A First Look at ARFome: Dual-Coding Genes in Mammalian Genomes

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Abstract
Coding of multiple proteins by overlapping reading frames is not a feature one would associate with eukaryotic genes. Indeed, codependency between codons of overlapping protein-coding regions imposes a unique set of evolutionary constraints, making it a costly arrangement. Yet in cases of tightly coexpressed interacting proteins, dual coding may be advantageous. Here we show that although dual coding is nearly impossible by chance, a number of human transcripts contain overlapping coding regions. Using newly developed statistical techniques, we identified 40 candidate genes with evolutionarily conserved overlapping coding regions. Because our approach is conservative, we expect mammals to possess more dual-coding genes. Our results emphasize that the skepticism surrounding eukaryotic dual coding is unwarranted: rather than being artifacts, overlapping reading frames are often hallmarks of fascinating biology. A textbook human gene encodes a protein using a single reading frame. Alternative splicing brings some variation to that picture, but the notion of a single reading frame remains. Although this is true for most of our genes, there are exceptions. Like viral counterparts, some eukaryotic genes produce structurally unrelated proteins from overlapping reading frames. The examples are spectacular (G-protein alpha subunit [Gnas1] or INK4a tumor suppressor), but scarce. The scarcity is anthropogenic in origin: we simply do not believe that dual-coding genes can occur in eukaryotes. To challenge this assumption, we performed the first genome-wide scan for mammalian genes containing alternative reading frames located out of frame relative to the annotated protein-coding region. Using a newly developed statistical framework, we identified 40 such genes. Because our approach is very conservative, this number is likely a significant underestimate, and future studies will identify more alternative reading frame–containing genes with fascinating biology.