There are now around 30 sequenced genomes of the monkeypox virus, which is currently causing the first major outbreak of the disease outside of Africa. And they make the sudden spread of the long-rare pathogen even more puzzling. On the one hand, the genetic data show that the virus is closely related to the West African lineage that had previously appeared in several countries outside of Africa. On the other hand, the genome contains an extremely large number of mutations – and nobody knows what that means.

At a total of 47 points in the genome, the current virus differs from the monkeypox virus, which appeared in Singapore, Israel, Nigeria and Great Britain after 2017 and whose genome was sequenced in 2018. The genome of smallpox viruses is very stable, the original human pox virus, for example, only changed in about one or two places per year. A similar rate is assumed for monkeypox. This would mean that monkeypox would have evolved about five to ten times faster than normal.

Experts have found this unusual collection of mutations in all the viruses in the outbreak that have been sequenced so far. It is therefore likely that all infections can be traced back to a single case, writes a working group led by João Paulo Gomes from the Portuguese National Health Institute in a preliminary publication on the genome data. However, the data do not reveal whether these mutations make the virus fitter and thereby caused the global outbreak.

It is reasonable to think that – analogous to the ever new variants of Sars-CoV-2 – this is a new variant of monkeypox that spreads faster and more easily. However, it is difficult to assess whether this is the case based on the mutations themselves. At around 200,000 base pairs, the monkeypox genome is much larger and more complicated than that of Sars-CoV-2 or influenza, for example.

The genome contains a total of 190 open reading frames. These are sections of the genome that probably encode individual proteins with a variety of functions. For example, some of the proteins are known to be produced very early in the infection and suppress the innate immune response, while others replicate the virus’ genome. In the last phase, the components of the newly emerging virus particles are formed.

In particular, there is no counterpart to the Sars-CoV-2 spike protein, the viral protein that binds highly specifically to a very specific cell receptor. Poxviruses make two different types of virus particles that are thought to bind to and enter cells in different ways. Therefore, with these viruses, it is much more difficult to assess from the mutations whether the virus has become more contagious or is escaping the antibodies that are present.

So it cannot be ruled out that the genetic changes represent an adaptation to humans – on the other hand, experts are currently discussing a completely different possibility. The observed mutations follow a very unusual pattern. 42 of the 47 mutations always affect the same dinucleotides, i.e. two genetic components right next to each other. In them, a cytosine has been converted into another tyrosine next to a tyrosine – or a guanine next to an adenine into another adenine, which is simply the same mutation, only on the opposite DNA strand.

It is extremely unlikely that an adaptation to a new host organism would produce such a specific pattern in the building blocks of the genome itself. Mutation and selection tend to start with the structure of proteins. In a forum discussion on the genetics of monkeypox, the evolutionary biologist Andrew Rambaut from the University of Edinburgh pointed out another possibility: an antiviral mechanism in the cells that attacks the DNA itself could have generated the mutation pattern in the viral genome.

Experts suspect a protein family called APOBEC3, which is part of a protective mechanism against retroviruses. These enzymes are so-called deaminases, they remove an amino group from up to 20 percent of all cytosine building blocks in the genome in the resulting DNA strand of the retrovirus. This creates the base uracil, which is read as thymine by the cell’s machinery. APOBEC3 proteins therefore cause a large number of mutations that potentially render the genome unusable.

However, smallpox viruses are not retroviruses. They do have a DNA genome, but a previous study showed that APOBEC3 proteins don’t target it effectively enough to stop poxviruses from replicating. But apparently, so the assumption, this antiviral mechanism of the cell is quite active and damages the genome of the virus considerably.

“What we see are the survivors,” explains University of Cambridge bioinformatician Cornelius Römer on Twitter. Only those viruses whose injuries from the antiviral system are not too severe propagate. This is also indicated by the fact that there are so many mutations that do not change the resulting protein, the researcher continues. Biophysicist Richard Neher of the University of Basel explains: “One should probably understand most of these mutations as ‘scars’ from the host’s defense system rather than as viral adaptations.”

But that’s only part of the story. There is also genetic evidence that the virus is beginning to adapt to humans. The team led by João Paulo Gomes reports on individual mutations that occur in many, but not all, of the virus genomes analyzed – an indication of the diversity of the virus genomes that evolution can begin with. In addition, the group found two viruses that lack a gene segment in a region that is believed to be responsible for binding to cells. This change is known from Central Africa. There it is suspected that it is related to more effective human-to-human transmission of monkeypox.

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