The landscape of human mutually exclusive splicing

Area of Science:

• Genomics
• Molecular Biology
• Evolutionary Biology

Background:

• Mutually exclusive splicing of exons (MXEs) drives gene and protein diversity.
• MXEs play critical roles in development and are implicated in human diseases like cancer and cardiomyopathy.

Purpose of the Study:

• To estimate the genome-wide extent and biological significance of MXEs in humans.
• To identify and validate novel MXEs and analyze their evolutionary conservation.

Main Methods:

• Analysis of 515 public RNA-Seq datasets.
• Prediction and validation of mutually exclusive exons (MXEs).
• Comparative analysis of MXE conservation across species.

Main Results:

• Identification of over 855 human MXEs, with 42% being novel, increasing the annotated exome fivefold.
• Evidence for large, multi-cluster MXEs in vertebrates, with significant conservation in mammals (82%) and homology in *Drosophila*.
• MXEs are significantly enriched in pathogenic mutations, suggesting a role in disease pathology.

Conclusions:

• This study provides the first genome-wide estimate of human MXEs, revealing their substantial contribution to genetic diversity.
• MXE evolution shows conservation across vertebrates and even invertebrates.
• The enrichment of pathogenic mutations in MXEs highlights their clinical relevance and potential as disease biomarkers.