Quantitative Activity Profile and Context Dependence of All Human 5' Splice Sites

Molecular Cell
Mandy S WongAdrian R Krainer

Abstract

Pre-mRNA splicing is an essential step in the expression of most human genes. Mutations at the 5' splice site (5'ss) frequently cause defective splicing and disease due to interference with the initial recognition of the exon-intron boundary by U1 small nuclear ribonucleoprotein (snRNP), a component of the spliceosome. Here, we use a massively parallel splicing assay (MPSA) in human cells to quantify the activity of all 32,768 unique 5'ss sequences (NNN/GYNNNN) in three different gene contexts. Our results reveal that although splicing efficiency is mostly governed by the 5'ss sequence, there are substantial differences in this efficiency across gene contexts. Among other uses, these MPSA measurements facilitate the prediction of 5'ss sequence variants that are likely to cause aberrant splicing. This approach provides a framework to assess potential pathogenic variants in the human genome and streamline the development of splicing-corrective therapies.

Citations

Dec 21, 2018·ELife·Talitha L ForcierJustin B Kinney
May 28, 2019·Nature Structural & Molecular Biology·Fangyuan Ding, Michael B Elowitz
Jul 13, 2019·Human Mutation·Christy L RhineWilliam G Fairbrother
May 1, 2019·The Journal of Clinical Investigation·Patrick G GallagherVincent P Schulz
Dec 11, 2019·Bioinformatics·Ammar Tareen, Justin B Kinney
Dec 4, 2019·Annual Review of Biochemistry·Max E WilkinsonKiyoshi Nagai
Jun 5, 2020·Cold Spring Harbor Symposia on Quantitative Biology·Tucker J Carrocci, Karla M Neugebauer
Aug 9, 2019·International Journal of Molecular Sciences·Shi-Yi ChenSong-Jia Lai
May 16, 2019·Annual Review of Genomics and Human Genetics·Justin B Kinney, David M McCandlish
Dec 10, 2020·Genome Biology·Simon M HoserAlexander Huettenhofer
Apr 7, 2021·Briefings in Bioinformatics·Yangjun ZhangHua Xu
May 14, 2021·Nature Communications·David T GliddenWilliam G Fairbrother
Jun 3, 2021·International Journal of Molecular Sciences·Maxime BlijlevensVictor W van Beusechem
Jun 24, 2021·Nucleic Acids Research·Kaushik SahaGourisankar Ghosh

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