Evidence A.2 lineage of monkeypox is mutating

By Dr. Chinta SidharthanReviewed by Emily Henderson, B.Sc.Sep 21 2022

In a recent study posted to the bioRxiv* preprint server, a team of researchers from India analyzed the whole genome sequences of the monkeypox virus isolated from monkeypox patients with and without international travel histories to understand the phylogenetic relations and genomic evolution of the virus that could contribute to higher transmission rates.

Study: Genome characterization of monkeypox cases detected in India: Identification of three sub clusters among A.2 lineage. Image Credit: NIAID

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

Background

The monkeypox virus, like the smallpox-causing Variola virus, is an Orthopoxvirus species belonging to the Poxviridae family. It is a double-stranded deoxyribonucleic acid (DNA) virus with a genome that encodes about 190 genes.

The first known human case of monkeypox was in 1970 in the Democratic Republic of Congo, which spread to countries in west and central Africa, with subsequent outbreaks in the United States (U.S) in 2003, and the United Kingdom (U.K) in 2018. The genome studies carried out by the World Health Organization (WHO) recognized two major clades — Clade I (Congo Basin clade) and Clade II (West African clade), with two subclades in Clade II. The 2022 global outbreak of monkeypox has been linked to Clade IIb.

Viruses from the Poxviridae family have exhibited high inter-and intra-species recombination frequencies. Clades I and II had a genetic distance of 900 bp. The genetic changes could render transmission and infection advantages to the virus. Therefore, whole genome analyses of the circulating strains of the monkeypox virus are essential in the surveillance of the disease.

About the study

The present study collected samples from nasopharyngeal and oropharyngeal swabs, lesion crusts, and fluids from 96 individuals suspected of having monkeypox. The positive cases were identified based on real-time polymerase chain reaction (PCR) using monkeypox-specific primers.

The final sample set included five samples from Kerala (with international travel histories) and five from Delhi (with no history of recent international travel). The negative samples were further screened for enterovirus and Varicella zoster virus.

Next-generation sequencing was used for the genomic characterization of the positive samples. In addition, phylogenetic analyses were carried out on a final dataset consisting of genome sequences generated in this study and 75 sequences from the NCBI (National Center for Biotechnology Information) and GISAID (Global Initiative on Sharing Avian Influenza Data) databases that were generated pre- and post-2022 monkeypox outbreak.

Results

The study retrieved 90% to 99% of the monkeypox genome from the lesion crust and fluid samples from all the positive cases. The phylogenetic trees placed the 10 samples from India in Clade IIb lineage A.2, along with eight other samples from the U.S., Thailand, and the U.K.

The genome-based analysis divided the A.2 lineage into three sub-clusters, with seven sequences (five from Kerala, and two from Delhi) branching with the UK-2022 OP331335.1 and USA-2022 ON674051.1 strains and forming one sub-cluster. Lineage-defining mutations at positions C 179537 T, C 25072 T, and A 140492 C further classified the five sequences from Kerala as sub-lineage A.2.1.

The remaining three sequences from Delhi branched with USA-2022 strain ON675438.1 and formed the second sub-cluster. The third sub-cluster consisted of sequences from other U.S. and U.K strains and samples from Thailand.

Studies have linked the short-term evolution of the monkeypox virus with mutations in the apolipoprotein B editing complex (APOBEC3) genes that result in cytidine deaminase activity. Genome analysis from the present study revealed 13 new APOBEC3 mutations and 16 single nucleotide polymorphisms (SNPs), which the authors believe to be lineage-defining changes within the A.2 lineage. The study also identified 25 additional APOBEC3 mutations in the monkeypox strains circulating in India.

The monkeypox sequences from India were divergent from earlier lineages, such as B.1 from European countries like Germany, Italy, and France, and the 2017-2018 A.1 lineage from Nigeria, Singapore, and Israel.

Conclusions

To summarize, the study reports 13 new mutations in the monkeypox virus APOBEC3 gene that could potentially be involved in the evolution of the virus. Additionally, the results also uncovered 16 new SNPs that, along with the APOBEC3 mutations, resulted in samples from India forming the lineage A.2.1. The authors believe that mutations in the Orthopoxvirus genes are associated with increased virulence through immune suppression in the host.

Furthermore, genes in the terminal region of the monkeypox virus and other Orthopoxvirus species are responsible for host adaptation and transmission. Therefore, genome-wide studies to understand the role of these genes and the monitoring of emergent mutations are imperative to contain the spread of monkeypox.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources