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Article ; Online: SCN1A: bioinformatically informed revised boundaries for promoter and enhancer regions.

Pagni, Susanna / Custodio, Helena Martins / Frankish, Adam / Mudge, Jonathan M / Mills, James D / Sisodiya, Sanjay M

2024 Volume 32, Issue 10, Page(s) 1753–1763

Abstract: Pathogenic variations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene are responsible for multiple epilepsy phenotypes, including Dravet syndrome, febrile seizures (FS) and genetic epilepsy with FS plus. Phenotypic heterogeneity is a ... ...

Abstract	Pathogenic variations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene are responsible for multiple epilepsy phenotypes, including Dravet syndrome, febrile seizures (FS) and genetic epilepsy with FS plus. Phenotypic heterogeneity is a hallmark of SCN1A-related epilepsies, the causes of which are yet to be clarified. Genetic variation in the non-coding regulatory regions of SCN1A could be one potential causal factor. However, a comprehensive understanding of the SCN1A regulatory landscape is currently lacking. Here, we summarized the current state of knowledge of SCN1A regulation, providing details on its promoter and enhancer regions. We then integrated currently available data on SCN1A promoters by extracting information related to the SCN1A locus from genome-wide repositories and clearly defined the promoter and enhancer regions of SCN1A. Further, we explored the cellular specificity of differential SCN1A promoter usage. We also reviewed and integrated the available human brain-derived enhancer databases and mouse-derived data to provide a comprehensive computationally developed summary of SCN1A brain-active enhancers. By querying genome-wide data repositories, extracting SCN1A-specific data and integrating the different types of independent evidence, we created a comprehensive catalogue that better defines the regulatory landscape of SCN1A, which could be used to explore the role of SCN1A regulatory regions in disease.
MeSH term(s)	Humans ; Mice ; Animals ; NAV1.1 Voltage-Gated Sodium Channel/genetics ; Epilepsies, Myoclonic/genetics ; Epilepsy/genetics ; Promoter Regions, Genetic ; Phenotype ; Seizures, Febrile/genetics ; Mutation
Chemical Substances	NAV1.1 Voltage-Gated Sodium Channel ; SCN1A protein, human ; Scn1a protein, mouse
Language	English
Publishing date	2024-04-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddad015
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Zs.A 3469: Show issues

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Article ; Online: Progress, Challenges, and Surprises in Annotating the Human Genome.

Zerbino, Daniel R / Frankish, Adam / Flicek, Paul

Annual review of genomics and human genetics

2020 Volume 21, Page(s) 55–79

Abstract: Our understanding of the human genome has continuously expanded since its draft publication in 2001. Over the years, novel assays have allowed us to progressively overlay layers of knowledge above the raw sequence of A's, T's, G's, and C's. The reference ...

Abstract	Our understanding of the human genome has continuously expanded since its draft publication in 2001. Over the years, novel assays have allowed us to progressively overlay layers of knowledge above the raw sequence of A's, T's, G's, and C's. The reference human genome sequence is now a complex knowledge base maintained under the shared stewardship of multiple specialist communities. Its complexity stems from the fact that it is simultaneously a template for transcription, a record of evolution, a vehicle for genetics, and a functional molecule. In short, the human genome serves as a frame of reference at the intersection of a diversity of scientific fields. In recent years, the progressive fall in sequencing costs has given increasing importance to the quality of the human reference genome, as hundreds of thousands of individuals are being sequenced yearly, often for clinical applications. Also, novel sequencing-based assays shed light on novel functions of the genome, especially with respect to gene expression regulation. Keeping the human genome annotation up to date and accurate is therefore an ongoing partnership between reference annotation projects and the greater community worldwide.
MeSH term(s)	Genome, Human ; Humans ; Molecular Sequence Annotation/methods ; Molecular Sequence Annotation/standards
Language	English
Publishing date	2020-05-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2037670-4
ISSN	1545-293X ; 1527-8204
ISSN (online)	1545-293X
ISSN	1527-8204
DOI	10.1146/annurev-genom-121119-083418
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Article ; Online: Non-coding regulatory elements: Potential roles in disease and the case of epilepsy.

Pagni, Susanna / Mills, James D / Frankish, Adam / Mudge, Jonathan M / Sisodiya, Sanjay M

Neuropathology and applied neurobiology

2021 Volume 48, Issue 3, Page(s) e12775

Abstract: Non-coding DNA (ncDNA) refers to the portion of the genome that does not code for proteins and accounts for the greatest physical proportion of the human genome. ncDNA includes sequences that are transcribed into RNA molecules, such as ribosomal RNAs ( ... ...

Abstract	Non-coding DNA (ncDNA) refers to the portion of the genome that does not code for proteins and accounts for the greatest physical proportion of the human genome. ncDNA includes sequences that are transcribed into RNA molecules, such as ribosomal RNAs (rRNAs), microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and un-transcribed sequences that have regulatory functions, including gene promoters and enhancers. Variation in non-coding regions of the genome have an established role in human disease, with growing evidence from many areas, including several cancers, Parkinson's disease and autism. Here, we review the features and functions of the regulatory elements that are present in the non-coding genome and the role that these regions have in human disease. We then review the existing research in epilepsy and emphasise the potential value of further exploring non-coding regulatory elements in epilepsy. In addition, we outline the most widely used techniques for recognising regulatory elements throughout the genome, current methodologies for investigating variation and the main challenges associated with research in the field of non-coding DNA.
MeSH term(s)	Epilepsy/genetics ; Genome ; Humans ; MicroRNAs/genetics ; RNA, Long Noncoding/genetics
Chemical Substances	MicroRNAs ; RNA, Long Noncoding
Language	English
Publishing date	2021-12-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80371-6
ISSN	1365-2990 ; 0305-1846
ISSN (online)	1365-2990
ISSN	0305-1846
DOI	10.1111/nan.12775
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Zs.A 1241: Show issues

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Article ; Online: GENCODE pseudogenes.

Frankish, Adam / Harrow, Jennifer

Methods in molecular biology (Clifton, N.J.)

2014 Volume 1167, Page(s) 129–155

Abstract: Historically pseudogenes were believed to represent nonfunctional genomic fossils; however, there is emerging evidence that many of them could be biologically active. This possibility has ignited interest in pseudogene loci and made the need for their ... ...

Abstract	Historically pseudogenes were believed to represent nonfunctional genomic fossils; however, there is emerging evidence that many of them could be biologically active. This possibility has ignited interest in pseudogene loci and made the need for their high-quality annotation more pressing as an accurate knowledge of all pseudogenes in the human reference genome sequence facilitates confident functional analysis. GENCODE have undertaken the first genome-wide pseudogene assignment for protein-coding genes combining both large-scale manual annotation and computational pseudogene prediction pipelines. Multiple computational predictions provide an unbiased set of hints for manual annotators to investigate, both during first-pass annotation and as part of QC to identify any potential missing pseudogene loci. Where a pseudogene is identified, the extent of its homology to the parent locus is fully investigated by a manual annotator; a pseudogene model is built and assigned to one of eight pseudogene biotypes depending on the mechanism of creation and on the presence of locus-specific transcriptional or proteomic data. The high-quality, information-rich set of pseudogenes created has been integrated with ENCODE functional genomics data, specifically expression level, transcription factor and RNA polymerase II binding, and chromatin marks. In this way we have been able to identify some pseudogenes that possess conventional characteristics of functionality as well as others with interesting patterns of partial activity, which might suggest that putatively inactive loci could be gaining a novel function, for example as long noncoding RNAs. The activity data associated with every pseudogene is stored in the psiDR resource.
MeSH term(s)	Animals ; Computational Biology/methods ; Databases, Nucleic Acid ; Genomics/methods ; Humans ; Internet ; Molecular Sequence Annotation ; Pseudogenes/genetics ; Software
Language	English
Publishing date	2014
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-0835-6_10
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Article ; Online: The value of primary transcripts to the clinical and non-clinical genomics community: Survey results and roadmap for improvements.

Morales, Joannella / McMahon, Aoife C / Loveland, Jane / Perry, Emily / Frankish, Adam / Hunt, Sarah / Armean, Irina M / Flicek, Paul / Cunningham, Fiona

Molecular genetics & genomic medicine

2021 Volume 9, Issue 12, Page(s) e1786

Abstract: Background: Variant interpretation is dependent on transcript annotation and remains time consuming and challenging. There are major obstacles for historical data reuse and for interpretation of new variants. First, both RefSeq and Ensembl/GENCODE ... ...

Abstract	Background: Variant interpretation is dependent on transcript annotation and remains time consuming and challenging. There are major obstacles for historical data reuse and for interpretation of new variants. First, both RefSeq and Ensembl/GENCODE produce transcript sets in common use, but there is currently no easy way to translate between the two. Second, the resources often used for variant interpretation (e.g. ClinVar, gnomAD, UniProt) do not use the same transcript set, nor default transcript or protein sequence. Method: Ensembl ran a survey in 2018 to sample attitudes to choosing one default transcript per locus, and to gather data on reference sequences used by the scientific community. This was publicised on the Ensembl and UCSC genome browsers, by email and on social media. Results: The survey had 788 responses from 32 different countries, the results of which we report here. Conclusions: We present our roadmap to create an effective default set of transcripts for resources, and for reporting interpretation of clinical variants.
MeSH term(s)	Animals ; Biomarkers ; Computational Biology/methods ; Databases, Genetic ; Genomics/methods ; Humans ; RNA, Messenger/genetics ; Software ; Web Browser
Chemical Substances	Biomarkers ; RNA, Messenger
Language	English
Publishing date	2021-08-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2734884-2
ISSN	2324-9269 ; 2324-9269
ISSN (online)	2324-9269
ISSN	2324-9269
DOI	10.1002/mgg3.1786
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Article: Getting the Entire Message: Progress in Isoform Sequencing.

Hardwick, Simon A / Joglekar, Anoushka / Flicek, Paul / Frankish, Adam / Tilgner, Hagen U

Frontiers in genetics

2019 Volume 10, Page(s) 709

Abstract: The advent of second-generation sequencing and its application to RNA sequencing have revolutionized the field of genomics by allowing quantification of gene expression, as well as the definition of transcription start/end sites, exons, splice sites and ... ...

Abstract	The advent of second-generation sequencing and its application to RNA sequencing have revolutionized the field of genomics by allowing quantification of gene expression, as well as the definition of transcription start/end sites, exons, splice sites and RNA editing sites. However, due to the sequencing of fragments of cDNAs, these methods have not given a reliable picture of complete RNA isoforms. Third-generation sequencing has filled this gap and allows end-to-end sequencing of entire RNA/cDNA molecules. This approach to transcriptomics has been a "niche" technology for a couple of years but now is becoming mainstream with many different applications. Here, we review the background and progress made to date in this rapidly growing field. We start by reviewing the progressive realization that alternative splicing is omnipresent. We then focus on long-noncoding RNA isoforms and the distinct combination patterns of exons in noncoding and coding genes. We consider the implications of the recent technologies of direct RNA sequencing and single-cell isoform RNA sequencing. Finally, we discuss the parameters that define the success of long-read RNA sequencing experiments and strategies commonly used to make the most of such data.
Language	English
Publishing date	2019-08-16
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2019.00709
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Article ; Online: Integrative transcriptomic analysis suggests new autoregulatory splicing events coupled with nonsense-mediated mRNA decay.

Pervouchine, Dmitri / Popov, Yaroslav / Berry, Andy / Borsari, Beatrice / Frankish, Adam / Guigó, Roderic

Nucleic acids research

2019 Volume 47, Issue 10, Page(s) 5293–5306

Abstract: Nonsense-mediated decay (NMD) is a eukaryotic mRNA surveillance system that selectively degrades transcripts with premature termination codons (PTC). Many RNA-binding proteins (RBP) regulate their expression levels by a negative feedback loop, in which ... ...

Abstract	Nonsense-mediated decay (NMD) is a eukaryotic mRNA surveillance system that selectively degrades transcripts with premature termination codons (PTC). Many RNA-binding proteins (RBP) regulate their expression levels by a negative feedback loop, in which RBP binds its own pre-mRNA and causes alternative splicing to introduce a PTC. We present a bioinformatic analysis integrating three data sources, eCLIP assays for a large RBP panel, shRNA inactivation of NMD pathway, and shRNA-depletion of RBPs followed by RNA-seq, to identify novel such autoregulatory feedback loops. We show that RBPs frequently bind their own pre-mRNAs, their exons respond prominently to NMD pathway disruption, and that the responding exons are enriched with nearby eCLIP peaks. We confirm previously proposed models of autoregulation in SRSF7 and U2AF1 genes and present two novel models, in which (i) SFPQ binds its mRNA and promotes switching to an alternative distal 3'-UTR that is targeted by NMD, and (ii) RPS3 binding activates a poison 5'-splice site in its pre-mRNA that leads to a frame shift and degradation by NMD. We also suggest specific splicing events that could be implicated in autoregulatory feedback loops in RBM39, HNRNPM, and U2AF2 genes. The results are available through a UCSC Genome Browser track hub.
MeSH term(s)	3' Untranslated Regions ; Alternative Splicing ; Codon, Nonsense ; Computational Biology ; Exons ; Frameshift Mutation ; Heterogeneous-Nuclear Ribonucleoprotein Group M/metabolism ; Humans ; Nonsense Mediated mRNA Decay ; Nuclear Proteins/metabolism ; RNA Precursors/metabolism ; RNA Splicing ; RNA, Messenger/metabolism ; RNA, Small Interfering/metabolism ; RNA-Binding Proteins/metabolism ; Serine-Arginine Splicing Factors/metabolism ; Spliceosomes ; Splicing Factor U2AF/metabolism ; Transcriptome
Chemical Substances	3' Untranslated Regions ; Codon, Nonsense ; HCC1 autoantigen ; HNRNPM protein, human ; Heterogeneous-Nuclear Ribonucleoprotein Group M ; Nuclear Proteins ; RNA Precursors ; RNA, Messenger ; RNA, Small Interfering ; RNA-Binding Proteins ; SRSF7 protein, human ; Splicing Factor U2AF ; U2AF1 protein, human ; U2AF2 protein, human ; Serine-Arginine Splicing Factors (170974-22-8)
Language	English
Publishing date	2019-03-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkz193
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Zs.A 1067: Show issues

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Article ; Online: Towards a complete map of the human long non-coding RNA transcriptome.

Uszczynska-Ratajczak, Barbara / Lagarde, Julien / Frankish, Adam / Guigó, Roderic / Johnson, Rory

Nature reviews. Genetics

2018 Volume 19, Issue 9, Page(s) 535–548

Abstract: Gene maps, or annotations, enable us to navigate the functional landscape of our genome. They are a resource upon which virtually all studies depend, from single-gene to genome-wide scales and from basic molecular biology to medical genetics. Yet present- ...

Abstract	Gene maps, or annotations, enable us to navigate the functional landscape of our genome. They are a resource upon which virtually all studies depend, from single-gene to genome-wide scales and from basic molecular biology to medical genetics. Yet present-day annotations suffer from trade-offs between quality and size, with serious but often unappreciated consequences for downstream studies. This is particularly true for long non-coding RNAs (lncRNAs), which are poorly characterized compared to protein-coding genes. Long-read sequencing technologies promise to improve current annotations, paving the way towards a complete annotation of lncRNAs expressed throughout a human lifetime.
MeSH term(s)	Chromosome Mapping ; Gene Expression Profiling ; Genome, Human ; Genome-Wide Association Study ; Humans ; RNA, Long Noncoding/biosynthesis ; RNA, Long Noncoding/genetics ; Transcriptome/physiology
Chemical Substances	RNA, Long Noncoding
Language	English
Publishing date	2018-05-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2035157-4
ISSN	1471-0064 ; 1471-0056
ISSN (online)	1471-0064
ISSN	1471-0056
DOI	10.1038/s41576-018-0017-y
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Zs.A 5474: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: The status of the human gene catalogue.

ArXiv

2023

Abstract: Scientists have been trying to identify all of the genes in the human genome since the initial draft of the genome was published in 2001. Over the intervening years, much progress has been made in identifying protein-coding genes, and the estimated ... ...

Abstract	Scientists have been trying to identify all of the genes in the human genome since the initial draft of the genome was published in 2001. Over the intervening years, much progress has been made in identifying protein-coding genes, and the estimated number has shrunk to fewer than 20,000, although the number of distinct protein-coding isoforms has expanded dramatically. The invention of high-throughput RNA sequencing and other technological breakthroughs have led to an explosion in the number of reported non-coding RNA genes, although most of them do not yet have any known function. A combination of recent advances offers a path forward to identifying these functions and towards eventually completing the human gene catalogue. However, much work remains to be done before we have a universal annotation standard that includes all medically significant genes, maintains their relationships with different reference genomes, and describes clinically relevant genetic variants.
Language	English
Publishing date	2023-03-24
Publishing country	United States
Document type	Preprint
ISSN	2331-8422
ISSN (online)	2331-8422
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Article: Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms.

Lambourne, Luke / Mattioli, Kaia / Santoso, Clarissa / Sheynkman, Gloria / Inukai, Sachi / Kaundal, Babita / Berenson, Anna / Spirohn-Fitzgerald, Kerstin / Bhattacharjee, Anukana / Rothman, Elisabeth / Shrestha, Shaleen / Laval, Florent / Yang, Zhipeng / Bisht, Deepa / Sewell, Jared A / Li, Guangyuan / Prasad, Anisa / Phanor, Sabrina / Lane, Ryan /

Campbell, Devlin M / Hunt, Toby / Balcha, Dawit / Gebbia, Marinella / Twizere, Jean-Claude / Hao, Tong / Frankish, Adam / Riback, Josh A / Salomonis, Nathan / Calderwood, Michael A / Hill, David E / Sahni, Nidhi / Vidal, Marc / Bulyk, Martha L / Fuxman Bass, Juan I

bioRxiv : the preprint server for biology

2024

Abstract: Most human Transcription factors (TFs) genes encode multiple protein isoforms differing in DNA binding domains, effector domains, or other protein regions. The global extent to which this results in functional differences between isoforms remains unknown. ...

Abstract	Most human Transcription factors (TFs) genes encode multiple protein isoforms differing in DNA binding domains, effector domains, or other protein regions. The global extent to which this results in functional differences between isoforms remains unknown. Here, we systematically compared 693 isoforms of 246 TF genes, assessing DNA binding, protein binding, transcriptional activation, subcellular localization, and condensate formation. Relative to reference isoforms, two-thirds of alternative TF isoforms exhibit differences in one or more molecular activities, which often could not be predicted from sequence. We observed two primary categories of alternative TF isoforms: "rewirers" and "negative regulators", both of which were associated with differentiation and cancer. Our results support a model wherein the relative expression levels of, and interactions involving, TF isoforms add an understudied layer of complexity to gene regulatory networks, demonstrating the importance of isoform-aware characterization of TF functions and providing a rich resource for further studies.
Language	English
Publishing date	2024-04-10
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.12.584681
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