Alternative splicing modulated by genetic variants demonstrates accelerated evolution regulated by highly conserved...

Area of Science:

• Genomics
• Evolutionary Biology
• Molecular Biology

Background:

• Identifying functional genetic variants and their regulatory mechanisms is crucial in the post-genomic era.
• The role of genetic variants in post-transcriptional RNA processing, particularly alternative splicing, remains poorly understood.
• Genomic, evolutionary, and regulatory features of genetically modulated alternative splicing (GMAS) are largely unknown.

Purpose of the Study:

• To systematically identify intronic tag variants involved in genetically modulated alternative splicing (GMAS).
• To analyze the genomic, evolutionary, and regulatory characteristics of GMAS.
• To understand the impact of genetic variants on splicing factor binding and splicing evolution.

Main Methods:

• Utilized RNA-sequencing data from specific cellular compartments to identify intronic tag variants for GMAS.
• Integrated previous methods for identifying exonic tags for GMAS.
• Analyzed evolutionary patterns (positive selection, accelerated evolution) and predicted splicing factor binding alterations.

Main Results:

• Identified 622 GMAS exons, with GMAS events showing high cell-type independence.
• GMAS genes, exons, and single-nucleotide variants (SNVs) exhibited positive selection or accelerated evolution in primates.
• GMAS SNVs frequently alter splicing factor binding, with SRSF1 being significantly affected; cis-regulatory variation is a key driver of splicing evolution.

Conclusions:

• This work identifies numerous GMAS events and provides insights into their evolutionary and regulatory features.
• GMAS variants have widespread functional implications across cell types due to their independence from specific cellular contexts.
• The findings highlight cis-regulatory variation as a primary mechanism shaping splicing evolution, with implications for understanding genetic disease.