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May 2022 :
Peculiar Evolution of the Monkeypox Virus Genomes
Jean Claude Perez, PhD Maths§Computer Science Bordeaux University; Retired (IBM
European Research center on Artificial Intelligence Montpellier France);
Bordeaux metropole France; https://orcid.org/0000-0001-6446-2042 France
and Luc Montagnier Foundation Scientific Council, Quai Gustave-Ador 62 1207 Genève,
Switzerland, jeanclaudeperez2@gmail.com
Valère Lounnas , PhD, EMBL Heidelberg alumni, Meyerhofstraße 1, 69117 Heidelberg,
Germany
KEYWORDS
Monkeypox virus, Biomathematics, Master code, Evolution, Genomics,
Proteomics.
ABSTRACT
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.
INTRODUCTION
Monkeypox is a zoonotic disease caused by the monkeypox virus, an orthopoxvirus
closely related to variola virus, the causative agent of smallpox. Monkeypox was first
discovered in 1958 in monkeys, although they are not the source of the virus. Human
cases were first described in 1970. There are 2 strains of monkeypox: the West
African and Central African strains.
Several cases of monkeypox have been identified in various geographically
countries. In May 2022 cases were reported in Australia, Austria, Belgium,
Canada, Denmark, France, Germany, Greece, Israel, Italy, the Netherlands, Portugal,
Spain, Sweden, Switzerland and the U.K (NCBI, 2022), (Antwerpen M, et al, 2022),
(Isidro et al, 2022).
Figure1 – Monkeypox tree (from https://virological.org/t/first-german-genome- sequence-of-
monkeypox-virus-associated-to-multi-country-outbreak-in-may-2022/812 )
Nextrain reference tree https://nextstrain.org/monkeypox?s=03
Monkeypox is classified as a zoonotic disease where transmission of the virus is
usually due to animal-human contact. Genetically, monkeypox viruses cluster into two
groups: the Congo basin and the west African clade.
Monkeypox virus
Monkeypox virus Zaire-96-I-16
This particular outbreak has been identified as due to a virus from the west African
clade which is often associated with milder disease and, in this case, human-to-
human spread is suspected. The first referenced human to human strain was located
in Israel in 2018: a case of monkeypox in a man who returned from Nigeria to Israel
in 2018 (Erez et al, 2018).
MATERIALS and METHODS
Monkeypox strains analyzed :
We analyzed 14 monkeypox whole genomes:
Gabon 1988 alias 2015 KJ642619.1
https://www.ncbi.nlm.nih.gov/nuccore/KJ642619.1
Cameroun 1990 alias 2015 KJ642618.1
https://www.ncbi.nlm.nih.gov/nuccore/KJ642618.1
Liberia 1970 DQ011156.1
https://www.ncbi.nlm.nih.gov/nuccore/DQ011156.1
Nigeria 1971) alias 2015 KJ642617.1
https://www.ncbi.nlm.nih.gov/nuccore/KJ642617.1
2018 Israel MN648051.1
https://www.ncbi.nlm.nih.gov/nuccore/MN648051.1
Zaire 2009 alias 2020 NC_003310.1
https://www.ncbi.nlm.nih.gov/nuccore/NC_003310.1
Rivers state 2020 MT903340.1
https://www.ncbi.nlm.nih.gov/nuccore/MT903340.1
UK 2020 MT903344.1
https://www.ncbi.nlm.nih.gov/nuccore/MT903344
USA 2022 ON563414.1
https://www.ncbi.nlm.nih.gov/nuccore/ON563414.1?report=GenBank&s=03
German 2022 ON568298.1
https://www.ncbi.nlm.nih.gov/nuccore/ON568298
Singaore 2020 MT903342.1
https://www.ncbi.nlm.nih.gov/nuccore/MT903342.1?report=genbank
Nigeria 2018 MG693723.1
https://www.ncbi.nlm.nih.gov/nucleotide/MG693723.1?
report=genbank&log$=nuclalign&blast_rank=1&RID=98T6WWFV016
UK 2020 MT903345.1
https://www.ncbi.nlm.nih.gov/nucleotide/MT903345.1?
report=genbank&log$=nuclalign&blast_rank=1&RID=98TT3F4E013
France 2022 ON602722.1
https://www.ncbi.nlm.nih.gov/nuccore/ON602722.1?report=genbank
Biomathematics methods, The Master Code analysis :
The "Master Code" method (Perez, 2009), (Perez, 2015) and (Perez§Montagnier,
2021) allows, from the atomic masses common only to DNA, RNA and amino acids
numerical values, to highlight a META-CODE which would unify the 3 codes of DNA,
RNA and amino acid sequences.
Particularly, the Master code coupling curves measures the level of correlation
unifying the expression of 2 Genomics (DNA) and Proteomics (amino acids) for any
sequence, coding for a protein, or not.
In (Perez, 2017a) we analyzed all types of Prions in the early 2000s mad cow
disease (plants, yeast, humans, cows, sheep, etc.). We had then highlighted a
"signature" or sort of invariant which would be common to all Prions: a typical
signature of the Master code taking the characteristic form of a "W" (or even of an
“M” symmetrically). We had extended this type of analysis to amyloids implicated in
Alzheimer's disease (Perez, 2017b).
RESULTS
Table 1 – Evolution of the « T » bases contiguous region for the 14 analysed
genomes.
Name Genbank ID Start T location Number of T
Gabon1988 (2015) KJ642619.1 0
Cameroun1990 (2015) KJ642618.1 0
Liberia1970 DQ011156.1 0
ZAire2009 NC_003310.1 0
Nigeria1971 (2015) KJ642617.1 133245 27
Israel2018 MN648051.1 133298 19
Rivers state 2020 MT903340.1 133081 25
UK2020A MT903344.1 133081 27
Singapore2020 MT903342.1 133093 28
Nigeria2018 MG693723.1 126745 29
UK2020B MT903345.1 133100 28
France2022 ON602722.1 132972 19
USA2022 ON563414.1 133094 30
Germany2022 ON568298.1 133201 30
The last 3 cases analyzed date from May 2022. It is of note that the 2022 French
genome is limited to a succession of 19 T. But in fact this sequence may also accept
C bases substituted for T as both ttt and ttc codons are translated in phenyl-alanine
residue. In that respect the length of the French sequence is actually equivalent to
21T. Sequencing errors are possible but not to that extent over 8 nucleotides. So the
difference of the French sequence raises some question as it is obviously not the
same as the other strains in that respect. It is also the case for the Italian sequence
(ON622721 from https://www.ncbi.nlm.nih.gov/nuccore/ON622721.1/).
DISCUSSION
This is by chance that we have discovered the presence of a 30-T long sequence in the
middle of the USA2022 monkeypox genome, between the DNA-dependent RNA
polymerase subunit rpo132 and the cowpox A-type inclusion protein, before a gene
complement region that may become coding under circumstances that need to be
specified by expert in the field.
For instance, if we look at the monkeypox strain Gabon-1988 we can identify in this
region a sequence of nucleotide coding straightforwardly for a 42-aa long polypeptide
that may constitute a small protein.
Number of codons : 42
MGYLRSFYKRFHVPDHVQPSYVSPSLYRVYQSSLSEGDRTP.
Figure 2a – Genome sequence extract of monkeypox strain Gabon-1988 potentially coding for a
small protein after the DNA-dependent RNA polymerase subunit rpo132 and before the gene
complement.
Number of codons : 42
MGYLRSFYKRFHVPDHVQPSYVSPSLYRVYQSSLSEGDRTP.
Figure 2b – Genome sequence extract of monkeypox strain USA2022 potentially coding for a small
protein after the DNA-dependent RNA polymerase subunit rpo132 and before the gene
complement.
Number of codons : 42
MGYLRSFYKRFHVPDHVQPSYVSPSLYRVYQSSLSEGDRTP.
This growing pattern of T-bases in succession follows a conserved nucleotide sequence
that is conserved and may code for a small protein. The functional role of this pattern at
the viral genome level is unknown to us.
While it long repeat are common finding at the terminaison of a genome, as for instance at
the end of the monkey encephlitis virus, it is almost never encountered fully inside a
sequence.
Simian hemorrhagic encephalitis virus isolate Sukhumi, complete genome
Sequence ID: NC_038293.1Length: 15370Number of Matches: 1
•See 1 more title(s) See all Identical Proteins(IPG)
Range 1: 15336 to 15370GenBank GraphicsNext MatchPrevious Match
Alignment statistics for match #1
Score Expect Identities Gaps Strand
55.4 bits(60) 1e-04 33/35(94%) 0/35(0%) Plus/Minus
Query 133098 ttttttttttttttttttttttttttCGAATTCAC 133132
|||||||||||||||||||||||||| |||||||
Sbjct 15370 TTTTTTTTTTTTTTTTTTTTTTTTTTTTAATTCAC 15336
Why it is located in this region ?
Its presence at the end of what seems to be a potential protein may indicate a
possible genome regulation role.
May it have another functional role ?
Also remarkable, although there is no evidence this nucleotide sequence is in a
genome section that may be translated in aa, we find that a sequence of 30 T-bases
codes for a polypeptide chain of 10 phenyl-alanine residues in succession, and that a
Blast search for this unorthodox protein sequence surprisingly retrieves a signal with
an expectation value significantly beyond randomness (E≤0.001) for a match with an
identical polypeptide reported as a hypothetical protein in Plasmodium falciparum,
Yersinia pestis, Escherichia coli and Penicillium nordicum !
However, the question of the functional role remains open as we note (Figure3) this
T-base long repeat is located at a peculiar position of the genome predicted to have a
marked functional role according to the Master code (44000 aa/ 132000 nt).
An analysis zooming on the small section of 100 bases both sides of the 30-T
sequence shows its new functionality (Figure 3) or for the 19-T one in Figure 4.
Figure3a – Master code analysis of the whole USA2022 Monkeypox genome. The
region 44000 amino acids where there is the 30 T bases insert.appears to be highly
functional.
Figure3b – 100 bases upload and download the 30 T bases region in USA2022.
Figure4 - 100 bases upload and download the 19 T bases region in FRANCE2022.
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.
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