A unified framework of overlapping genes: Towards the origination and endogenic regulation

Overlapping genes are pairs of adjacent genes whose genomic regions partially overlap. They are notable by their potential intricate regulation, such as cis-regulation of nested gene-promoter configurations, and post-transcriptional regulation of natural antisense transcripts. The originations and consequent detailed regulation remain obscure. Herein, we propose a unified framework comprising biological classification rules followed by extensive analyses, namely, exon-sharing analysis, a human–mouse conservation study, and transcriptome analysis of hundreds of microarrays and transcriptome sequencing data (mRNA-Seq). We demonstrate that the tail-to-tail architecture would result from sharing functional elements in 3′-untranslated regions (3′-UTRs) of pre-existing genes. Dissimilarly, we illustrate that the other gene overlaps would originate from a new gene arising in a pre-existing gene locus. Interestingly, these types of coupled overlapping genes may influence each other synergistically or competitively during transcription, depending on the promoter configurations. This framework discloses distinctive characteristics of overlapping genes to be a foundation for a further comprehensive understanding of them.

► We classify overlapping genes into five subgroups based on promoter configurations. ► Unlike others, the tail-to-tail overlaps are mainly composed by pre-existing genes. ► We disclose synergistic and competitive cis-regulations from transciptome analysis. ► We conclusively characterize each subgroup with distinctive biological traits.