Monkeypox virus genomic accordion strategies

The 2023 monkeypox (mpox) epidemic was caused by a subclade IIb descendant of a monkeypox virus (MPXV) lineage traced back to Nigeria in 1971. Person-to-person transmission appears higher than for clade I or subclade IIa MPXV, possibly caused by genomic changes in subclade IIb MPXV. Key genomic changes could occur in the genome's low-complexity regions (LCRs), which are challenging to sequence and are often dismissed as uninformative. Here, using a combination of highly sensitive techniques, we determine a high-quality MPXV genome sequence of a representative of the current epidemic with LCRs resolved at unprecedented accuracy. This reveals significant variation in short tandem repeats within LCRs. We demonstrate that LCR entropy in the MPXV genome is significantly higher than that of single-nucleotide polymorphisms (SNPs) and that LCRs are not randomly distributed. In silico analyses indicate that expression, translation, stability, or function of MPXV orthologous poxvirus genes (OPGs), including OPG153, OPG204, and OPG208, could be affected in a manner consistent with the established "genomic accordion" evolutionary strategies of orthopoxviruses. We posit that genomic studies focusing on phenotypic MPXV differences should consider LCR variability.We would like to thank the work of the Rapid Response Unit of the National Center for Microbiology, especially MªJosé Buitrago, and Cristobal Belda, ISCIII General Director. We also thank Anya Crane (Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health) for critically editing the manuscript and Jiro Wada (Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health) for helping with figure preparation. The work for this study performed at Instituto de Salud Carlos III was partially funded by Acción Estratégica “Impacto clínico y microbiológico del brote por el virus de la viruela del mono en pacientes en España (2022): proyecto multicéntrico MONKPOX-ESP22” (CIBERINFEC) (M.P.S.S.). The work for this study done at the Icahn School of Medicine at Mount Sinai Department of Microbiology as part of Global Health Emerging Pathogen Institute activities was funded by institutional funds (G.P.) from the Icahn School of Medicine at Mount Sinai Department of Microbiology in support of Global Health Emerging Pathogen Institute activities. This work was also supported in part through Laulima Govern ment Solutions, LLC, prime contract with the U.S. National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272201800013C. J.H.K. performed this work as an employee of Tunnell Government Services (TGS), a subcontractor of Laulima Government Solutions, LLC, under Contract No. HHSN272201800013C. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Army. The views and conclusions contained in this document are those of the authors and should not be interpreted as necessarily representing the official policies, either expressed or implied, of the U.S. Department of Health and Human Services or of the institutions and companies affiliated with the authors, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.S