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      Ensembl 2023

      research-article
      , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
      Nucleic Acids Research
      Oxford University Press

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          Abstract

          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.

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          Basic local alignment search tool.

          A new approach to rapid sequence comparison, basic local alignment search tool (BLAST), directly approximates alignments that optimize a measure of local similarity, the maximal segment pair (MSP) score. Recent mathematical results on the stochastic properties of MSP scores allow an analysis of the performance of this method as well as the statistical significance of alignments it generates. The basic algorithm is simple and robust; it can be implemented in a number of ways and applied in a variety of contexts including straightforward DNA and protein sequence database searches, motif searches, gene identification searches, and in the analysis of multiple regions of similarity in long DNA sequences. In addition to its flexibility and tractability to mathematical analysis, BLAST is an order of magnitude faster than existing sequence comparison tools of comparable sensitivity.
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            Highly accurate protein structure prediction with AlphaFold

            Proteins are essential to life, and understanding their structure can facilitate a mechanistic understanding of their function. Through an enormous experimental effort 1 – 4 , the structures of around 100,000 unique proteins have been determined 5 , but this represents a small fraction of the billions of known protein sequences 6 , 7 . Structural coverage is bottlenecked by the months to years of painstaking effort required to determine a single protein structure. Accurate computational approaches are needed to address this gap and to enable large-scale structural bioinformatics. Predicting the three-dimensional structure that a protein will adopt based solely on its amino acid sequence—the structure prediction component of the ‘protein folding problem’ 8 —has been an important open research problem for more than 50 years 9 . Despite recent progress 10 – 14 , existing methods fall far short of atomic accuracy, especially when no homologous structure is available. Here we provide the first computational method that can regularly predict protein structures with atomic accuracy even in cases in which no similar structure is known. We validated an entirely redesigned version of our neural network-based model, AlphaFold, in the challenging 14th Critical Assessment of protein Structure Prediction (CASP14) 15 , demonstrating accuracy competitive with experimental structures in a majority of cases and greatly outperforming other methods. Underpinning the latest version of AlphaFold is a novel machine learning approach that incorporates physical and biological knowledge about protein structure, leveraging multi-sequence alignments, into the design of the deep learning algorithm. AlphaFold predicts protein structures with an accuracy competitive with experimental structures in the majority of cases using a novel deep learning architecture.
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              The mutational constraint spectrum quantified from variation in 141,456 humans

              Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes 1 . Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.
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                Author and article information

                Contributors
                Journal
                Nucleic Acids Res
                Nucleic Acids Res
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                06 January 2023
                01 November 2022
                01 November 2022
                : 51
                : D1
                : D933-D941
                Affiliations
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton , CB10 1SD, Cambridge, UK
                Author notes
                To whom correspondence should be addressed. Tel: +44 1223 49 44 44; Email: fergal@ 123456ebi.ac.uk
                Author information
                https://orcid.org/0000-0002-1672-050X
                https://orcid.org/0000-0002-0935-7271
                https://orcid.org/0000-0003-4894-7773
                https://orcid.org/0000-0002-0380-7171
                https://orcid.org/0000-0002-7669-2934
                https://orcid.org/0000-0002-4333-628X
                https://orcid.org/0000-0002-8350-1235
                https://orcid.org/0000-0002-7445-2419
                https://orcid.org/0000-0001-8626-2148
                https://orcid.org/0000-0002-4007-2899
                https://orcid.org/0000-0002-8886-4772
                https://orcid.org/0000-0002-3897-7955
                Article
                gkac958
                10.1093/nar/gkac958
                9825606
                36318249
                d63aff80-bfe8-46dc-abe2-182bffda9c43
                © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 October 2022
                : 06 October 2022
                : 15 September 2022
                Page count
                Pages: 9
                Funding
                Funded by: Wellcome Trust, DOI 10.13039/100010269;
                Award ID: WT222155/Z/20/Z
                Award ID: WT200990/A/16/Z
                Award ID: WT108749/Z/15/A
                Award ID: WT212925/Z/18/Z
                Award ID: WT218328/B/19/Z
                Funded by: National Institutes of Health, DOI 10.13039/100000002;
                Award ID: 2U41HG007234
                Award ID: U41HG010972
                Award ID: R01 HG010485
                Funded by: Biotechnology and Biological Sciences Research Council, DOI 10.13039/501100000268;
                Award ID: BB/W019108/1
                Award ID: BB/S020152/1
                Award ID: BB/T01461X/1
                Funded by: Open Targets;
                Funded by: British Council, DOI 10.13039/501100000308;
                Award ID: 414710385
                Funded by: European Union's Horizon 2020;
                Award ID: 733161
                Award ID: 825575
                Award ID: 817923
                Award ID: 817998
                Award ID: 815668
                Categories
                AcademicSubjects/SCI00010
                Database Issue

                Genetics
                Genetics

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