Mutations are a natural phenomenon when viruses replicate. Generally, RNA viruses have a higher rate of mutations compared with DNA viruses. However, unlike other RNA viruses, coronaviruses have fewer mutations. This is because coronaviruses have a genetic “proofreading mechanism” that corrects some of the errors made during replication. This is applicable to SARS-CoV-2 viruses too. As a result, SARS-CoV-2 viruses have “higher fidelity in its transcription and replication process than that of other single-stranded RNA viruses” says a February 2021 paper in Nature.
Providing fitness
The fate of new mutations depends on whether such mutations increase the fitness of the virus such as increasing the infectiousness of the virus and in light of many people being infected and/or vaccinated, the ability of the mutations to allow the virus to escape from immunity. Such mutations that provide increased fitness to the virus increase in numbers and become the dominant strain or variant.
But changes to the virus through natural collection of mutations involves small changes in the genome. But like in the case of influenza viruses, when a person is simultaneously infected with two different SARS-CoV-2 variants or strains or sub-lineages, chunks of genetic material from one variant can get mixed with the other. This is called recombination.
In the case of SARS-CoV-2 virus, such recombination has been seen right after the Alpha variant emerged. Alpha was the first variant to emerge in late-2020 in the U.K. At that time, the dominant strain that had spread to most countries was the Wuhan strain with a mutation called the D614G, which increased the transmissibility of the virus. According to a paper published on September 30, 2021 in the journal Cell, recombinant SARS-CoV-2 viruses were found in late 2020-early 2021 in the U.K.
Recombinant sequences
The recombinant virus had a combination of the Alpha variant and the Wuhan strain. The recombinant virus had the mutations seen in the spike protein of the Alpha variant while the remaining genome with the wild strain. Since the mutations seen in the Alpha variant made the virus more transmissible, the recombinant virus was found to spread. The researchers were able to find four instances of the recombinant virus spreading, including “one transmission cluster of 45 sequenced cases over the course of two months”. The researchers identified 16 recombinant sequences from a large dataset of 2,79,000 genome sequenced by U.K. up to March 7, 2021. Despite the recombinant virus inheriting the spike region with mutations from the Alpha variant, it did not have better fitness than the Alpha variant and hence did not become dominant.
After Alpha, the variant to emerge was the Delta. There was a short window when both Delta and Alpha were present in many countries before Delta wiped out the Alpha variant. Another study found a SARS-CoV-2 recombinant of Alpha and Delta variants. In mid-August 2021, researchers in Japan found six clinical isolates that were recombinants of the Alpha and Delta variants. In a preprint posted in medRxiv on October 14, 2021, the researchers say the recombinant could have emerged through simultaneous infection by both variants in a person but were unable to find any patient with mixed infection. Again, this recombinant did not have added fitness to increase in frequency. It just died out.
Sub-lineages
After Delta, the Omicron variant emerged and it was soon split into two sub-lineages BA.1 and BA.2. With both the Delta and Omicron variants being present simultaneously in many countries, there were “lots of opportunities to co-infect, recombine and transmit onwards”, says virologist Tom Peacock from Imperial College, London in a tweet. Researchers have so far found two possible recombinants — 1) Delta and BA.1, and 2) BA.1 and BA.2. The recombinant of Delta and BA.1 has been found in the U.K and France, while the recombinant of the Omicron sub-lineages BA.1 and BA.2 has been found in the U.K.
The recombination of Delta and BA.1 found in France is called XD, and it contains the “Spike protein of BA.1 and the rest of the genome from Delta. It currently comprises several tens of sequences.
The recombination of Delta and Omicron sub-lineage BA.1 found in the U.K. is called XF. According to Dr Peacock, XF has the spike and structural proteins from BA.1 and the remaining part of the genome from Delta. “It comprises several tens of sequences currently,” he says.
The recombination of two Omicron sub-lineages BA.1 and BA.2 has been found in the U.K and is called XE. It was also recently reported in two passengers who had arrived in Israel. It has the spike and structural proteins from BA.2 and the remaining genome from BA.1. The XE is the most prevalent with hundreds of genomes already sequenced.
“XD is maybe a little more concerning. It has been found in Germany, Netherlands and Denmark and it contains the structural proteins from Delta. If any of these recombinants were to act much differently than its parent it might be XD,” Dr Peacock tweeted.
Cases in U.S.
Recombination of Delta and Omicron variants was found in the U.S. as well. The researchers found the “existence of these three unique mutation profiles that present compelling evidence that a recombinant virus was generated during co-infection…This recombinant replicated sufficiently to reach copy numbers that were detected by sequencing,” they write in a preprint posted in medRxiv on March 9, 2022. They identified “20 cases of co-infection with the Delta and Omicron variants, and two cases infected by a virus resulting from the recombination of Delta and Omicron”.
Different route
These two cases that contain only the recombinant virus of Delta and Omicron suggest that the actual recombination had happened in another person and increased in numbers in that person through replication and then effectively transmitted to a new host. “Yet, despite transmitting to a new host at least once, the transmission chain was not sustained; we have not observed any more of these recombinants in our sequencing data,” they write.
