Alternatively Spliced Dual-Coding Regions Contribute to the Human Gene Regulatory Program.

Area of Science:

• Genomics
• Molecular Biology
• Evolutionary Biology

Background:

• Alternative splicing enables single genes to encode multiple protein isoforms in eukaryotes.
• Dual coding regions (DCRs) allow distinct isoforms to utilize the same exon in different reading frames, yielding different amino acid sequences.
• The functional significance of DCRs has remained largely unexplored.

Purpose of the Study:

• To provide a genome-wide analysis of DCRs in humans.
• To investigate the conservation and functional implications of DCRs across species.
• To characterize the structural and regulatory roles of DCRs.

Main Methods:

• Genome-wide mapping of human UniProtKB/Swiss-Prot isoforms to the human genome.
• Tracking of reading frames utilized by each isoform.
• Comparative analysis of DCRs in human and mouse orthologs.
• Analysis of tissue-specific expression patterns.
• Structural prediction of protein domains.

Main Results:

• Identified 1296 DCR-containing genes in humans.
• Demonstrated conserved dual-coding potential in mouse orthologs, suggesting functional relevance.
• Observed differential tissue-specific expression of DCR isoforms.
• Found DCRs are typically short, exon-confined, and often introduce premature stop codons.
• Structural predictions indicate non-canonical frames yield disordered peptides, impacting isoform stability.

Conclusions:

• DCRs are a common, conserved byproduct of alternative splicing in eukaryotes.
• Dual coding contributes to gene regulation and functional diversity by modulating protein isoforms.
• DCRs primarily affect terminal regions and protein stability rather than creating new folded domains.
• This mechanism is a repeatedly co-opted strategy to fine-tune gene regulatory programs.