Ensembl 2024.

Ensembl (https://www.ensembl.org) is a freely available genomic resource that has produced high-quality annotations, tools, and services for vertebrates and model organisms for more than two decades. In recent years, there has been a dramatic shift in the genomic landscape, with a large increase in the number and phylogenetic breadth of high-quality reference genomes, alongside major advances in the pan-genome representations of higher species. In order to support these efforts and accelerate downstream research, Ensembl continues to focus on scaling for the rapid annotation of new genome assemblies, developing new methods for comparative analysis, and expanding the depth and quality of our genome annotations. This year we have continued our expansion to support global biodiversity research, doubling the number of annotated genomes we support on our Rapid Release site to over 1700, driven by our close collaboration with biodiversity projects such as Darwin Tree of Life. We have also strengthened support for key agricultural species, including the first regulatory builds for farmed animals, and have updated key tools and resources that support the global scientific community, notably the Ensembl Variant Effect Predictor. Ensembl data, software, and tools are freely available.

Using the live assessment to discriminate between Autism Spectrum Disorder and Disinhibited Social Engagement Disorder.

BACKGROUND: Children with Autism Spectrum Disorder (ASD) and children with Disinhibited Social Engagement Disorder (DSED) may present with similar social problems, despite differing aetiologies, resulting in diagnostic conundrums. METHODS: Thirty children: 10 with ASD, no maltreatment history, 10 with DSED and 10 typically developing children were assessed via 'gold standard' ASD assessments, including the Autism Diagnostic Observational Schedule (ADOS) and a unique unstructured observation known as the Live assessment. Live utilises a triadic interaction (2 assessors and child), playful teasing and social 'stress' scenarios to increase the social challenge. RESULTS: The ADOS supported discrimination of DSED from ASD to a degree. Where additional neurodevelopmental problems created ambiguity, the Live assessment was more supportive than the ADOS for unpicking the underlying nature of the social problems. CONCLUSION: Live supported differentiation between ASD, DSED and other neurodevelopmental problems. The greater social challenge presented by Live exacerbated core problems of ASD and, in DSED, core social skills stood out.

GENCODE: reference annotation for the human and mouse genomes in 2023.

GENCODE produces high quality gene and transcript annotation for the human and mouse genomes. All GENCODE annotation is supported by experimental data and serves as a reference for genome biology and clinical genomics. The GENCODE consortium generates targeted experimental data, develops bioinformatic tools and carries out analyses that, along with externally produced data and methods, support the identification and annotation of transcript structures and the determination of their function. Here, we present an update on the annotation of human and mouse genes, including developments in the tools, data, analyses and major collaborations which underpin this progress. For example, we report the creation of a set of non-canonical ORFs identified in GENCODE transcripts, the LRGASP collaboration to assess the use of long transcriptomic data to build transcript models, the progress in collaborations with RefSeq and UniProt to increase convergence in the annotation of human and mouse protein-coding genes, the propagation of GENCODE across the human pan-genome and the development of new tools to support annotation of regulatory features by GENCODE. Our annotation is accessible via Ensembl, the UCSC Genome Browser and https://www.gencodegenes.org.

Ensembl 2023.

Ensembl (https://www.ensembl.org) has produced high-quality genomic resources for vertebrates and model organisms for more than twenty years. During that time, our resources, services and tools have continually evolved in line with both the publicly available genome data and the downstream research and applications that utilise the Ensembl platform. In recent years we have witnessed a dramatic shift in the genomic landscape. There has been a large increase in the number of high-quality reference genomes through global biodiversity initiatives. In parallel, there have been major advances towards pangenome representations of higher species, where many alternative genome assemblies representing different breeds, cultivars, strains and haplotypes are now available. In order to support these efforts and accelerate downstream research, it is our goal at Ensembl to create high-quality annotations, tools and services for species across the tree of life. Here, we report our resources for popular reference genomes, the dramatic growth of our annotations (including haplotypes from the first human pangenome graphs), updates to the Ensembl Variant Effect Predictor (VEP), interactive protein structure predictions from AlphaFold DB, and the beta release of our new website.

A joint NCBI and EMBL-EBI transcript set for clinical genomics and research.

Comprehensive genome annotation is essential to understand the impact of clinically relevant variants. However, the absence of a standard for clinical reporting and browser display complicates the process of consistent interpretation and reporting. To address these challenges, Ensembl/GENCODE1 and RefSeq2 launched a joint initiative, the Matched Annotation from NCBI and EMBL-EBI (MANE) collaboration, to converge on human gene and transcript annotation and to jointly define a high-value set of transcripts and corresponding proteins. Here, we describe the MANE transcript sets for use as universal standards for variant reporting and browser display. The MANE Select set identifies a representative transcript for each human protein-coding gene, whereas the MANE Plus Clinical set provides additional transcripts at loci where the Select transcripts alone are not sufficient to report all currently known clinical variants. Each MANE transcript represents an exact match between the exonic sequences of an Ensembl/GENCODE transcript and its counterpart in RefSeq such that the identifiers can be used synonymously. We have now released MANE Select transcripts for 97% of human protein-coding genes, including all American College of Medical Genetics and Genomics Secondary Findings list v3.0 (ref. 3) genes. MANE transcripts are accessible from major genome browsers and key resources. Widespread adoption of these transcript sets will increase the consistency of reporting, facilitate the exchange of data regardless of the annotation source and help to streamline clinical interpretation.

Ensembl 2022.

Ensembl (https://www.ensembl.org) is unique in its flexible infrastructure for access to genomic data and annotation. It has been designed to efficiently deliver annotation at scale for all eukaryotic life, and it also provides deep comprehensive annotation for key species. Genomes representing a greater diversity of species are increasingly being sequenced. In response, we have focussed our recent efforts on expediting the annotation of new assemblies. Here, we report the release of the greatest annual number of newly annotated genomes in the history of Ensembl via our dedicated Ensembl Rapid Release platform (http://rapid.ensembl.org). We have also developed a new method to generate comparative analyses at scale for these assemblies and, for the first time, we have annotated non-vertebrate eukaryotes. Meanwhile, we continually improve, extend and update the annotation for our high-value reference vertebrate genomes and report the details here. We have a range of specific software tools for specific tasks, such as the Ensembl Variant Effect Predictor (VEP) and the newly developed interface for the Variant Recoder. All Ensembl data, software and tools are freely available for download and are accessible programmatically.

Ensembl 2021.

The Ensembl project (https://www.ensembl.org) annotates genomes and disseminates genomic data for vertebrate species. We create detailed and comprehensive annotation of gene structures, regulatory elements and variants, and enable comparative genomics by inferring the evolutionary history of genes and genomes. Our integrated genomic data are made available in a variety of ways, including genome browsers, search interfaces, specialist tools such as the Ensembl Variant Effect Predictor, download files and programmatic interfaces. Here, we present recent Ensembl developments including two new website portals. Ensembl Rapid Release (http://rapid.ensembl.org) is designed to provide core tools and services for genomes as soon as possible and has been deployed to support large biodiversity sequencing projects. Our SARS-CoV-2 genome browser (https://covid-19.ensembl.org) integrates our own annotation with publicly available genomic data from numerous sources to facilitate the use of genomics in the international scientific response to the COVID-19 pandemic. We also report on other updates to our annotation resources, tools and services. All Ensembl data and software are freely available without restriction.

Expert curation of the human and mouse olfactory receptor gene repertoires identifies conserved coding regions split across two exons.

BACKGROUND: Olfactory receptor (OR) genes are the largest multi-gene family in the mammalian genome, with 874 in human and 1483 loci in mouse (including pseudogenes). The expansion of the OR gene repertoire has occurred through numerous duplication events followed by diversification, resulting in a large number of highly similar paralogous genes. These characteristics have made the annotation of the complete OR gene repertoire a complex task. Most OR genes have been predicted in silico and are typically annotated as intronless coding sequences. RESULTS: Here we have developed an expert curation pipeline to analyse and annotate every OR gene in the human and mouse reference genomes. By combining evidence from structural features, evolutionary conservation and experimental data, we have unified the annotation of these gene families, and have systematically determined the protein-coding potential of each locus. We have defined the non-coding regions of many OR genes, enabling us to generate full-length transcript models. We found that 13 human and 41 mouse OR loci have coding sequences that are split across two exons. These split OR genes are conserved across mammals, and are expressed at the same level as protein-coding OR genes with an intronless coding region. Our findings challenge the long-standing and widespread notion that the coding region of a vertebrate OR gene is contained within a single exon. CONCLUSIONS: This work provides the most comprehensive curation effort of the human and mouse OR gene repertoires to date. The complete annotation has been integrated into the GENCODE reference gene set, for immediate availability to the research community.

Development and Examination of the Reactive Attachment Disorder and Disinhibited Social Engagement Disorder Assessment Interview.

The fifth edition of the Diagnostic and Statistical Manual (DSM) categorizes reactive attachment disorder (RAD) and disinhibited social engagement disorder (DSED) as two separate disorders, and their criteria are revised. For DSED, the core symptoms focus on abnormal social disinhibition, and symptoms regarding lack of selective attachment have been removed. The core symptoms of RAD are the absence of attachment behaviors and emotional dysregulation. In this study, an international team of researchers modified the Child and Adolescent Psychiatric Assessment for RAD to update it from DSM-IV to DSM-5 criteria for RAD and DSED. We renamed the interview the reactive attachment disorder and disinhibited social engagement disorder assessment (RADA). Foster parents of 320 young people aged 11 to 17 years completed the RADA online. Confirmatory factor analysis of RADA items identified good fit for a three-factor model, with one factor comprising DSED items (indiscriminate behaviors with strangers) and two factors comprising RAD items (RAD1: failure to seek/accept comfort, and RAD2: withdrawal/hypervigilance). The three factors showed differential associations with clinical symptoms of emotional and social impairment. Time in foster care was not associated with scores on RAD1, RAD2, or DSED. Higher age was associated with lower scores on DSED, and higher scores on RAD1.

Ensembl 2020.

The Ensembl (https://www.ensembl.org) is a system for generating and distributing genome annotation such as genes, variation, regulation and comparative genomics across the vertebrate subphylum and key model organisms. The Ensembl annotation pipeline is capable of integrating experimental and reference data from multiple providers into a single integrated resource. Here, we present 94 newly annotated and re-annotated genomes, bringing the total number of genomes offered by Ensembl to 227. This represents the single largest expansion of the resource since its inception. We also detail our continued efforts to improve human annotation, developments in our epigenome analysis and display, a new tool for imputing causal genes from genome-wide association studies and visualisation of variation within a 3D protein model. Finally, we present information on our new website. Both software and data are made available without restriction via our website, online tools platform and programmatic interfaces (available under an Apache 2.0 license) and data updates made available four times a year.

Discovery of high-confidence human protein-coding genes and exons by whole-genome PhyloCSF helps elucidate 118 GWAS loci.

The most widely appreciated role of DNA is to encode protein, yet the exact portion of the human genome that is translated remains to be ascertained. We previously developed PhyloCSF, a widely used tool to identify evolutionary signatures of protein-coding regions using multispecies genome alignments. Here, we present the first whole-genome PhyloCSF prediction tracks for human, mouse, chicken, fly, worm, and mosquito. We develop a workflow that uses machine learning to predict novel conserved protein-coding regions and efficiently guide their manual curation. We analyze more than 1000 high-scoring human PhyloCSF regions and confidently add 144 conserved protein-coding genes to the GENCODE gene set, as well as additional coding regions within 236 previously annotated protein-coding genes, and 169 pseudogenes, most of them disabled after primates diverged. The majority of these represent new discoveries, including 70 previously undetected protein-coding genes. The novel coding genes are additionally supported by single-nucleotide variant evidence indicative of continued purifying selection in the human lineage, coding-exon splicing evidence from new GENCODE transcripts using next-generation transcriptomic data sets, and mass spectrometry evidence of translation for several new genes. Our discoveries required simultaneous comparative annotation of other vertebrate genomes, which we show is essential to remove spurious ORFs and to distinguish coding from pseudogene regions. Our new coding regions help elucidate disease-associated regions by revealing that 118 GWAS variants previously thought to be noncoding are in fact protein altering. Altogether, our PhyloCSF data sets and algorithms will help researchers seeking to interpret these genomes, while our new annotations present exciting loci for further experimental characterization.

Ensembl 2019.

The Ensembl project (https://www.ensembl.org) makes key genomic data sets available to the entire scientific community without restrictions. Ensembl seeks to be a fundamental resource driving scientific progress by creating, maintaining and updating reference genome annotation and comparative genomics resources. This year we describe our new and expanded gene, variant and comparative annotation capabilities, which led to a 50% increase in the number of vertebrate genomes we support. We have also doubled the number of available human variants and added regulatory regions for many mouse cell types and developmental stages. Our data sets and tools are available via the Ensembl website as well as a through a RESTful webservice, Perl application programming interface and as data files for download.

IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients.

PURPOSE: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences. METHODS: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms. RESULTS: IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments. CONCLUSION: This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.

Correction: IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.

Consensus coding sequence (CCDS) database: a standardized set of human and mouse protein-coding regions supported by expert curation.

The Consensus Coding Sequence (CCDS) project provides a dataset of protein-coding regions that are identically annotated on the human and mouse reference genome assembly in genome annotations produced independently by NCBI and the Ensembl group at EMBL-EBI. This dataset is the product of an international collaboration that includes NCBI, Ensembl, HUGO Gene Nomenclature Committee, Mouse Genome Informatics and University of California, Santa Cruz. Identically annotated coding regions, which are generated using an automated pipeline and pass multiple quality assurance checks, are assigned a stable and tracked identifier (CCDS ID). Additionally, coordinated manual review by expert curators from the CCDS collaboration helps in maintaining the integrity and high quality of the dataset. The CCDS data are available through an interactive web page (https://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi) and an FTP site (ftp://ftp.ncbi.nlm.nih.gov/pub/CCDS/). In this paper, we outline the ongoing work, growth and stability of the CCDS dataset and provide updates on new collaboration members and new features added to the CCDS user interface. We also present expert curation scenarios, with specific examples highlighting the importance of an accurate reference genome assembly and the crucial role played by input from the research community.

Association between Reactive Attachment Disorder/Disinhibited Social Engagement Disorder and Emerging Personality Disorder: A Feasibility Study.

A systematic review of reactive attachment disorder (RAD)/disinhibited social engagement disorder (DSED) in adolescence highlighted that young people with the disorder had indiscriminate friendliness with difficulties in establishing and maintaining stable relationships. Most reported experiences of rejection. We were struck by similarities between the above and features of emergence of personality disorders (EPD). This feasibility study aimed to determine best ways of recruiting and retaining vulnerable young people and the proportion of participants with RAD/DSED who might have emerging borderline personality disorder (EBPD). Participants were referred to the study by their treating clinicians from local mental health teams. Results showed strong association between RAD/DSED and EBPD. Participant characteristics showed high levels of out of home placements, early termination of school careers, suicide attempts, quasipsychotic symptoms, and multiagency involvements. They experienced the project as an opportunity to talk about relationships and reported that they would like more of this in usual clinical contacts. They all agreed to be contacted for future studies. Previous studies have shown that early detection and treatment of emergent personality traits can alter trajectory. Future research will continue to explore these trajectories, explore detection of vulnerability factors, and evaluate interventions.

Challenges of Assessing Maltreated Children Coming into Foster Care.

Children who have experienced early adversity have been known to be at risk of developing cognitive, attachment, and mental health problems; therefore, it is crucial that children entering foster care can be properly assessed as early as possible. There are known difficulties in assessing children in foster care, for example, in finding a reliable informant. An ongoing randomised controlled trial in Glasgow, Scotland, recruiting infants entering foster care, provides a unique opportunity to explore some of the issues which need to be considered when assessing these children. The assessment data of 70 infants entering care is described while exploring the reliability of foster carers as informants and the importance of infant engagement with tasks. This group of infants was shown to be having more problems than children from the general population. While correlations were found between a carer's level of concern about a child and the severity of a child's problem, there were still a number of children displaying worrying problem scores whom foster carers did not report concern. The child's engagement in the cognitive task showed associations with the child's attainment on the task. Findings emphasise the importance of a holistic assessment for these children and all should be considered as potential cases with Maltreatment-Associated Psychiatric Problems (MAPP).

Social relationship difficulties in autism and reactive attachment disorder: Improving diagnostic validity through structured assessment.

BACKGROUND: Autism Spectrum Disorder (ASD) versus Reactive Attachment Disorder (RAD) is a common diagnostic challenge for clinicians due to overlapping difficulties with social relationships. RAD is associated with neglect or maltreatment whereas ASD is not: accurate differential diagnosis is therefore critical. Very little research has investigated the relationship between the two, and it is unknown if standardised measures are able to discriminate between ASD and RAD. The current study aimed to address these issues. METHODS: Fifty eight children with ASD, and no history of maltreatment, were group matched on age with 67 children with RAD. Group profiles on multi-informant measures of RAD were investigated and group differences explored. Discriminant function analysis determined assessment features that best discriminated between the two groups. RESULTS: Although, according to parent report, children with ASD presented with significantly fewer indiscriminate friendliness behaviours compared to the RAD group (p<0.001), 36 children with ASD appeared to meet core RAD criteria. However, structured observation clearly demonstrated that features were indicative of ASD and not RAD for all but 1 of these 36 children. CONCLUSIONS: Children with RAD and children with ASD may demonstrate similar social relationship difficulties but there appears to be a difference in the social quality of the interactions between the groups. In most cases it was possible to differentiate between children with ASD and children with RAD via structured observation. Nevertheless, for a small proportion of children with ASD, particularly those whose difficulties may be more subtle, our current standardised measures, including structured observation, may not be effective in differentiating RAD from ASD.

Reactive attachment disorder in the general population: a hidden ESSENCE disorder.

Reactive attachment disorder (RAD) is a severe disorder of social functioning. Previous research has shown that children with RAD may have poor cognitive and language abilities; however, findings mainly come from biased, institutionalised samples. This paper describes the characteristics of all children who were given a suspected or likely diagnosis of reactive attachment disorder in an epidemiological study of approximately 1,600 children investigating the prevalence of RAD in the general population. We found that children with RAD are more likely to have multiple comorbidities with other disorders, lower IQs than population norms, more disorganised attachment, more problem behaviours, and poorer social skills than would be found in the general population and therefore have a complex presentation than can be described as ESSENCE. We discuss the clinical and educational implications.