دورية أكاديمية
أعرض في EDS

Differences in 5'untranslated regions highlight the importance of translational regulation of dosage sensitive genes.

التفاصيل البيبلوغرافية
العنوان: Differences in 5'untranslated regions highlight the importance of translational regulation of dosage sensitive genes.
المؤلفون: Wieder N; Big Data Institute, University of Oxford, Oxford, UK.; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK., D'Souza EN; Big Data Institute, University of Oxford, Oxford, UK.; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK., Martin-Geary AC; Big Data Institute, University of Oxford, Oxford, UK.; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK., Lassen FH; Big Data Institute, University of Oxford, Oxford, UK.; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK., Talbot-Martin J; Imperial College London, London, UK., Fernandes M; Big Data Institute, University of Oxford, Oxford, UK.; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK., Chothani SP; Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore, Singapore, 169857, Singapore., Rackham OJL; Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore, Singapore, 169857, Singapore.; School of Biological Sciences, University of Southampton, Southampton, UK., Schafer S; Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore, Singapore, 169857, Singapore., Aspden JL; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom.; LeedsOmics, University of Leeds, Leeds, LS2 9JT, United Kingdom.; Astbury Centre of Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom., MacArthur DG; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, NSW, Australia.; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia., Davies RW; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.; Department of Statistics, University of Oxford, Oxford, UK., Whiffin N; Big Data Institute, University of Oxford, Oxford, UK. nwhiffin@well.ox.ac.uk.; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. nwhiffin@well.ox.ac.uk.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. nwhiffin@well.ox.ac.uk.
المصدر: Genome biology [Genome Biol] 2024 Apr 29; Vol. 25 (1), pp. 111. Date of Electronic Publication: 2024 Apr 29.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BioMed Central Ltd Country of Publication: England NLM ID: 100960660 Publication Model: Electronic Cited Medium: Internet ISSN: 1474-760X (Electronic) Linking ISSN: 14747596 NLM ISO Abbreviation: Genome Biol Subsets: MEDLINE
أسماء مطبوعة: Publication: London, UK : BioMed Central Ltd
Original Publication: London : Genome Biology Ltd., c2000-
مواضيع طبية MeSH: 5' Untranslated Regions* , Open Reading Frames* , Protein Biosynthesis*, Humans ; Gene Dosage ; Gene Expression Regulation ; Transcription Initiation Site ; Alternative Splicing ; Nucleic Acid Conformation
مستخلص: Background: Untranslated regions (UTRs) are important mediators of post-transcriptional regulation. The length of UTRs and the composition of regulatory elements within them are known to vary substantially across genes, but little is known about the reasons for this variation in humans. Here, we set out to determine whether this variation, specifically in 5'UTRs, correlates with gene dosage sensitivity.
Results: We investigate 5'UTR length, the number of alternative transcription start sites, the potential for alternative splicing, the number and type of upstream open reading frames (uORFs) and the propensity of 5'UTRs to form secondary structures. We explore how these elements vary by gene tolerance to loss-of-function (LoF; using the LOEUF metric), and in genes where changes in dosage are known to cause disease. We show that LOEUF correlates with 5'UTR length and complexity. Genes that are most intolerant to LoF have longer 5'UTRs, greater TSS diversity, and more upstream regulatory elements than their LoF tolerant counterparts. We show that these differences are evident in disease gene-sets, but not in recessive developmental disorder genes where LoF of a single allele is tolerated.
Conclusions: Our results confirm the importance of post-transcriptional regulation through 5'UTRs in tight regulation of mRNA and protein levels, particularly for genes where changes in dosage are deleterious and lead to disease. Finally, to support gene-based investigation we release a web-based browser tool, VuTR, that supports exploration of the composition of individual 5'UTRs and the impact of genetic variation within them.
(© 2024. The Author(s).)
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معلومات مُعتمدة: 220134/Z/20/Z United Kingdom WT_ Wellcome Trust; 203141/Z/16/Z United Kingdom WT_ Wellcome Trust
فهرسة مساهمة: Keywords: 5’ untranslated regions; 5’UTR; Dosage sensitivity; Loss-of-function; Translational regulation; Upstream open reading frame; uORF
المشرفين على المادة: 0 (5' Untranslated Regions)
تواريخ الأحداث: Date Created: 20240429 Date Completed: 20240430 Latest Revision: 20240702
رمز التحديث: 20240702
مُعرف محوري في PubMed: PMC11057154
DOI: 10.1186/s13059-024-03248-0
PMID: 38685090
قاعدة البيانات: MEDLINE
الوصف
تدمد:1474-760X
DOI:10.1186/s13059-024-03248-0