Shedding Light on the Dark Side of the Genome: Overlapping Genes in Higher Eukaryotes

Gene overlap, consisting of two or more adjacent genes with partially or totally overlapping expressible units, has very recently emerged as a common feature, rather than an exception to the rule, in a significant portion of eukaryotic genomes. Considering the lack of strong evolutionary pressure on genome size in eukaryotes, the frequent recurrence of such a gene disposition is unexpected. However, these findings, along with the recent estimate that fewer genes than expected are encoded in the human genome, strengthen the hypothesis that organism complexity may reside in the interaction within and among genome, transcriptome and proteome. In this context, overlapping genes could represent a hidden source of complexity to modulate gene expression. In fact, overlapping genes, when transcribed in the opposite directions, give rise to sense-antisense transcript pairs, which often exhibit reciprocal expression patterns. These natural antisense transcripts (NATs) have been demonstrated to play a role in a variety of processes, including mRNA splicing and stability, RNA editing, genomic imprinting and control of translation. Here we present the first review on eukaryotic overlapping genes, an attempt of shedding light on this dark side of the genome. We also report the most interesting and well-studied cases and depict a general frame of this phenomenon.