First report of natural recombination of the monkeypox virus genome

First report of natural recombination of the monkeypox virus genome

In a recently published study medRxiv * Preprint Server, researchers analyzed monkeypox virus (MPXV) sequences during the current outbreak in 2022 to investigate whether MPXV adapts for improved survival and viral transmission among humans.

Lernen: Rekombination prägt den Ausbruch der Affenpocken im Jahr 2022. Bildquelle: ART-ur/Shutterstock

*Important NOTE:medRxiv publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health-related behavior, or treated as established information.

background

The ongoing MPXV outbreak in 2022 has represented MPXVA transmission in non-endemic areas outside the western and central parts of Africa. MPXV was discovered in the United Kingdom (UK) in May 2022, and thereafter case numbers increased rapidly in Europe, Asia, Africa, Oceania, and the northern and southern parts of the Americas.

Subsequently, MPX was declared an international public health emergency by the World Health Organization (WHO) on July 23, 2022, and MPXV has affected several nations to date. Most viral sequences recovered from the ongoing MPXV outbreak have been reported to be B.1 MPXV clade sequences. Data on natural recombination of MPXV are lacking.

About studying

In the present study, researchers analyzed 415 B.1 clade MPXV sequences worldwide from the National Center for Biotechnology Information (NCBI) database between January 1 and July 20, 2022, by examining linkage disequilibrium [LD, a single nucleotide variant (SNV)-based analysis] and tandem repeats (TRs), with a focus on exploring the genomic variability of MPXV through recombination to determine the likely risks of new MPXV strains.

MPX recombination was assessed by analysis of tandem repeats (TRs), and LD analysis was performed to detect new MPXV lineages and viral recombination in the ongoing MPXV genome of the 2022 outbreak. The viral populations were divided into six groups based on the TR numbers (TRNs) of TRA/E. Single nucleotide polymorphism (SNPs) analysis was then performed.

Results

The analysis results showed that the MPXV population of the ongoing outbreak in 2022 has divided into four and 11 lineages and subgroups, respectively, and four lineages based on the TRs and CNs (copy numbers). Furthermore, the results of LD analysis showed that MPXV evolved into three new lineages. The team identified six, one and one new recombinant MPXV from Slovenia, Italy and Australia, respectively, by analysis of TRs and two and one MPXV recombinant from Germany and Spain, respectively, by LD analysis.

Six TRs with different copy numbers were identified, TR A/E had identical sequences of 16 base pairs (bp) with inverted TRs at both MPXV genome ends. In total, 378 cases (91%) and 14 cases (three percent) included TRNs 7,9 and 16, respectively, obtained from the United States of America (USA), Czech Republic and Belgium.

A case with TRN values ​​of six, four and three was detected in the United Kingdom (UK). The team identified 21 cases of mismatch with different TRN values ​​between TRs E and A. The results showed that genetic diversity could be categorized based on the TR polymorphisms in the current MPXV outbreak populations. TR B, TR C, TR D, and TR F were found to be direct repeats located in the intergenic regions or 3′-terminal (inverted) TRs. TR F and TR C comprised three and one 5′-TATGATGGA 3′-bp sequence copies, respectively.

While most virus sequences contained TR F (97%, TRN value of 3.5), 51% and 48% of virus samples contained TR C with TRN values ​​of 10 and 8, respectively. Based on the TR C/F patterns, MPXV populations could be categorized into four lineages (M, U, I, and uncategorized lineages with 210, 193, and one case, respectively.

Furthermore, in conjunction with TR A/E and TR C/F TRNs, the team divided MPXV populations into 11 viral subdivisions. TR D contained the nine bp 5′-ATATCATT-3′ sequence with varying CNs and TRNs ranging between 2.0 and 55, respectively. Interestingly, viral sequences with higher TR D TRNs (TRN greater than 30) also contained more TR A/E TRNs (20 cases with TRN greater than 16) in the U group, suggesting greater TR diversity in the U lineage than others MPXV lines.

Using TR polymorphisms, eight genomes of MPXV with recombinant viral crosses were identified. Case ON755039 (FVG-ITA-01) from Italy could originate from parental M and I group sequences. Case ON631963 (VIDRL01) from Australia was derived from parental viral sequences of the U and M groups, as were six Slovenian cases (ON631241, ON838178, ON754986, ON754985, ON609725, and ON754987). The results also showed that the six cases from Slovenia may have given rise to a new lineage.

LD analysis showed five SNP pairs at G148421A/G34305A, G74357A/C22736T, C188379T/G186153A (eight cases), G189246A/G148421A and G189246A/G34305A with high LOD (Log of Odds, greater than) values 10) and strong LD. G74357A/C22736T SNPs were detected in 28 MPX cases, including 25 cases, one case, one case, and one case in Germany, Austria, Portugal, and the United Kingdom, respectively.

In Germany, SNP pairs of C188379T/G186153A were detected in eight cases. Fourteen cases in Canada included G148421A/G189246A/G34305A SNPs. The results suggested evolution of MPXV into ≥3 new lineages. Furthermore, for SNP pairs G5592A/G78031A and C25641T/C70777T, the upper limits of the 95% confidence interval (CI) were 0.9 and 0.3, respectively, strongly suggesting MPXV recombination. The results showed that two cases in Germany (ON637939 and ON959149) and one case in Spain (ON720849) already acquired mutations through recombination.

Diploma

Overall, the study results showed that TRs diverged frequently during natural transmission in the B.1 clade and that the MPXV genome is rapidly evolving and expanding during the current outbreak in 2022. Furthermore, LD and TR analyzes combined with genomic surveillance are valuable techniques for monitoring and tracking the transmission dynamics of MPXV phylogenetic recombination.

*Important NOTE:medRxiv publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health-related behavior, or treated as established information.

Reference:

• Vorläufiger wissenschaftlicher Bericht.
  Ja, T. et al. (2022) „Rekombination prägt den Affenpockenausbruch 2022“. medRxiv. doi: 10.1101/2022.08.09.22278589. https://www.medrxiv.org/content/10.1101/2022.08.09.22278589v3

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