RNA VARIATION AS A DRIVER OF GENOMIC FUNCTION AND COMPLEXITY

Current annotation of mammalian genomes, including the human genome, indicates that the number of genes per genome falls within a range of 22,000 – 67,000, as predicted by our pioneers several decades ago. Therefore, how a finite genome gives rise to the vast phenotypic diversity observed in an organism remains unclear. Here, we review potential RNA mechanisms and roles in the functional design of genomes. At a genome level, protein-coding genes, non-coding genes, pseudogenes, and “jumping genes” make up 93% of the genome transcribed in at least one cell type. At a gene level, the usage of alternative transcript start, exon splicing, and polyadenylation sites allows a gene to produce more than one transcript. At a transcript level, RNA variants result from modification by more than 170 ways, contributing to enormous epitranscriptome events. The vast potential created by combining these three levels of RNA variation favors genetic efficiency, increases regulatory complexity, reduces excessive genomic burden, and fine-tunes genome function while maintaining a relatively low number of genes across species. This principle is especially evident in livestock species such as Karakul sheep, where extensive RNA variability, including alternative polyadenylation, enables a compact genome to support diverse tissue functions, physiological adaptations, and sex-specific phenotypes. In conclusion, RNA variants, rather than genes, are the smallest units to execute genome functions. In conclusion, RNA variants, rather than genes, are the smallest units to execute genome functions.