A basic framework to explain splice-site choice in eukaryotes

Changes in splicing can mediate phenotypic variation, ranging from flowering time differences in plants to genetic diseases in humans. Splicing changes occur due to differences in splice-site strength, often influenced by genetic variation and the environment. How genetic variation influences splice-site strength remains poorly understood, largely because splice-site usage across transcriptomes has not been empirically quantified. Here, we quantify the use of individual splice-sites in Arabidopsis, Drosophila and humans and treat these measurements as molecular phenotypes to map variation in splice-site usage through GWAS. We carry out more than 130,000 GWAS with splice-site usage phenotypes, cataloguing genetic variation associated with changes in the usage of individual splice-sites across transcriptomes. We find that most of the common, genetically controlled variation in splicing is cis and there are no major trans hotspots in the three species analyzed. We group splice-sites based on GT[N]<sub>4</sub> or [N]<sub>4</sub>AG sequence, quantify their average use, develop a ranking and show that these hexamer rankings provide a simple and comparable feature across species to explain most of the splice-site choice. Transcriptome analyses in several species suggest that hexamer rankings offer a rule that helps explain splice-site choices, forming a basis for a shared splicing logic in eukaryotes.

Authors

Institutions

Publication Details

Journal
Nature Communications
Published
2025-09-29
DOI
https://doi.org/10.1038/s41467-025-63622-9
Citations
2
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
1.61

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

A basic framework to explain splice-site choice in eukaryotes

Rucha D. Sarwade, David Powell, Partha Pratim Das, Sridevi Sureshkumar et al.
2 citations
Nature Communications
RNA Research and Splicing
1.61
article

A basic framework to explain splice-site choice in eukaryotes

Rucha D. Sarwade, David Powell, Partha Pratim Das, Sridevi Sureshkumar, Sureshkumar Balasubramanian, Alexandre Fournier‐Level, Joseph Rosenbluh, Ya‐Long Guo, Craig Dent, Mauro D’Amato, Aiswarya Balakrishnan, Jordyn Coutts, Aaryan Chhabra, Sourav Mukherjee, Richard Burke, Stefan Prodic, Michael Gitonobel, J. Georges
article en
2 citations

Abstract

Changes in splicing can mediate phenotypic variation, ranging from flowering time differences in plants to genetic diseases in humans. Splicing changes occur due to differences in splice-site strength, often influenced by genetic variation and the environment. How genetic variation influences splice-site strength remains poorly understood, largely because splice-site usage across transcriptomes has not been empirically quantified. Here, we quantify the use of individual splice-sites in Arabidopsis, Drosophila and humans and treat these measurements as molecular phenotypes to map variation in splice-site usage through GWAS. We carry out more than 130,000 GWAS with splice-site usage phenotypes, cataloguing genetic variation associated with changes in the usage of individual splice-sites across transcriptomes. We find that most of the common, genetically controlled variation in splicing is cis and there are no major trans hotspots in the three species analyzed. We group splice-sites based on GT[N]<sub>4</sub> or [N]<sub>4</sub>AG sequence, quantify their average use, develop a ranking and show that these hexamer rankings provide a simple and comparable feature across species to explain most of the splice-site choice. Transcriptome analyses in several species suggest that hexamer rankings offer a rule that helps explain splice-site choices, forming a basis for a shared splicing logic in eukaryotes.

Nature CommunicationsVol. 16(1)
Ikerbasque (ES), Australian National University (AU), Libera Università Maria SS. Assunta (IT), The University of Melbourne (AU), Discovery Institute (US), Monash Medical Centre (AU), University of Rochester Medical Center (US), Institute of Botany of the Slovak Academy of Sciences (SK), CIC bioGUNE (ES), Max Planck Institute for Plant Breeding Research (DE), Institute of Botany (CN), Monash University (AU)
Marshfield Clinic Research Foundation, Australian Government, Medical Research Council, National Health and Medical Research Council
Openalex Percentile: Top 15%
RNA Research and Splicing
1.61
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.