Abstract
The structure of eukaryotic genes is generally a combination of exons interrupted by intragenic non-coding DNA regions (introns) removed by RNA splicing to generate the mature mRNA. A fraction of genes, however, comprise a single coding exon with introns in their untranslated regions or are intronless genes (IGs), lacking introns entirely. The latter code for essential proteins involved in development, growth, and cell proliferation and their expression has been proposed to be highly specialized for neuro-specific functions and linked to cancer, neuropathies, and developmental disorders. The abundant presence of introns in eukaryotic genomes is pivotal for the precise control of gene expression. Notwithstanding, IGs exempting splicing events entail a higher transcriptional fidelity, making them even more valuable for regulatory roles. This work aimed to infer the functional role and evolutionary history of IGs centered on the mouse genome. IGs consist of a subgroup of genes with one exon including coding genes, non-coding genes, and pseudogenes, which conform approximately 6% of a total of 21,527 genes. To understand their prevalence, biological relevance, and evolution, we identified and studied 1,116 IG functional proteins validating their differential expression in transcriptomic data of embryonic mouse telencephalon. Our results showed that overall expression levels of IGs are lower than those of MEGs. However, strongly up-regulated IGs include transcription factors (TFs) such as the class 3 of POU (HMG Box), Neurog1, Olig1, and BHLHe22, BHLHe23, among other essential genes including the β-cluster of protocadherins. Most striking was the finding that IG-encoded BHLH TFs fit the criteria to be classified as microproteins. Finally, predicted protein orthologs in other six genomes confirmed high conservation of IGs associated with regulating neural processes and with chromatin organization and epigenetic regulation in Vertebrata. Moreover, this study highlights that IGs are essential modulators of regulatory processes, such as the Wnt signaling pathway and biological processes as pivotal as sensory organ developing at a transcriptional and post-translational level. Overall, our results suggest that IG proteins have specialized, prevalent, and unique biological roles and that functional divergence between IGs and MEGs is likely to be the result of specific evolutionary constraints.
Highlights
Most eukaryotic genes contain introns, nucleotide DNA sequences that after transcription as part of the messenger RNA are removed by splicing during its maturation
Our analysis revealed that all up-regulated intronless genes” (IGs) are exclusively enriched in biological pathways in eye and sensory organ development processes compared to multiple exon genes (MEGs) involved in other developmental and neural function pathways (Figures 5C,D)
To further our insight into the structure and the evolution of mouse IGs, we examined their function, differential expression in the developing brain, the signatures for post-translational modifications of their encoded proteins, their potential as modulators of multiprotein complexes, as well as their evolutionary dynamics in comparison to their orthologs in other vertebrates
Summary
Most eukaryotic genes contain introns, nucleotide DNA sequences that after transcription as part of the messenger RNA are removed by splicing during its maturation. Diverse studies of genes of this type have been performed over the past decades and have been variously referred to as “single-exon genes” (SEGs) and “intronless genes” (IGs), both terms carrying some ambiguity as genes containing an intron in their 5 UTR are often included among them (Sunahara et al, 1990; Gentles and Karlin, 1999; Sakharkar et al, 2002, 2005a, 2006; Tine et al, 2011; Zou et al, 2011; Yan et al, 2014). A recent ontology defines SEGs as nuclear genes with functional protein-coding capacity whose coding sequence comprises only one exon, including genes with introns in their untranslated regions termed uiSEGs, as well as those lacking introns entirely, termed “Intronless Genes” (Jorquera et al, 2018). To avoid any possible ambiguity, in this article we use the term “Intronless genes” in the narrow definition of Jorquera et al (2018) as protein-coding nuclear genes completely devoid of introns
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