Discussion - Genetics: Monkeypox virus has managed 50 years worth of mutations in only 4 years - how?

[Emily]

Hat tip to Pathfinder.

https://www.statnews.com/2022/06/02/mutations-in-monkeypox-virus-explainer/

[Emily]

https://www.mdpi.com/1999-4915/12/11/1257#cite

Alakunle, E.; Moens, U.; Nchinda, G.; Okeke, M.I. Monkeypox Virus in Nigeria: Infection Biology, Epidemiology, and Evolution. Viruses 2020, 12, 1257. https://doi.org/10.3390/v12111257
...
4.2. Recombination

Poxviruses undergo high-frequency recombination during infection of cells [182,183]. Among OPVs, naturally occurring inter-specie recombination events have been detected between CPXV and ECTV [182,184] and intra-species recombination between strains of VARV [185] and VACV [186]. However, natural recombination events have not been reported for MPXVs. Recombination is believed to be one of the drivers of poxvirus evolution [182], but Babkin did not find evidence in support of the role of recombination in OPV evolution [187]. Nevertheless, there is substantial evidence that tandem gene duplications are a result of recombination [188,189].

Estep et al. used homologous recombination to replace the D14L gene with an EGFP-GPT cassette in MPXV-Z genome in order to determine the role of MOPICE in MPXV pathogenesis [190], and a recombinant MPXV encoding green fluorescent protein was engineered in order to study MPXV infection in a monkey model [191]. The ease of construction of recombinant MPXVs in the lab raises the possibility that such recombination may occur or have occurred in nature between co-infecting MPXVs, MPXVs, and naturally occurring OPVs, including VARV, as well as smallpox vaccine strains. Genome-wide recombination analysis of Nigerian MPXVs isolated from humans and animals will shed light on the role of recombination, if any, on the evolution of MPXVs in Nigeria...

[sharon sanders]

bump this

[Pathfinder]

...
arambaut
ARTIC Network
9 9d
...
Initial observations about putative APOBEC3 deaminase editing driving short-term evolution of MPXV since 2017.
...
Áine O’Toole & Andrew Rambaut
Institute of Evolutionary Biology
University of Edinburgh
Edinburgh, UK

The first MPXV genome sequences from monkeypox cases in 2022 (Isidro et al. 2022; Selhorst et al. 2022) showed, phylogenetically, that these viruses had descended from a clade sampled in 2017-2019 from cases diagnosed in Singapore, Israel, Nigeria and the UK. Comparing 2022 genomes from Portugal, Belgium, USA, Australia, and Germany (see Table 1) with the closest earlier genomes (denoted UK_P2 and UK_P3), identified 47 shared single nucleotide differences (Figure 1).

The long term evolutionary rate of the related variola virus (VARV; the smallpox virus) has previously been estimated to be about 9x10-6 (with 95% credible intervals of 7.8x10-6 – 10.2x10-6) substitutions per site per year (Firth et al. 2010) translating into about 1-2 nucleotide changes per year for a nearly 200,000 nucleotide genome. This makes 47 substitutions in the space of 3-4 years an unexpectedly large number. As MPXV is considered a zoonotic virus with limited human to human transmission, this long branch may be evidence of adaptation to humans allowing for the sustained transmission that is now observed.

However, 42 out of 47 of these nucleotide changes are of a particular type, a dinucleotide change from TC→TT or its reverse complement GA→AA. This specific mutation is characteristic of the action of the APOBEC3 family of deaminases. These act on single stranded DNA to deaminate cytosine to uracil causing a G→A mutation in the other strand when it is synthesised. Most human APOBEC3 molecules have a strong bias towards deaminating 5’TC dinucleotides , with the exception being APOBEC3G which prefers 5’CC dinucleotides (Yu et al. 2004).
...
This observation prompts a number of questions: Is this putative APOBEC3 editing occurring in a non-human animal reservoir host prior to emergence into humans in limited chains of human transmission? Or does this tree represent a multi-year history of sustained human transmission? Is the action of APOBEC3 acting as a driver of adaptation to humans as a host?
...
If APOBEC3 deamination is characteristic of replication in humans then we would expect to see very little evidence of it prior to the 2017 outbreak as this would primarily represent replication in the non-human reservoir. To examine this, we selected a further outgroup from Liberia, 1970 (accession number DQ011156.1; Likos et al. 2005) and identified 28 mutations that occur on the branch leading to the common ancestor of the 2017 MPXV genomes (Figure 3A). The mutations on this branch do not show such a strong signal, with only 10 of 28 SNPs matching the signature for APOBEC3 editing (Figure 3B). We therefore suggest that the pattern we see in these MPXV genomes since 2017 is indicative of replication in humans and the inheritance of the specific changes that occurred between 2017 and 2018 and then in the viruses from 2022 means that there has been sustained human to human transmission since at least 2017. The 10 mutations that do fit the APOBEC3 profile may represent an additional period of human to human transmission prior to the 2017 cases. Given that this is fewer APOBEC3 type mutations than seen in the branch between 2017 and 2018 (branch C in Figure 1), it is not likely that this represents a long period.
...

https://virological.org/t/initial-observations-about-putative-apobec3-deaminase-editing-driving-short-term-evolution-of-mpxv-since-2017/830

[Emily]

Pathfinder, the article you posted here does have the information Malone thought should be discussed. I think there has been confusion because another paper didn't reference this one, but a discussion page instead. See -

https://flutrackers.com/forum/forum/welcome-to-the-scientific-library/poxviridae-including-monkeypox/950366-discussion-of-on-going-mpxv-genome-sequencing-virological

[Emily]

ETA: See my comment to Pathfinder above.

APOBEC3 theory doesn't hold water. Dr. Malone writes in his substack:

• Here is the rub. While APOBEC3 is associated with cellular resistance (yet another form of “innate immunity” - isn’t molecular virology and cell biology amazing!) to HIV (and presumably other retroviruses), a quick pubmed search reveals that Poxviruses are resistant to the mutational effects of APOBEC3! For example, see this 2006 paper published in “Virology”. Frankly, whether through lack of curiosity or fear of attack from government controlled media and journals, the failure of the authors to even mention this Virology article is a major oversight at best. My inference and interpretation? On the basis of this sequence analysis report from the INSA team cited above, to me this is looking more like a laboratory manipulated strain than a naturally evolved strain. Bad news.

[Emily]

I'd assume the strain was manipulated before the 2022 outbreak. Or there was accidental recombination in Nigeria. I think there were some pox-vectored vaccines tested there recently.

[JJackson]

I do not think the linked 2006 paper has any bearing on the argument being made in the Virological threads.

"Results
The replication of vaccinia virus, a prototype poxvirus, was not, however, inhibited in APOBEC3G-expressing cells, nor did other members of the APOBEC3 family alter vaccinia virus replication."

Rambaut et al. are looking at the relative ratio of the base pairs and inferring the change detected is due to APOBEC not that it is inhibiting replication.

I can see no reason anyone should think the currently circulating MPX virus has been manipulated, the sequence data over the last 10 years shows a drift in the direction of the current form which is very much what you would expect from a normal zoonosis event.
Malone seems to have an opinion on everything but few of them make much sense.

[Emily]

The paper Malone referenced had the wrong link. That's why he got the impression Rambaut had overlooked the 2006 paper. It was relevant enough that he discussed it here. https://virological.org/t/initial-ob...since-2017/830

Everyone has opinions on everything. It's clear that the UK is where this virus changed dramatically - much more transmissible and possibly less virulent. There's a lot to explain about that.

[Emily]

Sounds like a mouse was running around nibbling on cell cultures in a biodefense lab.

https://www.researchgate.net/publication/360973596_May_2022_Peculiar_Evolution_of_the_Monkeypox_Virus_Genomes

May 2022 : Peculiar Evolution of the Monkeypox Virus Genomes

Perez, jean-claude & Lounnas, Valère. (2022). May 2022 : Peculiar Evolution of the Monkeypox Virus Genomes. We compare the evolution of 14 monkeypox virus genomes til that of May 2022 that is currently spreading across humans in numerous countries outside Africa. Our aim was to discover mutations or other viral evolutions (recombination) that may explain the sudden impact of this very low-level circulating epidemic or alert on a potential peculiar pathogenic character.

We have evidenced the presence of a large number of T bases in succession, at the level of the polymerase, between the DNA-dependent RNA polymerase subunit rpo132 and the cowpox A-type inclusion protein, progressively rising from the absence of a characteristically long pattern of T-bases in succession (≤ 10) in the early genomes of 1971, up to 19 T-bases in the Israel 2018 strain of reference, and 30 T bases thereafter in the 2022 strains. We find a complementary match for this long T bases sequence only in the simian hemorrhagic encephalitis virus, at the very 3' end of the genome after the stop codon, with a long succession of 28 A bases. More strikingly, we find that the corresponding 10 phenyl-alanine aa chain is reported as matching uniquely (E≤0.001) a hypothetical protein element in Plasmodium falciparum, Yersinia pestis, Escherichia coli and Penicillium nordicum. We wonder about the possibility that this region of the monkeypox genome may potentially code for a not yet identified polypeptides with a functional role situated right upstream this long T-repeat.

...
CONCLUSIONS
The objective was here to present a genome characteristic that may partly explain
the sudden propagation of the monkeypox virus in the form we observe in May 2022
in quite a number of countries.
The role of the peculiar 30-T base long sequence right in the middle of the virus
genome is still to be determined

[Pathfinder]

Hat tip Shiloh and Mary Wilson for the link.

https://www.gov.uk/government/public...cal-briefing-1

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3.2 Biological implications of the genome findings


The current UK monkeypox strain contains 48 single mutations in its genome relative to the 2018 UK monkeypox strain. Twenty-seven of these mutations are silent in that they do not change any of the viral proteins. Twenty-one of the mutations cause changes in viral proteins.

Mutations are classed in our assessment as low, medium and high priority for investigation, based on the known function of the viral proteins. These assessments are based on the effect of full deletion of these proteins from the virus. It is important to qualify that at present we cannot predict the effect of single mutations compared to full protein deletions. There are 2 mutations of low priority:

• C9L(R48C): Interferon agonist, when deleted the virus replicates worse in the presence of interferon
• A46L(H221Y): Virulence factor, deletion of gene reduces virus virulence in mice.

There are 4 mutations at medium priority:

• C23L(S105L): Chemokine binding protein, deletion of this gene from the virus increases disease severity in rabbits
• C22L(S54F): Tumour necrosis factor (TNF) receptor-like protein – deletion may increase lung pathology in mice
• C19L(D266N): Ankyrin repeat protein (unknown function-might be host range or virulence)
• F13L(E353K): Target of antiviral drug tecovirimat. Tecovirimat resistance has been shown to be conferred by a single mutation at F13L(G277C)

There are 3 mutations in one protein which are classed as high priority:

• B21/B22(D209N, P722S, M1741I): T-cell inhibitor also found in cowpox, camelpox and horsepox, knock-in of this protein into non-virulent cowpox strains increased disease severity and mortality in rats.

Whilst outbreak clade mutations are distributed across the genome, there is a small subset of mutations in proteins that are involved in virus transmission, virulence or interaction with antiviral drugs. Structural modelling is required to assess the impact of the individual mutations on the proteins.

...

[Pathfinder]

Translation Google


Numerous mutations – This is why the virus is successful

Status: 12:48 p.m | Reading time: 4 minutes

Why is monkeypox suddenly spreading? The virus is apparently mutating stronger and faster than previously thought. Astonishing insights into the development of the disease can be gained from the analysis of the mutations.

The current cases of monkeypox are causing great concern to authorities and scientists. So far, the disease, which currently affects young men in particular, has hardly spread outside of Africa. What has caused thousands of cases to appear in dozens of countries since May?

A new study in which the genome of monkeypox viruses was analyzed and compared could provide an answer to this question . Accordingly, the causative agent of the current outbreak has mutated surprisingly strongly. Compared to related viruses from 2018 and 2019, there are around 50 differences in the genome, writes a team from Portugal in the journal "Nature Medicine". This is about six to twelve times more than what would have been expected based on previous estimates for this type of pathogen.

The divergent branch could be a sign of accelerated evolution. The work is based on analyzes of Portuguese cases. So far, experts had spoken of a generally rather slow development with regard to this type of virus - especially in comparison with the frequent mutations of Sars-CoV-2.

The authors of the study suspect one or more imports from a country in which the virus is permanently present behind the current outbreak. Superspreader events and international travel then seemed to have fueled further spread.

"Our data provide additional evidence of ongoing viral evolution and possible adaptation to humans," writes the team led by João Paulo Gomes from the National Institute of Health Doutor Ricardo Jorge (INSA) in Lisbon.

The expert on the evolution of viruses, Richard Neher from the Biozentrum of the University of Basel, explained that the mutation rate was "indeed surprisingly high". The mutations would have a very specific pattern. The authors suspected that enzymes of the human immune system are responsible for these changes in the genome.

Even within the current outbreak, we are seeing this accelerated mutation. The rate is roughly one mutation per genome per month - with some uncertainty," said Neher. Sars-CoV-2 has about two mutations per genome per month, but the genome is about seven times smaller. However, such comparisons of mutation rates are not very meaningful and say little about the relative evolutionary mutability of the viruses.

When asked whether the mutations made the current spread possible in the first place, the scientist explained that to his knowledge there was no evidence of this, but that it could not be ruled out. Most of the mutations would "probably have no dramatic effects".

However, other researchers see evidence that the virus has been circulating largely unnoticed for several years. According to evolutionary biologist Trevor Bedford, the data available so far suggests that the virus became more transmissible from person to person at some point during this period. "The genetic patterns indicate that this happened around 2018," the scientist from the Fred Hutchinson Cancer Research Center in Seattle told the New York Times.

The enzyme APOBEC3 , which was discovered during research into HIV , seems to play a special role here . The enzyme helps the immune system fight off certain viruses by forcing them to introduce serious errors into the genetic material, thus preventing them from multiplying.

The increased mutations associated with the enzyme since 2018 could indicate that monkeypox viruses switched to using humans as hosts, according to Trevor Bedford.

WHO chief is concerned

Around 5,000 monkeypox infections have been reported worldwide this year alone. In more than 40 countries outside of Africa, where the disease was practically unknown until May, there were 3,308 cases, according to current information from the US health authority CDC. According to statistics from the World Health Organization (WHO), there are also around 1,600 suspected or confirmed cases in eight African countries, many of which have known such outbreaks for years.

WHO chief Tedros Adhanom Ghebreyesus expressed his concern about the current development in an emergency committee in Geneva on Thursday: "Human-to-human transmission is ongoing and is likely to be underestimated." Most of the reported cases involve men who have sex with men .

According to Ghebreyesus, people with a compromised immune system, pregnant women and small children are at risk of serious illnesses if they become infected. "It is important that countries remain vigilant and strengthen their capacities to prevent spread."

Most cases outside of Africa were reported in 29 countries in the WHO European region: a total of 2746, as reported by the EU health authority ECDC and the Regional Office for Europe of the World Health Organization WHO in a joint analysis. As can be seen from the data, almost all of the confirmed cases are male. Around 44 percent of those affected were between 31 and 40 years old.

https://www.welt.de/wissenschaft/article239546141/Affenpocken-Zahlreiche-Mutationen-Darum-ist-das-Virus-erfolgreich.html

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Study: Monkeypox virus mutates faster than previously thought


As of June 24, 2022, 1:21 p.m

A study on the first monkeypox genomes in Europe shows amazing results. The virus is a clearly new variant and is mutating faster than normal.

The analysis of the monkeypox virus is giving researchers more and more mysteries. The pathogen was actually considered very rare for a long time. As scientists have now found out in a study, the causative agents of the first major outbreak outside of Africa are a clear mutant, which, however, changes exceptionally quickly. This is what a working group led by João Paulo Gomes from the Portuguese National Health Institute writes in a study on the genome data that has been published in the scientific journal "Nature".

WHO emergency committee convened for monkeypox

"The strain of virus sequenced in May 2022 and associated with the current outbreak in Europe is a clearly distinct branch from the monkeypox viruses of the 2018/19 outbreak in African countries," the study said. The results also pointed to mutations in an ongoing evolution in human-to-human transmission. According to the researchers, this "continued accelerated evolution" could also explain the increasing transmission of the strain in Europe

First transnational outbreak in spring 2022

Monkeypox is a rare infectious disease that spreads between different species, including from animals to humans. It is caused by the monkeypox virus (MPXV) from the orthopoxvirus genus (which also includes the smallpox virus). To date, monkeypox has been localized primarily in West and Central African countries, with rare reports of cases outside of these regions being associated with imports from these countries. Until spring 2022. For the first time, the monkeypox virus spread across countries - also in Europe. More than 2,500 confirmed cases have been confirmed worldwide. (as of June 18).

How did the scientists come to accept the rapid mutation?

To study how the Spring 2022 outbreak began, João Paulo Gomes and colleagues reconstructed the genome sequences of the monkeypox virus (MPXV), which has been linked to the outbreak. Their conclusion: The MPXV from 2022 belongs to MPXV clone 3 and probably has a single origin. It differs from the related viruses from 2018 and 2019 by having about 50 single nucleotide polymorphisms (the occurrence of multiple gene variants), or genetic variations -- more than are usually expected for orthopoxviruses. Such a divergent branch could represent ongoing accelerated evolution, the authors believe.

Mutations during human-to-human transmission

In further analyses, the scientists actually found indications of ongoing evolution. During the human-to-human transmission of the current outbreak, they analyzed 15 single nucleotide polymorphisms, minor variants and the loss of a stretch of DNA (technical term gene deletions).

The monkeypox genome was first sequenced in 2018

Researchers first sequenced the genome, originally found in countries in West and Central Africa, in 2018 after previously appearing in Singapore, Israel, Nigeria and the UK. At that time, however, the virus was still associated with importation from African countries. The monkeypox outbreak in spring 2022 revealed for the first time a large number of diseases in Europe and also in Germany, which, as the researchers have just discovered, can be transmitted directly and also mutate from person to person. The current virus differs from the monkeypox virus of 2018 at a total of 47 points in the genome.
...

https://www.mdr.de/wissen/mensch-alltag/affenpocken-ausbruch-studie-schnelle-evolution-viele-mutationen-100.html

[Emily]

They must be frightened if they are clinging to the APOBEC3 theory. I think they should just say they don't know what is happening.

[Emily]

Too late to prevent monkeypox, but perfect timing to facilitate recombination between the wild virus and the live vaccine virus? The new strain circulated without recognition until now.

ETA: It could have circulated silently because the vaccinia virus from the vaccine attenuated the monkeypox virus in the cases that got ill after exposure to patient 3. Then as some live vaccine viruses do - it reverted to virulence.

https://flutrackers.com/forum/forum/...m-october-2018

[Mary Wilson]

1 day ago
By Ben Turner

The virus is mutating up to 12 times faster than expected.

... As a large double-stranded DNA virus, monkeypox is much more able to correct replication errors than an RNA virus such as HIV, meaning that the current monkeypox strain should have really only accumulated a handful of mutations since it first started circulating in 2018. But, after collecting DNA from 15 monkeypox viral samples and reconstructing their genetic information, the researchers found that the real mutation rate was six to 12 times higher than they expected.

The massive jump in the monkey virus's rate of mutation "is far more than one would expect considering previous estimates of the substitution rate for Orthopoxviruses," the researchers wrote in the paper. "Our data reveals additional clues of ongoing viral evolution and potential human adaptation."

Historically, monkeypox is transmitted from person to person by close skin contact with open skin lesions, bodily fluids, contaminated material or respiratory droplets coughed into the air. But the unprecedented speed of new infections could suggest that something may have changed about how the virus infects its hosts — and the new mutations could be a possible cause.

Many of the mutations identified by the researchers also carry telltale clues that they may have emerged due to the virus's contact with the human immune system, specifically a family of the virus-fighting enzymes called APOBEC3. These enzymes attack viruses by forcing them to make mistakes when they copy their genetic code, an act which usually causes the virus to break apart.

https://www.livescience.com/monkeypox-mutating-fast

[Emily]

This is the link from post #4 from Pathfinder. I think Rambaut might be saying he sees loss of fitness occurring in the mpxv virus.

https://virological.org/t/initial-observations-about-putative-apobec3-deaminase-editing-driving-short-term-evolution-of-mpxv-since-2017/830

Given the directional nature of these mutations this may act as a ratchet, irreversibly accumulating fitness-reducing mutations with other mutational processes, occurring at a much lower rate, unable to overcome this. Indeed, additional APOBEC3 type mutations have been observed within 8 genomes sampled from the outbreak in Portugal (Isidro et al. 2022) including 2 that are shared by 2 genomes suggesting ongoing transmission of these.

[Pathfinder]

Monkeypox may not mutate as fast as coronaviruses, but that doesn’t mean it can’t adapt to its new hosts

Published: June 24, 2022 11.37am EDT

Connor Bamford
Research Fellow, Virology, Queen's University Belfast
...
In general, large DNA viruses such as monkeypox are no different from other viruses, and their mutability is the basis for our ability to track and trace monkeypox outbreaks. They make mistakes and errors accumulate, which can be used as fuel for evolution and biological changes. There’s even evidence from the recent monkeypox outbreak that the host cell is directly mutating the virus genome.

Studies focusing on related poxviruses like the vaccinia virus have even uncovered new tricks they can use, which include rapidly amplifying the number of genes they use to attack our immune system. They could even borrow some of our own genes to help them infect us.

We can’t predict the trajectory that monkeypox evolution will take, so we must take the threat of this virus adapting to its new hosts (humans) seriously. And we need to use all the public health tools at our disposal to halt the current outbreak in all countries – including those where it is endemic.

...
https://theconversation.com/monkeypo...w-hosts-183855

[Pathfinder]

Translation Google

Monkey pox: rather different symptoms in Europe

Posted today

The first British patients with monkeypox, a disease that is spreading around the world, showed symptoms distinct from those usually spotted in African countries, according to a study. The bouts of fever and the skin lesions differ.

While a flare-up of fever was considered almost systematic in monkeypox in West Africa, where this condition had hitherto been limited, just over half of the patients studied in the United Kingdom had it, note this study published Saturday in the Lancet Infectious Diseases.

Carried out on about fifty patients, this work, still limited, is one of the first to characterize the clinical specificities of the current epidemic of monkeypox.

This disease was previously limited to ten African countries. But, for several months many cases, more than 3000 according to the latest news from the World Health Organization (WHO), have been recorded in Europe, including in Switzerland, and on the American continent.

In the study sample of half of the cases that arose in the UK, monkeypox manifested markedly differently from what was known in Africa. Not only are bouts of fever less frequent, but they also appear much shorter and require far fewer hospitalizations.

No genetic modification

As for the typical lesions of the disease, they are most often concentrated around the genitals. In the previous cases, they were generally larger, reaching for example the face or the nape of the neck.

For the authors of the study, this specificity suggests that the first British cases were contaminated by contact during sexual relations. This hypothesis, to be clearly distinguished from the idea that the disease has become sexually transmitted, corresponds to the well-established notion that contamination is possible by touching a skin lesion in another patient.

However, these different symptoms do not mean that the current epidemic is due to a new version of the virus, as other researchers point out. "There is no major genetic modification" in the viruses sequenced in current patients, noted pulmonologist Hugh Adler.

He argues that in Africa, many cases, without fever or with limited lesions, may have gone undetected, biasing comparisons.

https://www.laliberte.ch/news-agence/detail/variole-du-singe-des-symptomes-plutot-differents-en-europe/652083

[Pathfinder]

Monkeypox virus mutations 'challenging' what we know

New research suggests that monkeypox is mutating surprisingly fast in Europe and North America. The study shows how little we know about the virus.

Date 04.07.2022
Author Clare Roth

The monkeypox virusspreading across the US, Europe and the UKis mutating surprisingly fast, according to a study conducted by Portuguese researchers and published in the journal Nature Medicine. The study offers the most in-depth look at the genetic makeup of the virus so far.
...
There are a few things we know about monkeypox, and this new genome sequencing has helped researchers understand the current outbreak better.

First, the strain of the virus in the current outbreak is mutating at an unusually fast rate.

Second, the outbreak probably started with a single case infecting others at a large superspreader event.
...
The World Health Organization has identified the "index case" — the first confirmed case — as a person who traveled from Nigeria to the United States in early May.

But the researchers in Portugal dispute that idea because, they say, there were confirmed cases in Portugal and the United Kingdom in late April.

If the researchers in Portugal are correct, we know less than we thought about the current outbreak, including how it has evolved and what it is likely to do next.
...
"The authors describe an unexpectedly high number of mutations in the virus, but their implications for disease severity or transmissibility are unclear," Hugh Adler, a researcher at the Liverpool School of Tropical Medicine, said in response to the paper. He was not involved with the research.

"We have not identified any change in the severity of clinical disease in patients diagnosed in the current outbreak," said Adler, who has worked with monkeypox patients in the United Kingdom during previous outbreaks.
...
Monkeypox is a double-stranded DNA zoonotic virus. DNA viruses mutate slower than RNA viruses, such as the one that causes COVID-19.

But we generally lack a lot of knowledge about monkeypox. The researchers in Portugal, for instance, cite only a single other study on the genetics of the virus.

Adler said the study of the virus's genetics was "still in its infancy."

"We have the genome sequence, so we have an idea of what the genes are," Adler said. "But, in terms of really understanding what they do and the implications for evolution, if the genes change — there's very little research done on that compared to a lot of the other big viruses that we know."
...

https://www.dw.com/en/monkeypox-virus-mutations-challenging-what-we-know/a-62349012

[Emily]

https://www.scientificamerican.com/article/why-is-monkeypox-evolving-so-fast/

Why is Monkeypox Evolving So Fast?


The virus circulating in the current outbreak has mutated 50 times in the past four years

• By Sara Reardon on July 20, 2022

...
Thus far, Neher wrote on Twitter, there is no indication that the mutations have helped the virus adapt to humans. In fact, most random mutations do nothing at all, so the new changes in the monkeypox genome may just be markers of human infection rather than the cause. Most of the mutations that Gomes’s team identified were small, although one gene had been deleted.

Orthopoxviruses seem to be able to survive a great deal of mutation. One study that analyzed smallpox in the skeletons of sixth-century Vikings found numerous genes that are inactivated in modern smallpox strains, suggesting that gene deletions are a normal part of how orthopoxviruses and host species adapt to one another.

That observation doesn’t mean mutations that help the monkeypox virus infect and spread in humans won’t appear in the future, says Geoffrey Smith, a virologist at the University of Cambridge. Several of the genes Gomes’s team identified occurred in proteins that interact with the human immune system, although there is no evidence that these strengthened the virus.

Roper isn’t so sure. “It’s my belief it mutated in some way early in this jump to become more transmissible in humans,” she says. Roper suspects that one of these fitter forms of the virus ended up in a so-called superspreader event. HIV followed a similar pattern: it jumped from animals into people several different times before becoming widespread. “This time [monkeypox] really got a foothold,” she says.

If mutations that helped the virus did appear, Smith says, scientists would be able to spot them. He and many others have spent decades studying the smallpox genome, whose central region is 96 percent identical to that of monkeypox. They know which proteins allow the virus to escape the immune system, for instance, or to spread more easily. “We know what to look for and haven’t seen it yet,” Smith says.

Still, Roper thinks it will likely be years before scientists can pinpoint which of the mutations that occurred are important and why. “These experiments are really hard to do,” she says. With SARS-CoV-2, for example, certain combinations of mutations seem to affect the virus’s ability to spread while other combinations do not...