How would a virus “evolve” if someone is infected with both the omicron and delta variants at the same time?

Question

If someone is infected with both variants (let’s say within a day or two), what are some of the likely outcomes with respect to the virus “evolution”?

1. is it most likely that only 1 of the 2 variants survives?

2. if both survive, is it likely that the 2 strains “mix” with each other to produce a 3rd strain? Obviously 2 viruses don’t have “sex” per se, but I read https://www.cnbc.com/2021/12/05/omicron-variant-may-have-picked-up-a-piece-of-common-cold-virus.html that the omicron strain actually has a gene that is found in the common cold virus.

By what mechanism could that have happened? Somehow a common cold gene got inserted into the virus, or did that just happen by random mutation?

My primary question is by what mechanism would a virus insert a snippet of RNA from another virus into its own RNA?

On further study, I found this link to an OSF preprint which talks about “template switching”. https://osf.io/f7txy/

Here is the text:

This highly mutated Spike variant harbors a novel insertion mutation ins214EPE. Although the position 214 appears to be an insertion hotspot10the EPE insertion in Omicron appears to be novel. Previous analyses of sequences deposited in GISAID suggested that insertions in the SARS-CoV-2 genome likely arise from polymerase slippage or template switching.10,21Template switching is a normal event during RNA synthesis for coronaviruses, as this process is used to generate sub-genomic RNAs (sgRNAs).22,23In this process, also known as copy-choice recombination, the RNA-directed RNA polymerase (RdRp) and the nascent strand dissociate from the template RNA strand and reassociate with a new template (or the same template at a different position), and then RNA synthesis continues. Typically, such recombination involves templates with high sequence similarity (“homologous recombination”), although non-homologous (or “illegitimate”) recombination between dissimilar sequences can also occur.

Could someone boil down the meaning here in simpler terms? For starters, I don’t understand how recombination applies to viruses? Isn’t recombination a DNA process? How does it relate to viral RNA?

Answer 1

Basically your options 1 and 2 are the the only likely outcomes from a co-infection with two SARS-CoV-2 viruses. There is a 3rd option, which is that there is a co-infection, producing some amount of both viruses.

Total competition (i.e. one being completely gone, the other 100% output, your option 1) is unlikely unless one of the co-infecting strains has low initial input (i.e small amount infected), and low replicative ability compared to the other strain. In this case, you might see that one of the viruses doesn't survive the competition. However, this would be hard to detect with current technology and hard to prove experimentally as well unless the strains had sufficient differences (i.e. not just single base mutations) and you could survey the entire viral population to look for levels of output.

One of the reasons for these difficulties is that viruses, particularly RNA viruses exist as what is known as a quasispecies, this is where there is a pool of virions with variant genomes as the output from any particular infection. This is caused by errors in replication of the genome (RNA polymerases tend to be more error prone than DNA polymerases and/or not have a proof-reading mechanism, though SARS-CoV-2 (RNA virus) does have a proof-reading RdRP¹ (PDF)). Because of this, and because of the way we do most sequencing - by chopping the genetic material into small bits, then assembling a consensus sequence computationally - it can be difficult to tell if there is a population of virions that are one strain or not, as the computation methods lead to missing of the non-dominant sequences. There are methods (computational and new technological) to look at these sorts of things, so we may have a better idea soonish.

For option 2: Recombination is common where-ever there is a genome, be it DNA or RNA. RNA polymerases are particularly prone to recombination events, and this is a major driver of evolution of RNA viruses². Indeed it seems that this is a common feature of Coronaviruses in general³. Basically what is happening here is that there are multiple strands of RNA present at replication and the RNA pol can jump from one to another, often in a sequence dependent manner (i.e. at regions of high similarity) or sometimes where there is secondary structure of the RNA that causes the polymerase to jump from one location to another based on proximity, skipping the bits in-between.

Now, there's a bit of complexity here - there are multiple different genera of coronavirus called Alphacoronavirus to Deltacoronavirus (nothing to do with the SARS-CoV-2 variants, just unfortunate naming choice from someone(s) when dealing with this virus). The different coronavirus types have the same overall RNA structure (i.e. encode the same genes), but have quite diverse sequences, so an Alphacoronavirus has a different sequence to a Gammacoronavirus, meaning that homology based recombination is less likely than within the genus. Having said that, there are still highly conserved parts of the genome within the family as a whole, so those might be sites where recombination could occur.

1: Robson et al., Molecular Cell 2020; 79(3):710-727.

2: Tackas et al., Plant Virus-Host Adaption: Molecular Approaches and Viral Evolution. 2014; 385-394 (paywalled?)

3: Kek et al., Adv Exp Med Biol. 1987; 218:99-107.

Answer 2

bob1's answer describes the general mechanisms very well.

One must not forget that the emerging recombinations still underly the pressure of evolution: They need to survive and to spread with a rate at least comparable to the original strains.

Nature has done this big experiment and now we can see several small clusters of Delta/Omicron recombinations, see pango designation issues #473, #439, #444—now assigned pango lineage XD, #445—pango lineage XF, and #446 for details.

It is interesting that the successful recombinations follow some pattern: The Spike gene is completely or at least to the greatest part from Omicron, ORF1ab is completely or partly from Delta. Most interesting is the recombination described in #444: It has just an Omicron spike in a Delta backbone.

EDIT: More than half a year later, more Delta/Omicron recombinants have shown up(XAW, XAY, XBC, and XBD), some of them with considerable spread. For an overview of the current state of affairs (27-NOV-2022) see this article by C. Roemer et al. on virological org.