Gene overlapping: A double-edge sword in the evolution of RNA viruses

Fast evolution of RNA viruses is partly due to their ability to generate overlapping genes. A research effort led by CBGP uncovers an associated cost in their adaptive capacity, with possible implications in antiviral design.

RNA viruses are part of our daily life. They are causal agents of some of the most common diseases in humans (Flu, Measles…), and frequently infect important crops such as tomato or pepper. Moreover, RNA viruses are at the root of devastating epidemics such as AIDS in humans, or that caused by Pepino mosaic virus in tomato crops all across Europe during the last 20 years. Two of the most striking characteristics of RNA viruses are their fast evolutionary rates and their small genome sizes even among viruses at large. The combination of these two features provides RNA viruses with a high adaptive capacity, as they can generate new mutations and large population sizes in a short period of time, allowing them to overcome antiviral strategies. But, how viruses can generate this genetic novelty that fast and keep the small size of their genomes at the same time? The best-documented mechanism to achieve this goal is known as gene overlapping, which is the ability to encode for more than one protein in the same genomic space. Although gene overlapping clearly represents a selective advantage, it has been hypothesized that it also comes at the cost of hypersensitivity to deleterious mutations, as these affect more than one gene. This in turn reduces the evolutionary rate of RNA viruses. However, to date the effect of gene overlapping in the rate of evolution of RNA viruses, and consequently in their adaptive capacity, has not been explored in deep.

A group of researchers lead by CBGP members has performed a comprehensive analysis of the effect of gene overlapping in the rate of evolution of RNA viruses, using a comparative genomics approach. Israel Pagán and his collaborators collected sequence data from 117 instances of gene overlapping across 19 families, 30 genera and 55 species of RNA viruses. On these data the variation of the rate of evolution, selective pressures, the distribution of RNA secondary structures and of protein conserved functional domains between overlapping and non-overlapping regions was analyzed. Results from this work show that gene overlapping generally decreases the rate of RNA virus evolution through a reduction in the frequency of synonymous mutations (those that do not change the amino acid sequence of the encoded protein). This effect is exponentially correlated with the length of the overlapping region, and modulated by the presence of protein conserved functional domains in non-overlapping regions.

Thus, this work provides novel information on the role of gene overlapping as a modulator of the evolutionary rates of RNA viruses. Moreover, the slower evolutionary rates exhibited by overlapping genes, and consequently their reduced adaptive capacity, opens the door to explore their use as targets to generate more durable antiviral therapies.

"The effect of gene overlapping on the rate of RNA virus evolution"