Gene overlapping and size constraints in the viral world

Continuing the discussion from Gauger: Alternate Reading Frames Unlike Human Design:

This is an excellent paper worth discussing further.

A strong characteristic observed in most viruses is an abundance of overlapping open reading frames (ORFs). Many of these ORFs lack a known function [25]. Overlapping is a universal phenomenon, ubiquitous throughout the entire tree of life, including mammals [26], yet only in viruses it is present in a major scale [27]. Gene overlapping originates from various mechanisms, most notably the use of alternative start codons, ribosomal read-throughs and frame shifts [28]. The tendency for overlapping events is even higher in RNA viruses and in viruses with shorter genomes [29, 30].

Several studies have suggested various explanations for the abundance of overlapping genes (OGs) in viruses. One theory states that since viruses (especially RNA viruses) have a high mutation rate, overlapping events can increase their fitness in various ways [28]. For example, OGs can act as a safety mechanism by amplifying the deleterious effect of mutations occurring within them, thus quickly eliminating such mutations from the viral population [31].

Another theory argues that overlapping has a role in gene regulation by providing an inherent mechanism for coordinated expression. In support of this theory is the presence of OGs that are functionally related or coupled by a regulatory circuit (e.g., a feedback loop) [28, 32].

A third theory describes overlapping as an effective mechanism for generating novel genes, by introducing a new reading frame on top of an existing one [2]. According to this theory, pairs of OGs are usually composed of an old well-founded gene, and a novel gene that was overprinted on top of it [2, 33].

The most accepted theory argues for genome compression as the driving evolutionary force [1, 28, 34, 35]. Multiple arguments were raised to explain the need of viruses to have compact genomes: (i) The high mutation rate of viruses prevents them from having a long genome, as the likelihood of a deleterious mutation in each generation is length dependent [28]. (ii) The advantage for infectivity of shorter genome that lead to faster replication. (iii) The physical size constraint imposed by the capsid’s volume [1]. The physical size constraint is argued to be most dominant in icosahedral viruses due to the discrete nature of the T number, allowing only non-continuous changes in capsid size [34, 36]. Small viruses are also argued to be subject to an even greater evolutionary pressure towards compactness, hence their high abundance of overlapping [37].

The motivation for this study is to systematically assess the different theories that aim to explain long-term evolution.

Thanks for pointing to this article @Zachary_Ardern.

Do these article’s conclusions demonstrate that genome size constraints are not relevant to overlapping (or overprinting)? No. It seems that they show it is related. So I’m not sure what to make of the summary that was given of the findings…

Regardless, I had not seen this paper yet. It is quite a good read.

Hey, a candidate for the first post-summer paper for my evolutionary reading group.


I did not say that size constraints “are not relevant” to viral overlaps. You seem to be looking to disagree with everything I write.

I cited it because it shows that size constraints are not a sufficient or primary explanation, as is very commonly believed among molecular biologists based on older literature and/or intuition. I don’t know what you yourself believed about the topic, you haven’t stated that clearly.

“Our findings undermine the generality of the compression theory, which emphasizes optimal packing and length dependency to explain overlapping genes and capsid size in viral genomes.”

If I have misread this paper, or misstated its conclusions, then please clarify how. Otherwise it would be reasonable for you to state that the paper was in fact appropriate to refer to in the way that I did.

@Zachary_Ardern it’s an interesting and appropriate reference. I liked the paper. Thank you.

I think the confusion here might just be about definitions. Normally misunderstanding between us isn’t so thick! Not sure why it’s different today, but I appreciate you sticking it out.

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