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

[Emily]

https://www.biorxiv.org/content/10.1101/2022.06.18.496696v1.full

A peculiar evolutionary feature of monkeypox virus

Yicong Dai, Xucong Teng, Difei Hu, Qiushuang Zhang, Jinghong Li

bioRxiv 2022.06.18.496696; doi: https://doi.org/10.1101/2022.06.18.496696

...We report a non-canonical RNA secondary structure, G-quadruplex (RG4), that surprisingly evolved stepwise with various variants. The RG4 motif is located in the coding sequence region of MPXV C9L gene that is functional in inhibiting host innate immune response. The evolution decreases the stability of this RG4 and promotes C9L protein level in living cells. Importantly, all the reported MPXV genomes in 2022 contain the most unstable RG4 variant, which may be the reason of the increasing spread of MPXV. These findings recommend that health authorities and researchers pay attention to the genomic evolution of MPXV.

[Emily]

The new injectable smallpox vaccine, (same vaccine approved for monkeypox now), had been in trials and used experimentally in the UK since 2017.

https://www.mdpi.com/1999-4915/14/2/388/htm#B10-viruses-14-00388

Babkin, I.V.; Babkina, I.N.; Tikunova, N.V. An Update of Orthopoxvirus Molecular Evolution. Viruses 2022, 14, 388. https://doi.org/10.3390/v14020388
...

As was first established by Babkina et al. [37], all VARV strains of the 20th century are divided into two clades, namely P1 and P2 (Figure 2). According to our updated data, their separation took place around 1694 AD (Table 2); this is consistent with the dating of Mühlemann et al. [2], Pajer et al. [14], Smithson et al. [15], and Duggan et al. [12]. tMRCA of VARV strains of PI and P2 groups in our work was estimated as 1908 and 1878 AD, respectively (Table 2). These time estimates indicate the recent origin of the biodiversity of the studied VARV strains, and it has been suggested that large-scale vaccination may be the main reason for this [12,38]. In addition, the analysis of a limited set of strains isolated mostly during large outbreaks of smallpox, may not reflect the entire genetic diversity of the VARV strains circulated in the middle of the 20th century. There is little genetic diversity within the P1 group; however, historical records indicate the existence of VARV strains with different pathogenicity [1]. Indeed, analysis of the variability of viral genomes caused by large-scale vaccination can be a very interesting task. The variability of VARV genomes was suggested to be decreased after the large-scale administration of the VACV vaccination. Such reduction of the number of circulating strains was noted for some RNA-viruses after the use of vaccines and therapies [38,39]. However, a small set of available VARV strains circulated before the vaccination program does not allow for such an observation.

[Pathfinder]

bioRxiv preprint doi: https://doi.org/10.1101/2022.07.23.501239; this version posted July 25, 2022
...
Genetic variability, including gene duplication and deletion, in early sequences from the 2022 European monkeypox outbreak

Terry C. Jones1,2,3,§, Julia Schneider1,2, Barbara Mühlemann1,2, Talitha Veith1,2, Jörn
Beheim-Schwarzbach1
, Julia Tesch1
, Marie Luisa Schmidt1
, Felix Walper1
, Tobias Bleicker1
,
Caroline Isner4
, Frieder Pfäfflin5
, Ricardo Niklas Werner6
, Victor M. Corman1,2,7, Christian
Drosten1,2,*
...

Abstract

Genome sequences from 47 monkeypox virus infections detected in a German university
virology laboratory were analyzed in context of other sequences from the 2022 outbreak and
earlier monkeypox genomes. Identical non-synonymous amino acid changes in six genes and
the signature of APOBEC editing match other sequences from the European outbreak.
Non-synonymous changes that were present in one to three sequences were found in 34 other
genes. In sequences from two lesions of one patient, an 856 nucleotide translocation between
genome termini resulted in the duplication of an initial 5’ gene, and the disruption or complete
deletion of four genes near the 3’ genome end. Orthopoxvirus genome rearrangements of this
nature are known to confer fitness advantages in the face of selection pressure. This change
may therefore represent an early virus adaptation in the novel widespread and sustained
human-to-human context of the current monkeypox outbreak.
...

Discussion

Changed host population conditions, including absence of VARV- or VACV-derived immunity in
those aged under ~45 years and an altered contact pattern in the involved index population,
now appear to favor sustained human-to-human transmission, which is a novelty in MPXV3,42
.
There is evidence that poxvirus specialization in a new host involves inactivation of host-specific
genes influencing host range, immunomodulation, and virulence16,17. The ongoing outbreak
raises concerns regarding the potential of virus establishment in the human population. Among
the most pressing issues in surveillance is the identification of potential markers of human
adaptation. The dearth of genome information from humans infected prior to the present
outbreak is a major challenge. The NCBI database query retrieved 76 complete pre-2022 MPXV
genomes. This offers only a very modest and uneven representation of the genetic diversity of
MPXV in the 64 years since its original detection in 1958. In addition to the paucity of data, a
combination of factors makes it currently impossible to draw unequivocal conclusions regarding
the evolution of MPXV. These include the high likelihood of multiple non-human interspecies
transmissions, multiple zoonotic spillovers and possibly reverse-zoonosis, the possibility of
multiple reservoir species with differing evolutionary rates, latent subclinical infections (already
documented for several orthopoxviruses, possibly including MPXV43), and the distorting
influence of genome editing by host enzymes from the APOBEC family.
...
The dynamics of previous MPXV outbreaks may have no relevance to future evolution now that
the virus has apparently achieved relatively sustained and widespread human-to-human
transmission. The consequence of changes in poxvirus genes whose products are no longer
required in a new host or otherwise altered context is unpredictable49. For example, genes
promoting virulence in VACV are inactivated in VARV, yet VARV is much more virulent50–52, and
the loss or inactivation of host immune system-modulating genes in VACV can result in
increased virulence40. We should not be complacent regarding the current outbreak, based on
the prior history of MPXV in humans. The phenotypic potential of a poxvirus finding itself in a
new host population should not be discounted, as evidenced by the impact of the introductions
of myxoma virus in Australia and squirrelpox in the UK. The poxvirus that eventually became the
human-specific VARV was also originally a non-human virus. As with MPXV, VARV may have
had a long early history of dead-end zoonoses; it has been convincingly argued that VARV
caused only mild disease prior to the seventeenth century53. The MPXV phenotype we have
known for the last 64 years may not resemble near-future human MPXV.
...
https://www.biorxiv.org/content/10.1...239v1.full.pdf

https://www.biorxiv.org/content/10.1...07.23.501239v1

[sharon sanders]

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Monkey pox: ongoing studies on its genetic mutations

AFP , published on August 18, 2022 at 02:17


Studies are underway to determine whether genetic mutations in the monkeypox virus are behind the rapid spread of the disease, the World Health Organization (WHO) told AFP on Wednesday.


The two distinct clades or variants of the virus were called the Congo Basin (Central Africa) and West Africa clades, after the two regions where they are endemic. On Friday, the WHO renamed these groups Clade I and Clade II respectively, in order to avoid any risk of geographical stigmatization.

She also announced that clade II has two subclades, IIa and IIb, with viruses from the latter identified as the source of the current global epidemic.

On Wednesday, the WHO clarified that clades IIa and IIb are related and share a recent common ancestor – therefore IIb is not an offshoot of IIa.

"Looking at the genome, indeed there are some genetic differences between the viruses in the current outbreak and the older clade IIb viruses," the WHO told AFP. "However, nothing is known about the significance of these genetic changes, and research is ongoing to establish the effects (if any) of these mutations on disease transmission and severity."

“It is still early, both in the epidemic and in laboratory studies, to say whether the increase in infections could be due to the genome changes observed in the virus, or if it is due to factors related to the host (human),” according to the WHO.

...

https://www.rtl.be/info/magazine/science-nature/variole-du-singe-etudes-en-cours-sur-ses-mutations-genetiques-1396595.aspx

[Emily]

https://www.medrxiv.org/content/10.1101/2022.08.10.22278644v1.full

Wide mismatches in the sequences of primers and probes for Monkeypox virus diagnostic assays
Fuqing Wu, Jeremiah Oghuan, Anna Gitter, Kristina D. Mena, Eric L. Brown
medRxiv 2022.08.10.22278644; doi: https://doi.org/10.1101/2022.08.10.22278644
...

Genetic variations across real-time PCR assays for MPV or OPV detection and epidemiological analysis

We next investigated genomic sequences in conserved regions that differ between the real-time PCR assays. About 96% of genomes have a G->T mutation in the probe of MPV_O2L assay, and this mutation is present across all MPV-2022 outbreak genomes (Figure 2A). Further analysis using the sample collection date found that this G->T mutation appeared in two samples in 1962 and 1970, was not detected in samples from 1978 to 2007, and re-emerged from 2017 onward (Figure 2B). For the OPV_I7L assay reverse primer, a C->T mutation was observed at the 3’ end in about 92% of all genomes and in 98.7% of genomes sequenced in 2022. It is interesting that this mutation is mostly observed in samples from Europe, South, and North America whereas the original sequence was more common in samples from Africa and Asia (Figure 2C). A G->C substitution in the probe sequence of OPV_B2R was observed in nearly all genomes sequenced in the MPV-2022 outbreak (Figure 2A).

[Pathfinder]

Related to:
Comparison of Monkeypox virus genomes from the 2017 Nigeria outbreak and the 2022 outbreak - SFAM

https://flutrackers.com/forum/forum/welcome-to-the-scientific-library/poxviridae-including-monkeypox/959500-comparison-of-monkeypox-virus-genomes-from-the-2017-nigeria-outbreak-and-the-2022-outbreak-sfam

UAMS Researchers Find Changes in Monkeypox Genome That May Explain Its Recent Rapid Spread


By David Robinson


Sept. 26, 2022 | LITTLE ROCK — The rapid spread of monkeypox is unlike the virus’ past outbreaks and may be a result of genetic mutations identified by University of Arkansas for Medical Sciences (UAMS) researchers.

Led by UAMS’ David Ussery, Ph.D., the UAMS team published its findings this month in the Journal of Applied Microbiology.

The team compared the genomes of the 2022 virus to monkeypox genomes from a 2017 outbreak in Nigeria, plus sequenced genomes from localized outbreaks in 1965 and 1970. None of the previous monkeypox variants spread beyond their place of origin in Africa.

The UAMS team’s bioninformatics analysis using advanced genomic sequencing methods revealed 25 mutations, 14 of which appear to change protein function and bear further research, said Ussery, a professor in the College of Medicine Department of Biomedical Informatics and director of the Arkansas Center for Genomic and Epidemiology Medicine at UAMS.

“At least one of the differences we found could be responsible for why the current virus is causing a pandemic while past strains of monkeypox viruses did not,” he said.

The team’s article notes that the current monkeypox virus outbreak is not only the largest known outbreak to date, the infections result in much different clinical and epidemiological features compared to previous outbreaks.

In July, the World Health Organization declared the monkeypox outbreak a global health emergency.

While the virus is not usually lethal, its genetic makeup is strikingly similar to smallpox, Ussery said, so health officials and researchers are monitoring it closely. Smallpox killed an estimated 300–500 million people in the 20^th century before a vaccine campaign eradicated the virus by 1979.

“Monkeypox is 99.5% identical to smallpox,” Ussery said. “It is so closely related that if you are old enough to have been vaccinated for smallpox, you are likely protected against monkeypox.”

The research team’s findings are a starting point for additional investigation in the lab, he said. A follow-up study will be needed to identify the changed properties of the monkeypox virus and to test which mutations are responsible for the virus’ increased ability to spread.

Co-authors on the publication are:

• Visanu Wanchai, Ph.D., postdoctoral fellow, UAMS College of Medicine Department of Biomedical Informatics
• Trudy Wassenaar, Ph.D., a UAMS genomics consultant and frequent collaborator

...

https://news.uams.edu/2022/09/26/uams-researchers-find-changes-in-monkeypox-genome-that-may-explain-its-recent-rapid-spread/

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RESEARCH HIGHLIGHT
16 November 2023

Mpox virus evolving due to sustained human transmission

Virus has been transmitting among people for longer than expected.

Gilbert Nakweya

Human-to-human transmission, rather than zoonotic spillover, is the driving force behind a surge in Mpox virus cases, according to a study in Science.
...
“MPXV genome sequences show more mutations than would be expected of a poxvirus over such a short period of time. Our analysis shows that APOBEC3 has been generating these mutations as part of an antiviral mechanism, raising questions of longer-term viral fitness,” said O’Toole.

O’Toole says estimates show that these mutations began accumulating at least as early as 2016, suggesting MPXV has been transmitting in the human population since then, a big change from its previous classification as a primarily zoonotic virus.

...https://www.nature.com/articles/d44148-023-00318-6

------------------------------------------

APOBEC3 deaminase editing in mpox virus as evidence for sustained human transmission since at least 2016

ÁINE O’TOOLE https://orcid.org/0000-0001-8083-474X , RICHARD A. NEHER https://orcid.org/0000-0003-2525-1407, NNAEMEKA NDODO https://orcid.org/0000-0003-2792-8311, VITOR BORGES https://orcid.org/0000-0003-3767-2209, BEN GANNON https://orcid.org/0009-0005-9588-6063, JOÃO PAULO GOMES https://orcid.org/0000-0002-2697-2399, NATALIE GROVES https://orcid.org/0000-0002-3832-3484, DAVID J. KING https://orcid.org/0000-0003-0093-6549, DANIEL MALONEY, [...], AND ANDREW RAMBAUT https://orcid.org/0000-0003-4337-3707 +11 authorsAuthors Info & Affiliations

SCIENCE
2 Nov 2023
Vol 382, Issue 6670
pp. 595-600
DOI: 10.1126/science.adg8116
7,741 Metrics

...
Editor’s summary

In March 2022, an international epidemic of human Mpox was detected, showing that it was not solely a zoonotic infection. A hallmark of the approximately 88,000 cases that have been reported were TC>TT and GA>AA mutations in Mpox viruses, which were acquired at a surprisingly high evolutionary rate for a pox virus. Knowing that these types of mutation are a sign of activity by a host antiviral enzyme called APOBEC3, O’Toole et al. investigated whether the mutations reflected human-to-human transmission rather than repeated zoonotic spillover. Bayesian evolutionary analysis showed that Mpox virus recently diversified into several lineages in humans that display elevated numbers of mutations, signaling APOBEC exposure and sustained human-to-human transmission rather than zoonosis as the source of new cases. —Caroline Ash

Abstract

Historically, mpox has been characterized as an endemic zoonotic disease that transmits through contact with the reservoir rodent host in West and Central Africa. However, in May 2022, human cases of mpox were detected spreading internationally beyond countries with known endemic reservoirs. When the first cases from 2022 were sequenced, they shared 42 nucleotide differences from the closest mpox virus (MPXV) previously sampled. Nearly all these mutations are characteristic of the action of APOBEC3 deaminases, host enzymes with antiviral function. Assuming APOBEC3 editing is characteristic of human MPXV infection, we developed a dual-process phylogenetic molecular clock that—inferring a rate of ~6 APOBEC3 mutations per year—estimates that MPXV has been circulating in humans since 2016. These observations of sustained MPXV transmission present a fundamental shift to the perceived paradigm of MPXV epidemiology as a zoonosis and highlight the need for revising public health messaging around MPXV as well as outbreak management and control.


...

https://www.science.org/doi/10.1126/science.adg8116