Signal peptides restrict genome evolution and A-to-I RNA editing

The genetic information flows from DNA to RNA to protein with high fidelity. While highly essential or conserved genomic sequences are often thought to be compensated by post-transcriptional mechanisms such as alternative splicing (AS) and RNA editing to enhance molecular diversity, this pattern does not necessarily hold true across all genomic regions. Signal peptides are short N-terminal sequences that direct the localization of proteins. By analyzing the genomes and transcriptomes of <i>Drosophila melanogaster</i> and several other commonly studied species, we observed a consistent pattern that genes encoding signal peptides tend to produce fewer protein isoforms than those without. Moreover, AS events at the N-terminal region are significantly underrepresented in signal peptide-containing genes. In both fruitfly and human, RNA recoding events are notably avoided in signal peptide regions. These observations suggest that the presence of signal peptides imposes constraints on both genomic evolution and transcriptomic diversity. Our results provide new insight into the relationship between genome conservation and post-transcriptional regulation, showing that conserved genomic elements, such as signal peptides, do not necessarily coincide with increased post-transcriptional diversification. This study advances our understanding of the evolutionary principles governing RNA-based regulatory mechanisms.