Regulatory Divergence of Transcript Isoforms in a Mammalian Model System

Area of Science:

• Genomics
• Molecular Biology
• Evolutionary Biology

Background:

• Phenotypic variation between species arises from altered gene expression and transcriptome regulation.
• Previous studies on mammalian transcriptome divergence focused on bulk expression and splicing.
• Understanding regulatory mechanisms is key to explaining species differences.

Purpose of the Study:

• To quantify the contribution of various regulatory systems to transcriptome divergence in Mus musculus.
• To investigate the impact of alternative isoform usage on protein-coding sequences and regulatory elements.
• To explore the coordination and cross-talk between different regulatory systems.

Main Methods:

• Utilized allele-specific expression analysis in inter-strain hybrids of Mus musculus.
• Examined multiple regulatory systems: alternative promoter usage, transcription start site selection, cassette exon usage, alternative last exon usage, and alternative polyadenylation site choice.
• Analyzed variations in gene isoform usage and their effects on UTRs and amino acid sequences.

Main Results:

• One-fifth of genes exhibit isoform usage variations contributing to transcriptomic changes between mouse strains.
• Half of these variations alter the encoded amino acid sequence.
• Nearly all isoform divergence impacted post-transcriptional regulatory elements within gene UTRs.
• Most genes with isoform differences showed changes from multiple regulatory systems, indicating cross-talk.
• Isoform usage divergence occurs in parallel with and independently of gene expression evolution.

Conclusions:

• Multiple cellular regulatory systems contribute significantly to transcriptome divergence.
• Widespread cross-talk and coordination exist among different regulatory systems.
• Isoform usage evolution is a key, yet distinct, driver of transcriptomic differences between species.