Has the coronavirus passed from animals to humans twice?

SARS-CoV-2, the virus that causes COVID-19, could have spread multiple times from animals to humans, according to a preliminary analysis of viral genomes sampled from people infected in China and elsewhere at the start of the pandemic.

If confirmed by further analysis, the results would add weight to the hypothesis that the pandemic originated in several Wuhan markets and make the hypothesis that SARS-COV-2 escaped from Wuhan less likely. a laboratory, according to some researchers. But the data needs to be verified and the analysis has yet to be peer reviewed.

The first viral sequences, taken from people infected in late 2019 and early 2020, are divided into two major lineages, called A and B, which have key genetic differences.

The B line has become the dominant line in the world and includes samples taken from people who visited the Huanan seafood market in Wuhan, which also sold wild animals. Lineage A has spread to China and includes samples from people linked to other markets in Wuhan.

A crucial question is how the two viral lineages relate. If the A lineage viruses evolved from those of the B lineage, or vice versa, this would suggest that the ancestor of the virus only passed once from animals to humans. But if the two lineages have separate origins, then there could have been multiple overflow events.

Dagger in the heart

The latest analysis – posted on the virological.org discussion forum – adds weight to the second possibility by questioning the existence of genomes linking lineages.

The discovery could be the “dagger at the heart” of the hypothesis that SARS-CoV-2 escaped from a lab, rather than coming from the wildlife trade, says Robert Garry, virologist at the Tulane University in New Orleans, Louisiana. But others say more research is needed, especially given the limited genomic data from the start of the pandemic.

“This is a very important study,” says Garry. “If you can show that A and B are two separate lineages and there has been two fallout, that virtually eliminates the idea that it came from a lab.”

The results are “consistent with the fact that there have been at least two introductions of SARS-CoV-2 into the human population,” said David Robertson, a virologist at the University of Glasgow, UK.

Lines A and B are defined by two key nucleotide differences. But some of the early genomes show a combination of these differences. Researchers previously thought that these genomes could be those of viruses at intermediate stages of evolution linking the two lineages.

But the researchers behind the new analysis examined them in detail and noticed a few issues.

Fine tooth comb

They analyzed 1,716 SARS-CoV-2 genomes in a popular online genome repository called GISAID that was collected before February 28, 2020, and identified 38 of these “intermediate” genomes.

But when they took a closer look at the sequences, they found that many of them also contained mutations in other regions of their genomes. And they say these mutations are definitely associated with lineage A or lineage B – which discredits the idea that the corresponding viral genomes date from an intermediate stage of evolution between the two lineages.

The authors suggest that a laboratory or computer error probably occurred while sequencing one of the two mutations in these “intermediate” genomes. “The more we dug, the more it looked like, maybe we can’t trust any of the ‘transitional’ genomes,” says study co-author Michael Worobey, evolutionary biologist at the University of ‘Arizona, in Tucson.

Such sequencing errors are not unusual, according to the researchers. Software can sometimes fill in gaps in raw data with incorrect sequences, and virus samples can be contaminated, notes Richard Neher, a computer biologist at the University of Basel in Switzerland. “Such mishaps are not surprising,” he says. “Especially at the start of the pandemic, when the protocols weren’t very established and people were trying to generate data as fast as they could.”

Several researchers contacted by Nature, who sequenced some of the samples included in the study, says their sequences are unlikely to contain errors in the two key nucleotides. But the study authors counter that even though some of the genomes were sequenced correctly, other parts of the same genomes, or the locations from which the samples were taken, still make it clear that they belong to one. or the other line, he said.

“It is very unlikely” that any of the so-called intermediate genomes are actually transitional genomes, says study co-author Joel Wertheim, molecular epidemiologist at the University of California, San Diego.

Xiaowei Jiang, an evolutionary biologist at Xi’an Jiaotong-Liverpool University in Suzhou, China, said the team behind the study must verify the results by obtaining “the raw sequencing data. origin for as many genomes as possible ”.

Many markets

While the virus has jumped between animals and humans on multiple occasions, the fact that lineages A and B are linked to people who have visited different markets in Wuhan suggests that several individual animals, of one or more species, are carriers of the virus. ‘an ancestor of SARS- CoV-2 could have been transported through Wuhan, infecting people in at least two places.

A study published in June¹ found that live animals susceptible to SARS-CoV-2, such as raccoon dogs and mink, were sold in many markets in Wuhan. Previous studies² of the virus that caused Severe Acute Respiratory Syndrome (SARS) concluded that it had also probably jumped from animals to humans several times.

The latest study, if verified, would mean that the scenario of a researcher accidentally infected in a lab, then spreading the virus to the general population, should have happened twice, Garry says. The pandemic is much more likely to have its roots in the wildlife trade, he says.

To gather more evidence, the team behind the new analysis now plans to run computer simulations to test how well the multiple fallout would accommodate the diversity of known SARS-CoV-2 genomes.