Monkeypox virus genomic accordion strategies
Sara Monzón, Sarai Varona, Anabel Negredo, Santiago Vidal-Freire, Juan Ángel Patiño-Galindo, N.M. Ferressini Gerpe, Ángel Zaballos, Eva Orviz, Oskar Ayerdi, Ana Muñoz‐Gómez, Alberto Delgado‐Iribarren, Vicente Estrada, Cristina García-Beltrán, Francisca Molero, Patricia Sánchez, Montserrat Torres, Ana Vázquez, Juan Carlos Galán, Ignacio Torres, Manuel Causse del Río, Laura Merino-Díaz, Marcos López, Alicia Galar, Laura Cardeñoso, Almudena Gutiérrez, Cristina Loras, Isabel Escribano, Marta Elena Álvarez‐Argüelles, Leticia del Río, María Simón, María Ángeles Meléndez, Juan Pedro M. Camacho, Laura Herrero, Pilar Jiménez, Marı́a Luisa Navarro-Rico, Isabel Jado, Elaina Giannetti, Jens H. Kuhn, Mariano Sánchez-Lockhart, Nicholas Di Paola, Jeffrey R. Kugelman, Susana Guerra, Adolfo García‐Sastre, Isabel Cuesta, María Paz Sánchez‐Seco, Gustavo Palacios
Abstract
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.