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Quantitative Activity Profile and Context Dependence of All Human 5' Splice Sites.
Mol Cell. 2018 09 20; 71(6):1012-1026.e3.MC

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.

Authors+Show Affiliations

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: jkinney@cshl.edu.Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: krainer@cshl.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30174293

Citation

Wong, Mandy S., et al. "Quantitative Activity Profile and Context Dependence of All Human 5' Splice Sites." Molecular Cell, vol. 71, no. 6, 2018, pp. 1012-1026.e3.
Wong MS, Kinney JB, Krainer AR. Quantitative Activity Profile and Context Dependence of All Human 5' Splice Sites. Mol Cell. 2018;71(6):1012-1026.e3.
Wong, M. S., Kinney, J. B., & Krainer, A. R. (2018). Quantitative Activity Profile and Context Dependence of All Human 5' Splice Sites. Molecular Cell, 71(6), 1012-e3. https://doi.org/10.1016/j.molcel.2018.07.033
Wong MS, Kinney JB, Krainer AR. Quantitative Activity Profile and Context Dependence of All Human 5' Splice Sites. Mol Cell. 2018 09 20;71(6):1012-1026.e3. PubMed PMID: 30174293.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Quantitative Activity Profile and Context Dependence of All Human 5' Splice Sites. AU - Wong,Mandy S, AU - Kinney,Justin B, AU - Krainer,Adrian R, Y1 - 2018/08/30/ PY - 2018/03/23/received PY - 2018/06/18/revised PY - 2018/07/23/accepted PY - 2018/9/4/pubmed PY - 2019/4/12/medline PY - 2018/9/4/entrez SP - 1012 EP - 1026.e3 JF - Molecular cell JO - Mol. Cell VL - 71 IS - 6 N2 - 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. SN - 1097-4164 UR - https://www.unboundmedicine.com/medline/citation/30174293/Quantitative_Activity_Profile_and_Context_Dependence_of_All_Human_5'_Splice_Sites_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1097-2765(18)30602-6 DB - PRIME DP - Unbound Medicine ER -