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

Wieder, N.; D'Souza, E. N.; Martin-Geary, A. C.; Lassen, F. H.; Talbot-Martin, J.; Fernandes, M.; Chothani, S. P.; Rackham, O. J. L.; Schafer, S.; Aspden, J. L.; MacArthur, D. G.; Davies, R. W.; Whiffin, N.

doi:10.1101/2023.05.15.540809

bioRxiv · 10.1101/2023.05.15.540809

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

Wieder, N.·D'Souza, E. N.·Martin-Geary, A. C.·Lassen, F. H.·Talbot-Martin, J.·Fernandes, M.·Chothani, S. P.·Rackham, O. J. L.·Schafer, S.·Aspden, J. L.·MacArthur, D. G.·Davies, R. W.·Whiffin, N.

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Abstract

BackgroundUntranslated 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 5UTRs, correlates with gene dosage sensitivity. ResultsWe investigated 5UTR 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 5UTRs to form secondary structures. We explored 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 5UTR length and complexity. Genes that are most intolerant to LoF have longer 5UTRs (P<1x10-15), greater TSS diversity (P<1x 10-15), 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. ConclusionsOur results confirm the importance of post-transcriptional regulation through 5UTRs 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 (https://vutr.rarediseasegenomics.org/), that supports exploration of the composition of individual 5UTRs and the impact of genetic variation within them.

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Wieder, N., D'Souza, E. N., Martin-Geary, A. C., Lassen, F. H., Talbot-Martin, J., Fernandes, M., Chothani, S. P., Rackham, O. J. L., Schafer, S., Aspden, J. L., MacArthur, D. G., Davies, R. W., Whiffin, N.. 2023-05-15. Differences in 5'untranslated regions highlight the importance of translational regulation of dosage sensitive genes. https://doi.org/10.1101/2023.05.15.540809

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