A basic framework to explain splice-site choice in eukaryotes

Area of Science:

• Genetics
• Molecular Biology
• Bioinformatics

Background:

• Splicing variations influence phenotypic traits and are linked to diseases.
• Genetic and environmental factors affect splice-site strength, but the mechanisms are unclear.
• Empirical quantification of splice-site usage across transcriptomes is lacking.

Purpose of the Study:

• To quantify individual splice-site usage in Arabidopsis, Drosophila, and humans.
• To map genetic variation influencing splice-site usage using genome-wide association studies (GWAS).
• To identify conserved rules governing splice-site selection across eukaryotes.

Main Methods:

• Quantification of splice-site usage as molecular phenotypes.
• Performance of over 130,000 GWAS for splice-site usage variation.
• Analysis of splice-site sequences (GT[N]4 or [N]4AG) and their usage patterns.

Main Results:

• Cataloged genetic variation associated with changes in splice-site usage across transcriptomes.
• Identified that most common, genetically controlled splicing variation is cis-acting, with no major trans hotspots.
• Developed hexamer rankings based on sequence (GT[N]4 or [N]4AG) that effectively explain splice-site choice across species.

Conclusions:

• Hexamer rankings provide a conserved, simple rule for splice-site selection in eukaryotes.
• This study establishes a basis for understanding shared eukaryotic splicing logic.
• Findings advance the understanding of how genetic variation impacts gene expression through splicing.