Factuais , Linguagens de Programação , Software , Variação Genética , Genômica , HumanosRESUMO
Ensembl (http://www.ensembl.org) is a genomic interpretation system providing the most up-to-date annotations, querying tools and access methods for chordates and key model organisms. This year we released updated annotation (gene models, comparative genomics, regulatory regions and variation) on the new human assembly, GRCh38, although we continue to support researchers using the GRCh37.p13 assembly through a dedicated site (http://grch37.ensembl.org). Our Regulatory Build has been revamped to identify regulatory regions of interest and to efficiently highlight their activity across disparate epigenetic data sets. A number of new interfaces allow users to perform large-scale comparisons of their data against our annotations. The REST server (http://rest.ensembl.org), which allows programs written in any language to query our databases, has moved to a full service alongside our upgraded website tools. Our online Variant Effect Predictor tool has been updated to process more variants and calculate summary statistics. Lastly, the WiggleTools package enables users to summarize large collections of data sets and view them as single tracks in Ensembl. The Ensembl code base itself is more accessible: it is now hosted on our GitHub organization page (https://github.com/Ensembl) under an Apache 2.0 open source license.
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Bases de Dados de Ácidos Nucleicos , Genômica , Animais , Epigênese Genética , Variação Genética , Genoma Humano , Humanos , Internet , Camundongos , Anotação de Sequência Molecular , Sequências Reguladoras de Ácido Nucleico , SoftwareRESUMO
BACKGROUND: The main limitations in the analysis of viral metagenomes are perhaps the high genetic variability and the lack of information in extant databases. To address these issues, several bioinformatic tools have been specifically designed or adapted for metagenomics by improving read assembly and creating more sensitive methods for homology detection. This study compares the performance of different available assemblers and taxonomic annotation software using simulated viral-metagenomic data. RESULTS: We simulated two 454 viral metagenomes using genomes from NCBI's RefSeq database based on the list of actual viruses found in previously published metagenomes. Three different assembly strategies, spanning six assemblers, were tested for performance: overlap-layout-consensus algorithms Newbler, Celera and Minimo; de Bruijn graphs algorithms Velvet and MetaVelvet; and read probabilistic model Genovo. The performance of the assemblies was measured by the length of resulting contigs (using N50), the percentage of reads assembled and the overall accuracy when comparing against corresponding reference genomes. Additionally, the number of chimeras per contig and the lowest common ancestor were estimated in order to assess the effect of assembling on taxonomic and functional annotation. The functional classification of the reads was evaluated by counting the reads that correctly matched the functional data previously reported for the original genomes and calculating the number of over-represented functional categories in chimeric contigs. The sensitivity and specificity of tBLASTx, PhymmBL and the k-mer frequencies were measured by accurate predictions when comparing simulated reads against the NCBI Virus genomes RefSeq database. CONCLUSIONS: Assembling improves functional annotation by increasing accurate assignations and decreasing ambiguous hits between viruses and bacteria. However, the success is limited by the chimeric contigs occurring at all taxonomic levels. The assembler and its parameters should be selected based on the focus of each study. Minimo's non-chimeric contigs and Genovo's long contigs excelled in taxonomy assignation and functional annotation, respectively.tBLASTx stood out as the best approach for taxonomic annotation for virus identification. PhymmBL proved useful in datasets in which no related sequences are present as it uses genomic features that may help identify distant taxa. The k-frequencies underperformed in all viral datasets.
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Algoritmos , Biologia Computacional/métodos , Bases de Dados Genéticas , Intestinos/virologia , Metagenômica , Vírus/genética , Bactérias/classificação , Bactérias/genética , Análise por Conglomerados , Biologia Computacional/normas , Simulação por Computador , Mapeamento de Sequências Contíguas , Humanos , Internet , Intestinos/microbiologia , Análise de Componente Principal , Interface Usuário-Computador , Vírus/classificaçãoRESUMO
Ensembl (http://www.ensembl.org) creates tools and data resources to facilitate genomic analysis in chordate species with an emphasis on human, major vertebrate model organisms and farm animals. Over the past year we have increased the number of species that we support to 77 and expanded our genome browser with a new scrollable overview and improved variation and phenotype views. We also report updates to our core datasets and improvements to our gene homology relationships from the addition of new species. Our REST service has been extended with additional support for comparative genomics and ontology information. Finally, we provide updated information about our methods for data access and resources for user training.
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Bases de Dados Genéticas , Genômica , Animais , Cordados/genética , Variação Genética , Humanos , Internet , Camundongos , Anotação de Sequência Molecular , Fenótipo , RatosRESUMO
TreeFam (http://www.treefam.org) is a database of phylogenetic trees inferred from animal genomes. For every TreeFam family we provide homology predictions together with the evolutionary history of the genes. Here we describe an update of the TreeFam database. The TreeFam project was resurrected in 2012 and has seen two releases since. The latest release (TreeFam 9) was made available in March 2013. It has orthology predictions and gene trees for 109 species in 15,736 families covering â¼2.2 million sequences. With release 9 we made modifications to our production pipeline and redesigned our website with improved gene tree visualizations and Wikipedia integration. Furthermore, we now provide an HMM-based sequence search that places a user-provided protein sequence into a TreeFam gene tree and provides quick orthology prediction. The tool uses Mafft and RAxML for the fast insertion into a reference alignment and tree, respectively. Besides the aforementioned technical improvements, we present a new approach to visualize gene trees and alternative displays that focuses on showing homology information from a species tree point of view. From release 9 onwards, TreeFam is now hosted at the EBI.
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Bases de Dados Genéticas , Família Multigênica , Filogenia , Animais , Genoma , InternetRESUMO
The unique anatomical features of turtles have raised unanswered questions about the origin of their unique body plan. We generated and analyzed draft genomes of the soft-shell turtle (Pelodiscus sinensis) and the green sea turtle (Chelonia mydas); our results indicated the close relationship of the turtles to the bird-crocodilian lineage, from which they split â¼267.9-248.3 million years ago (Upper Permian to Triassic). We also found extensive expansion of olfactory receptor genes in these turtles. Embryonic gene expression analysis identified an hourglass-like divergence of turtle and chicken embryogenesis, with maximal conservation around the vertebrate phylotypic period, rather than at later stages that show the amniote-common pattern. Wnt5a expression was found in the growth zone of the dorsal shell, supporting the possible co-option of limb-associated Wnt signaling in the acquisition of this turtle-specific novelty. Our results suggest that turtle evolution was accompanied by an unexpectedly conservative vertebrate phylotypic period, followed by turtle-specific repatterning of development to yield the novel structure of the shell.
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Tartarugas/genética , Exoesqueleto/metabolismo , Animais , Padronização Corporal/genética , Embrião de Galinha , Galinhas/genética , Desenvolvimento Embrionário/genética , Evolução Molecular , Regulação da Expressão Gênica no Desenvolvimento , Genoma , MicroRNAs/genética , MicroRNAs/metabolismo , Anotação de Sequência Molecular , Dados de Sequência Molecular , Filogenia , Receptores Odorantes/genética , Proteínas de Répteis/genética , Proteínas de Répteis/metabolismo , Análise de Sequência de DNA , Transcriptoma , Tartarugas/embriologia , Proteínas Wnt/genética , Proteínas Wnt/metabolismoRESUMO
Lampreys are representatives of an ancient vertebrate lineage that diverged from our own â¼500 million years ago. By virtue of this deeply shared ancestry, the sea lamprey (P. marinus) genome is uniquely poised to provide insight into the ancestry of vertebrate genomes and the underlying principles of vertebrate biology. Here, we present the first lamprey whole-genome sequence and assembly. We note challenges faced owing to its high content of repetitive elements and GC bases, as well as the absence of broad-scale sequence information from closely related species. Analyses of the assembly indicate that two whole-genome duplications likely occurred before the divergence of ancestral lamprey and gnathostome lineages. Moreover, the results help define key evolutionary events within vertebrate lineages, including the origin of myelin-associated proteins and the development of appendages. The lamprey genome provides an important resource for reconstructing vertebrate origins and the evolutionary events that have shaped the genomes of extant organisms.